Asymmetric synthesis of the polyol subunit of the polyene macrolide antibiotic RK-397

Article abstract of DOI:10.1002/ejoc.200500670

A total asymmetric synthesis of the polyol subunit of the polyene macrolide antibiotic RK-397 has been developed by the stereoselective functionalization of (1R,1′S,6S,6′R)-3,3′-methylenebis(cyclohept-3-ene-1,6-diol) . The pathway generates a large variet

Full text of DOI:10.1002/ejoc.200500670

FULL PAPER
DOI: 10.1002/ejoc.200500670
Asymmetric Synthesis of the Polyol Subunit of the Polyene Macrolide
Antibiotic RK-397
Sandrine Gerber-Lemaire,*[a] Ana T. Carmona,[a] Kai T. Meilert,[a] and Pierre Vogel[a]
Keywords: Antibiotics / Asymmetric synthesis / Dihydroxylation / Natural products / Stereoselective functionalization
A total asymmetric synthesis of the polyol subunit of the
polyene macrolide antibiotic RK-397 has been developed by
the stereoselective functionalization of (1R,1ЈS,6S,6ЈR)-3,3Ј-
can be applied to the preparation of analogues of this natural
antibiotic.
methylenebis(cyclohept-3-ene-1,6-diol). The pathway gener- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ates a large variety of stereoisomeric intermediates and thus
Germany, 2006)
stereoselective reduction process. The starting diolefin can
be derived from meso-3 by a Merweein–Pondorf–Verley re-
duction.[10]
Introduction
A great variety of natural products of biological interest
include polyketides (1,3-polyoxo, 1,3-polyols, aldols), in
particular the large family of polyene macrolides.[1] Repre-
sentative members of this family are amphotericins, nysta-
tin, and mycoticins. In 1993, RK-397 was isolated from
streptomyces from a Japanese soil sample and its structure
was elucidated by Osada et al.[2] This macrolide exhibits
antifungal and antibacterial activity as well as promising
anticancer activity (Scheme 1). Two total syntheses of this
antibiotic macrolide have been reported by the groups of
McDonald[3] and Denmark,[4] and some approaches to the
preparation of the polyol subunit have also been pre-
sented.[5] We have recently developed a new, noniterative
asymmetric synthesis of C15 1,3-polyols based on the se-
quential stereoselective functionalization of dialkenes of
type meso-5,[6] which are readily obtained from the meso-
bicycloadduct resulting from the double [4+3] cycloaddition
of 2,2Ј-methylenebis(furan) to the 1,1,3-trichloro-2-oxyallyl
cation.[7] The threo compound 4 has been converted ef-
ficiently into long-chain polyketides[8] and 6,6-spiroketal
derivatives[9] by a double elongation strategy. Applying
these methodologies, we report here our studies toward the
asymmetric synthesis of a protected form of the C11–C28
polyol subunit of RK-397.
Results and Discussion
The previously reported diacetate meso-12[10] was treated
with Bu3SnH and AIBN (toluene, 80 °C), followed by
methanolysis under classical conditions, to provide meso-11
(66% yield). Then, we submitted dialkene meso-11 to
double oxidative cleavage. This was followed by a diastereo-
selective reduction of the ozonide intermediate to provide a
mixture of hemiacetals 13, which was treated with NaBH4
to provide the targeted polyol fragment ( )-14 (Scheme 3).
In the presence of an excess of Me4NBH(OAc)3[11] in a mix-
ture of MeCN and acetic acid at 0 °C, the reduction led to
a mixture of desired ( )-14 and unwanted meso-15 in a 3:1
ratio (65% yield). These products could be separated by
flash chromatography. Unfortunately, ( )-14 was contami-
nated with traces of a polyol presenting the anti/anti config-
uration of the diol moieties at C(5)/C(7) and C(9)/C(11).
All our attempts to purify ( )-14 were unsuccessful. The
relative configuration of the newly formed stereogenic cen-
ters was assigned by analysis of the 13C NMR spectra of
the corresponding bis-acetonides ( )-16 and 17.[12] The use
of different solvents, as well as variation of the temperature
(–20 to 25 °C), did not improve the diastereoselectivity of
the reduction. Other reducing agents such as - and -se-
lectride, led to decomposition of the intermediate product
obtained after ozonolysis. Despite this lack of selectivity,
we continued our explorations and submitted the major po-
lyol ( )-16 to the Swern oxidation. This provided the corre-
sponding dialdehyde (80% yield), a very unstable com-
pound that was not isolated but directly submitted to vari-
ous allylation procedures. In particular, Brown’s [(+)-
Ipc2BCl, allylmagnesium bromide][13] and Keck’s [Ti(OiPr)4,
Our initial retrosynthetic plan envisaged the assembly of
the polyol fragment 9 by an enantioselective allylation to
introduce the C25–C28 skeleton and to perform the kinetic
resolution of the corresponding dialdehyde 10 (Scheme 2).
This derivative was expected to be obtained by the double
oxidative cleavage of dialkene meso-11 followed by a dia-
[a] Institute of Chemical Sciences and Engineering, Swiss Institute
of Technology (EPFL),
BCH, 1015 Lausanne, Switzerland
Fax: +41-21-693-9355
E-mail: Sandrine.Gerber@epfl.ch
Eur. J. Org. Chem. 2006, 891–900
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Gerber-Lemaire, A. T. Carmona, K. T. Meilert, P. Vogel
FULL PAPER
Scheme 1.
Attempts to desymmetrize the diol meso-11 by a trans-
acylation catalyzed by lipases (from Candida cylindracea,
Pseudomonas fluorescens, pig pancreas, Pseudomonas cepa-
cia, and Candida antartica) were also performed, but only
very low conversion into the corresponding monoacetate
was observed.
In view of these unsatisfactory results, another approach
based on the sequential functionalization of dialkene meso-
20 was developed. For that purpose, the previously reported
exo-diacetate meso-18[10] was treated with BCl3 to afford the
corresponding dichlorodiol intermediate, which was sub-
sequently converted into the bis(p-methoxybenzoate) meso-
19 in 87% yield (two steps). Dechlorination with Bu3SnH
and AIBN (toluene, 80 °C) afforded meso-20 (75% yield).
This compound was desymmetrized into diol (–)-21 by
Sharpless asymmetric dihydroxylation[15] with an enantio-
meric excess of 94% (90% yield), as measured for the corre-
sponding Mosher ester (+)-22 (Scheme 4). Because of the
poor solubility of the starting dialkene meso-20 in the reac-
tion mixture, it was necessary to introduce an enriched AD-
mix-α portionwise, over a period of 24 hours. Moreover, the
presence of p-methoxybenzoyl groups was necessary to
reach good enantioselectivities. The acetyl groups were then
selectively removed in the presence of an excess of
Mg(OMe)2 to afford tetraol (–)-23 in 76%yield. Cleavage of
the cycloheptadiol unit was performed with NaIO4. With-
Scheme 2. Retrosynthetic plan.
(S)-BINOL, allyltributylstannane][14] conditions were ap-
plied. Unfortunately, only mixtures of allylated compounds
were formed and we were unable to perform the expected
kinetic resolution.
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Synthesis of the Polyol Subunit of the Macrolide Antibiotic RK-397
FULL PAPER
Scheme 3. Double elongation strategy for the synthesis of the polyol subunit of RK-397.
out isolating it, the intermediate oxoaldehyde was treated conditions (Et2BOMe, NaBH4).[16] This gave the corre-
with an excess of Me4NBH(OAc)3 to afford the correspond- sponding 1,3-syn diol (only one isomer detected by NMR
ing 1,3-anti diol (–)-24 with a diastereoselectivity higher spectroscopy). The latter compound was not purified but
than 15:1. The primary alcohol was selectively silylated was directly protected as the acetonide to afford (+)-27
(tBuSiMe2Cl or Et3SiCl, 1 , imidazole) and the remaining [48% overall yield based on (+)-25]. As we previously re-
diol was protected as an acetonide to give compounds (+)- ported for related compounds,[6a] the absolute configuration
25 and (–)-26 in 55 and 42% yield, respectively, over four of (–)-21 was established by circular dichroism (CD) of de-
steps. This sequence could be efficiently carried out without rivative (+)-25, the CD spectrum of which displays a posi-
intermediate purification. In the following steps, the trieth- tive Cotton effect.
ylsilyl protecting group proved to be too labile and the syn-
At this stage, it was necessary to oxidize the alcohol moi-
thesis was thus continued with derivative (+)-25. Its cyclo- ety at C(25) to perform a diastereoselective allylation, in
heptene moiety was submitted to a similar cleavage process order to complete the polyol skeleton of RK-397. Prelimi-
using dihydroxylation of the double bond, followed by oxi- nary assays of oxidation of the other terminal alcohol led
dative cleavage with NaIO4 and reduction under Narasaka to elimination of the corresponding β-para-methoxybenzo-
Scheme 4. Synthesis of the C11–C25 skeleton of the polyol subunit of RK-397.
Eur. J. Org. Chem. 2006, 891–900
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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893

S. Gerber-Lemaire, A. T. Carmona, K. T. Meilert, P. Vogel
FULL PAPER
yloxy aldehyde and prompted us to change the protecting diols at C(19)/C(21) and C(23)/C(25) and for the 1,2-diol at
groups of the alcohol moieties at C(13) and C(23) C(27)/C(28). Moreover, polyol (–)-30 was protected at
(Scheme 5). Methanolysis of the p-methoxybenzoates with –10 °C as the corresponding triacetonide 31, the 13C NMR
KOMe, followed by selective transacetylation of the pri- spectrum of which displays two different sets of signals at δ
mary alcohol catalyzed by Candida cylindracea lipase, pro- = 30.5 ppm (doubled peak) and δ = 20.3, 20.2 ppm typical
vided (–)-28 with 79% yield. Benzyloxymethyl ethers were of syn relative configurations of the diols at C(15)/C(17)
introduced at C(13) and C(23) and the C(25) silyl ether was and C(25)/C(27).
cleaved (HF·pyridine, –20 °C) to afford the corresponding
primary alcohol. Oxidation in the presence of a catalytic
amount of Pr4NRuO4 and NMO[17] gave an intermediate
aldehyde that was directly submitted to an allylation reac-
tion under Keck’s conditions.[13] This sequence afforded the
homoallylic alcohol (–)-29 as a single diastereoisomer in
60% yield. In order to get the C11–C28 fragment of RK-
397, a last asymmetric dihydroxylation step in the presence
of an enriched AD-mix-β was performed and gave the ex-
pected polyol (–)-30 as the major diastereoisomer (dr = 7:1),
in 68% yield. A comparable diastereoselectivity was ob-
served with (DHQD)2PYR but the yield was lower.
Conclusions
The complete polyol subunit of the polyene macrolide
antibiotic RK-397 has been derived from dialkene meso-20
in 17 steps, with the need to isolate only seven intermedi-
ates. In theory, our strategy can be used to generate a high
diversity of stereoisomers by varying the conditions of re-
duction of oxoaldehyde intermediates resulting from the
oxidative cleavage of our starting material.
Experimental Section
General: Commercial reagents (Fluka, Aldrich) were used without
purification. Solvents were filtered prior to use (Innovative Tech-
nology). Light petroleum ether refers to the fraction with the boil-
ing range 40–60 °C. Solutions after reactions and extractions were
evaporated on a rotary evaporator under reduced pressure. Liquid/
solid flash chromatography (FC): columns of silica gel (0.040–
0.63 mm, Merck no. 9385 silica gel 60, 240–400 mesh). TLC for
reaction monitoring: Merck silica gel 60F254 plates; detection by
UV light; Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O]
or KMnO4. IR spectra: Perkin–Elmer 1420 spectrometer. 1H NMR
spectra: Bruker-ARX-400 spectrometer (400 MHz); δ in ppm rela-
tive to the solvent’s residual 1H signal (CHCl3: δ = 7.27 ppm;
CH3OD: δ = 3.34 ppm; C6H6: δ = 7.3 ppm) as internal reference;
all 1H assignments were confirmed by 2D-COSY-45 spectra. 13C
NMR spectra: same instrument as above (100.6 MHz); δ in ppm
relative to solvent’s C signal (CDCl3: δ = 77.0 ppm; CD3OD: δ =
48.5 ppm; C6D6: δ = 128.5 ppm) as internal reference. MS: Nermag
R-10-10C, chemical ionization (NH3) mode. MALDI-TOF mass
spectra were obtained at the Swiss Institute of Technology Mass
Spectral Facility. Elemental analyses: Ilse Beetz, 96301 Kronach,
Germany.
(1R,1ЈS,6R,6ЈS)-3,3Ј-Methylenebis{6-[(benzyloxy)methoxy]cyclo-
hept-3-en-1-ol} (meso-11): Bu3SnH (7.8 mL, 29.6 mmol) and AIBN
(280 mg) were added to a solution of meso-12[10] (4.90 g,
7.41 mmol) in toluene (30 mL). The mixture was stirred at 80 °C
for 3 h. The solvent was then evaporated, the residue taken up in
MeCN (90 mL), and the solution washed with pentane (20 mL, 4
times) and concentrated in vacuo. Flash chromatography on silica
gel (EtOAc/light petroleum ether, 1:3) afforded a colorless oil that
was taken up in MeOH containing K2CO3 (1.03 g, 7.41 mmol).
This mixture was vigorously stirred at 25 °C for 4 h. The solution
was then poured into water (100 mL) and extracted with CHCl3
(100 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography on sil-
ica gel (CH2Cl2/MeOH, 97:3) afforded meso-11 as a white solid
Scheme 5. Completion of the polyol synthesis. 1. MeOK, MeOH;
2. vinyl acetate, Candida cylindracea lipase; 3. BOMCl, (iPr)2NEt,
Bu4NI cat., 40 °C; 4. HF·pyridine, –20 °C; 5. Pr4NRuO4 0.2 equiv.,
NMO, molecular sieves; 6. Ti(OiPr)4 (0.1 equiv.), (S)-BINOL
(0.2 equiv.), (allyl)SnBu3, 0 °C; 7. AD-mix-β, MeSO2NH2; 8. ace-
tone/Me2C(OMe)2, CSA cat., –10 °C; 9. (a) K2CO3, MeOH; (b)
H2, Pd(OH)2/C; 10. acetone/Me2C(OMe)2, CSA cat.
The relative configurations at C(25) and C(27) were con-
firmed by Rychnovsky’s 13C NMR method.[12] Meth-
anolysis (K2CO3, MeOH) of the polyol (–)-30, followed by
hydrogenolysis of the benzyloxymethyl ethers and treatment
with a mixture of acetone/Me2C(OMe)2 in the presence of a (2.48 g, 66%).
catalytic amount of camphorsulfonic acid, provided penta-
Intermediate (1R,1ЈS,6R,6ЈS)-3,3Ј-Methylenebis{6-[(benzyloxy)-
acetonide 32. The 13C NMR spectrum of 32 exhibits signals
at δ = 25.8, 25.6, 24.8 (doubled peak), 24.4, and 24.3 ppm
methoxy]cyclohept-3-en-1-yl} Diacetate: IR (film): ν = 3090, 3065,
˜
3030, 2940, 1740, 1610, 1495, 1455, 1370, 1240, 1165, 1100, 1080,
that are typical for an anti/anti relative configuration of the 1045, 975, 735, 700, 645 cm–1. 1H NMR (CDCl3, 400 MHz, 25 °C):
894
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Synthesis of the Polyol Subunit of the Macrolide Antibiotic RK-397
FULL PAPER
11.9 Hz, 2 H, CH2(BOM)], 4.81 [d, JH,H = 11.9 Hz, 2 H,
3
3
2
δ = 7.39–7.29 (m, 10 H arom.), 5.54 (t, J4,5a = J4,5b = 6.8 Hz, 2
H, 4-H, 4Ј-H), 4.79, 4.77 [2 d, 2JH,H = 14.2 Hz, 4 H, 2 CH2(BOM)], CH2(BOM)], 4.65 (s, 4 H, 2 CH2Ph), 4.13–3.93 (m, 6 H, 3-H, 5-H,
2
3
4.63, 4.60 (2 d, JH,H = 12.6 Hz, 4 H, 2 CH2Ph), 4.52 (m, 2 H, 1-
7-H, 9-H, 11-H, 13-H), 3.72 (t, JH,H = 6.7 Hz, 4 H, 1-H2, 15-H2),
2
H, 1Ј-H), 3.56 (m, 2 H, 6-H, 6Ј-H), 2.73 (d, JH,H = 13.9 Hz, 1 H,
1.97–1.47 (m, 14 H, 2-H2, 4-H2, 6-H2, 8-H2, 10-H2, 12-H2, 14-H2)
ppm. 13C NMR (CD3OD, 100.6 MHz, 25 °C): δ = 139.3 (s, 2 C
arom.), 129.4, 128.9, 128.7 (3 d, 10 C arom.), 94.7 [t, 2 CH2(BOM)],
2
8-H), 2.64 (d, JH,H = 13.9 Hz, 1 H, 8-H), 2.42–2.36 (m, 6 H, 2-H,
2Ј-H, 5-H, 5Ј-H, 7-H, 7Ј-H), 2.26 (m, 2 H, 5-H, 5Ј-H), 2.09 (br. d,
2JH,H = 12.6 Hz, 2 H, 2-H, 2Ј-H), 2.03 [s, 6 H, 2 CH3(OAc)], 1.82 74.5, 74.4 [2 d, C(3), C(13)], 70.7 (t, 2 CH2Ph), 68.3, 68.1, 66.6,
2
(m, JH,H = 11.4 Hz, 2 H, 7-H, 7-H) ppm. 13C NMR (CDCl3, 66.5 [4 d, C(5), C(7), C(9), C(11)], 46.5, 46.2, 46.0, 45.9, 44.1, 44.0,
100.6 MHz, 25 °C): δ = 170.0 (s, 2 C=O), 137.8 (s, 2 C arom.),
137.1 [s, C(3), C(3Ј)], 128.4, 127.9, 127.8 (3 d, 10 C arom.), 124.5
[d, JC,H = 156 Hz, C(4), C(4Ј)], 92.7 [t, JC,H = 163 Hz, 2 calcd. C 64.12, H 8.33; found C 64.37, H 8.30.
43.6 [7 t, C(2), C(4), C(6), C(8), C(10), C(12), C(14)] ppm.
MALDI-MS: m/z (%) = 604 (100) [M + Na+]. C31H48O10 (580.71):
1
1
1
1
CH2(BOM)], 72.2 [d, JC,H = 144 Hz, C(6), C(6Ј)], 69.5 (t, JC,H
=
15: IR (film): ν = 3380, 3030, 2940, 1495, 1455, 1435, 1385, 1165,
˜
1
143 Hz, 2 CH2Ph), 69.2 [d, JC,H = 149 Hz, C(1), C(1Ј)], 49.8 [t,
C(8)], 44.7 [t, JC,H = 129.6, C(7), C(7Ј)], 36.8 [t, JC,H = 126 Hz,
C(2), C(2Ј)], 34.0 [t, JC,H = 128 Hz, C(5), C(5Ј)], 21.4 [q, JC,H
1045, 850, 740, 700, 665 cm–1
.
1H NMR (CD3OD, 400 MHz,
1
1
2
25 °C): δ = 7.38–7.27 (m, 10 H arom.), 4.82 [d, JH,H = 9.2 Hz, 2
H, CH2(BOM)], 4.81 [d, 2JH,H = 9.2 Hz, 2 H, CH2(BOM)], 4.65 [s,
4 H, 2 CH2Ph], 4.02–3.92 [m, 6 H, 3-H, 5-H, 7-H, 9-H, 11-H, 13-
H], 3.73–3.68 [m, 4 H, 1-H2, 15-H2], 1.93–1.54 [2 m, 14 H, 2-H2,
4-H2, 6-H2, 8-H2, 10-H2, 12-H2, 14-H2] ppm. 13C NMR [CD3OD,
1
1
=
129 Hz, 2 CH3(OAc)] ppm. MALDI-MS: m/z (%) = 615 (100) [M
+ Na+].
meso-11: IR (film): ν = 3426, 2932, 2890, 1599, 1454, 1377, 1163,
˜
1109, 1032, 945, 743, 698 cm–1
.
1H NMR (CDCl3, 400 MHz, 100.6 MHz]: δ = 139.3 [s, 2 C arom.], 129.4, 128.9, 128.7 [3 d, 10
3
1
1
25 °C): δ = 7.37–7.29 (m, 10 H arom.), 5.53 (t, J4,5a
=
3J4,5b
=
C arom.], 94.7 [t, JC,H = 161 Hz, 2 CH2(BOM)], 74.5 [d, JC,H =
2
1
6.8 Hz, 2 H, 4-H, 4Ј-H), 4.80, 4.78 [2 d, JH,H = 10.2 Hz, 4 H, 2
142 Hz, C(3), C(13)], 70.7 [t, JC,H = 141 Hz, 2 CH2Ph], 70.3, 68.7
CH2(BOM)], 4.65, 4.61 (2 d, 2JH,H = 12.0 Hz, 4 H, 2 CH2Ph), 3.70– [2 d, JC,H = 140, 161 Hz, C(5), C(7), C(9), C(11)], 59.6 [t, JC,H
=
1
1
2
3.55 (m, 4 H, 1-H, 1Ј-H, 6-H, 6Ј-H), 2.73–2.69 (2 d, JH,H
=
142 Hz, C(1), C(15)], 47.1, 45.4, 45.3, 43.7 [4 t, C(2), C(4), C(6),
15.1 Hz, 2 H, 8-H2), 2.39–2.28 (m, 8 H, 2-H, 2Ј-H, 5-H2, 5Ј-H2, 7- C(8), C(10), C(12), C(14)] ppm. MALDI-MS: m/z (%) = 604 (100)
2
H, 7Ј-H), 2.18 (br. d, JH,H = 14.2 Hz, 2 H, 2-H, 2Ј-H), 1.88 (m, 2
H, 7-H, 7Ј-H) ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ =
138.0 [s, 2 C arom, C(3), C(3Ј)], 128.6, 128.0, 127.8 (3 d, 10 C
[M + Na+].
(3S)-3-[(Benzyloxy)methoxy]-4-[{(4R,6R)-6-[(4R,6S)-6-{(2R)-2-
[(benzyloxy)methoxy]-4-hydroxybutyl}-2,2-dimethyl-1,3-dioxan-4-
yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl]butan-1-ol [( )-16]: A solu-
tion of ( )-14 (260 mg, 0.448 mmol) in 2,2-dimethoxypropane/ace-
tone (20 mL/2 mL) was stirred in the presence of pTsOH (35 mg)
at 0 °C for 45 min. The mixture was then neutralized with solid
Na2CO3, filtered, and concentrated. The residue was taken up in
CH2Cl2 (15 mL), PPTS (30 mg) was added, and the mixture was
stirred for 15 min at 25 °C. After neutralization with solid Na2CO3,
filtration and evaporation, the residue was purified by flash
chromatography (CH2Cl2/MeOH, 97:3) to afford ( )-16 (190 mg,
1
1
arom.), 123.9 [d, JC,H = 156 Hz, C(4), C(4Ј)], 92.8 [t, JC,H
=
1
163 Hz, 2 CH2(BOM)], 72.5 [d, JC,H = 143 Hz, C(6), C(6Ј)], 69.7
(t, 1JC,H = 142 Hz, 2 CH2Ph), 67.5 [d, 1JC,H = 153 Hz, C(1), C(1Ј)],
50.7 [t, 1JC,H = 125 Hz, C(8)], 47.2 [t, 1JC,H = 126 Hz, C(7), C(7Ј)],
40.1 [t, JC,H = 127 Hz, C(2), C(2Ј)], 33.7 [t, JC,H = 121 Hz, C(5),
C(5Ј)] ppm. CI-MS: m/z (%) = 509 (100) [M + H+]. MALDI-MS:
m/z = 531 [M + Na+]. C31H40O6 (508.651): calcd. C 73.20, H 7.93;
found C 72.48, H 7.79.
1
1
(3S,5R,7R,9R,11S,13R)-3,13-Bis[(benzyloxy)methoxy]pentadecane-
1,5,7,9,11,15-hexaol [( )-14] and (3S,5R,7R,3ЈS,5ЈS,7ЈR)-3,13-
Bis[(benzyloxy)methoxy]pentadecane-1,5,7,9,11,15-hexaol (15): A
solution of meso-11 (0.30 g, 0.59 mmol) in anhydrous CH2Cl2
(15 mL) was ozonolyzed at –78 °C for 5 min. A stream of dry O2
was then passed through the solution for 2 min, and Me2S (175 µL,
2.36 mmol) was added dropwise. After stirring at –78 °C for
64%) as a pale-yellow oil. IR (film): ν = 3455, 2985, 2940, 1450,
˜
1380, 1220, 1165, 1110, 1040, 740, 700 cm–1. 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 7.36–7.28 (m, 10 H arom.), 4.79 [s, 4 H, 2
CH2(BOM)], 4.67, 4.61 (2 d, 2JH,H = 11.8 Hz, 4 H, 2 CH2Ph), 4.04–
3.90 (m, 6 H, 3-H, 4Ј-H, 6Ј-H, 4ЈЈЈ-H, 6ЈЈЈ-H, 2IV-H), 3.80–3.72 (m,
4 H, 1-H2, 4IV-H2), 2.48 (t, JH,OH = 5.9 Hz, 2 H, 2 OH), 1.92–1.86
15 min, the solvent was evaporated at –20 °C. The residue was (m, 4 H, 4-H, 5Ј-H, 5ЈЈЈ-H, 1IV-H), 1.75–1.72 (m, 3 H, 4-H, 1ЈЈ-H,
taken up in MeCN/AcOH (3:1, 10 mL) at 0 °C, and (Me4N)
BH(OAc)3 (2.75 g, 10.6 mmol) was added portionwise. After the
mixture had been stirred at 0 °C for 4 h, the solvents were evapo-
rated. The residue was diluted with EtOAc (30 mL) and poured
onto ice (20 mL). The mixture was neutralized with solid NaHCO3
and extracted with EtOAc (10 mL, 4 times). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo. The crude
hemiacetals were dissolved in MeOH (8 mL) and treated with
NaBH4 (180 mg, 4.72 mmol) at 25 °C for 30 min. AcOH was then
added (500 µL), and after stirring at 25 °C for 5 min, the solution
was poured into a sat. aq. solution of NaHCO3 (15 mL) and ex-
tracted with EtOAc (15 mL, 5 times). The combined organic ex-
tracts were dried (MgSO4) and concentrated in vacuo. Flash
chromatography on silica gel (CH2Cl2/MeOH, 14:1, 1% NEt3) af-
forded 15 (55 mg) and ( )-14 (166 mg; 65% combined yield), both
as colorless oils.
1IV-H), 1.67–1.55 (m, 4 H, 2-H, 5Ј-H, 5ЈЈЈ-H, 3IV-H), 1.52–1.41 (m,
3 H, 2-H, 1ЈЈ-H, 3IV-H), 1.39, 1.35, 1.33, 1.30 [4 s, 12 H, 2 CH3-
C(2Ј), 2 CH3C(2ЈЈЈ)] ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C):
δ = 137.6 (s, 2 C arom.), 128.5, 127.8, 127.7 (3 d, 10 C arom.),
100.4 [s, C(2Ј)], 98.5 [s, C(2ЈЈЈ)], 93.7 [t, 2 CH2(BOM)], 73.9, 73.6
[2 d, C(3), C(2IV)], 69.9 (t, 2 CH2Ph), 66.0, 64.9, 63.5, 62.2 [4 d,
C(4Ј), C(6Ј), C(4ЈЈЈ), C(6ЈЈЈ)], 59.8 [t, C(1), C(4IV)], 42.1, 41.0, 40.6,
39.1, 37.6 [5 t, C(4), C(5Ј), C(1ЈЈ), C(5ЈЈЈ), C(1IV)], 36.5, 36.4 [2 t,
C(2), C(3IV)], 30.2, 19.8 [2 q, 2 CH3C(5ЈЈЈ)], 24.6 [q, 2 CH3C(5Ј)]
ppm. MALDI-MS: m/z (%) = 683 (100) [M + Na+]. C37H56O10
(660.84): calcd. C 67.25, H 8.54; found C 67.13, H 8.49.
(3S,5R,7R,3ЈS,5ЈS,7ЈR)-3,13-Bis[(benzyloxy)methoxy]-5,7;9,11-di-
O-isopropylidenepentadecane-1,5,7,9,11,15-hexaol (17): A solution
of 15 (20 mg, 0.034 mmol) in 2,2-dimethoxypropane/acetone
(1.5 mL/0.15 mL) was stirred in the presence of pTsOH (3 mg) at
0 °C for 45 min. The mixture was then neutralized with solid
( )-14: IR (film): ν = 3385, 3065, 3030, 2940, 1560, 1460, 1380, Na2CO3, filtered, and concentrated. The residue was taken up in
˜
1210, 1165, 1035, 825, 740, 700, 670 cm–1
.
1H NMR (CD3OD, CH2Cl2 (2 mL), PPTS (3 mg) was added, and the mixture was
2
400 MHz, 25 °C): δ = 7.39–7.27 (m, 10 H arom.), 4.83 [d, JH,H
=
stirred for 15 min at 25 °C. After neutralization with solid Na2CO3,
Eur. J. Org. Chem. 2006, 891–900
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
895

S. Gerber-Lemaire, A. T. Carmona, K. T. Meilert, P. Vogel
FULL PAPER
filtration, and evaporation, the residue was purified by flash
residue taken up in MeCN (300 mL). The solution was washed
chromatography (CH2Cl2/MeOH, 97:3) to afford 17 (10 mg, 44%) with pentane (50 mL, 4 times) and concentrated in vacuo. Flash
as a pale-yellow oil. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.39– chromatography on silica gel (Et2O/pentane, 2:1) afforded meso-20
2
7.28 (m, 10 H arom.), 4.82, 4.80 [2 d, JH,H = 8.6 Hz, 4 H, 2
(7.4 g, 75%) as a white solid. M.p. 94–95 °C. IR (KBr): ν = 3060,
˜
CH2(BOM)], 4.70, 4.64 (2 d, 2JH,H = 11.9 Hz, 4 H, 2 CH2Ph), 4.07– 2955, 2850, 1735, 1705, 1605, 1515, 1465, 1440, 1370, 1345, 1245,
3.95 (m, 6 H, 3-H, 5-H, 7-H, 9-H, 11-H, 13-H), 3.87–3.74 (m, 4 H,
1175, 1105, 1025, 985, 950, 905 cm–1. 1H NMR (CDCl3, 400 MHz,
1-H2, 15-H2), 2.44 (t, 3JOH,H = 5.5 Hz, 2 H, 2×OH), 1.96–1.87 (m, 25 °C): δ = 8.07, 6.62 (2 d, JH,H = 8.8 Hz, 8 H arom.), 5.42 (t,
3
3
4 H, 4-H, 6-H, 10-H, 12-H), 1.82–1.74 (m, 3 H, 4-H, 8-H, 12-H),
1.67–1.61 (m, 2 H, 6-H, 10-H), 1.48 (dt, JH,H = 12.8, JH,H
3JH,H = 6.9 Hz, 2 H, 3-H, 3Ј-H), 4.96 (dddd, JH,H = 10.5, 10.5,
2
3
3
=
3.1, 3.1 Hz, 2 H, 1-H, 1Ј-H), 4.67 (dddd, JH,H = 10.6, 10.6, 2.1,
2.3 Hz, 2 H, 2-H, 14-H), 1.42 (m, 1 H, 8-H), 1.41, 1.37 (2 s, 6 H, 2.1 Hz, 2 H, 6-H, 6Ј-H), 3.21 (s, 6 H, 2 OCH3), 2.72, 2.51 (2 d,
4 CH3), 1.19 (m, 2 H, 2-H, 14-H) ppm. 13C NMR (CDCl3, 3JH,H = 13.2 Hz, 2 H, 8-H), 2.46 (m, 2 H, 7-H, 7Ј-H), 2.39 (m, 4
100.6 MHz, 25 °C): δ = 137.7 (s, 2 C arom.), 128.7, 128.0, 127.8
(3 d, 10 C arom.), 98.5 [s, 2 C(CH3)2], 93.8 [t, JC,H = 159 Hz, 2 5-H, 5Ј-H), 1.98 (m, 2 H, 7-H, 7Ј-H), 1.64 [s, 6 H, 2 CH3(OAc)]
H, 2-H2, 2Ј-H2), 2.38 (m, 2 H, 5-H, 5Ј-H), 2.27 (d, 2JH,H = 13.2 Hz,
1
1
CH2(BOM)], 73.8 [d, 1JC,H = 141 Hz, C(3), C(13)], 70.1 (t, JC,H
=
ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ = 169.8 (s, 2 C=O),
165.2 (s, 2 C arom.), 163.2 (s, 2 C=O), 137.3 [s, C(4), C(4Ј)], 131.5
143 Hz, 2 CH2Ph), 66.0, 65.3 [2 d, 1JC,H = 137, 141 Hz, C(5), C(7),
1
1
1
1
C(9), C(11)], 60.0 [t, JC,H = 143 Hz, C(1), C(15)], 42.8 [t, JC,H
=
(d, JC,H = 163 Hz, 4 C arom.), 124.0 [d, JC,H = 156 Hz, C(3),
1
1
1
125 Hz, C(8)], 41.2, [t, JC,H = 126 Hz, C(6), C(10)], 37.1 [t, JC,H C(3Ј)], 122.7 (s, 2 C arom.), 113.4 (d, JC,H = 160 Hz, 4 C arom.),
= 126 Hz, C(2), C(14)], 36.6 [t, JC,H = 126 Hz, C(4), C(12)], 30.3,
19.9 (2 q, JC,H = 130, 126 Hz, 2 CH3), 19.9 (q, JC,H = 126 Hz,
CH3) ppm. MALDI-MS: m/z (%) = 684 (100) [M + H + Na+], 700
(60) [M + H+ K+].
1
69.3 [d, 1JC,H = 151 Hz, C(6), C(6Ј)], 68.7 [d, 1JC,H = 150 Hz, C(1),
1
1
1
1
C(1Ј)], 55.3 (q, JC,H = 144 Hz, 2 OCH3), 49.8 [t, JC,H = 132 Hz,
C(8)], 43.3 [t, 1JC,H = 124 Hz, C(5), C(5Ј)], 36.5 [t, JC,H = 131 Hz,
1
1
1
C(7), C(7Ј)], 33.3 [t, JC,H = 130 Hz, C(2), C(2Ј)], 21.1 [q, JC,H
=
125 Hz, 2 CH3(OAc)]. CI-MS: m/z (%) = 638 (100) [M + NH4+],
256 (6), 196 (16), 135 (21). C35H40O10 (620.69): calcd. C 67.73, H
6.50; found C 67.60, H 6.47.
4,4Ј-Methylenebis[(1R,1ЈS,2S,2ЈR,6R,6ЈS)-6-acetoxy-2-chlorocyclo-
hept-3-en-1-yl]bis(4-methoxybenzoate) (meso-19): BCl3 (1  in
CH2Cl2, 168 mmol, 168 mL) was added dropwise to a solution of
meso-18 (13 g, 37.71 mmol) in CH2Cl2 (650 mL) at 0 °C. After
30 min at 0 °C, the mixture was poured into a sat. aq. solution of
NaHCO3 (800 mL) and extracted with CH2Cl2 (600 mL, twice).
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue was taken up in pyridine (220 mL) and
treated with PMBzCl (15.2 mL, 112 mmol) and DMAP (400 mg)
at 0 °C. After 30 min the reaction was allowed to reach 25 °C and
stirred for 12 h. The solvent was evaporated in vacuo. The residue
was taken up in EtOAc (500 mL) and washed with 1  HCl
(80 mL) and a sat. aq. solution of NaHCO3 (60 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo. Flash
chromatography on silica gel (Et2O/pentane, 1:1) afforded meso-19
(1S,6R)-6-Acetoxy-4-[{(1ЈR,2ЈS,4ЈR,6ЈS)-6-acetoxy-1,2-dihydroxy-
4-[(4-methoxybenzoyl)oxy]cyclohept-1-yl}methyl]cyclohept-3-en-1-yl
4-Methoxybenzoate [(–)-21]: A suspension of meso-20 (14 g,
22.56 mmol) in a mixture of tBuOH, H2O, and MeCN (140/140/
28 mL) was heated at 80 °C for 30 min. The solution was then co-
oled to 0 °C and Me2SO2NH2 (4.3 g, 45.12 mmol) was added. An
enriched AD-mix-α [70 g; K3Fe(CN)6 (47.7 g), K2CO3 (20.05 g),
(DHQ)2PHAL (1.88 g), K2OsO2(OH)4 (370 mg)] was added in four
equivalent portions every 6 h. After stirring for 24 h at 0 °C, the
mixture was diluted with EtOAc (100 mL) and H2O (100 mL).
Na2SO3 (5.7 g, 45.12 mmol) was then added and the solution was
stirred at 25 °C for 45 min. The solution was poured into H2O
(200 mL) and extracted with EtOAc (200 mL, 3 times). The com-
bined organic layers were dried (MgSO4) and concentrated in
as a pale-yellow foam (22.6 g, 87%). IR (KBr): ν = 3450, 2925,
˜
2855, 1740, 1715, 1605, 1510, 1460, 1370, 1255, 1170, 1105, 1030,
1
965, 850, 770, 695 cm–1. H NMR (CDCl3, 400 MHz, 25 °C): δ =
vacuo. Flash chromatography on silica gel (CH2Cl2/MeOH, 98:2)
20
afforded (–)-21 (13.3 g, 90%) as a white foam. [α]2D0 = –1, [α]
=
8.01, 6.92 (2 d, 3JH,H = 8.6 Hz, 8 H arom.), 5.89 (d, 3JH,H = 8.0 Hz,
577
20
20
20
3
–13, [α] = –53, [α] = –314, [α] = –370 (c = 0.90, CHCl3). IR
2 H, 3-H, 3Ј-H), 5.28 (dt, JH,H = 10.5, 3.1 Hz, 2 H, 1-H, 1Ј-H),
546
435
405
3
3
(film): ν = 3495, 2930, 2850, 1720, 1605, 1510, 1460, 1370, 1255,
˜
4.77 (br. d, JH,H = 8.0 Hz, 2-H, 2Ј-H), 4.75 (tt, JH,H = 10.5,
2.5 Hz, 2 H, 6-H, 6Ј-H), 3.87 (s, 6 H, 2 OCH3), 2.80 (m, 4 H, 5-H,
8-H2, 5Ј-H), 2.72 (q, 2JH,H = 3JH,H = 10.5 Hz, 7-H, 7Ј-H), 2.31 (br.
1170, 1105, 1025, 985, 950, 905, 850, 815, 770 cm–1
.
1H NMR
(CDCl3, 400 MHz, 25 °C): δ = 7.96, 6.90 (2 d, 3JH,H = 8.8 Hz, 8 H
arom.), 5.71 (t, JH,H = 6.2 Hz, 1 H, 3-H), 5.18 (tt, JH,H = 10.6,
4.4 Hz, 1 H, 1-H), 4.92 (m, 1 H, 6-H), 4.90 (m, 1 H, 6Ј-H), 4,83
(m, 1 H, 4Ј-H), 3.86 (s, 6 H, 2 OCH3), 3.50 (d, JH,H = 8.8 Hz, 1
H, 2Ј-H), 2.59 (d, JH,H = 13.2 Hz, 1 H, 5-H), 2.56 (m, 2 H, 5Ј-H,
3
3
2
2
3
d, JH,H = 10.5 Hz, 2 H, 7-H, 7Ј-H), 2.19 (dd, JH,H = 14.2, JH,H
= 2.5 Hz, 5-H, 5Ј-H), 2.05 [s, 6 H, 2 CH3(OAc)] ppm. 13C NMR
3
(CDCl3, 100.6 MHz, 25 °C): δ = 169.9 (s, 2 C=O), 165.3 (s, 2 C
2
1
arom.), 163.6 (s, 2 C=O), 141.7 (s, 2 C arom.), 131.8 (d, JC,H
=
1
8-H), 2.51 (m, 1 H, 5Ј-H), 2.44, 2.41 (2 m, 2 H, 2-H2), 2.35 (m, 1
162 Hz, 4 C arom.), 125.3 [d, JC,H = 162 Hz, C(3), C(3Ј)], 122.0
2
[s, C(4), C(4Ј)], 113.6 (d, 1JC,H = 157 Hz, 4 C arom.), 70.0 [d, 1JC,H
H, 5-H), 2.33 (m, 2 H, 3-H), 2.30 (m, 1 H, 8-H), 2.21 (d, JH,H
=
1
14.1, 1 H, 7Ј-H), 2.06, 2.04 [2 s, 6 H, 2 CH3(OAc)], 2.04 (m, 1 H,
= 143 Hz, C(1), C(1Ј)], 68.6 [d, JC,H = 137 Hz, C(6), C(6Ј)], 59.2
2
[d, 1JC,H = 150 Hz, C(2), C(2Ј)], 55.3 (q, 1JC,H = 144 Hz, 2 OCH3),
51.4 [t, 1JC,H = 128 Hz, C(8)], 36.5 [t, 1JC,H = 128 Hz, C(7), C(7Ј)],
7Ј-H), 2.02 (m, 2 H, 3Ј-H), 1.97 (d, JH,H = 12.4 Hz, 1 H, 7-H)
ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ = 171.2, 169.9 (2 s,
1
1
2 C=O), 165.5, 165.2 (2 s, 2 C arom.), 163.4 (s, 2 C=O), 136.9 [s,
36.0 [t, JC,H = 128 Hz, C(5), C(5Ј)], 21.1 [q, JC,H = 129 Hz, 2
CH3(OAc)]. CI-MS: m/z (%) = 706 (88) [M + NH4+], 689 (4)
[M]+, 670 (44), 170 (100), 135 (85). C35H38Cl2O10 (689.58): calcd.
C 60.96, H 5.55; found C 61.05, H 5.72.
C(4)], 131.6, 131.5 (2 d, 1JC,H = 163 Hz, 4 C arom.), 127.3 [d, 1JC,H
1
= 161 Hz, C(3)], 122.7, 122.5 (s, 2 C arom.), 113.6 (d, JC,H
=
1
160 Hz, 4 C arom.), 74.2 [s, C(1Ј)], 72.7 [d, JC,H = 141 Hz, C(2Ј)],
69.5 [d, JC,H = 144 Hz, C(1)], 69.3 [d, JC,H = 142 Hz, C(6)], 69.2
1
1
1
1
4,4Ј-Methylenebis[(1R,1ЈS,6S,6ЈR)-6-acetoxycyclohept-3-en-1-
yl]bis(4-methoxybenzoate) (meso-20): Bu3SnH (12.7 mL,
47.85 mmol) and AIBN (500 mg) were added to a solution of meso-
19 (11 g, 15.95 mmol) in toluene (80 mL) and the mixture was
stirred at 80 °C for 8 h. The solvent was then evaporated and the
[d, JC,H = 142 Hz, C(6Ј)], 66.2 [d, JC,H = 141 Hz, C(4Ј)], 55.4 (q,
1JC,H = 144 Hz, 2 OCH3), 47.9 [t, 1JC,H = 125 Hz, C(8)], 43.3, 42.6,
1
40.7, 39.4, 33.7 [4 t, JC,H = 131, 128, 134, 128 Hz, C(2), C(7),
1
C(3Ј), C(5Ј), C(7Ј)], 37.6 [t, JC,H = 131 Hz, C(5)], 21.3, 21.2 [2 q,
1JC,H = 131 Hz, 2 CH3(OAc)] ppm. CI-MS: m/z (%) = 672 (74) [M
896
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 891–900

Synthesis of the Polyol Subunit of the Macrolide Antibiotic RK-397
FULL PAPER
1
+ NH4+], 613 (9), 595 (32), 170 (100), 135 (52). C35H42O12 (654.70):
calcd. C 64.21, H 6.47; found C 64.35, H 6.41.
C(3)], 122.6, 122.5 (2 s, 2 C arom.), 113.6 (d, JC,H = 169 Hz, 4 C
arom.), 77.8 [s, C(1Ј)], 73.3 [d, 1JC,H = 147 Hz, C(2Ј)], 69.9 [d, 1JC,H
1
1
= 147 Hz, C(4Ј)], 69.1 [d, JC,H = 142 Hz, C(1)], 66.5 [d, JC,H
=
=
(αS,1S,3S,5R,7R)-5-Acetoxy-7-[{(4S,6R)-6-acetoxy-4-[(4-methoxy-
benzoyl)oxy]cyclohept-1-en-1-yl}methyl]-3-[(4-methoxybenzoyl)oxy-
7-hydroxycyclohept-1-yl] α-Methoxy-α-(trifluoromethylphenyl)ace-
tate [(+)-22]: (S)-(+)-MPTACl (20 µL) and DMAP (3 mg) were
added to a solution of (–)-21 (20 mg, 0.03 mmol) in pyridine
(500 µL) at 0 °C and the mixture stirred at 0 °C for 1 h. It was then
poured into a sat. aq. solution of NaHCO3 (10 mL) and extracted
with CH2Cl2 (10 mL, 3 times). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
on silica gel (CH2Cl2/MeOH, 99:1) afforded (+)-22 (25 mg, 98%)
1
1
141 Hz, C(6Ј)], 65.6 [d, JC,H = 145 Hz, C(6)], 55.4 (q, JC,H
1
145 Hz, 2 OCH3), 49.4, 42.7, 42.4, 40.0 [4 t, JC,H = 128, 128, 135,
136 Hz, C(5), C(7), C(5Ј), C(7Ј)], 46.0 [t, JC,H = 132 Hz, C(3Ј)],
1
1
33.5 [t, JC,H = 133 Hz, C(8)] ppm. CI-MS: m/z (%) = 571 (10) [M
+ H], 152 (57), 135 (100). C31H38O10·H2O (588.64): calcd. C 63.25,
H 6.84; found C 63.03, H 6.59.
(1S,6R)-6-Hydroxy-4-{(2R,4S,6R)-2,4,8-trihydroxy-6-[(4-methoxy-
benzoyl)oxy]octyl}cyclohept-3-en-1-yl 4-Methoxybenzoate [(–)-24]:
NaIO4 (1.42 g, 6.66 mmol) was added to a solution of (–)-23 (1.9 g,
3.33 mmol) in dioxane/H2O (68 mL/11 mL). The mixture was
stirred at 25 °C for 13 h and then poured into brine (200 mL). The
aqueous layer was extracted with CHCl3 (100 mL, 3 times). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The residual solid was taken up in acetic acid (40 mL)
and treated with Me4NBH(OAc)3 (11.1 g, 42.20 mmol) at 25 °C for
14 h. The solvent was then evaporated and the residue taken up
into EtOAc/ice (50 mL/100 mL). The mixture was vigorously
stirred for 10 min and solid NaHCO3 was added to reach pH 7.
The mixture was then extracted with EtOAc (80 mL, 4 times). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo to afford a pale-yellow foam that was either used directly for
the next steps. An analytical sample was purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 12:1) to afford (–)-
20
20
20
as a colorless oil. [α]2D0 = +0.4, [α] = +9, [α] = +21, [α]
=
546
435
405
+24 (c = 0.5, CHCl ). IR (film): ν = 3415, 2955, 2845, 1730, 1715,
˜
3
1605, 1580, 1510, 1460, 1420, 1370, 1315, 1255, 1170, 1100, 1025,
955, 850, 830, 770, 735, 720 cm–1. 1H NMR (CDCl3, 400 MHz,
25 °C): δ = 7.96, 6.91 [2 m, 8 H arom(PMBz)], 7.56, 7.38 [2 m, 5
3
H arom(MPTA)], 5.62 (t, JH,H = 6.2 Hz, 1 H, 2Ј-H), 5.30 (dddd,
3JH,H = 10.5, 10.5, 4.9, 4.9 Hz, 1 H, 4Ј-H), 4.83 (m, 2 H, 6Ј-H, 5-
3
H), 4.79 (dd, JH,H = 9.2, 1.2 Hz, 1 H, 1-H), 4.76 (m, 1 H, 3-H),
3.87 (s, 6 H, 2 OCH3), 3.63 (s, 3 H, OCH3), 2.61–1.83 (m, 16 H,
2-H2, 4-H2, 6-H2, 8-H2, 3Ј-H2, 5Ј-H2, 7Ј-H2), 2.05, 2.01 [2 s, 6 H,
2 CH3(OAc)] ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ =
170.4, 170.0 (2 s, 2 C=O), 165.6 (s, C=O), 165.2, 165.0 (2 s, 2 C
arom.), 163.5, 163.4 (s, 2 C=O), 135.6 (s, C arom.), 132.3 [s, C(1Ј)],
1
131.6, 131.5 (2 d, JC,H = 162 Hz, 4 C arom.), 129.6, 128.4 (2 d,
1
1JC,H = 162, 158 Hz, 4 C arom.), 127.5 [d, JC,H = 159 Hz, C(2Ј)],
20
20
20
24 as a white foam. [α]2D0 = –8, [α] = –12, [α] = –13, [α] = –
577
546
435
127.1 (d, 1JC,H = 162 Hz, 2 C arom.), 122.7, 122.4 (2 s, 2 C arom.),
17, [α]20 = –20 (c = 0.2, CH Cl ). IR (film): ν = 3420, 2935, 1705,
˜
405
2
2
1
113.6, 113.5 (2 d, JC,H = 161 Hz, 4 C arom.), 78.5 [d, C(5)], 73.8
1605, 1510, 1460, 1420, 1320, 1260, 1170, 1100, 1025, 950, 915,
1
1
[s, C(7)], 69.2 [d, JC,H = 142 Hz, C(6Ј)], 68.8 [d, JC,H = 140 Hz,
C(3)], 68.5 [d, 1JC,H = 141 Hz, C(4Ј)], 66.1 [d, 1JC,H = 148 Hz, C(1)],
55.8 (q, 1JC,H = 143 Hz, OCH3), 55.4 (q, 1JC,H = 142 Hz, 2 OCH3),
845, 770, 730 cm–1. H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.91,
1
3
6.85 (2 m, 8 H arom.), 5.56 (t, JH,H = 6.2 Hz, 3-H), 5.42 (m, 1 H,
6Ј-H), 4.85 (m, 1 H, 1-H), 4.14 (m, 1 H, 4Ј-H), 4.11 (m, 1 H, 2Ј-
1
1
46.6 [t, JC,H = 128 Hz, C(8)], 41.5 [t, JC,H = 131 Hz, C(6)], 40.8
H), 3.83, 3.80 (2 s, 6 H, 2 OCH3), 3.79 (m, 1 H, 6-H), 3.71 (t, 3JH,H
1
1
[t, JC,H = 130 Hz, C(4)], 40.1 [t, JC,H = 129 Hz, C(5Ј)], 39.5 [t,
2
3
= 4.9 Hz, 8Ј-H2), 2.49 (dt, JH,H = 11.7, JH,H = 9.8 Hz, 1 H, 7-
1JC,H = 133 Hz, C(7Ј)], 34.0 [t, 1JC,H = 132 Hz, C(3Ј)], 33.7 [t, 1JC,H
H), 2.46 (m, 1 H, 5-H), 2.38 (m, 2 H, 2-H2), 2.35 (m, 1 H, 5-H),
1
= 130 Hz, C(2)], 21.2, 20.7 [2 q, JC,H = 131, 127 Hz, 2 CH3(OAc)]
2
3
2.16 (m, 2 H, 1Ј-H2), 2.06 (dt, JH,H = 13.5, JH,H = 4.9 Hz, 1 H,
5Ј-H), 2.04 (m, 1 H, 5Ј-H), 1.93 (m, 1 H, 7-H), 1.83 (m, 1 H, 7Ј-
H), 1.81 (m, 1 H, 5Ј-H), 1.53 (m, 2 H, 3Ј-H2) ppm. 13C NMR
(CDCl3, 100.6 MHz, 25 °C): δ = 166.8, 165.5 (2 s, 2 C arom.),
ppm. 19FNMR (377 MHz, CDCl3/CFCl3, 25 °C): δ = –71.78 (s, 3
F, CF3) ppm. CI-MS: m/z (%) = 888 (30) [M + NH4+], 672 (23),
657 (58), 642 (15), 570 (100). C45H49F3O14 (654.70): calcd. C 62.06,
H 5.67; found C 61.86, H 5.72.
1
163.5, 163.3 (2 s, 2 C=O), 138.0 [s, C(4)], 131.7, 131.6 (2 d, JC,H
= 162 Hz, 4 C arom.), 124.1 [d, 1JC,H = 157 Hz, C(3)], 122.8, 122.3
(1S,6R)-6-Hydroxy-4-[{(1R,2S,4S,6R)-1,2,6-trihydroxy-4-[(4-meth-
oxybenzoyl)oxy]cyclohept-1-yl}methyl]cyclohept-3-en-1-yl 4-Meth-
oxybenzoate [(–)-23]: Mg(OMe)2 (0.8  in MeOH, 122 mmol,
153 mL) was added dropwise to a solution of (–)-21 (10 g,
15.27 mmol) in MeOH (500 mL), and the mixture was stirred at
25 °C for 7 h. Oxalic acid (122 mmol, 11 g) was then added and the
mixture was stirred at 0 °C for 1 h. The solution was filtered
through a pad of silica gel and concentrated in vacuo. Flash
chromatography on silica gel (CH2Cl2/MeOH, 96:4) afforded (–)-
1
(2 s, 2 C arom.), 113.6, 113.5 (2 d, JC,H = 167 Hz, 4 C arom.),
69.9 [d, 1JC,H = 138 Hz, C(2Ј)], 69.8 [d, 1JC,H = 135 Hz, C(6Ј)], 66.8
1
1
[d, JC,H = 146 Hz, C(1)], 66.1 [d, JC,H = 139 Hz, C(6)], 65.7 [d,
1JC,H = 144 Hz, C(4Ј)], 58.4 [t, JC,H = 142 Hz, C(8Ј)], 55.4 (q,
1
1JC,H = 145 Hz, 2 OCH3), 48.5 [t, JC,H = 125 Hz, C(1Ј)], 46.3 [t,
1
1JC,H = 129 Hz, C(7)], 43.5 [t, 1JC,H = 127 Hz, C(3Ј)], 42.1 [t, 1JC,H
1
1
= 127 Hz, C(5Ј)], 41.1 [t, JC,H = 129 Hz, C(5)], 36.9 [t, JC,H
=
127 Hz, C(7Ј)], 33.4 [t, 1JC,H = 129 Hz, C(2)] ppm. CI-MS: m/z (%)
= 573 (100) [M + H], 555 (8), 403 (2), 135 (2). C31H40O10 (572.65):
calcd. C 65.02, H 7.04; found C 65.16, H 7.13.
23 (6.62 g, 76%) as a white solid. M.p. 146–148 °C. [α]2D0 = –6,
20
[α]
= –13 (c = 0.2, CHCl ). IR (KBr): ν = 3430, 2935, 2850,
˜
3
577
1735, 1715, 1710, 1685, 1610, 1585, 1510, 1460, 1420, 1355, 1320,
1285, 1165, 1115, 1085, 1060, 1030, 990, 840, 770, 695 cm–1. 1H
(1S,6R)-6-Hydroxy-4-{[(4R,6S)-6-{(2R)-2-(4-methoxybenzoyl)oxy}-
NMR (CDCl3, 400 MHz, 25 °C): δ = 7.91, 6.90 (2 m, 8 H arom.), 4-{[tert-butyldimethylsilyloxy]butyl}-2,2-dimethyl-1,3-dioxan-4-
3
5.62 (t, 3JH,H = 6.2 Hz, 1 H, 3-H), 5.03 (t, JH,H = 9.2 Hz, 1 H, 4Ј-
yl]methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate [(+)-25]: Imid-
azole (190 mg, 2.974 mmol) and TBDMSCl (1  in DMF,
1.538 mmol, 1.54 mL) were added dropwise to a solution of crude
(–)-24 (400 mg, 0.699 mmol) in DMF (7 mL) at 0 °C. After 30 min
H), 4.93 (t, 3JH,H = 9.8 Hz, 1 H, 1-H), 4.12 (m, 1 H, 6-H), 3.91 (m,
1 H, 6Ј-H), 3.84 (s, 6 H, 2 OCH3), 3.57 (d, JH,H = 8.6 Hz, 1 H,
2Ј-H), 2.61, 2.18 (2 m, 2 H, 3ЈH2), 2.61–2.18, 2.49–2.00, 2.26–1.75
3
(3m, 8 H, 5-H2, 7-H2, 5Ј-H2, 7Ј-H2), 2.47 (m, 2 H, 8-H2), 2.39 (dd, the reaction was warmed to 25 °C and stirred for 15 min. The solu-
3
2
2JH,H = 14.7, JH,H = 6.2 Hz, 1 H, 2-H), 2.15 (d, JH,H = 14.7 Hz, tion was poured into H2O (20 mL) and extracted with Et2O
1 H, 2-H) ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ = 165.7,
163.5 (2 s, 2 C arom.), 158.7, 157.6 (2 s, 2 C arom.), 137.9 [s, C(4)],
131.6 (d, JC,H = 169 Hz, 4 C arom.), 126.7 [d, JC,H = 158 Hz,
(20 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to afford a pale-yellow oil that
was taken up in acetone/Me2C(OMe)2 (11 mL/3 mL) at 0 °C. Cam-
1
1
Eur. J. Org. Chem. 2006, 891–900
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
897

S. Gerber-Lemaire, A. T. Carmona, K. T. Meilert, P. Vogel
FULL PAPER
phorsulfonic acid (10 mg) was then added and the solution was
stirred at 0 °C for 20 min. The mixture was poured into a sat. aq.
(1R)-3-[(tert-Butyl)dimethyl]silyl)oxy)-1-(((4S,6R)-6-[{(4R,6R)-6-
[(2S)-4-hydroxy-2-{[4-methoxybenzoyl)oxy]butyl}-2,2-dimethyl-1,3-
solution of NaHCO3 (25 mL) and extracted with CH2Cl2 dioxan-4-yl]methyl-2,2-dimethyl-1,3-dioxan-4-yl}methyl]propyl 4-
(3×25 mL). The combined organic extracts were dried (MgSO4)
and concentrated in vacuo. Flash chromatography on silica gel
(EtOAc/pentane, 1:2) afforded (+)-25 [432 mg, 55% from (–)-23, 4
Methoxybenzoate [(+)-27]: NMO·H2O (372 mg, 2.751 mmol) and
OsO4 (0.1  in H2O, 1.38 mL, 0.138 mmol) were added to a solu-
tion of (+)-25 (1 g, 1.376 mmol) in acetone/H2O (24 mL/3 mL) and
the mixture was stirred at 25 °C for 1 h. Na2S2O5 (785 mg,
4.128 mmol) was then added and the solution was stirred at 25 °C
20
20
steps] as a colorless oil. [α]2D0 = +8, [α] = +8, [α] = +12 (c =
435
405
0.5, CH Cl ). IR (film): ν = 3500, 2930, 2855, 1700, 1605, 1580,
˜
2
2
1510, 1460, 1370, 1250, 1165, 1095, 1030, 955, 845, 770, 695 cm–1. for 15 min. The mixture was poured into H2O (60 mL) and ex-
3
1H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.99, 7.98 (2 d, JH,H
=
tracted with EtOAc (60 mL, 3 times). The combined organic ex-
3
8.9 Hz, 4 H arom.), 6.92, 6.91 (2 d, JH,H = 8.9 Hz, 4 H arom.), tracts were dried (MgSO4) and concentrated in vacuo to afford a
5.57 (t, JH,H = 6.9 Hz, 1 H, 3-H), 5.36 (m, 1 H, 2ЈЈЈ-H), 4.88 (m,
1 H, 1-H), 3.95 (m, 2 H, 4ЈЈ-H, 6ЈЈ-H), 3.86 (s, 6 H, 2 OCH3), 3.74
(tm, JH,H = 9.0 Hz, 1 H, 6-H), 3.70 (t, JH,H = 6.9 Hz, 2 H, 4ЈЈЈ- stirred at 25 °C for 12 h. The solution was poured into brine
H2), 2.47 (m, 2 H, 5-H, 3ЈЈЈ-H), 2.41 (t, JH,H = 6.9 Hz, 2 H, 2-
3
pale-yellow oil that was taken up in dioxane/H2O (28 mL/5.2 mL).
NaIO4 (589 mg, 2.752 mmol) was added and the mixture was
3
3
3
(60 mL) and extracted with CHCl3 (3×60 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated in vacuo to
afford an intermediate hemiacetal that was taken up in THF
(28 mL). Et2BOMe (1  in THF, 3.9 mL, 3.90 mmol) was added
dropwise and the mixture was stirred at 25 °C for 1 h. The solution
2
2
H2), 2.30 (d, JH,H = 15.8 Hz, 1 H, 5-H), 2.27 (dd, JH,H = 13.9,
3JH,H = 7.2 Hz, 1 H, 1Ј-H), 2.12 (dd, 2JH,H = 13.9, JH,H = 5.5 Hz,
3
2
3
1 H, 1Ј-H), 2.02 (dd, JH,H = 10.2, JH,H = 6.9 Hz, 1 H, 3ЈЈЈ-H),
2
3
1.98–1.89 (m, 3 H, 7-H2, 1ЈЈЈ-H), 1.82 (dt, JH,H = 14.2, JH,H
=
9.1 Hz, 1 H, 1ЈЈЈ-H), 1.71–1.54 (m, 2 H, 5Ј-H2), 1.29, 1.28 [2 s, 6 was cooled to 0 °C and MeOH (3.2 mL) and NaBH4 (197 mg,
H, 2 CH3–C(2ЈЈ)], 0.89 [s, 9 H, C(CH3)3], 0.01 [s, 6 H, Si(CH3)2] 5.2 mmol) were added. The mixture was stirred at 0 °C for 30 min.
ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ = 165.7, 165.4 (2 s,
2 C arom.), 163.3, 163.2 (2 s, 2 C=O), 137.3 [s, C(4)], 131.5 (d, 4
The solution was poured into a sat. aq. solution of NaHCO3
(80 mL) and extracted with EtOAc (60 mL, 3 times). The combined
C arom.), 123.3 [d, C(3)], 113.5 (d, 4 C arom.), 100.3 [s, C(2ЈЈ)], organic extracts were dried (MgSO4) and concentrated in vacuo.
69.6 [d, C(1)], 69.3 [d, C(2ЈЈ)], 66.6 [d, C(6)], 65.2 [d, C(6ЈЈ)], 63.9
[d, C(4ЈЈ)], 59.5 [t, C(4ЈЈЈ)], 55.4 (q, 2 OCH3), 46.8 [t, C(3ЈЈЈ)], 45.8
[t, C(1Ј)], 41.3 [t, C(5)], 40.4 [t, C(1ЈЈЈ)], 38.1 [t, C(5ЈЈЈ)], 37.5 [t,
C(7)], 33.4 [t, C(2)], 25.9 [q, C(CH3)3], 24.9, 24,7 [2 q, 2 CH3–
C(2ЈЈ)], 18.2 [s, C(CH3)3], –5.4 [q, Si(CH3)2]. MALDI-TOF: m/z
The residue was taken up in MeOH (10 mL) and concentrated in
vacuo (twice). The residual yellow oil was dissolved in acetone/
Me2C(OMe)2 (12 mL/4 mL) at 0 °C. Camphorsulfonic acid (15 mg)
was added and the solution was stirred at 0 °C for 20 min. The
mixture was poured into a sat. aq. solution of NaHCO3 (25 mL)
(%) = 749 (100) [M + Na]+, 765 (40) [M + K]+. C40H58O10Si and extracted with CH2Cl2 (25 mL, 3 times). The combined organic
(726.97): calcd. C 66.09, H 8.04, Si 3.86; found C 66.15, H 7.96, Si
3.89.
extracts were dried (MgSO4) and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/pentane, 1:1) afforded (+)-27
20
(530 mg, 48%, 4 steps) as a colorless oil. [α]2D0 = +18, [α] = +30,
435
20
(1S,6R)-6-Hydroxy-4-{[{(4R,6S)-6-[(2R)-2-(4-methoxybenzoyl)oxy]-
4-[(triethylsilyl)oxy]butyl}-2,2-dimethyl-1,3-dioxan-4-
yl]methyl}cyclohept-3-en-1-yl 4-Methoxybenzoate [(–)-26]: The same
procedure as above was applied with crude (–)-24 and Et3SiCl, at
0 °C, to afford (–)-26 as a colorless oil [42% from (–)-23, 4 steps].
[α]
= +37 (c = 0.5, CH Cl ). IR (film): ν = 3520, 2955, 2870,
˜
2 2
405
1710, 1605, 1515, 1455, 1415, 1380, 1260, 1170, 1100, 845, 730,
1
695, 665 cm–1. H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.99, 7.98
3
3
(2 d, JH,H = 9.1 Hz, 4 H arom.), 6.94, 6.91 (2 d, JH,H = 9.1 Hz,
4 H arom.), 5.51–5.44 (m, 1 H, 2VI-H), 5.37–5.31 (m, 1 H, 1-H),
4.06–3.89 (m, 4 H, 4ЈЈ-H, 6ЈЈ-H, 4IV-H, 6IV-H), 3.87, 3.86 (2 s, 6 H,
[α]2D0 = –6, [α]20 = –11, [α]20 = –13 (c = 0.5, CH Cl ). IR (film): ν
˜
435
405
2
2
3
2
= 3520, 2955, 2870, 1710, 1605, 1515, 1455, 1415, 1380, 1260, 1170,
2 OCH3), 3.70 (t, JH,H = 6.7 Hz, 3-H2), 3.68 (dm, JH,H = 9.7 Hz,
1 H, 2IV-H), 3.59 (m, 1 H, 2IV-H), 2.05–1.73 (m, 10 H, 1Ј-H2, 5ЈЈ-
H2, 1ЈЈЈ-H2, 5IV-H2, 1V-H2), 1.57–1.40 (m, 4 H, 2-H2, 3VI-H2), 1.33,
1.24, 1.21, 1.18 [4 s, 12 H, 2 CH3C(2ЈЈ), 2 CH3C(2IV)], 0.87 [s, 9 H,
C(CH3)3], 0.02, 0.01 [2 s, 6 H, Si(CH3)3] ppm. 13C NMR (CDCl3,
100.6 MHz, 25 °C): δ = 166.9, 165.6 (2 s, 2 C arom.), 163.5, 163.2
1100, 845, 730, 695, 665 cm–1. 1H NMR (CDCl3, 400 MHz, 25 °C):
3
δ = 7.99, 7.98 (2 d, JH,H = 8.9 Hz, 4 H arom.), 6.92, 6.91 (2 d,
3
3JH,H = 8.9 Hz, 4 H arom.), 5.54 (t, JH,H = 6.6 Hz, 1 H, 3-H),
5.34 (m, 1 H, 2ЈЈЈ-H), 4.80 (m, 1 H, 1-H), 3.98 (m, 1 H, 4ЈЈ-H),
3.90 (dd, 3JH,H = 6.4, 6.3 Hz, 6ЈЈ-H), 3.87, 3.86 (2 s, 6 H, 2 OCH3),
3
3
1
3.71 (t, JH,H = 7.1 Hz, 2 H, 4ЈЈЈ-H2), 3.61 (ddm, JH,H = 12.0,
(2 s, 2 C=O), 131.6, 131.4 (2 d, JC,H = 162, 160 Hz, 4 C arom.),
2
3
123.0, 122.2 (2 s, 2 C arom.), 133.7, 133.5 (2 d, 1JC,H = 161, 162 Hz,
11.9 Hz, 1 H, 6-H), 2.36 (dd, JH,H = 14.0, JH,H = 11.9 Hz, 1 H,
5-H), 2.29 (m, 1 H, 3ЈЈЈ-H), 2.29 (t, JH,H = 6.6 Hz, 2 H, 2-H2),
2.30 (dd, JH,H = 14.1, JH,H = 6.4 Hz, 1Ј-H), 2.19 (d, JH,H
14.0 Hz, 5-H), 2.05 (dd, JH,H = 14.1, JH,H = 6.3 Hz, 1 H, 1Ј-H),
3
4 C arom.), 100.5 [s, C(2ЈЈ)], 98.6 [s, C(2IV)], 69.2, 68.3 [2 d, JC,H
1
2
3
2
= 147 Hz, C(1), C(2VI)], 65.7, 64.9, 63.3, 62.1 [4 d, JC,H = 146,
1
=
2
3
148, 145, 147 Hz, C(4ЈЈ), C(6ЈЈ), C(4IV), C(6IV)], 59.6 [t, JC,H
=
1
2
3
140 Hz, C(3)], 58.3 [t, 1JC,H = 142 Hz, C(4VI)], 55.4, 55.3 (2q, 1JC,H
2.05 (dd, JH,H = 14.1, JH,H = 6.3 Hz, 1 H, 1Ј-H), 2.02–1.89 (m,
2
3
= 145 Hz, 2 OCH3), 42.0, 41.6 [2 t, JC,H = 126 Hz, C(2), C(3VI)],
1
4 H, 7-H2, 1ЈЈЈ-H, 3ЈЈЈ-H), 1.82 (dt, JH,H = 14.3, JH,H = 5.2 Hz,
1ЈЈЈ-H), 1.60 (m, 2 H, 5ЈЈ-H2), 1.29, 1.28 [2 s, 6 H, 2 CH3C(2ЈЈ)],
0.95 [t, 3JH,H = 8.1 Hz, 9 H, 3 CH3(TES)], 0.58 [q, 3JH,H = 8.1 Hz,
6 H, 3 CH2(TES)] ppm. 13C NMR (CDCl3, 100.6 MHz, 25 °C): δ
= 165.7, 165.4 (2 s, 2 C arom.), 163.3, 163.2 (2 s, 2 C=O), 137.6 [s,
C(4)], 131.5 (d, 4 C arom.), 123.1 [d, C(4)], 122.7 (s, 2 C arom.),
113.5 (d, 4 C arom.), 100.2 [s, C(2ЈЈ)], 69.7 [d, C(1)], 69.4 [d,
C(2ЈЈЈ)], 67.3 [d, C(6)], 65.0 [d, C(6ЈЈ)], 63.9 [d, C(4ЈЈ)], 59.3 [t,
C(4ЈЈЈ)], 55.4 (q, 2 OCH3), 47.9 [t, C(3ЈЈЈ)], 45.9 [t, C(1Ј)], 42.3 [t,
C(5)], 40.4 [t, C(1ЈЈЈ)], 38.5 [t, C(5Ј)], 37.5 [t, C(7)], 33.5 [t, C(2)],
40.9, 39.0, 38.1, 37.6 [4 t, JC,H = 125 Hz, C(1Ј), C(5ЈЈ), C(5IV),
1
C(1V)], 38.0 [t, JC,H = 123 Hz, C(1ЈЈЈ)], 30.1, 19.5 [2 q, JC,H
=
1
1
125, 124 Hz, 2 CH3C(2IV)], 25.8 [q, 1JC,H = 126 Hz, C(CH3)3], 24.3,
1
24.0 [2 q, JC,H = 124 Hz, 2 CH3C(2ЈЈ)], 18.1 [s, C(CH3)3], –5.5 [q,
1JC,H = 118 Hz, Si(CH3)2] ppm. MALDI-TOF: m/z (%) = 826 (100)
[M + Na]+. C43H66O12Si (803.07): calcd. C 64.31, H 8.28; found C
64.31, H 8.28.
(3S)-4-{(4S,6S)-6-[{(4S,6R)-6-[(2R)-4-{[(tert-Butyl)dimethyl]-
24.8, 24.7 [2 q, 2 CH3C(2ЈЈ)], 6.73 [q, 3 CH3(TES)], 4.74 [t, 3 silyl}oxy-2-hydrobutyl]-2,2-dimethyl-1,3-dioxan-4-yl}methyl]-2,2-di-
CH2(TES)] ppm. C40H58O10Si (726.97): calcd. C 66.09, H 8.04 Si
3.86; found C 66.16, H 8.08 Si 3.87.
methyl-1,3-dioxan-4-yl}-3-hydroxybutyl Acetate [(–)-28]: KOMe
(665 mg, 9.480 mmol) was added to a solution of (+)-27 (190 mg,
898
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 891–900

Synthesis of the Polyol Subunit of the Macrolide Antibiotic RK-397
0.237 mmol) in MeOH (7 mL) at 0 °C. After 30 min the solution MeOH, 97:3) afforded (–)-29 (54 mg, 60%, 4 steps) as a pale-yellow
FULL PAPER
20
20
was warmed to 25 °C and stirred for 15 h. The mixture was poured
into a sat. aq. solution of NH4Cl (15 mL) and extracted with
EtOAc (15 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to afford a pale-yellow oil
(114 mg, 90% crude), which was taken up in vinyl acetate (4 mL)
and treated with Candida cylindracea lipase (4800 U per mmol,
3.86 U per mg, 265 mg). The mixture was stirred at 25 °C for 1 h,
then filtered and concentrated in vacuo. Flash chromatography on
oil. [α]2D0 = –57, [α] = –102, [α] = –122 (c = 0.4, CH2Cl2). IR
435 435
(film): ν = 3495, 2985, 2920, 1735, 1645, 1450, 1380, 1240, 1165,
˜
1105, 1035, 740, 700 cm–1. H NMR (C6D6, 400 MHz, 25 °C): δ =
1
7.35, 7.20 (2 m, 10 H arom.), 5.83 (m, 1 H, 6IV-H), 5.11 (d, JH,H
3
= 17.1 Hz, 1 H, 7IV-H), 5.09 (m, 1 H, 7IV-H), 4.82 [s, 2 H,
2
CH2(BOM)], 4.80, 4.78 [2 d, JH,H = 8.2 Hz, 2 H, CH2(BOM)],
6.68, 4.65 (2 d, 2JH,H = 9.1 Hz, 2 H, CH2Ph), 4.62 (s, 2 H, CH2Ph),
3
4.20 (t, JH,H = 6.6 Hz, 2 H, 1-H2), 4.09–3.96 (m, 5 H, 3-H, 4Ј-H,
silica gel (CH2Cl2/MeOH, 97:3) afforded (–)-28 (108 mg, 79%, 2 6Ј-H, 4ЈЈЈ-H, 6ЈЈЈ-H), 3.94 (m, 1 H, 2IV-H), 3.87 (m, 1 H, 4IV-H),
steps). [α]2D0 = –9, [α]
= –48 (c = 0.18, MeOH). IR (film): ν =
2.25 (dd, 3JH,H = 6.2, 5.9 Hz, 5IV-H), 2.04 [s, 3 H, CH3(OAc)], 1.99–
1.82 (m, 2 H, 2-H2), 1.80 (m, 1 H, 1ЈЈ-H), 1.73–1.60 (m, 8 H, 5Ј-
H2, 5ЈЈЈ-H2, 1IV-H2, 3IV-H2), 1.46 (m, 1 H, 1ЈЈ-H), 1.44 (m, 1 H, 4-
20
˜
577
3415, 2985, 2935, 2870, 1735, 1645, 1440, 1380, 1255, 1165, 1100,
1
1055, 940, 835, 775 cm–1. H NMR (CD3OD, 400 MHz, 25 °C): δ
= 4.15–4.04 (m, 4 H, 4Ј-H, 6Ј-H, 4ЈЈЈ-H, 6ЈЈЈ-H), 3.95–3.81 (m, 2 H), 1.35, 1.34, 1.31, 1.26 [4 s, 2 CH3C(2Ј), 2 CH3C(2ЈЈЈ)], 1.17 (m,
3
H, 3-H, 2IV-H), 3.80 (dd, JH,H = 6.0, 5.5 Hz, 2 H, 1-H2), 3.71 (t,
1 H, 4-H) ppm.13C NMR (C6D6, 100.6 MHz, 25 °C): δ = 169.9 (s,
3JH,H = 6.4 Hz, 2 H, 4IV-H2), 2.08 [s, 3 H, CH3(OAc)], 1.78–1.53
C=O), 137.6 (s, 2 C arom.), 135.0 [d, C(6IV)], 128.5, 127.8, 127.7
(m, 14 H, 2-H2, 4-H2, 5Ј-H2, 1ЈЈ-H2, 5ЈЈЈ-H2, 1IV-H2, 3IV-H2), 1.48, (3 d, 8 C arom.), 128.4 (s, 2 C arom.), 117.3 [t, C(7IV)], 100.5 [s,
1.37 [2 s, 6 H, 2 CH3C(2Ј)], 1.36, 1.34 [2 s, 6 H, 2 CH3C(2ЈЈЈ)], 0.94 C(2ЈЈЈ)], 98.5 [s, C(2Ј)], 94.7, 94.2 [2 t, 2 CH2(BOM)], 72.1 [d,
[s, 9 H, C(CH3)3], 0.11 [s, 6 H, Si(CH3)3] ppm. 13C NMR (CDCl3, C(4IV)], 70.1 [d, C(3), C(2IV)], 69.5 (t, 2 CH2Ph), 67.2, 65.5, 65.2 [3
100.6 MHz, 25 °C): δ = 171.2 (s, C=O), 100.5 [s, C(2ЈЈЈ)], 98.7 [s,
d, C(4Ј), C(6Ј), C(4ЈЈЈ), C(6ЈЈЈ)], 61.1 [t, C(1)], 44.0, 42.9, 42.5 [3 t,
1
C(2Ј)], 68.2, 67.2 [2 d, JC,H = 146, 142 Hz, C(3), C(2IV)], 65.5,
C(4), C(5Ј), C(5ЈЈЈ), C(1IV)], 38.5 [t, C(1ЈЈ)], 34.5 [t, C(2), C(3IV)],
65.3, 65.0, 64.0 [4 d, 1JC,H = 143, 142, 140 Hz, C(4Ј), C(6Ј), C(4ЈЈЈ), 30.2, 19.8 [2 q, 2 CH3C(2ЈЈЈ)], 24.9 [q, 2 CH3C(2ЈЈЈ)], 21.0 [q,
1
1
C(6ЈЈЈ)], 62.2 [t, JC,H = 140 Hz, C(1)], 61.6 [t, JC,H = 141 Hz, CH3(OAc)] ppm. MALDI-TOF: m/z (%) = 765 (100) [M + Na]+.
C(4IV)], 42.8, 42.0 [2 t, JC,H = 126, 125 Hz, C(2), C(3IV)], 38.9, C42H62O11 (742.94): calcd. C 67.90, H 8.41; found C 68.01, H 8.47.
1
1
1
38.7 [2 t, JC,H = 124 Hz, C(5Ј), C(5ЈЈЈ)], 36.7 [t, JC,H = 122 Hz,
(3S)-4-[(4R,6R)-6-{[(4R,6S)-6-{(2R,4S)-4,6-Dihydroxy-2-
[{[(phenylmethyl)oxy]methyl}oxy]heptan-1-yl}-2,2-dimethyl-1,3-di-
oxan-4-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl]-3-[{[(phenylmethyl)-
oxy]methyl}oxy]butyl Acetate [(–)-30]: Me2SO2NH2 (17 mg,
0.128 mmol) and AD-mix-β (1486 mg per mmol, 95 mg) were
added to a solution of (–)-29 (50 mg, 0.064 mmol) in a mixture of
tBuOH and H2O (700 µL/700 µL) cooled to 0 °C. AD-mix-β (70 g)
was prepared from K3Fe(CN)6 (47.7 g), K2CO3 (20 g), (DHQD)2-
PHAL (1.88 g), and K2OsO2(OH)4 (370 mg). The mixture was
stirred at 0 °C for 13 h. EtOAc (2 mL), H2O (1 mL), and Na2SO3
(24 mg, 0.256 mmol) were added. After stirring for 30 min at 25 °C,
the mixture was poured into H2O (5 mL) and extracted with EtOAc
(4×5 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. Flash chromatography on silica gel
(CH2Cl2/MeOH, 16:1) afforded (–)-30 (34 mg, 68 %, major dia-
stereoisomer) as a colorless oil. [α]2D0 = –11 (c = 0.2, CH2Cl2). IR
C(1ЈЈ)], 36.2 [t, 1JC,H = 125 Hz, C(4), C(1IV)], 30.2, 19.6 [2 q, JC,H
1
1
= 125 Hz, 124, 2 CH3C(2Ј)], 25.8 [q, JC,H = 126 Hz, C(CH3)3],
24.7, 24.6 [2 q, JC,H = 122, 125 Hz, 2 CH3C(2ЈЈЈ)], 21.0 [q, JC,H
1
1
1
= 124 Hz, CH3(OAc)], 18.1 [s, C(CH3)3], –5.5 [q, JC,H = 119 Hz,
Si(CH3)3] ppm. MALDI-TOF: m/z (%) = 599 (100) [M + Na]+.
C29H56O9Si (576.84): calcd. C 60.38, H 9.78; found C 60.16, H
9.60.
(3S)-4-[(4R,6R)-6-{[(4R,6S)-6-{(2R,4S)-4-Hydroxy-2-
[{[(phenylmethyl)oxy]methyl}oxy]-6-hepten-1-yl}-2,2-dimethyl-1,3-di-
oxan-4-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl]-3-[{[(phenylmethyl)-
oxy]methyl}oxy]butyl Acetate [(–)-29]: (iPr)2NEt (251 µL,
1.464 mmol), BnOCH2Cl (136 µL, 0.976 mmol), and Bu4NI (5 mg)
were added to a solution of (–)-28 (100 mg, 0.122 mmol) in CH2Cl2
(3 mL) at 0 °C. After 30 min the mixture was heated to 40 °C for
3 h. The solution was poured into a sat. aq. solution of NaHCO3
(12 mL) and extracted with CH2Cl2 (12 mL, 3 times). The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo to afford a yellow oil that was taken up in THF (6 mL)
and treated with HF·pyridine (400 mL) at –20 °C. After stirring for
20 min at –20 °C, the mixture was poured into a sat. aq. solution
of NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. Filtration over a pad of silica gel (10 cm, CH2Cl2/MeOH,
95:5) afforded a pale-yellow oil. This crude alcohol (69 mg,
0.098 mmol) was dissolved in CH2Cl2 (1.2 mL) and treated with
activated 4-Å molecular sieves (30 mg), NMO·H2O (27 mg,
0.196 mmol), and Pr4NRuO4 (7 mg, 0.020 mmol). After stirring for
30 min at 25 °C the solution was directly filtered through a pad of
silica gel and concentrated in vacuo. Ti(OiPr)4 (0.1  in CH2Cl2,
98 mL) was added to a solution of (S)-BINOL (6 mg, 0.020 mmol)
in CH2Cl2 (300 µL) and the solution was stirred at 25 °C for
45 min. The mixture was cooled to –78 °C. A solution of the crude
aldehyde (67 mg, 0.098 mmol) in CH2Cl2 (700 µL) and allyltribu-
tylstannane (45 µL, 0.147 mmol) were added. After 10 min the
solution was warmed to 0 °C and stirred for 50 min. EtOAc (2 mL)
and a sat. aq. solution of NaHCO3 (1 mL) were added and the
(film): ν = 3440, 3090, 3030, 2960, 1730, 1606, 1495, 1480, 1455,
˜
1400, 1285, 1160, 970, 865 cm–1. 1H NMR (CD3OD, 400 MHz,
25 °C): δ = 7.38–7.31 (m, 10 H arom.), 4.87, 4.85, 4.84, 4.83 [4 d,
2JH,H = 5.6 Hz, 4 H, 2 CH2(BOM)], 4.67, 4.64 (2 d, 2JH,H = 7.1 Hz,
2 H, CH2Ph), 4.64 (s, 2 H, CH2Ph), 4.21 (m, 2 H, 3-H, 2IV-H),
4.19–4.00 (m, 5 H, 4Ј-H, 6Ј-H, 4ЈЈЈ-H, 6ЈЈЈ-H, 6IV-H), 3.85 (m, 1
3
3
H, 4IV-H), 3.69 (t, JH,H = 6.7 Hz, 2 H, 2 H, 1-H2), 3.49 (t, JH,H
= 6.1 Hz, 2 H, 2 H, 7IV-H2), 2.03 [s, 3 H, CH3(OAc)], 1.95–1.40
(m, 16 H, 2-H2, 4-H2, 5Ј-H2, 1ЈЈ-H2, 5ЈЈЈ-H2, 1IV-H2, 3IV-H2, 5IV-
H2), 1.36, 1.33, 1.32, 1.31 [4 s, 12 H, 2 CH3C(2Ј), 2 CH2C(2ЈЈЈ)]
ppm. 13CNMR (CD3OD, 100.6 MHz, 25 °C): δ = 170.1 (s, C=O),
138.8 (s, 2 C arom.), 128.9, 128.4, 128.2 (3 d, 10 C arom.), 101.0
[s, C(2ЈЈЈ)], 99.4 [s, C(2Ј)], 95.3, 95.2 [2 t, 2 CH2(BOM)], 74.3, 73.5
[2 d, C(3), C(2IV)], 71.3, 69.7 [2 d, C(4IV), C(6IV)], 70.3 (t, 2
CH2Ph), 67.4, 66.5, 64.3 [3 d, C(4Ј), C(6Ј), C(4ЈЈ), C(6ЈЈ)], 63.8 [t,
C(1)], 58.9 [t, C(7IV)], 44.5, 44.0, 42.9, 40.5, 40.2, 39.4, 38.9, 38.1
[8 t, C(2), C(4), C(5Ј), C(1ЈЈ), C(5ЈЈЈ), C(1IV), C(3IV), C(5IV)], 30.0,
19.7 [2 q, 2 CH3C(2Ј)], 24.9, 24.8 [2 q, 2 CH3C(2ЈЈЈ)], 20.8 [q,
CH3(OAc)] ppm. MALDI-TOF: m/z (%) = 758 (100) [M – H2O]+.
C42H64O13 (776.956): calcd. C 64.93, H 8.30; found C 64.12, H
8.12.
mixture was stirred for 30 min at 0 °C, then filtered and concen- NMR Spectroscopic Data for Triacetonide 31: Numbering accord-
trated in vacuo. Flash chromatography on silica gel (CH2Cl2/
ing to RK-397. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 7.27–7.30
Eur. J. Org. Chem. 2006, 891–900
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
899

S. Gerber-Lemaire, A. T. Carmona, K. T. Meilert, P. Vogel
FULL PAPER
(m, 10 H arom.), 4.85 [m, 4 H, 2 CH2(BOM)], 4.73, 4.58 (2 d, 2JH,H
= 11.9 Hz, 2 H, CH2Ph), 4.68, 4.57 (2 d, JH,H = 11.8 Hz, 2 H,
1645–1656; b) S. B. Zotchev, Curr. Med. Chem. 2003, 10, 211–
223; c) S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021–2040; d)
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dall, R. L. Hamill, Bacteria 1986, 9, 355–401; f) S. Omura, H.
Tanaka, Macrolide Antibiotics: Chemistry, Biology and Prac-
tice, Academic Press, New York, 1984.
2
CH2Ph), 4.20 (t, 3JH,H = 6.8 Hz, 2 H, 11-H2), 4.15, 4.07–3.94 (2 m,
8 H, 13-H, 15-H, 17-H, 19-H, 21-H, 23-H, 25-H, 27-H), 3.85, 3.73
(2 m, 2 H, 28-H2), 2.03 [s, 3 H, CH3(OAc)], 1.95–1.80, 1.78–1.35
(2 m, 16 H, 12-H2, 14-H2, 16-H2, 18-H2, 20-H2, 22-H2, 24-H2, 26-
H2), 1.39, 1.36, 1.35, 1.32, 1.30 [5 s, 18 H, 6CH3(acetonide)] ppm.
13C NMR (CD3OD, 100.6 MHz, 25 °C): δ = 172.9 (s, C=O),
133.6 (s, 2 C arom.), 129.4, 128.9, 128.7 (3 d, 10 C arom.), 101.5
[s, Cquat(acetonide anti)], 99.8 [s, 2 Cquat(acetonide syn)], 95.7, 95.6
[2 d, 2 CH2(BOM)], 73.9, 73.8 [2 d, C(13), C(23)], 70.7 (t, 2
CH2Ph), 70.6, 67.0, 66.9, 66.3, 64.8, 64.2 [6 d, C(15), C(17), C(19),
C(21), C(25), C(27)], 62.4 [t, C(1)], 59.4 [t, C(28)], 43.9, 43.3, 43.1,
39.6, 39.5, 38.5, 35.5, 35.4 [8 t, C(12), C(14), C(16), C(18), C(20),
C(22), C(24), C(26)], 30.5 (doubled peak), 20.3, 20.2 [3 q, 4
CH3(acetonide syn)], 25.4, 25.3 [2 q, 2 CH3(acetonide anti)], 20.9
[s, CH3(OAc)] ppm.
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NMR Spectroscopic Data for Pentaacetonide 32: Numbering ac-
cording to RK-397. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 4.12–
3.92 (m, 8 H, 13-H, 15-H, 17-H, 19-H, 21-H, 23-H, 25-H, 27-H),
3.82 (m, 4 H, 11-H2, 28-H2), 1.82, 1.65–1.48 (2 m, 16 H, 12-H2,
14-H2, 16-H2, 18-H2, 20-H2, 22-H2, 24-H2, 26-H2), 1.46, 1.45, 1.37,
1.36, 1.33 [5 s, 30 H, 10 CH3(acetonide)] ppm. 13C NMR (CDCl3,
100.6 MHz, 25 °C): δ = 104.0, 100.4, 100.2, 98.4, 98.3 [5 s, 5
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Cquat(acetonide)], 65.5, 64.8, 63.2 (doubled peak), 63.0, 62.8, 62.1,
61.2 [7 d, C(13), C(15), C(17), C(19), C(21), C(23), C(25), C(27)],
60.0, 59.9 [2 t, C(11), C(28)], 42.4, 41.8, 38.6, 38.3, 37.1 (doubled
peak), 31.8, 30.7 [7 t, C(12), C(14), C(16), C(18), C(20), C(22),
C(24), C(26)], 29.9, 29.8, 19.2, 19.1 [4 q, 4 CH3(acetonide syn)],
25.8, 25.6 [2 q, 2 CH3 [acetonide C(27),C(28)], 24.8 (doubled peak),
24.4, 24.3 [3 q, 2 CH3 (acetonide anti)] ppm. MALDI-TOF: m/z
(%) = 637 [100] [M + Na]+.
Acknowledgments
This work was supported by the Swiss National Science Founda-
tion. We thank Martial Rey, Francisco Sepùlveda, and Annabelle
Gillig for technical help.
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[1] For leading reviews, see: a) J. F. Aparicio, M. V. Mendes, N.
Received: September 2, 2005
Anton, E. Recio, J. F. Martin, Curr. Med. Chem. 2004, 11,
Published Online: December 12, 2005
900
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 891–900