A convergent total synthesis of (-)-mucocin: An acetogenin from Annonaceae

Article abstract of DOI:10.1002/1521-3765(20000703)6:13<2382::AID-CHEM2382>3.0.CO;2-C

A total synthesis of the Annonaceous acetogenin mucocin has been accomplished. The synthesis follows a convergent strategy, wherein at a very late stage the left part of the molecule is connected with the right part. The key reaction is the stereocontrolled addition of an organomagnesium compound 2 to the aldehyde 3. The THP ring of mucocin is build by a 6-endo epoxide cyclization of an epoxyacetonide precursor (16 → 17). The new modular synthetic approach developed herein should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogues.

Full text of DOI:10.1002/1521-3765(20000703)6:13<2382::AID-CHEM2382>3.0.CO;2-C

FULL PAPER
A Convergent Total Synthesis of (À)-Mucocin:
An Acetogenin from Annonaceae
Sabine Hoppen, Stefan Bäurle, and Ulrich Koert*[a]
Abstract: A total synthesis of the Annonaceous acetogenin mucocin has been
accomplished. The synthesis follows a convergent strategy, wherein at a very late
stage the left part of the molecule is connected with the right part. The key reaction is
the stereocontrolled addition of an organomagnesium compound 2 to the aldehyde 3.
The THP ring of mucocin is build by a 6-endo epoxide cyclization of an
epoxyacetonide precursor (16 ! 17). The new modular synthetic approach
developed herein should be useful for the synthesis of other related natural products
as well as pharmacologically interesting analogues.
Keywords: Annonaceous acetoge-
nins ´ antitumor agents ´ mucocin
´ natural products ´ total synthesis
O
Introduction
O
HO
HO
O
O
More than 250 acetogenins from various plant species of
Annonaceae have been isolated and characterised.[1] This class
of natural products shows potent biological properties, for
example as antitumor agents, immunosuppressants or pesti-
cides.[1] As mode of action a blockage of mitochondrial
complex I (NADH-ubiquinone oxidoreductase) of mamma-
lian and insects is discussed.[2] The membrane conformation of
Annonaceous acetogenins and its relation to complex I
inhibition has been investigated.[3] Furthermore, these com-
pounds inhibit a NADH oxidase, that is found in the plasma
membrane of tumors but not in normal cells.[4] As a
consequence, the ATP level of the tumor cells decreases. This
has an inhibitory effect on multiple drug resistance caused by
ATP-driven transporter systems.
OH H
HO
H
H
H
(-)-mucocin
O
O
HO
OH
H
O
O
H
H
H
HO
muconin
OH
O
O
HO
OH
O
OH
H
H
pyranicin
OH
O
O
HO
OH
Common structural features of the acetogenins from
Annonaceae are a central cyclic ether part with one left and
one right side chain. A butenolide unit is located at the right
terminus of the molecule. The 2,5-disubstituted tetrahydro-
furan (THF) moiety is part of many acetogenins. Mono-THF,
bis-THF and ter-THF substructures are known and subject to
intensive synthetic efforts.[5] Within the acetogenins a group of
compounds exists also bearing a THP-ring in the molecular
scaffold. Representative members of that group are muco-
cin,[6] muconin,[7] pyranicin,[8] and pyragonicin.[8]
O
OH
H
H
pyragonicin
(lung cancer) and PACA-2 (pancreatic cancer) cell lines with
a selectivity up to 10000 times that of the known antitumor
agent adriamycin. Here we report in detail on a convergent
total synthesis of mucocin.[9]
Mucocin was isolated from Rollinia mucosa.[6] The mole-
cule shows a highly selective inhibitory effect against A-549
Results and Discussion
[a] Prof. Dr. U. Koert, Dipl.-Chem. S. Hoppen, Dipl.-Chem. S. Bäurle
Institut für Chemie der Humboldt-Universität zu Berlin
Hessische Strasse 1 ± 2, 10115 Berlin (Germany)
Fax : (‡49)302093 7266
Our retrosynthetic analysis of mucocin leads to a disconnec-
tion at C(16) C(17) (Scheme 1). The target structure could be
constructed by addition of a THP organometallic compound 1
À
E-mail: koert@lyapunov.chemie.hu-berlin.de
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Chem. Eur. J. 2000, 6, No. 13

2382±2396
O
1
O
23
H
O
HO
18 17
HO
4
36
37
a,b,c
6
12
24
20
15
HO
O
OH
Br
OR
19
16
2
3
5
11
O
O
35
OH
H
HO
H
H
6
7
mucocin
R = TBDMS
34
OH
d
OR
Br
OR
RO
O
H
HO OH
O
M
O
RO
8
O
9
H
H
OR
H
e
O
1
O
H
H
2
f
Br
OR
OR
OR
OR
O
O
O
O
HO
O
O
RO
10
11
O
O
OR
g
h
OH
HO
O
OH
5
OR
PPh3
O
O
O
O
O
O
RO
HO
H
H
4
3
12
13
Scheme 1. Retrosynthetic analysis of mucocin.
i
O
O
OH
to a THF aldehyde 2. In this step, critical attention has to be
paid to the stereocontrol as well as to the compatibility of the
butenolide with the reaction conditions. For the construction
of the THP-ring in 1 a double-bond directed 6-endo opening
of the epoxide in 3 was planned. The THF aldehyde 2 was
deduced from a Wittig-type reaction of the ylide 4 and the
aldehyde 5. The resulting modular strategy using three
building blocks 3, 4, and 5 is versatile and not restricted to
mucocin only.
Starting point for the synthesis of the left half of the
molecule was (E)-dihydromuconic acid 6 (Scheme 2). Reduc-
tion of the dimethyl ester of 6 gave a diol, which was
monosilylated[10] and subsequently transformed into the
bromide 7. Asymmetric dihydroxylation[11] of 7 provided the
diol 8 (ee 86%). The diol 8 easily underwent an undesired
intramolecular Williamson side reaction to the THF alcohol 9
upon evaporation of the solvent during the work up at room
temperature or attempts of chromatographic purification.
Therefore work up of the dihydroxylation was done below
108C and the crude product was directly converted into the
acetonide 10. The alkylation of 10 to 11, followed by an (E)-
selective reduction[12] provided the allylic alcohol 12. The
optimized solvent combination NH3/THF/DMPU 5:5:2 was
necessary for a yield of 91% in the alkylation step. The
14
Scheme 2. a) 1) TMSCl, MeOH; 2) LiAlH4, THF, 92%; b) NaH
(1.0 equiv), TBDMSCl (1.0 equiv), THF, 08C, 1 h, 54%; c) 1) p-TsCl
(2.0 equiv), py (10 equiv), CH2Cl2, 08C, 12 h; 2) LiBr (4.0 equiv),
acetone, 12 h, 85% over two steps; d) AD-mix a, MeSO2NH2, H2O/
tBuOH 1:1, 08C ! rt, 24 h; e) p-TsOH (5 mol%), 2,2-dimethoxypropane
(4.0 equiv), CH2Cl2, 1 h, 92% over two steps; f) propargylic alcohol
(3.0 equiv), nBuLi (6.0 equiv), NH3/THF/DMPU (5:5:2), À408C, 6 h,
91%; g) Red-Al (2.0 equiv), THF, 08C, 4 h, 95%; h) TBHP (2.0 equiv),
(À)-DIPT (12 mol%), Ti(OiPr)4 (10 mol%), CH2Cl2, À208C, 3.5 h, 85%;
i) TBHP (2.0 equiv), (‡)-DIPT (12 mol%), Ti(OiPr)4 (10 mol%), CH2Cl2,
À208C, 3.5 h, 79%. TMS ˆ trimethylsilyl, TBDMS ˆ tert-butyldimethylsil-
yl, p-Ts ˆ p-toluenesulfonyl, py ˆ pyridine, TBHP ˆ tert-butylhydroperox-
ide, DIPTˆ diisopropyltartrate.
elaboration of the THP-ring was addressed next. An 6-endo
attack of the C(20)-oxygen on an C(23) C(24) epoxide by an
activation of the C(24) position by an C(25) C(26) double
bond was envisaged to construct the THP-ring.[13] Sharpless
epoxidation[14] of the allylic alcohol 12 with (À)-diisopropyl-
tartrate afforded the epoxy alcohol 13. The diastereomeric
epoxide 14 was also prepared in order to study the intra-
molecular epoxide cyclization in more detail (vide infra).
Dess ± Martin oxidation[15] of 13 delivered the aldehyde 15
À
À
À
(Scheme 3). A Wittig reaction of 15 with the C(25) C(34)
phosphonium ylide introduced the left side chain of mucocin
and provided the epoxyalkene 16 as a 1:1 E/Z mixture. THFas
solvent and the addition of the ylide to a cooled solution of the
aldehyde were the requirements for a 85% yield in this Wittig
reaction.
With the epoxyalkene 16 in hand, the crucial cyclization to
the THP ring was investigated next. This reaction (16 ! 17)
deserves further comments: Starting from an acetonide an
acid catalysed intramolecular 6-endo attack on the alkenyl
epoxide had to occur. Possible intermolecular side reactions at
the epoxide and cleavage of the silyl group had to be
suppressed. The weak nucleophilic protic co-solvent isopropyl
alcohol allowed a clean conversion of 16 to 17. After the
selective opening of the epoxide the double bond at
Abstract in German: Berichtet wird über die Totalsynthese des
Annoninnaturstoffs Mucocin. Die Synthese folgt einer konver-
genten Strategie, bei der auf einer sehr späten Stufe der linke
Teil des Moleküls mit dem rechten verknüpft wird. Eine
Schlüsselreaktion ist die stereokontrollierte Addition der
Organomagnesiumverbindung 2 an den Aldehyd 3. D er
THP-Ring von Mucocin wird über eine 6-endo Epoxicyclisie-
rung einer Epoxiacetonidvorstufe aufgebaut (16 ! 17). Der
hier entwickelte modulare Weg sollte nicht nur zur Synthese
von strukturell verwandten Naturstoffen von Nutzen sein,
sondern sich auch zur Herstellung pharmakologisch interes-
santer Analoga eignen.
Chem. Eur. J. 2000, 6, No. 13
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2383

U. Koert et al.
FULL PAPER
observed as a by-product. Silyl ether 22 results from an
intermolecular attack of MeOH on the epoxide, showing the
intermolecular lability of the epoxide relative to the aceto-
nide. Examples are known in the literature[16] for the
intermolecular opening of alkenyl epoxides, where a remote
acetonide function is left intact. If 16 was allowed to react with
an excess of TBDMS-OTf only 23, not 24, was observed.
Herein, the TBDMS group plays the electrophilic role of the
proton from 16 ! 17. The free diol cannot be an intermediate
in this reaction, because it would have given rise to the
formation of the tris-silyl ether 24. All these observations
favor a concerted mechanism and disfavor the occurrence of
the free diol intermediate.
a
b
O
OTBDMS
13
O
O
O
15
HO
H
O
OTBDMS
OTBDMS
c
O
OH
O
O
H
16
17
HO
TBDMSO
e
d
OTBDMS
R
O
O
OH
H
H
OTBDMS
H
H
Furthermore the cyclisation of the diastereomeric epoxide
27 was investigated (Scheme 5). Compound 27 is accessible
from the epoxy alcohol 14 along the same route as described
for 16. However, this time the Z olefin was isolated as the
18
19 R = OTBDMS
20 R = I
f,g
Scheme 3. a) Dess ± Martin periodinane (2.0 equiv), py (10 equiv),
CH2Cl2, 08C, 3 h, 89 %; b) H19C9PPh3Br (1.4 equiv), NaHMDS (1.2 equiv),
THF, À788C, 5 min, 85% E:Z ˆ 1:1; c) CSA (8 mol%), CH2Cl2/iPrOH
(30:1), À40 ! 08C, 3.5 h, 89%; d) 5% Pt/C, 1 bar H2, EtOAc, 08C, 5 h,
95%; e) TBDMS-OTf (3.0 equiv), 2,6-lutidine (5.0 equiv), CH2Cl2, 08C,
1 h, 97%; f) CSA (0.25 equiv), CH2Cl2/MeOH (2:1), 08C, 30 min, 74%;
g) I2 (1.2 equiv), PPh3 (1.1 equiv), imidazole (3.0 equiv), CH2Cl2, 08C, 3 h,
80%. NaHMDS ˆ sodiumhexamethyldisilazide, CSA ˆ camphersulfonic
acid.
HO
OTBDMS
O
O
O
H15C7
28
O
a
OTBDMS
+
O
O
HO
H15C7
OTBDMS
À
27
C(25) C(26) was removed by hydrogenation(17 ! 18). A
O
O
subsequent TBDMS protection gave the bis-silyl ether 19.
Selective deprotection of the primary silyl ether followed by
the conversion of the resulting alcohol into an iodide 20
provided the complete left half of mucocin.
O
H15C7
29
HO
OTBDMS
Two mechanistic pathways are possible for the conversion
of 16 to 17 (Scheme 4). First, the acetonide could be cleaved to
the free diol intermediate 21 and a subsequent intramolecular
attack of the OH group on the allylic position of the epoxide
would give rise to the observed product. Second, the opening
of the epoxide could possibly happen in a concerted manner
(25 ! 26) without the free diol 21 as an intermediate. If the
epoxide opening reaction was carried out in a MeOH/CH2Cl2
mixture instead of iPrOH/CH2Cl2 mixture compound 22 was
O
OH
H
H
H15C7
30
Scheme 5. a) CSA (8 mol%), CH2Cl2/iPrOH (30:1), À60 ! 208C, 16 h,
28: 13%, 29: 23%.
main product in the Wittig reaction. All attempts to convert
27 into the THP-derivative 30 failed. At the low temperatures
used for the successful tranfor-
mation of 16 into 17, no turn-
over was observed in the case of
HO
O
O
OTBDMS
OTBDMS
OTBDMS
see text
O
OH
O
O
HO OH
H
H
27. At higher temperature only
28 and 29, products from the
intermolecular attack of iPrOH
on the epoxide were observed.
Notice that the acetonide func-
tion in 28 and 29 remained
intact. This leads to the conclu-
sion, that the intramolecular
opening of 16 to 17 is strongly
favored, while it is not for the
reaction of 27 to 30. In addition,
the observation, that the ster-
eoisomer 27 does not form the
THP product explains the
whereabouts of the 7% of the
wrong enantiomer of the dihy-
droxylation step (7 ! 8). This
H15C7
HO
17
H15C7
H15C7
16
21
a
OTBDMS
TBDMSO
H15C7
TBDMSO
O
O
OMe
OTBDMS
OTBDMS
OTBDMS
O
O
OH
H
H
H
H
H15C7
22
H15C7
23
24
HO
R1
R1
H
O
O
R2
O
O
O
H
H
R2
25
26
Scheme 4. A mechanistic alternative for the epoxycyclization from 16 to 17. A two-step mechanism via the free
diol (16 ! 21 ! 17) or a concerted-type mechanism (25 ! 26). a) TBDMS-OTf, 2,6-lutidine, CH2Cl2, À78 !
À408C, 61%.
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(À)-Mucocin
2382±2396
minor stereoisomer ent-8 led to ent-27, which in contrast to 16
did not cyclize to a THP product. Therefore, the minor isomer
from the dihydroxylation step left the synthetic way at this
point.
O
O
O
OH
c,d
a,b
OBn
MeO
MeO
40
41
TIPS-protected (R)-glycidol 31 was the synthetic entrance
for the preparation of the THF part of mucocin (Scheme 6). A
regioselective opening of the epoxide with allyl magnesium
bromide gave the homoallylic alcohol 32. The latter was
silylated and ozonized to the aldehyde 33. Addition of the
RO OR
RO OR
f,g
e
OBn
OH
42
43
R = TBDMS
OR
O
RO
RO OR
i
h
O
OH
O
TIPSO
TIPSO
a
b,c
45
44
O
O
O
O
HO
k
j
RO OR
RO OR
32
31
O
O
O
O
TIPSO
NHTf
NHTf
PhSe
OPiv
H
Zn
O
47
46
TIPSO
2
34
33
35
O
l
O
OR
HO OR
d
TIPSO
TIPSO
OPiv
49
48
HO
36
37
Scheme 7. a) NaH (1.5 equiv), nBuLi (1.5 equiv), THF, À30 ! À158C,
15 min, then Br(CH2)2OBn (0.85 equiv), À108C, 2.5 h, 72%; b) H2 (5 bar),
RuII-(S)-(À)-BINAP (0.6 mol%), 958C, 18 h, 90%, ee ˆ 97% (HPLC:
Chiralcel OD-H, 10% iPrOH in n-hexane, 1.0 mLminÀ1); c) BH3 ´ Me2S
(2.2 equiv), THF, 608C, 30 min, 83%; d) TBDMSCl (2.4 equiv), imidazole
(3.0 equiv), DMAP (0.1 equiv), CH2Cl2, RT, 16 h, 88%; e) H2 (1 atm),
10%Pd/C (5 mass%), EtOAc, 98%; f) (COCl)2 (2.0 equiv), DMSO
(4.0 equiv), NEt3 (5.0 equiv), CH2Cl2, À78 ! À408C, 1.5 h; g) NaOCl2
(3.0 equiv), NaH2PO4 ´ 2H2O (4.0 equiv), methyl-2-butene (20 equiv),
tBuOH/H2O 1:1, 3 h, 95% from 43; h) 1) LDA (2.5 equiv), THF, 08C,
45 min, then (S)-(À)-propenoxide (3.0 equiv), rt, 3 h, 2) PivCl (1.1 equiv),
NEt3 (2.0 equiv), CH2Cl2, rt, 10 min, 73%; i) KHMDS (3.0 equiv), THF,
08C, 30 min, then PhSeCl (3.0 equiv), 1 h; j) MMPP (4.0 equiv), THF/
MeOH 1:1, rt, 30 min, 88% from 45; k) CSA (0.25 equiv), CH2Cl2/MeOH
1:1, 08C, 30 min, 79%; l) Dess ± Martin periodinane (1.5 equiv), py
(10 equiv), CH2Cl2, 08C ! rt, 4.5 h, 90%. BINAP ˆ 2,2'-bis(diphenyl-
phosphino)-1,1'-binaphthyl, MMPP ˆ magnesiummonoperoxophthalate.
OPiv
OH
e,f
O
HO
H
H
g,h
i,j
O
O
TESO
TESO
H
H
38
39
PPh3
I
H
H
ˆ
Scheme 6. a) H2C CHCH2MgBr (5 equiv), CuI (3 mol%), THF, À308C,
1 h, 91%; b) TIPS-OTf (1.2 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, rt,
12 h, 96%; c) O3, CH2Cl2, À758C, PPh3 (1.0 equiv) ! rt, 98%; d) 34
(1.8 equiv), 35 (0.1 equiv), Ti(OiPr)4 (2.0 equiv), xylene, À258C, 16 h, 70%
over two steps; e) p-TsCl (4.0 equiv), py/CH2Cl2 1:1, rt, 12 h, 93%; f) TBAF
(3.0 equiv), THF, rt, 45 min, 95%, trans:cis ˆ 95:5 (HPLC); g) 1) TES-Cl
(1.2 equiv), imidazole (2.0 equiv), CH2Cl2, RT, 2 h, 86%; h) DIBAH
(2.5 equiv), THF, À208C, 1 h, 93%; i) I2 (1.2 equiv), PPh3 (1.1 equiv),
imidazole (3.0 equiv), CH2Cl2, 08C ! RT, 1.5 h, 84%; j) PPh3 (5.0 equiv),
CH3CN/toluene 1:1, 708C, 20 h. TIPS ˆ triisopropylsilyl, TBAF ˆ tetrabu-
tylammoniumfluoride.
C4-OH group of mucocin. The enantioselectivity of the
reaction was determined to ee ˆ 96% by chiral HPLC. The b-
hydroxyester 41 was reduced to a diol which was double
protected to the bis-silyl ether 42. Hydrogenolysis of the
benzyl ether function provided the alcohol 43, which was
oxidized to the carboxylic acid 44 by a two-step procedure
(Swern/chlorite).[19] Treatment of dianion of 44 with (S)-
propene oxide afforded a hydroxy carboxylic acid which was
cyclized via a mixed anhydride to the butyrolactone 45. The
new stereocenter in 45 was formed with a 2:1 selectivity as
determined by inspection of the 1H-NMR spectra. The
functionalized diorganozinc compound 34 to the aldehyde 33
gave the alcohol 36. Following Knochelꢁs protocol the chiral
ligand 35 was used and a diastereoselectivity of 95:5 was
achieved.[17] The use of xylene instead of toluene was
beneficial. Its higher boiling point facilitated the removal of
excess diethyl zinc in the preparation of 34. After tosylation of
the secondary OH group in 36 a subsequent TBAF-induced
intramolecular Williamson reaction delivered the trans-2,5-
disubstituted THF-derivative 37 together with 5% of the
corresponding cis isomer. Both isomers, which resulted from
the 95:5 stereoselectivity in the formation of 36, were
separated on the stage of 37 by chromatography. The primary
OH group of 37 was protected as triethylsilyl (TES) ether and
reductive cleavage of the pivalate gave compound 38. Trans-
formation of the alcohol into an iodide followed by reaction
with triphenylphosphine provided the phosphonium salt 39.
The synthesis of the butenolide aldehyde 49 is summarized
in Scheme 7. Starting point was the alkylation of the dianion
of the b-ketoester 40 followed by a Noyori reduction with
BINAP[18] to yield the b-hydroxyester 41 containing the later
ˆ
C(2) C(35) double bond was introduced by selenation(45
! 46) and thermal syn-elimination of the selenium oxide.
Only the endocyclic olefin 47 was formed.[20] In comparison to
the selenium group the introduction of the corresponding
phenyl thioether was less clean and gave a lower yield. Slightly
acidic conditions were suited to deprotect the primary
TBDMS group in 47. The resulting alcohol 48 could be
oxidized to the aldehyde 49 by the Dess ± Martin protocol.
The synthesis of the butenolide aldehyde 49 should be of
interest for other acetogenin syntheses as well.
A Wittig reaction was used to connect the THF subunit 39
with the butenolide aldehyde 49 (Scheme 8). The resulting
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U. Koert et al.
FULL PAPER
chemical assignment[25] was based on 13C-NMR data (new
chiral center: d ˆ 73.8 for 57 and 72.1 for 58).
O
TBDMSO
O
a
39
O
Next, the coupling of the iodide 20, containing the complete
left half of mucocin with the test aldehyde 56 was examined
(Scheme 10). It was found, that two coupling products 59 and
60 could be isolated in 50% yield with a 4:1 diastereoselec-
tivity. However, the precise choice of temperature and time
TESO
H
H
50
O
O
TBDMSO
O
O
b,c
O
O
HO
H
H
H
H
51
TBDMSO
TBDMSO
d
O
O
OTBDPS
OTBDPS
H
H
HO
H
H
O
TBDMSO
52
59
Scheme 8. a) 39, NaHMDS (1.0 equiv), THF, 08C, 30 min, then 49, À708C
! 08C, 20 min, 60%; b) [(PPh3)3RhCl] (0.15 equiv), H2 (1 atm), benzene,
rt, 3 h, 95%; c) CSA (0.08 equiv), CH2Cl2/MeOH 5:1, À208C, 10 min,
76%; d) Dess ± Martin periodinane (2.0 equiv), py (10 equiv), CH2Cl2, 08C
! rt, 4.5 h, 91%.
a
20
+
TBDMSO
O
O
H
H
HO
H
H
TBDMSO
60
TBDMSO
TBDMSO
alkene 50 was formed as a mixture of E/Z isomers. The
hydrogenation of the isolated double bond[21] of compound 50
followed by a selective cleavage of the TES ether gave the
alcohol 51. A Dess ± Martin oxidation of 51 to 52 completed
the synthesis of the right half of the target molecule.
Si
O
O
tBu
OH
H
H
H
H
TBDMSO
62
61
HO
The final part of the synthesis required a coupling of the left
half and the right half of the target molecule. The stereo-
selective coupling of an organometallic species of type 2 with
the aldehyde 52 under chelation-controlled conditions should
lead to the desired product. Organomagnesium compounds
were known to produce the chelation-controlled product for
simpler THF aldehydes. Due to the small scale of the coupling
reaction (<1 mmol) a heterogeneous Grignard-type chemis-
try with magnesium turnings was not very suitable. Instead a
homogeneous generation of the corresponding organolithium
compound followed by transmetalation to magnesium was
used. The iodide 55[22] which was available from (R)-b-
hydroxy methyl butyrate 53 via the alcohol 54 was used as a
model substrate for the left half first (Scheme 9). The iodide
b
O
O
OH
59
H
H
HO
H
H
OH
63
Scheme 10. a) 20 (1.2 equiv), tBuLi (2.4 equiv), Et2O, À1058C, 5 min; then
MgBr2 ´ OEt2 (2.4 equiv), À100 ! À108C, 1.5 h; ! À788C, 56 (1.0 equiv),
! À108C, 1.5 h, 50%; b) HF (5 equiv), CH3CN/CH2Cl2, 08C, 6 h, 74%.
was crucial for the success of the reaction. If the trans-
metallation did not take place within 5 min after the iodine-
lithium exchange and if the temperature rose above À908C
the silane 62 was obtained as the main product. The formation
of 62 can be explained by retro-Brook migration[26] from the
À
silyl group at O C(19) to C(17). The alkane 61 was formed as
side product (10 ± 15%) in most of the coupling reactions
using the iodide 20. The tris-silyl ether 59 was deprotected to
the tetraol 63. Compound 63 contains the complete THP/THF
part of mucocin. The NMR data for the THP part matched the
related data from mucocin already.
OMe
a,b
c
OH
O
HO
TBDMSO
54
53
H
Encouraged by the results from the test coupling and
equipped with experience concerning the reaction conditions
the convergent final of the synthesis was addressed
(Scheme 11). At À1058C an iodine-lithium exchange in 20
could be realized followed by a transmetallation to magne-
sium. Addition of the aldehyde 52 and subsequent warm up to
À158C gave the desired product 64 in 53% yield. 34% of
unreacted aldehyde 52 was reisolated. Noteworthy, only
1.2 equivalents of iodide 20 compared with 1 equivalent of
aldehyde 52 were necessary. The stereoselectivity of the
reaction was 4:1 in favor of the desired epimer 64. The
synthetically undesired but pharmacologically interesting
C(16) minor epimer 65 could be separated by chromatog-
raphy. Cleavage of the silyl protecting groups in 64 provided
(À)-mucocin ([a]D ˆ À12.7, c ˆ 0.27 in CH2Cl2) which was
found to be identical with the natural occurring product in
respect to the spectroscopical data. In addition, deprotection
of the minor epimer 65 gave 16-epi mucocin.
I
O
O
H
OR
TBDMSO
H
55
56
R = TBDPS
+
d
O
O
TBDMSO
OR
HO
OR
TBDMSO
HO
H
H
H
H
57
58
Scheme 9. a) TBDMSCl, imidazole, 93%; b) DIBAH, toluene, 81%; c) I2,
PPh3, CH2Cl2, 89%; d) 55 (1.0 equiv), tBuLi (1.8 equiv), Et2O, À1058C,
5 min; then MgBr2 ´ OEt2 (2.0 equiv), À100 ! À258C, 1.5 h; ! À788C, 56
(1.0 equiv), ! À108C, 1.5 h, 73%.
55 was subjected to a iodine-lithium exchange[23] in Et2O at
À1008C and subsequently treated with a solution of magne-
sium bromide in Et2O at À908C. Addition of the test
aldehyde 56[24] gave the two secondary alcohols 57 and 58 as
coupling products with a 6:1 stereoselectivity. The major
epimer 57 is the chelation-controlled product. The stereo-
2386
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2386 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 13

(À)-Mucocin
2382±2396
TBDMSCl (6.49 g, 150.7 mmol) dissolved in THF (15 mL) was added
dropwise and stirring was continued overnight. The reaction was quenched
by addition of a sat. aq. sodium bicarbonate solution (100 mL). After
extraction with Et2O (4 Â 75 mL), washing of the combined organic layers
with a sat. aq. NaCl (2 Â 40 mL) solution and drying with MgSO4, the
solvents were evaporated and the resulting crude oil was purified by CC
(150 g silica gel, hexane/MTBE 30:1 ! 2:1 ! ethyl acetate) to provide
(5.34 g, 23.2 mmol, 54%) of the monoprotected alcohol as a colorless oil.
24% diol (1.2 g, 10.3 mmol) was reisolated. Additionally the diprotected
alcohol (2.8 g, 8.2 mmol, 19%) was obtained, which could be recycled.
Conclusion
A modular strategy for the assembly of mucocin was
successfully developed. A distinctive feature of this synthesis
is its high convergence. New variations of mucocin with
pharmacological importance should be easily available by
combination of different modules. The butenolide fragment
proved to be compatible with the coupling reaction. The
synthetic route presented here is a new, efficient, and flexible
approach to the Annonaceous acetogenins, a biological
important class of compounds.
(E)-1-tert-Butyldimethylsilyloxy-6-hydroxy-hex-3-ene: Rf ˆ 0.41 (n-hex-
ane/MTBE 2:1); IR (film): nÄ ˆ 3349, 2955, 2929, 2858, 1650, 1472, 1386,
1255, 1100, 1048, 969, 836, 776, 664 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ
0.02 (s, 6H, SiCH3), 0.86 (s, 9H, SiC(CH3)3), 1.79 (brs, 1H, OH), 2.16 ± 2.25
(m, 4H, 2,5-H2), 3.54 ± 3.62 (m, 4H, 1,6-H2), 5.37 ± 5.49 (m, 2H, 3,4-H2);
13C NMR (75 MHz, CDCl3): d ˆ À5.3 (SiCH3), 18.3 [C(CH3)], 25.9
[C(CH3)], 36.0 (C-2), 36.2 (C-5), 61.8 (C-1), 62.9 (C-6), 128.0 (C-4), 130.2
(C-3); C12H26O2Si (230.424): calcd C 62.55, H 11.37; found: C 62.60, H
11.45.
Experimental Section
General: All b.p.s and m.p.s are uncorrected values. IR: Biorad FTS
3000MX. NMR: Bruker AC-300, DPX-300 and AMX-600. For H NMR,
1
4. Tosylation: Pyridine (37 mL) and toluenesulfonyl chloride (17.9 g,
94 mmol) were added at 08C to the monoprotected alcohol (10.9 g,
47 mmol) dissolved in CH2Cl2 (200 mL). The solution was stirred for 16 h
before the reaction was quenched with H2O (100 mL). After 2 h the
aqueous phase was extracted with CH2Cl2 (2 Â 50 mL). Washing of the
combined organic layers with a sat. aq. NaCl solution (100 mL), drying with
MgSO4, and evaporation of the solvent led to the crude product which was
treated with toluene (2 Â 20 mL) and used for the following step without
further purification.
CDCl3 as solvent dH ˆ 7.24, [D6]benzene as solvent dH ˆ 7.20, [D4]MeOH as
solvent dH ˆ 4.78; for 13C NMR, CDCl3 as solvent dC ˆ 77.0, [D6]benzene as
solvent dC ˆ 128.0, [D4]MeOH as solvent dC ˆ 49.0. Elemental analysis:
CHN Rapid (Heraeus), CHNS-932 Analysator (Leco). HR-MS: Finnigan
MAT 95. All reactions were performed under an inert atmosphere of argon
in oven- or flame-dried glassware. HPLC: Rainin-Dynamax, SD-200 and
SD-1, PDA1. Dry solvents: THF, Et2O, benzene, xylene, and toluene were
distilled from sodium benzophenone. Pyridine, triethylamine, and CH2Cl2
were distilled from CaH2. All commercially available reagents were used
without purification unless otherwise noted. All reactions were monitored
by thin-layer chromatography (TLC) carried out on Merck F-254 silica
glass plates visualized with UV light and/or heat-gun treatment with 5%
phosphomolybdic acid in ethanol. Column chromatography (CC) and flash
column chromatography (FCC) was performed with Merck silica gel 60
(70 ± 200 mesh and 230 ± 400 mesh). PE: light petroleum ether, b.p. 40 ±
608C. MTBE: methyl tert-butyl ether. V nomenclature: configuration
unspecified.
5. Bromination to 7: The crude toluene sulfonate was dissolved in acetone
(300 mL) and LiBr (16 g, 188 mmol) was added. After stirring for 24 h at
258C the solution was quenched with water (150 mL) and extracted with
hexane (3 Â 60 mL). The combined organic layers were washed with a sat.
aq. NaCl solution (50 mL) and dried with MgSO4. The solvents were
removed in vacuo. The residue was purified by CC (200 g silica gel, hexane/
MTBE 40:1) to yield bromide 7 (11.8 g, 40 mmol, 85% for two steps) as a
colorless oil.
(E)-1-Bromo-6-tert-butyldimethylsilyloxy-hex-3-ene (7): Rf ˆ 0.30 (n-hex-
ane/MTBE 40:1); IR (film): nÄ ˆ 3033, 2955, 2930, 2857, 1667, 1472, 1386,
(E)-1-Bromo-6-tert-butyldimethylsilyloxyhex-3-ene (7)
1. Esterification of 6: Dihydromuconic acid 6 (8.0 g, 55.5 mmol) was
suspended in methanol (150 mL) at 08C. TMSCl (14 mL, 111 mmol) was
added and the mixture was stirred for 36 h. Then methanol (50 mL) was
evaporated, H2O (100 mL) was added and the aqueous layer was extracted
with Et2O (3 Â 100 mL). After washing of the combined organic layers with
subsequently a sat. aq. NaHCO3 solution (100 mL) and NaCl (100 mL) and
drying with MgSO4, the solvents were removed in vacuo. The residue was
purified by distillation under reduced pressure to yield the diester (9.02 g,
52.4 mmol, 94%) as a colorless solid.
1255, 1103, 1006, 969, 940, 836, 775, 724, 662 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d ˆ 0.03 (s, 6H, SiCH3), 0.87 (s, 9H, SiC(CH3)3), 2.18 ± 2.25 (m,
2H, 5-H2), 2.50 ± 2.57 (m, 2H, 2-H2), 3.34 (t, J ˆ 7.2 Hz, 2H, 1-H2), 3.61 (t,
J ˆ 6.8 Hz, 2H, 6-H2), 5.39 ± 5.60 (m, 2H, 3,4-H); 13C NMR (75 MHz,
CDCl3): d ˆ À5.3 (SiCH3), 18.3 [C(CH3)], 25.9 [C(CH3)], 32.6 (C-1),
36.1, 36.2 (C-2, C-5), 62.9 (C-6), 128.5 (C-3), 130.2 (C-4); C12H25OSiBr
(293.320): calcd C 49.14, H 8.59, Br 27.24; found C 49.20, H 8.53,
Br 27.17.
(3S,4S)-1-Bromo-6-tert-butyldimethylsilyloxy-3,4-O-isopropyliden-hex-
ane-3,4-diol (10): Alkene 7 (1.25 g, 4.26 mmol), AD-mix a (5.96 g) and
CH3SO2NH2 (0.41 g) were suspended in H2O (21 mL) and tBuOH (21 mL)
at 08C. After stirring for 6 h the reaction mixture was quenched with
Na2S2O3 (6.5 g). The suspension was stirred for another hour, then diluted
with a half sat. aq. NH4Cl solution (20 mL) and extracted with MTBE (3 Â
20 mL). After washing of the combined organic layers with phosphate
buffer (pH 7, 20 mL) and sat. aq. NaCl solution (20 mL) and drying with
MgSO4 the solvents were evaporated at 58C. The residue was instantly
dissolved in CH2Cl2 (50 mL). Dimethoxypropane (4 mL, 26.8 mmol) and p-
toluene sulfonic acid (30 mg, 0.14 mmol) were added at 08C. After 1 h the
reaction mixture was quenched with a sat. aq. sodium bicarbonate solution
(20 mL). After extraction with CH2Cl2 (3 Â 20 mL), washing of the
combined organic layers with sat. aq. NaCl solution (20 mL) and drying
with MgSO4 the solvent was removed in vacuo. The residue was purified by
CC (110 g silica gel, hexane/MTBE 30:1) to yield the bromide 10 (1.44 g,
3.93 mmol, 92%) as a colorless oil. Rf ˆ 0.29 (n-hexane/MTBE 30:1);
[a]2D2 ˆ À34.3 (c ˆ 0.93, CHCl3) (93:7 mixture of enantiomers); IR (film):
nÄ ˆ 2986, 2954, 2931, 2883, 2858, 1472, 1463, 1444, 1418, 1379, 1370, 1341,
1253, 1225, 1174, 1149, 1093, 1047, 1006, 993, 971, 939, 836, 812, 776, 731,
(E)-1,6-Dihex-3-enoic acid dimethyl ester: Rf ˆ 0.28 (hexanes/MTBE 2:1);
IR (film): nÄ ˆ 3002, 2955, 2847, 1740, 1437, 1363, 1255, 1198, 1166, 1012, 973,
845 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 3.05 (dd, J ˆ 1.6, 3.8 Hz, 4H,
2,5-H2), 3.64 (s, 6H, OCH3), 5.63 ± 5.67 (m, 2H, 3,4-H); 13C NMR (75 MHz,
CDCl3): d ˆ 37.5 (C-2, C-5), 51.7 (OCH3), 125.8 (C-3, C-4), 171.8 (C-1, C-6);
C8H12O4 (172.181): calcd C 55.81, H 7.03; found C 55.82, H 6.84.
2. Reduction with LiAlH4: The diester (6.42 g, 37.3 mmol), dissolved in THF
(50 mL), was added dropwise to
a suspension of LiAlH4 (4.25 g,
111.9 mmol) in THF (150 mL) at 08C. After stirring for 2 h at rt the
reaction was quenched by slow addition of H2O (4.2 mL), 2n NaOH
(13 mL) and H2O (4.2 mL). The suspension was refluxed for 10 min and
filtered through a pad of Celite. After washing with THF, the solvents were
removed in vacuo. CC (100 g silica gel, AcOEt/Et2O 1:1) of the residue led
to the diol (4.25 g, 36.6 mmol, 98%) as a colorless oil.
(E)-Hex-3-en-1,6-diol: Rf ˆ 0.20 (AcOEt/Et2O 1:1) IR (film): nÄ ˆ 3339,
3033, 2932, 2880, 1657, 1428, 1372, 1233, 1045, 969, 861, 652; 1H NMR
(300 MHz, CDCl3): d ˆ 2.00 ± 2.29 (m, 4H, 2,5-H2), 2.48 (s, 2H, OH), 3.59
(t, J ˆ 6.1 Hz, 4H, 1,6-H2), 5.41 ± 5.49 (m, 2H, 3,4-H); 13C NMR (75 MHz,
CDCl3): d ˆ 35.9 (C-2, C-5), 61.6 (C-1, C-6), 129.5 (C-3, C-4); C6H12O2
(116.161): calcd C 62.04, H 10.41; found C 62.17, H 10.15.
663, 571, 517 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 6H, SiCH3),
3. Monosilylation: A solution of the diol (5.0 g, 43.0 mmol) in THF (40 mL)
was added dropwise at 08C to a suspension of NaH (1.72 g, 60% in mineral
oil, 43.0 mmol) in THF (100 mL). The mixture was stirred for 45 min at rt.
0.88 (s, 9H, SiC(CH3)3), 1.34 (s, 3H, acetonide-CH3), 1.37 (s, 3H, acetonide-
CH3), 1.73 ± 1.77 (m, 2H, 5-H2), 2.04 ± 2.08 (m, 2H, 2-H2), 3.46 ± 3.54 (m,
2H, 1-H2), 3.70 ± 3.80 (m, 4H, 3,4-H, 6-H2); 13C NMR (75 MHz, CDCl3):
Chem. Eur. J. 2000, 6, No. 13
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2387 $ 17.50+.50/0
2387

U. Koert et al.
FULL PAPER
d ˆ À5.4 (SiCH3), 18.3 [C(CH3)], 25.9 [C(CH3)], 27.2, 27.3 (acetonide-
CH3), 29.6 (C-1), 35.8, 36.2 (C-2, C-5), 59.7 (C-6), 77.4, 78.8 (C-3, C-4), 108.4
(acetal); C15H31BrO3Si (367.401): calcd C 49.04, H 8.51; found C 49.06, H
8.50.
through a pad of Celite. After washing with Et2O, the solvents were
removed in vacuo. CC (20 g silica gel, hexane/MTBE 1:1) of the residue led
to the epoxide 13 (266 mg, 0.74 mmol, 85%) as a colorless oil. Rf ˆ 0.23 (n-
hexane/MTBE 1:1); [a]2D2 ˆ À13.7 (c ˆ 1.01, CHCl3) ee (AE) >98%
(1H NMR); IR (film): nÄ ˆ 3452, 2985, 2930, 2858, 1642, 1472, 1379, 1253,
(2S, 3S)-2-(2'-tert-Butyldimethylsilyloxy)-ethyl-3-hydroxy-tetrahydrofuran
(9): 1H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 6H, SiCH3), 0.87 (s, 9H,
SiC(CH3)3), 1.89 ± 2.14 (m, 4H, 4,1'-H2), 3.32 ± 3.40 (brs, 1H, OH), 3.57 ±
3.85 (m, 4H, 5,2'-H2, 2-H), 3.98 (dt, J ˆ 7.5, 7.9 Hz, 1H, 5-H2), 4.24 ± 4.26 (m,
1H, 3-H); 13C NMR (75 MHz, CDCl3): d ˆ À5.6 (SiCH3), 18.2 [C(CH3)],
25.8 [C(CH3)], 31.7, 34.7 (C-4, C-1'), 60.3 (C-2'), 66.0 (C-5), 72.0 (C-3), 82.8
(C-2).
1168, 1090, 1034, 1006, 940, 837, 777, 724, 664, 512 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d ˆ 0.02 (s, 6H, SiCH3), 0.87 (s, 9H, SiC(CH3)3), 1.33
(s, 6H, acetonide-CH3), 1.65 ± 1.75 (m, 6H, 4,5,8-H2), 2.89 ± 2.94 (m, 2H,
2,3-H), 3.59 ± 3.78 (m, 6H, 6,7-H, 1,9-H2); 13C NMR (75 MHz, CDCl3): d ˆ
À5.4 (SiCH3), 18.3 [C(CH3)], 25.9 [C(CH3)], 27.2, 27.3 (acetonide-CH3),
28.8, 29.0 (C-4, C-5), 35.9 (C-8), 56.1, 58.2 (C-2, C-3), 59.8, 61.9 (C-1, C-9),
77.7, 80.8 (C-6, C-7), 108.2 (acetal); C18H36O5Si (360.569): calcd C 59.96, H
10.06; found C 60.12, H 10.17.
(6S,7S)-9-tert-Butyldimethylsilyloxy-6,7-O-isopropyliden-2-nonyne-1,6,7-
triol (11): NH3 (20 mL) was dried with sodium and condensed into a
reaction flask at À788C. nBuLi (5 mL, 12.5 mmol 2.5m in hexane) was
added dropwise. Then the reaction mixture was allowed to reflux at À338C
and propargylic alcohol (0.35 mL, 6 mmol), dissolved in THF (10 mL), was
added. After 10 min DMPU (8 mL, distilled from CaH2) was added slowly.
After another 10 min, bromide 10 (735 mg, 2.00 mmol) dissolved in THF
(10 mL) was added dropwise. The reaction mixture was refluxed for 6 h.
After quenching with NH4Cl, the NH3 was allowed to evaporate at rt.
Water (50 mL) and MTBE (30 mL) were added and the aqueous layer was
extracted with MTBE (3 Â 50 mL). The combined organic layers were
washed with sat. aq. NaCl solution (40 mL), dried with MgSO4, and the
solvents were removed under reduced pressure. The crude product was
purified by CC (30 g silica gel, hexane/MTBE 2:1) to afford the alkyne 11
(621 mg, 1.81 mmol, 91%) as a colorless oil. Rf ˆ 0.22 (n-hexane/MTBE
2:1); [a]2D2 ˆ À28.5 (c ˆ 1.02, CHCl3); IR (film): nÄ ˆ 3453, 2986, 2931, 2289,
(2S,3S,6S,7S)-9-tert-Butyldimethylsilyloxy-2,3-epoxy-6,7-O-isopropyliden-
nonane-1,6,7-triol (14): The other diastereomer was prepared on the same
way as 13 with l-(‡)-diisopropyl-tartrate. Yield 79%. Rf ˆ 0.23 (n-hexane/
MTBE 1:1); [a]2D2 ˆ À36.0 (c ˆ 0.99, CHCl3); 1H NMR (300 MHz, CDCl3):
d ˆ 0.03 (s, 6H, SiCH3), 0.87 (s, 9H, SiC(CH3)3), 1.34 (s, 6H, acetonide-
CH3), 1.64 ± 1.74 (m, 6H, 4,5,8-H2), 2.89 ± 3.01 (m, 2H, 2,3-H), 3.56 ± 3.90
(m, 6H, 6,7-H, 1,9-H2); 13C NMR (75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 18.3
[C(CH3)], 25.9 [C(CH3)], 27.2, 27.3 (acetonide-CH3), 28.0, 28.4 (C-4, C-5),
35.9 (C-8), 55.4, 58.2 (C-2, C-3), 59.8, 61.7 (C-1, C-9), 77.6, 80.1 (C-6, C-7),
108.1 (acetal).
(2R,3R,6S,7S)-9-tert-Butyldimethylsilyloxy-6,7-dihydroxy-2,3-epoxy-6,7-
O-isopropyliden-nonanal (15): The epoxide 13 (419 mg, 1.17 mmol) was
dissolved in CH2Cl2 (10 mL) and cooled to 08C. Pyridine (1.1 mL) and
Dess ± Martin periodinane (738 mg, 1.76 mmol) were added and the
reaction mixture was stirred for 3 h. Then a sat. aq. sodium bicarbonate
solution (20 mL) was added and the aqueous layer was extracted with
MTBE (3 Â 15 mL). After washing of the combined organic layers with sat.
aq. NaCl solution (20 mL) and drying with MgSO4, the solvents were
removed in vacuo. The residue was purified at the same day by FCC (30 g
silica gel, hexane/MTBE 3:1) to yield aldehyde 15 (371 mg, 1.04 mmol,
2225, 1473, 1379, 1253, 1165, 1093, 1007, 939, 837, 777, 664, 514 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.03 (s, 6H, SiCH3), 0.86 (s, 9H,
SiC(CH3)3), 1.33 (s, 3H, acetonide-CH3), 1.34 (s, 3H, acetonide-CH3),
1.66 ± 1.80 (m, 4H, 5,8-H2), 2.20 (d, J ˆ 5.8 Hz, 1H, OH), 2.32 ± 2.37 (m, 2H,
4-H2), 3.66 ± 3.78 (m, 4H, 6,7-H, 9-H2), 4.19 (d, J ˆ 5.8 Hz, 2H, 1-H2);
13C NMR (75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 15.5 (C-4), 18.3 [C(CH3)],
25.9 [C(CH3)], 27.1, 27.2 (acetonide-CH3), 31.7 (C-5), 35.8 (C-8), 51.1 (C-1),
59.4 (C-9), 77.2, 79.6 (C-6, C-7), 78.9, 85.4 (C-2, C-3), 108.1 (acetal);
C18H34O4Si (342.553): calcd C 63.11, H 10.00; found C 63.07, H 9.76.
89%) as
a
colorless oil. Rf ˆ 0.38 (n-hexane/MTBE 2:1); 1H NMR
(600 MHz, CDCl3): d ˆ 0.03 (s, 6H, SiCH3), 0.87 (s, 9H, SiC(CH3)3), 1.32
(s, 3H, acetonide-CH3), 1.33 (s, 3H, acetonide-CH3), 1.57 ± 1.85, (m, 6H,
4,5,8-H2), 3.12 (dd, J ˆ 6.3 Hz, 2.0 Hz, 1H, 2-H2), 3.26 (dt, J ˆ 2.0, 5.3 Hz,
1H, 3-H), 3.61 ± 3.77 (m, 4H, 6,7-H, 9-H2), 8.99 (d, J ˆ 6.3, 1H, 1-H);
13C NMR (75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 18.3 [C(CH3)], 25.9
[C(CH3)], 27.2 (acetonide-CH3), 28.5, 28.6 (C-4, C-5), 35.8 (C-8), 56.7,
59.4 (C-2, C-3), 59.7 (C-9), 77.7, 80.4 (C-6, C-7), 108.2 (acetal), 198.2 (C-1).
(2E,6S,7S)-9-tert-Butyldimethylsilyloxy-6,7-O-isopropyliden-2-nonene-
1,6,7-triol (12): Red-Al (15.7 mL, 52 mmol, 3.4m in toluene), dissolved in
THF (50 mL), was added dropwise to alkyne 11 (8.90 g, 26.0 mmol)
dissolved in THF (120 mL) at 08C. The reaction mixture was stirred for 4 h.
The reaction mixture was then cooled to À788C and water (2.5 mL) was
added dropwise. After 30 min at rt the suspension was extracted with Et2O
(3 Â 50 mL). The combined organic layers were washed with sat. aq. NaCl
solution (50 mL), dried with MgSO4, and the solvents were removed in
vacuo. The residue was purified by CC (400 g silica gel, hexane/MTBE 2:1)
to yield alkene 12 (8.51 g, 24.7 mmol, 95%) as a colorless oil. Rf ˆ 0.19 (n-
hexane/MTBE 2:1); [a]2D2 ˆ À17.0, (c ˆ 1.12, CHCl3); IR (film): nÄ ˆ 3413,
2988, 2931, 2858, 1672, 1472, 1463, 1378, 1369, 1255, 1093, 1006, 970, 872,
(3S,4S,7R,8R,9V)-1-tert-Butyldimethylsilyloxy-7,8-epoxy-3,4-O-isopropy-
liden-octadec-9-ene-3,4-diol (16): The phosphonium salt of nonyl bromide
(4.87 g, 10.4 mmol) was dissolved in THF (25 mL) and cooled to 08C.
NaHMDS (8.88 mL, 8.88 mmol, 1m in THF) was added dropwise. After
stirring for 30 min the orange solution was cooled to À788C and added to a
solution of cooled (À1008C) aldehyde 15 (2.65 g, 7.40 mmol) in THF
(25 mL) via syringe. After 5 min the reaction was quenched with H2O. The
aqueous layer was extracted with Et2O (3 Â 20 mL). The combined organic
layers were washed with sat. aq. NaCl solution (10 mL) and phosphate
buffer (pH 7, 10 mL) and dried with MgSO4. The solvents were removed in
vacuo. The residue was purified by CC (80 g silica gel, hexane/MTBE 10:1)
to yield the vinyl epoxide 16 (2.96 g, 6.32 mmol, 85%) as a colorless oil.
E/Z ˆ 1:1 (1H NMR).
1
837, 813, 777, 733, 664, 512 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 0.04 (s,
6H, SiCH3), 1.04 (s, 9H, SiC(CH3)3), 1.35 (s, 6H, acetonide-CH3), 1.59 ±
1.74 (m, 4H, 5,8-H2), 2.08 ± 2.27 (m, 2H, 4-H2), 3.61 ± 3.80 (m, 4H, 6,7-H,
9-H2), 4.07 (d, J ˆ 4.0 Hz, 2H, 1-H2), 5.64 ± 5.71 (m, 2H, 2,3-H); 13C NMR
(75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 18.3 [C(CH3)], 25.9 [C(CH3)], 27.2,
27.3 (acetonide-CH3), 28.6 (C-4), 32.0 (C-8), 36.0 (C-5), 59.9 (C-9), 63.6 (C-
1), 77.6, 80.3 (C-6, C-7), 108.1 (acetal), 129.5, 132.2 (C-2, C-3); C18H36O4Si
(344.569): calcd C 62.74, H 10.53; found C 62.93, H 10.38.
16: (Z isomer): Rf ˆ 0.24 (n-hexane/MTBE 12:1); [a]2D2 ˆ À4.4, (c ˆ 1.05,
CHCl3); IR (film): nÄ ˆ 2984, 2955, 2928, 2856, 1658,1463, 1378, 1368, 1252,
1168, 1091, 1006, 940, 882, 837, 777, 724, 664, 511 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 0.06 (s, 6H, SiCH3), 0.83 ± 0.87 (m, 12H, SiC(CH3)3, 18-H3),
1.21 ± 1.27, 1.60 ± 1.61 (m, 12H, 12,13,14,15,16,17-H2), 1.38 (s, 6H, acetonide-
CH3), 1.70 ± 1.76 (m, 6H, 2,5,6-H2), 2.15 ± 2.21 (m, 2H, 11-H2), 2.83 ± 2.86
(m, 1H, 7-H), 3.35 (dd, J ˆ 2.0 Hz, 9.0 Hz, 1H, 8-H), 3.61 ± 3.77 (m, 4H,
1-H2, 3,4-H), 5.02 (dd, J ˆ 9.0 Hz, 11.0 Hz, 1H, 9-H), 5.68 (dt, J ˆ 7.7 Hz,
11.0 Hz, 1H, 10-H); 13C NMR (150 MHz, CDCl3): d ˆ À5.4 (SiCH3), 14.1
(C-18), 18.3 [C(CH3)], 22.7 (C-17), 25.9 [C(CH3)], 27.3 (acetonide-CH3),
27.8 (C-11), 29.0, 29.1, 29.3, 29.4, 29.5, 29.6, 31.9 (C-5, C-6, C-12, C-13, C-14,
C-15, C-16), 36.0 (C-2), 54.4 (C-8), 59.9 (C-7), 60.0 (C-1), 77.6, 80.6 (C-3,
C-4), 108.1 (acetal), 126.8 (C-9), 136.7 (C-10); C27H52O4Si (468.795): calcd
C 69.18, H 11.18; found C 69.21, H 10.87.
(2R,3R,6S,7S)-9-tert-Butyldimethylsilyloxy-2,3-epoxy-6,7-O-isopropyli-
den-nonane-1,6,7-triol (13): A suspension of powdered 4 Š molecular
sieves (100 mg) in CH2Cl2 (10 mL) was cooled to 08C. d-(À)-Diisopropyl-
tartrate (24 mg, 0.10 mmol) and Ti(OiPr)4 (25 mg, 0.087 mmol) were added
sequentially. After the reaction mixture was cooled to À258C, TBHP
(0.32 mL, 1.74 mmol, 5.5m in nonane), which had been treated 15 min with
molecular sieves 4 Š, was added and the resulting mixture was stirred for
25 min. During that time the allylic alcohol 12 (300 mg, 0.87 mmol) was
dissolved in CH2Cl2 (1 mL) and dried with molecular sieves 4 Š. Then it
was added to the reaction mixture and the suspension was stirred for 4 h at
À208C. After quenching with NaOH (0.4 mL of a 10% NaOH in a sat. aq.
NaCl solution) and addition of Et2O (4 mL), the mixture was allowed to
warm up to 108C. Stirring was maintained for an additional 10 min at 108C,
then MgSO4 (400 mg), and Celite (50 mg) were added. After 15 min of
stirring the mixture was allowed to settle and the clear solution was filtered
E isomer: 1H NMR (300 MHz, CDCl3): d ˆ 0.06 (s, 6H, SiCH3), 0.83 ± 0.87
(m, 12H, SiC(CH3)3, 18-H3), 1.21 ± 1.27, 1.60 ± 1.61 (m, 12H,
2388
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2388 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 13

(À)-Mucocin
2382±2396
12,13,14,15,16,17-H2), 1.38 (s, 6H, acetonide-CH3), 1.70 ± 1.76 (m, 6H, 2,5,6-
H2), 1.91 ± 2.01 (m, 2H, 11-H2), 2.83 ± 2.86 (m, 1H, 7-H), 3.06 (dd, J
ˆ2.3 Hz, 7.9 Hz, 1H, 8-H), 3.61 ± 3.77 (m, 4H, 1-H2, 3,4-H), 5.15 (dd, J ˆ
7.9 Hz, 15.4 Hz, 1H, 9-H), 5.88 (dt, J ˆ 6.8 Hz, 15.4 Hz, 1H, 10-H);
13C NMR (75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 14.1 (C-18), 18.3
[C(CH3)], 22.7 (C-17), 25.9 [C(CH3)], 27.3 (acetonide-CH3), 29.0, 29.1,
29.3, 29.4, 29.5, 29.6, 31.9 (C-5, C-6, C-12, C-13, C-14, C-15, C-16), 32.0 (C-
11), 36.0 (C-2), 58.8 (C-8), 60.0 (C-1), 60.2 (C-7), 77.6, 80.6 (C-3, C-4), 108.1
(acetal), 127.3 (C-9), 136.8 (C-10).
ration of the solvents the residue was purified by CC (80 g silica gel,
hexane/CH2Cl2 8:1) to afford 19 (3.13 g, 4.76 mmol, 97%) as a colorless oil.
Rf ˆ 0.28 (n-hexane/CH2Cl2 8:1); [a]2D3 ˆ À39.6, (c ˆ 0.98, CHCl3); IR
(film): nÄ ˆ 2955, 2929, 2857, 1472, 1388, 1361, 1256, 1095, 1006, 873, 836,
775, 669 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.02 ± 0.03 (brs, 18H,
SiCH3), 0.85 ± 0.89 (m, 30H, SiC(CH3)3, 10''-H3), 1.20 ± 1.39 (m, 16H, 2'', 3'',
4'', 5'', 6'', 7'', 8'', 9''-H2), 1.39 ± 1.84 (m, 7H, 1'', 2', 4,5-H2), 1.93 ± 2.04 (m, 1H,
4-H2), 2.93 ± 3.02 (m, 1H, 2-H), 3.19 ± 3.24 (m, 2H, 3,6-H), 3.61 ± 3.69 (m,
2H, 3'-H2), 3.74 ± 3.78 (m, 1H, 1'-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.8,
À4.4, À4.3 (SiCH3), 14.1 (C-10''), 18.2 [C(CH3)], 22.7 (C-9''), 25.7, 25.9,
26.0 [C(CH3)], 25.1, 25.2, 29.4, 29.7, 29.8, 31.9, 32.0 (C-4, C-5, C-1'', C-2'',
C-3'', C-4'', C-5'', C-6'', C-7'', C-8''), 35.5 (C-2'), 60.1 (C-3'), 70.9, 71.1 (C-3,
C-1'), 79.8 (C-6), 82.3 (C-2); HR-MS (C36H79O4Si3): calcd 659.5286; found
659.5280.
(2S,3R,6S,1'S,1''V)-2-Decenyl-3-hydroxy-6-(3'-tert-butyl-dimethylsilyloxy-
1'-hydroxy)-propyl-tetrahydropyran (17): Vinyl epoxide 16 (110 mg,
0.235 mmol) was dissolved in CH2Cl2/2-propanol (10 mL, 30:1) and cooled
to À608C. CSA (5 mg, 0.022 mmol) was added. After 4 h (À608C !
À158C) the reaction was quenched by addition of Et3N (1 mL). The
solvents were evaporated and the residue was purified by FCC (15 g silica
gel, hexane/MTBE 2:1) to provide the tetrahydopyran 17 (90 mg,
0.210 mmol, 89%) as a colorless oil. E/Z ˆ 1:1 (1H NMR). 17: (Z isomer):
Rf ˆ 0.30 (n-hexane/MTBE 1:1); [a]2D5 ˆ À29.9, (c ˆ 0.85, CHCl3); IR
(film): nÄ ˆ 3400, 3012, 2927, 2856, 1657, 1463, 1408, 1362, 1261, 1255, 1083,
978, 938, 872, 836, 776, 722, 666 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 0.05
(s, 6H, SiCH3), 0.86 ± 0.89 (m, 12H, SiC(CH3)3, 10''-H3), 1.25 ± 1.29, 1.30 ±
1.38 (m, 12H, 4'', 5'', 6'', 7'', 8'', 9''-H2), 1.49 ± 1.52 (m, 2H, 4-H2), 1.59 ± 1.60
(m, 1H, 5-H2), 1.65 ± 1.68 (m, 2H, 2'-H2), 1.74 ± 1.76 (m, 1H, 5-H2), 2.09 ±
2.18 (m, 3H, 3''-H2, 3-OH), 2.95 (d, J ˆ 2.8 Hz, 1H, 1'-OH), 3.27 ± 3.30 (m,
2H, 3,6-H), 3.65 ± 3.67 (m, 1H, 1'-H), 3.78 ± 3.83 (m, 2H, 3'-H2), 3.87 (dd,
J ˆ 8.7 Hz, 9.1 Hz, 1H, 2-H), 5.36 (dd, J ˆ 9.1 Hz, 10.7 Hz, 1H, 1''-H),
5.75 ± 5.81 (m, 1H, 2''-H); 13C NMR (150 MHz, CDCl3): d ˆ À5.4 (SiCH3),
14.1 (C-10''), 18.3 [C(CH3)], 22.7 (C-9''), 25.9 [C(CH3)], 26.3 (C-4), 28.4,
29.2, 29.3, 29.4, 29.7, 30.9, 31.9 (C-3'', C-4'', C-5'', C-6'', C-7'', C-8'', C-5), 35.2
(C-2'), 60.9 (C-3'), 70.2 (C-3), 72.0 (C-1'), 78.3 (C-2), 80.1 (C-6), 127.2 (C-
1''), 137.0 (C-2''); C24H48O4Si (428.728): calcd C 67.24, H 11.29; found C
67.41, H 11.30.
E isomer: 1H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 6H, SiCH3), 0.86 ± 0.89
(m, 12H, SiC(CH3)3, 10''-H3), 1.25 ± 1.76, (m, 18H, 4,5,2',4'',5'',6'',7'',8'',9''-
H2), 2.09 ± 2.18 (m, 3H, 3''-H2, 3-OH), 2.95 (s, 1H, 1'-OH), 3.27 ± 3.30 (m,
2H, 3,6-H), 3.49 ± 3.51 (m, 1H, 2-H), 3.65 ± 3.67 (m, 1H, 1'-H), 3.78 ± 3.83
(m, 2H, 3'-H2), 5.38 ± 5.41 (m, 1H, 1''-H), 5.80 ± 5.85 (m, 1H, 2''-H);
13C NMR (75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 14.1 (C-10''), 18.3
[C(CH3)], 22.7 (C-9''), 25.9 [C(CH3)], 26.3 (C-4), 28.4, 29.0, 29.2, 29.4,
29.7, 30.9, 32.4 (C-3'', C-4'', C-5'', C-6'', C-7'', C-8'', C-5), 35.2 (C-2'), 60.9 (C-
3'), 71.9 (C-3), 72.0 (C-1'), 80.1 (C-6), 83.7 (C-2), 127.5 (C-1''), 136.6 (C-2'').
(2S,3R,6S,1'S)-2-Decyl-3-tert-butyldimethylsilyloxy-6-(1'-tert-butyldime-
thylsilyloxy-3'-iodo)-propyl-tetrahydropyran (20): 1. Monodeprotection
with CSA: Compound 19 (550 mg, 0.83 mmol) was dissolved in CH2Cl2
(10 mL) and MeOH (5 mL) at 08C. CSA (25 mg, 0.10 mmol) dissolved in
MeOH (5 mL) was added under stirring. The reaction was quenched after
30 min by the addition of a sat. aq. sodium bicarbonate solution (8 mL).
After extraction with MTBE (4 Â 10 mL), washing of the combined organic
layers with sat. aq. NaCl solution (10 mL) and drying with MgSO4 the
solvents were evaporated and the resulting crude oil was purified by CC
(20 g silica gel, MTBE/hexane 1:5) to obtain the corresponding alcohol
(332 mg, 0.61 mmol, 74%) as a colorless oil. 14% silyl ether 19 (80 mg,
0.12 mmol) could also be regained.
(2S,3R,6S,1'S)-2-Decyl-3-tert-butyl-dimethylsilyloxy-6-(1'-tert-butyldime-
thylsilyloxy-3'-hydroxy)-propyl-tetrahydropyran: Rf ˆ 0.35 (n-hexane/
MTBE 5:1); [a]2D3 ˆ À47.5, (c ˆ 2.26, CHCl3); IR (film): nÄ ˆ 3401, 2930,
2858, 1466, 1368, 1253, 1100, 1013, 840, 776, 672 cmÀ1; 1H NMR (300 MHz,
CDCl3): d ˆ 0.04 (brs, 12H, SiCH3), 0.84 ± 0.87 (m, 21H, SiC(CH3)3, 10''-
H3), 1.21 ± 1.49 (m, 21H, 1'',2'',3'',4'',5'',6'',7'',8'',9'',4,5-H2), 1.54 ± 1.74 (m,
1H, 2'-H2), 1.76 ± 1.91 (m, 1H, 2'-H2), 1.93 ± 2.05 (m, 1H, 4-H2), 2.85 (t, 1H,
3'-OH), 3.02 ± 3.10 (m, 1H, 2-H), 3.19 ± 3.24 (m, 1H, 3-H), 3.25 ± 3.34 (m,
1H, 6-H), 3.62 ± 3.70 (m, 2H, 3'-H2), 3.79 ± 3.84 (m, 1H, 1'-H); 13C NMR
(75 MHz, CDCl3): d ˆ À4.8, À4.3 (SiCH3), 14.1 (C-10''), 17.9, 18.0
[C(CH3)], 22.7 (C-9''), 25.8, 25.9 [C(CH3)], 24.5, 25.0, 29.3, 29.5, 29.6,
29.6, 29.7, 31.8, 31.9, 33.3 (C-4, C-5, C-1'', C-2'', C-3'', C-4'', C-5'', C-6'', C-7'',
C-8''), 35.4 (C-2'), 60.2 (C-3'), 70.9 (C-3), 73.0 (C-1'), 80.0 (C-6),
82.7 (C-2); C30H64O4Si2 (545.008) calcd C 66.12, H 11.84; found C 66.17,
H 11.67.
(2S,3R,6S,1'S)-2-Decyl-3-hydroxy-6-(3'-tert-butyldimethylsilyloxy-1'-hy-
droxy)-propyl-tetrahydropyran (18): Pt/C (90 mg, 0.023 mmol Pt, 5% on
C) was suspended in ethyl acetate (25 mL) at 08C. The mixture was
degassed and stirred under hydrogen atmosphere (1 atm) for 5 min. Alkene
17 (1.20 g, 2.80 mmol) dissolved in ethyl acetate (5 mL) was added and the
mixture was stirred vigorously for 5 h. Then the solution was filtered
through a pad of silica gel, washed with ethyl acetate, and the solvent was
evaporated. The residue (1.14 g, 2.65 mmol, 95%) was a colorless oil, which
was spectroscopically pure and needed no further purification. Rf ˆ 0.27
(n-hexane/MTBE 1:1); [a]2D5 ˆ À33.1, (c ˆ 0.94, CHCl3); IR (film): nÄ ˆ
2. Iodation: Iodine (88 mg, 0.348 mmol) was added to a solution of
imidazole (59 mg, 0.870 mmol) and PPh3 (84 mg, 0.319 mmol) in CH2Cl2
(2 mL) at 08C. After stirring for 5 min, the alcohol (158 mg, 0.290 mmol)
dissolved in CH2Cl2 (1 mL) was added slowly. The reaction mixture was
stirred for 2.5 h with exclusion of light. Then it was quenched by the
addition of a aqueous Na2S2O3 solution (10 mL). The aqueous layer was
extracted with MTBE (3 Â 10 mL). The combined organic layers were
washed with sat. aq. NaCl solution (10 mL), dried with MgSO4, and the
solvents were removed in vacuo. The crude product was purified by FCC
(8 g silica gel, hexane/MTBE 30:1) to yield 20 (152 mg, 0.232 mmol, 80%)
as a colorless oil. Rf ˆ 0.31 (n-hexane/CH2Cl2 8:1); [a]2D3 ˆ À47.7 (c ˆ 0.44,
CHCl3); IR (film): nÄ ˆ 2929, 2857, 1466, 1367, 1253, 1098, 937, 837, 774,
3410, 2926, 2856, 1466, 1388, 1361, 1256, 1094, 1006, 938, 836, 776 cmÀ1
,
1H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 6H, SiCH3), 0.87 ± 0.90 (m, 12H,
SiC(CH3)3, 10''-H3), 1.10 ± 1.35 (m, 16H, 2'',3'',4'',5'',6'',7'',8'',9''-H2), 1.36 ±
1.55 (m, 4H, 1'',4,5-H2), 1.64 ± 1.74 (m, 3H, 2',5-H2), 1.78 ± 1.82 (m, 1H,
3-OH), 2.07 ± 2.13 (m, 1H, 4-H2), 2.86 ± 2.87 (m, 1H, 1'-OH), 3.00 ± 3.06 (m,
1H, 2-H), 3.15 ± 3.18 (m, 1H, 6-H), 3.24 ± 3.31 (m, 1H, 3-H), 3.59 ± 3.65 (m,
1H, 1'-H), 3.78 ± 3.84 (m, 2H, 3'-H2); 13C NMR (75 MHz, CDCl3): d ˆ À5.4
(SiCH3), 14.1 (C-10''), 18.3 [C(CH3)], 22.7 (C-9''), 25.9 [C(CH3)], 25.5, 25.6,
26.7, 29.3, 29.6, 29.7, 31.9, 32.0, 32.7 (C-4, C-5, C-1'', C-2'', C-3'', C-4'', C-5'',
C-6'', C-7'', C-8''), 35.6 (C-2'), 60.6 (C-3'), 70.6 (C-3), 71.9 (C-1'), 80.1 (C-6),
82.1 (C-2); C24H50O4Si (430.744): calcd C 66.92, H 11.70; found C 66.76, H
11.48.
672 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.03 ± 0.07 (m, 12H, SiCH3),
0.86 (m,
21H,
SiC(CH3)3,
10''-H3),
1.23 ± 1.75 (m,
21H,
1'',2'',3'',4'',5'',6'',7'',8'',9'',4,5-H2), 1.82 ± 1.93 (m, 1H, 2'-H2), 1.93 ± 2.02 (m,
1H, 4-H2), 2.02 ± 2.16 (m, 1H, 2'-H2), 2.96 ± 3.04 (m, 1H, 2-H), 3.10 ± 3.31
(m, 4H, 3,6-H, 3'-H2), 3.65 ± 3.74 (m, 1H, 1'-H); 13C NMR (75 MHz,
CDCl3): d ˆ À4.8, À4.3 (SiCH3), 3.5 (C-3'), 14.1 (C-10''), 17.9, 18.0
[C(CH3)], 22.7 (C-9''), 25.8, 25.9 [C(CH3)], 25.0, 29.4, 29.6, 29.6, 29.7,
31.8, 31.9, 33.5 (C-4, C-5, C-1'', C-2'', C-3'', C-4'', C-5'', C-6'', C-7'', C-8''),
36.6 (C-2'), 70.9 (C-3), 74.0 (C-1'), 79.4 (C-6), 82.5 (C-2); HR-MS
‡
(C30H63O3ISi2): calcd 639.3126; found: 639.3122 [M À CH3] .
(2S,3R,6S,1'S)-2-Decyl-3-tert-butyldimethylsilyloxy-6-(1',3'-di-tert-butyldi-
methylsilyloxy)-propyl-tetrahydropyran (19): Diol 18 (2.10 g, 4.88 mmol)
was dissolved in CH2Cl2 (40 mL) and cooled to 08C. 2,6-Lutidine (2.9 mL,
25.0 mmol) and TBDMS-OTf (3.5 mL, 15 mmol) were added under
stirring. After 30 min the reaction was quenched with a sat. aq. sodium
bicarbonate solution (20 mL). The aqueous layer was extracted with
MTBE (3 Â 20 mL) and the combined organic layers were washed with a
sat. aq. NaCl solution (2 Â 15 mL) and dried with MgSO4. After evapo-
(3S,4S,7R,8V,9V)-1-tert-Butyldimethylsilyloxy-3,4-O-isopropyliden-7-hy-
droxy-8-methoxy-octadec-9-ene-3,4-diol (22): 1:1 mixture of diastereomers
at C-8; 1H NMR (300 MHz, CDCl3): d ˆ 0.03 (s, 6H, SiCH3), 0.88 ± 0.97 (m,
12H, SiC(CH3)3, 18-H3), 1.21 ± 1.89 (m, 12H, 12,13,14,15,16,17-H2), 1.34 (s,
6H, acetonide-CH3), 1.63 ± 2.07 (m, 8H, 2,5,6,11-H2), 2.26 ± 2.32, 2.63 ± 2.66
(m, 1H, OH), 3.24 ± 3.29 (m, 3H, OMe), 3.59 ± 3.79 (m, 5H, 1-H2, 3,4,7-H),
3.41 ± 3.46, 3.88 ± 3.96 (m, 1H, 8-H), 5.29 ± 5.40 (m, 1H, 9-H), 5.64 ± 5.79 (m,
1H, 10-H); 13C NMR (75 MHz, CDCl3): d ˆ À5.2 (SiCH3), 14.1 (C-18), 18.5
Chem. Eur. J. 2000, 6, No. 13
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2389 $ 17.50+.50/0
2389

U. Koert et al.
FULL PAPER
[C(CH3)], 21.5 (C-17), 26.1 [C(CH3)], 27.6 (acetonide-CH3), 21.6, 23.0, 23.5,
28.3, 29.2, 29.6, 29.7, 29.9, 31.1, 32.2 (C-5, C-6, C-11, C-12, C-13, C-14, C-15,
C-16), 36.0 (C-2), 56.0 (OMe), 60.0 (C-1), 73.2, 73.4 (C-7), 77.7, 81.2 (C-3,
C-4), 80.8, 85.7 (C-8), 108.0 (acetal), 125.8, 136.8 (C-9, C-10).
(2S)-2,3-Epoxy-1-(triisopropylsilyloxy)propane (31): Imidazole (3.55 g,
52.2 mmol) and DMAP (530 mg, 4.34 mmol) were added to a solution of
(R)-glycidol (3.00 mL, 43.4 mmol) in CH2Cl2 (75 mL). The mixture was
treated with TIPSCl (10.00 g, 51.9 mmol) at 08C. After stirring at rt for
90 min, the reaction mixture was filtered through a pad of Celite and
diluted with water (100 mL) and n-hexane (50 mL). The aqueous layer was
extracted with n-hexane (2 Â 30 mL). The combined organic layers were
washed with water (1 Â 30 mL), sat. aq. NaCl solution (2 Â 30 mL) and
dried with MgSO4. The solvents were removed in vacuo and the residue
was purified by FCC (200 g silica gel, PE/MTBE 10:1) to yield 31 (9.7 g,
97%) as a colorless oil. Rf ˆ 0.45 (n-hexane/MTBE 10:1); [a]2D5 ˆ À3.7 (c ˆ
1.0, CHCl3); IR (film): nÄ ˆ 3049 w (epoxide-CH), 2943/2866 vs (CH), 1464 s,
1384 m, 1254 m (epoxide-ROR), 1161 s, 1137 s, 1102 s, 883 s, 682 s; 1H NMR
(300 MHz, CDCl3): d ˆ 1.03 ± 1.09 (m, 21H, TIPS), 2.64 (dd, J ˆ 5.3, 2.6 Hz,
1H, 3-Ha), 2.75 (dd, J ˆ 5.3, 4.1 Hz, 1H, 3-Hb), 3.06 ± 3.12 (m, 1H, 2-H), 3.72
(dd, J ˆ 11.7, 4.5 Hz, 1H, 1-Ha), 3.89 (dd, J ˆ11.5, 3.2 Hz, 1H, 1-Hb);
13C NMR (75 MHz, CDCl3): d ˆ 11.9 (SiCH(CH3)2), 17.9 (SiCH(CH3)2),
44.4 (C-1), 52.6 (C-2), 63.9 (C-3); C12H26O2Si (230.42): calcd C 62.55, H
11.37; found C 62.48, H 11.49.
(2S,3R,6S,1'S,1''V)-2-Decenyl-3-tert-butyldimethylsilyloxy-6-(3'-tert-bu-
tyldimethylsilyloxy-1'-hydroxy)-propyl-tetrahydropyran (23): TBDMS-
OTf (44 mL, 0.192 mmol) and 2,6-lutidine (45 mL, 0.384 mmol) were
dissolved in CH2Cl2 (0.8 mL). After 30 min vinyl epoxide 16 (30 mg,
0.064 mmol), dissolved in CH2Cl2 (0.3 mL), was added at À788C. After 1 h
the reaction was quenched with phosphate buffer (pH 7, 1 mL) The
aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and the combined
organic layers were washed with a sat. aq. NaCl solution (5 mL) and dried
with MgSO4. After evaporation of the solvents the residue was purified by
CC (2 g silica gel, hexane/MTBE 20:1) to afford 23 (21 mg, 0.039 mmol,
61%) as a colorless oil. Rf ˆ 0.42 (n-hexane/MTBE 20:1); 1H NMR
(300 MHz, CDCl3): d ˆ 0.03 ± 0.04 (brs, 12H, SiCH3), 0.83 ± 0.87 (m, 21H,
SiC(CH3)3, 10''-H3), 1.25 ± 1.38 (m, 12H, 4'', 5'', 6'', 7'', 8'', 9''-H2), 1.39 ± 1.79
(m, 6H, 2',4,5-H2), 2.09 ± 2.18 (m, 2H, 3''-H2), 2.92 (d, J ˆ 2.4 Hz, 1H, 1'-
OH), 3.21 ± 3.36 (m, 2H, 3,6-H), 3.59 ± 3.66 (m, 1H, 1'-H), 3.75 ± 3.87 (m,
3H, 3'-H2, 2-H), 5.26 ± 5.33 (m, 1H, 1''-H), 5.55 ± 5.62 (m, 1H, 2''-H);
13C NMR (75 MHz, CDCl3): d ˆ À5.4, À4.4 (SiCH3), 14.1 (C-10''), 18.3
[C(CH3)], 22.7 (C-9''), 25.8, 25.9 [C(CH3)], 26.4 (C-4), 28.2, 29.3, 29.5, 29.6,
31.9, 33.1 (C-3'', C-4'', C-5'', C-6'', C-7'', C-8'', C-5), 35.2 (C-2'), 60.8 (C-3'),
71.2 (C-3), 71.9 (C-1'), 78.2 (C-2), 80.0 (C-6), 128.5 (C-1''), 135.4 (C-2'');
HR-MS (C30H62O4Si2): calcd 542.4187; found: 542.4189.
(2S)-(1-Triisopropylsilyloxy)-hex-5-en-2-ol (32): For the preparation of the
Grignard reagent, a solution of allyl bromide (15.7 g, 130 mmol) in THF
(100 mL) was added dropwise at 08C to flame-dried magnesium (4.1 g,
170 mmol) in THF (50 mL) to which 1,2-dibromoethane (2 drops) was
added before. The mixture was stirred at 08C for additional 30 min. After
that the grey suspension was cooled to À308C and solid copper iodide
(742 mg, 3.9 mmol) was added. The color of the suspension turned to light
green. At À308C a solution of TIPS-glycidol 31 (6.06 g, 26.3 mmol) in THF
(40 mL) was added. The temperature was allowed to rise to À108C during
another hour of stirring. At 08C half sat. aq. NH4Cl solution (40 mL) was
added. The mixture was filtered through a pad of Celite, diluted with
MTBE (80 mL), and water (80 mL). The aqueous layer was extracted with
MTBE (3 Â 30 mL) and the combined organic layers were washed with sat.
aq. NaCl solution (2 Â 40 mL) and dried with MgSO4. The solvents were
removed in vacuo and the residue was purified by CC (180 g silica gel, PE/
MTBE 10:1) to yield 32 (6.55 g, 91%) as a colorless liquid. Rf ˆ 0.32 (n-
hexane/MTBE 10:1); [a]2D2 ˆ 4.5 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3576/3444
Reaction of 27 with CSA: Vinyl epoxide 27 (100 mg, 0.213 mmol) was
dissolved in CH2Cl2 (8 mL) and 2-propanol (0.3 mL). CSA (10 mg,
0.044 mmol) was added at À608C. After 4 h (À608C ! rt) no conversion
was observed (TLC). After stirring for another 12 h at rt, NEt3 (1 mL) was
added. The solvents were removed in vacuo and the residue was purified by
FCC (10 g silica gel, hexanes/MTBE 2:1) to provide 28 (15 mg, 0.028 mmol,
13%) and 29 (26 mg, 0.049 mmol, 23%) as major products.
(3S,4S,7S,8V,9Z)-1-tert-Butyldimethylsilyloxy-3,4-O-isopropyliden-7-hy-
droxy-8-isopropyloxy-octadec-9-ene-3,4-diol (28): (mixture of diastereom-
ers at C-8: 2:1 1H NMR) Rf ˆ 0.81 (n-hexane/MTBE 2:1); major isomer:
1H NMR (300 MHz, C6D6): d ˆ 0.06 (s, 6H, SiCH3), 0.88 ± 0.93 (m, 3H, 18-
H3), 0.97 (s, 9H, SiC(CH3)3), 1.02 ± 1.12 (m, 6H, (CH3)2CHO), 1.21 ± 1.31
(m, 12H, 12,13,14,15,16,17-H2), 1.40 (s, 3H, acetonide-CH3), 1.41 (s, 3H,
acetonide-CH3), 1.63 ± 2.05 (m, 8H, 2,5,6,11-H2), 2.29 ± 2.31 (m, 1H, OH),
3.60 ± 3.66 (m, 1H, (CH3)2CHO), 3.72 ± 3.90 (m, 5H, 1-H2, 3,4,7-H), 4.17 ±
4.20 (m, 1H, 8-H), 5.49±5.56 (m, 2H, 9,10-H); 13C NMR (75 MHz, C6D6):
d ˆ À5.2 (SiCH3), 14.3 (C-18), 18.5 [C(CH3)], 21.5 (C-17), 26.1 [C(CH3)],
27.6 (acetonide-CH3), 21.6, 23.0, 23.5, 28.3, 29.2, 29.6, 29.7, 29.9, 31.1, 32.2
(C-5, C-6, C-11, C-12, C-13, C-14, C-15, C-16, propyl-CH3), 36.4 (C-2), 60.3
(C-1), 68.5 (OCHMe2), 73.6 (C-7), 75.8 (C-8), 78.0, 81.2 (C-3, C-4), 108.1
(acetal), 127.9, 134.9 (C-9, C-10); minor isomer: 1H NMR (300 MHz, C6D6):
d ˆ 0.06 (s, 6H, SiCH3), 0.88 ± 0.93 (m, 3H, 18-H3), 0.97 (s, 9H, SiC(CH3)3)
1.02±1.12 (m, 6H, (CH3)2CHO), 1.21 ± 1.31 (m, 12H, 12,13,14,15,16,17-H2),
1.40 (s, 3H, acetonide-CH3), 1.41 (s, 3H, acetonide-CH3), 1.63 ± 2.05 (m,
8H, 2,5,6,11-H2), 2.29 ± 2.31 (m, 1H, OH), 3.60 ± 3.66 (m, 1H, (CH3)2CHO),
3.72 ± 3.90 (m, 6H, 1-H2, 3,4,7,8-H), 5.49 ± 5.56 (m, 2H, 9,10-H); 13C NMR
(75 MHz, C6D6): d ˆ À5.2 (SiCH3), 14.3 (C-18), 18.5 [C(CH3)], 21.5 (C-17),
26.1 [C(CH3)], 27.6 (acetonide-CH3), 21.6, 23.0, 23.5, 28.3, 29.2, 29.6, 29.7,
29.9, 31.1, 32.2 (C-5, C-6, C-11, C-12, C-13, C-14, C-15, C-16, propyl-CH3),
36.4 (C-2), 60.3 (C-1), 68.3 (OCHMe2), 73.6 (C-7), 78.0, 81.2 (C-3, C-4), 81.6
(C-8), 108.1 (acetal), 127.9, 134.9 (C-9, C-10); HR-MS (C29H57O5Si): calcd
ˆ
ˆ
br (OH), 3077 w ( CH2), 2943/2866 s (CH), 1641 m (C C), 1463 s, 1116 s,
1068 m, 882 m; 1H NMR (300 MHz, CDCl3): d ˆ 0.92 ± 0.18 (m, 21H,
TIPS), 1.40 ± 1.60 (m, 2H, 4-H), 2.04 ± 2.28 (m, 2H, 3-H), 2.52 (brs, 1H,
OH), 3.43 ± 3.51 (m, 1H, 2-H), 3.62 ± 3.72 (m, 2H, 1-H), 4.91 ± 5.05 (m, 2H,
6-H), 5.74 ± 5.88 (m, 1H, 5-H); 13C NMR (75 MHz, CDCl3): d ˆ 11.9
(SiCH(CH3)2), 17.9 (SiCH(CH3)2), 29.8 (C-4), 32.0 (C-3), 67.4 (C-1), 71.4
(C-2), 114.7 (C-6), 138.4 (C-5); C15H32O2Si (272.50): calcd C 60.11, H 11.84;
found C 60.27, H 10.86.
(4S)-4,5-Bis(triisopropylsilyloxy)-pentanal (33): 1. TIPS-protection:
A
solution of the secondary alcohol 32 (6.70 g, 24.6 mmol) and 2,6-lutidine
(7.2 mL, 61.5 mmol) in CH2Cl2 (100 mL) was treated with TIPS-OTf
(9.04 g, 29.5 mmol) at 08C. The solution was stirred at rt for 2.5 h, then sat.
aq. NH4Cl solution (100 mL) was added. The aqueous layer was extracted
with MTBE (3 Â 30 mL) and the combined organic layers were washed
with sat. aq. NaCl solution (2 Â 30 mL) and dried with MgSO4. The solvents
were removed in vacuo and the residue was purified by CC (100 g silica gel,
PE) to afford the desired product (9.97 g, 96%) as a colorless oil.
(2S)-1,2-Bis(triisopropylsilyloxy)-hex-5-ene: Rf ˆ 0.75 (n-hexane/MTBE
10:1); [a]2D3 ˆ À24.9 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3077 w ( CH2), 2943/
ˆ
ˆ
2867 s (CH), 1642 w (C C), 1464 m, 1384/1366 w (tBu), 1122 m, 882 m, 681
1
m; H NMR (300 MHz, CDCl3): d ˆ 1.00 ± 1.11 (m, 42H, 2  TIPS), 1.51 ±
‡
513.3975; found 513.3977 [M À CH3] .
1.84 (m, 2H, 3-H2), 2.11 ± 2.23 (m, 2H, 4-H2), 3.50 (dd, J ˆ 9.4, 7.9 Hz, 1H,
1-Ha), 3.71 (dd, J ˆ 9.4, 4.9 Hz, 1H, 1-Hb), 3.83 ± 3.92 (m, 1H, 2-H), 4.89 ±
5.05 (m, 2H, 6-H2), 5.77 ± 5.91 (m, 1H, 5-H); 13C NMR (75 MHz, CDCl3):
d ˆ 12.0, 12.6 (2  SiCH(CH3)2), 18.0, 18.2 (2  SiCH(CH3)2), 28.5 (C-4),
33.6 (C-3), 66.7 (C-1), 72.5 (C-2), 114.0 (C-6), 139.3 (C-5); C24H52O2
(428.84): calcd C 67.22, H 12.22; found C 67.29, H 12.48.
(3S,4S,7S,8V,9V)-1-tert-Butyldimethylsilyloxy-3,4-O-isopropyliden-7-hy-
droxy-10-isopropyloxy-octadec-8-ene-3,4-diol (29): Rf ˆ 0.58 (n-hexane/
MTBE 2:1); 1H NMR (300 MHz, CDCl3): d ˆ 0.03 (s, 6H, SiCH3), 0.82 ±
0.87 (m, 12H, SiC(CH3)3, 18-H3), 1.06 ± 1.09 (m, 6H, (CH3)2CHO), 1.21 ±
1.50 (m, 14H, 11,12,13,14,15,16,17-H2), 1.35 (s, 6H, acetonide-CH3), 1.63 ±
1.81 (m, 6H, 2,5,6-H2), 2.49 (s, 1H, OH), 3.48 ± 3.80 (m, 6H, 1-H2, 3,4,10-H,
(CH3)2CHO), 4.08 ± 4.19 (m, 1H, 7-H), 5.43 ± 5.65 (m, 2H, 8,9-H); 13C NMR
(75 MHz, CDCl3): d ˆ À5.4 (SiCH3), 14.1 (C-18), 18.3 [C(CH3)], 22.7 (C-
17), 25.9 [C(CH3)], 27.3 (acetonide-CH3), 21.6, 23.5, 25.6, 28.8, 29.3, 29.6,
29.6, 31.8, 34.4, 35.8 (C-5, C-6, C-11, C-12, C-13, C-14, C-15, C-16, propyl-
CH3), 36.1 (C-2), 59.8 (C-1), 68.5 (OCHMe2), 72.2 (C-7), 77.3 (C-10), 77.7,
80.9 (C-3, C-4), 108.1 (acetal), 132.6, 134.0 (C-8, C-9); HR-MS (C30H60O5-
Si): calcd 528.4210; found 528.4207.
2. Ozonolysis: Ozone (Fischer OZ 503, 100 L O2 hÀ1) was bubbled through
a solution of (2S)-1,2-bis(triisopropylsilyloxy)-hex-5-ene (3.0 g, 7.0 mmol)
in CH2Cl2 (120 mL) at À758C until the color began to turn blue. The excess
of ozone was removed by bubbling argon through the solution. PPh3 (1.84 g,
7.0 mmol) was added at À758C and the mixture was stirred at rt for 1 h. The
solution was concentrated in vacuo and the residue was purified by FCC
(200 g silica gel, PE/CH2Cl2 4:1) to yield aldehyde 33 (2.96 g, 98%) as a
colorless oil. Rf ˆ 0.36 (n-hexane/MTBE 20:1); [a]2D5 ˆ À23.1 (c ˆ 1.0,
2390
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2390 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 13

(À)-Mucocin
2382±2396
CHCl3); IR (film): nÄ ˆ 2942/2866 s (CH), 2724 w (aldehyde-CH), 1731 s
for 1 h, then sat. NH4Cl solution (10 mL), water (10 mL) and MTBE
(20 mL) were added. The aqueous layer was extracted with MTBE (2 Â
10 mL) and the combined organic layers were washed with sat. aq. NaCl
solution (2 Â 15 mL) and dried with MgSO4. The solvents were removed in
vacuo and the residue was purified by CC (45 g silica gel, PE/MTBE 1:2) to
yield the THF alcohol 37 (834 mg, 93%) as a colorless oil. The C-5 epimers
were separated by preparative HPLC (Rainin Si 60, 41.4 Â 250 mm, n-
hexane/iPrOH 96:4, 40 mLminÀ1). 37: Rf ˆ 0.19 (n-hexane/MTBE 1:1);
HPLC: tR ˆ 24.7 min (Superspher Si 60, n-hexane/iPrOH 96:4,
1
ˆ
(C O), 1463 m, 1157 s, 1120 m, 1013 m, 883 m, 681 m; H NMR (300 MHz,
CDCl3): d ˆ 1.00 ± 1.07 (m, 42H, 2  TIPS), 1.84 ± 2.07 (m, 2H, 3-H2), 2.43 ±
2.63 (m, 2H, 2-H2), 3.41 ± 3.49 (m, 1H, 5-Ha), 3.72 (dd, J ˆ 9.6, 4.7 Hz, 1H,
5-Hb), 3.89 ± 3.97 (m, 1H, 4-H), 9.78 (t, J ˆ 1.9 Hz, 1H, 1-H); 13C NMR
(75 MHz, CDCl3): d ˆ 11.9, 12.5 (2  SiCH(CH3)2), 17.9, 18.1 (2 Â
SiCH(CH3)2), 26.5 (C-2), 38.6 (C-3), 66.0 (C-5), 71.4 (C-4), 203.0 (C-1);
C23H50O3Si2 (430.81): calcd C 64.12, H 11.70; found C 64.19, H 11.64.
(6S,9S)-6-Hydroxy-9,10-bis(triisopropylsilyloxy)decyl pivalate (36): 1.
Preparation of the dialkylzinc reagent 34: Diethylzinc (4.6 mL, 45 mmol)
was added to 5-iodopentylpivalate (8.94 g, 30 mmol) and CuI (85 mg,
0.45 mmol) at rt. The mixture was stirred at 508C for 26 h. The black
precipitate was allowed to settle and the solution was transferred to
another flask via a PTFE tube. Xylene (4 mL) was used as rinsing liquid.
The xylene and the excess of diethylzinc were condensed off at 408C and
reduced pressure (ca. 0.1 mbar). After 18 h more xylene (4 mL) was added
and evaporated again to make the removal of ZnEt2 as complete as
possible.
1.0 mLminÀ1); [a]D23
ˆ
5.3 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3437 brm
ˆ
(OH), 2934/2865 s (CH), 1728 s (C O), 1541/1480 m, 1398/1366 w (tBu),
1285 s, 1159 s, 1038 s; H NMR (300 MHz, CDCl3): d ˆ 1.14 (s, 9H, tBu),
1
1.23 ± 1.68, 1.85 ± 2.03 (m, 12H, 3',4',2,3,4,5-H2), 2.25 (brs, 1H, OH), 3.43
(dd, J ˆ 11.5, 6.2 Hz, 1H, 1''-Ha), 3.57 (dd, J ˆ 11.7, 3.4 Hz, 1H, 1''-Hb),
3.83 ± 3.93 (m, 1H, 2'-H), 3.96 ± 4.09 (m, 1H, 5'-H), 4.00 (t, J ˆ 6.6 Hz, 2H,
1-H2); 13C NMR (75 MHz, CDCl3): d ˆ 25.8, 26.0, 27.5, 28.5, 32.0, 35.5 (C-
3',4',2 ± 5), 27.1 (C(CH3)3), 38.7 (C(CH3)3), 64.2 (C-1), 65.0 (C-1''), 78.9 (C-
5'), 79.2 (C-2'), 178.6 (COOtBu); C15H28O4 (272.38): calcd C 66.14, H 10.36;
found C 65.69, H 10.04.
2. Preparation of the catalyst: Ti(OiPr)4 (4.8 mL, 16 mmol), the chiral
diamine 35 (303 mg, 0.8 mmol), and xylene (5 mL) were stirred at 508C for
30 min.
5-[(2'R,5'S)-5'-(Triethylsilyloxymethyl)-tetrahydrofuran-2'-yl]-pentan-1-ol
(38): 1. TES-protection: Imidazole (222 mg, 3.70 mmol) and powdered
molecular sieves (4 Š, 50 mg) were added to a solution of the alcohol 37
(505 mg, 1.85 mmol) in CH2Cl2 (20 mL). The mixture was treated with
TESCl (0.37 mL, 2.22 mmol) at 08C. After stirring at rt for 2 h, the reaction
mixture was filtered through a pad of Celite and diluted with MTBE
(20 mL), phosphate buffer solution (10 mL) and water (5 mL). The
aqueous layer was extracted with MTBE (3 Â 7 mL) and the combined
organic layers were washed with sat. aq. NaCl solution (2 Â 20 mL) and
dried with MgSO4. The solvents were evaporated and the residue was
purified by CC (25 g silica gel, PE/MTBE 2:1) to yield the protected
alcohol (617 mg, 86%) as a colorless liquid.
3. Reaction with aldehyde 33: The catalyst suspension was cooled to À408C
and the prepared dialkylzinc 34 was added through a PTFE tube. Xylene
was used to wash any residual 34 into the reaction flask. The reaction
mixture was stirred at À408C for 5 min, then a solution of aldehyde 33
(3.45 g, 8.0 mmol) in xylene (5 mL) was added. The color of the mixture
turned to light green. It was allowed to warm up to À258C and was stirred
at this temperature for 18 h. The reaction mixture was allowed to warm up
to 08C and water (5 mL), sat. aq. NH4Cl solution (40 mL), and MTBE
(40 mL) were added. The mixture was filtered through a pad of Celite. The
aqueous layer was extracted with MTBE (3 Â 30 mL) and the combined
organic layers were washed with sat. aq. NaCl solution (2 Â 40 mL) and
dried with MgSO4. The solvents were evaporated in vacuo and the residue
was purified by FCC (180 g silica gel, gradient PE/MTBE 20:1 ! MTBE)
to obtain 36 (3.52 g, 70%) as a colorless liquid. Rf ˆ 0.12 (n-hexane/MTBE
5-[(2'R,5'S)-5'-(Triethylsilyloxymethyl)-tetrahydrofuran-2'-yl]-pentyl piva-
late: Rf ˆ 0.67 (n-hexane/MTBE 1:1); [a]2D5 ˆ À3.8 (c ˆ 1.0, CHCl3); IR
(film): nÄ ˆ 2930/2875/2856 s (CH), 1760 s (C O); 1H NMR (300 MHz,
ˆ
CDCl3): d ˆ 0.51 ± 0.63 (m, 6H, 3  SiCH2CH3), 0.87 ± 0.98 (m, 9H, 3 Â
SiCH2CH3), 1.16 (s, 9H, tBu), 1.21 ± 1.76 (m, 10H, 5 Â alkyl-CH2), 1.88 ±
2.02 (m, 2H, alkyl-CH2), 3.50 (dd, J ˆ 10.4, 5.5 Hz, 1H, 1''-Ha), 3.60 (dd, J ˆ
10.4, 5.1 Hz, 1H, 1''-Hb), 3.83 ± 3.93 (m, 1H, 2'-H), 3.97 ± 4.06 (m, 1H, 5'-H),
4.01 (t, J ˆ 6.6 Hz, 2H, 1-H2); 13C NMR (75 MHz, CDCl3): d ˆ 4.4
(SiCH2CH3)3, 6.7 (SiCH2CH3)3, 25.9, 26.1, 28.3, 28.6, 31.8, 35.7 (C-
3',4',2 ± 5), 27.2 (C(CH3)3), 38.7 (C(CH3)3), 64.3 (C-1), 65.7 (C-1''), 79.0
(C-5'), 79.3 (C-2'), 178.6 (COOtBu); C21H42O4Si (386.64): calcd C 65.23, H
10.95; found C 64.98, H 10.85.
ˆ
10:1); IR (film): nÄ ˆ 3446 brw (OH), 2842/2866 s (CH), 1731 m (C O), 1463
m, 1284/1366 w (tBu), 1285 m, 1157 m, 1066 m, 882 m, 680 m; 1H NMR
(300 MHz, CDCl3): d ˆ 0.99 ± 1.07 (m, 42H, 2  TIPS), 1.16 (s, 9H, tBu),
1.28 ± 1.77 (m, 12H, 3,4,6,7,8,9-H2), 3.50 ± 3.59 (m, 2H, 1-H2), 3.66 ± 3.74 (m,
1H, 5-H), 3.86 ± 3.96 (m, 1H, 2-H), 4.02 (t, J ˆ 6.4 Hz, 2H, 10-H2); 13C NMR
(75 MHz, CDCl3): d ˆ 11.9, 12.4 (2  SiCH(CH3)2), 18.0, 18.1 (2 Â
SiCH(CH3)2), 25.4, 26.1, 28.6, 30.5, 31.8, 37.3 (C-3,4,6 ± 9), 27.2 (C(CH3)3),
38.7 (C(CH3)3), 64.4 (C-10), 65.8 (C-1), 72.1 (C-5), 72.5 (C-2), 178.6
(COOtBu); C33H70O5Si2 (603.08): calcd C 65.72, H 11.70; found C 65.85, H
11.61.
2. Cleavage of the pivalate: A solution of the pivalate (510 mg, 1.32 mmol)
in THF (15 mL) was treated with DIBAH (3.30 mL, 3.30 mmol, 1m in
hexanes) at À408C. The reaction mixture was allowed to warm up to
À158C during 1 h. The reaction was quenched by addition of MeOH
(1.5 mL), sat. aq. NaHCO3 solution (4 mL) and ethyl acetate (15 mL). The
mixture was stirred for 30 min at rt, then solid Na2SO4 (10 g) was added and
the mixture was stirred vigorously for 1 h. The mixture was filtered through
a pad of Celite and the solvents were removed in vacuo. The crude product
was purified by CC (25 g silica gel, PE/MTBE 2:1) to obtain alcohol 38
5-[(2'R,5'S)-5'-(Hydroxymethyl)-tetrahydrofuran-2'-yl]-pentyl
pivalate
(37): 1. Tosylation: A solution of the secondary alcohol 36 (3.37 g,
5.59 mmol) in CH2Cl2 (20 mL) and pyridine (20 mL) was treated with
tosyl chloride (4.26 g, 22.4 mmol) at 08C. The solution was stirred at rt for
15 h, then sat. aq. NH4Cl solution (40 mL) and MTBE (40 mL) were added.
The aqueous layer was extracted with MTBE (3 Â 10 mL). The combined
organic layers were washed with 0.2m HCl (2 Â 10 mL), sat. aq. NaHCO3
solution (3 Â 10 mL), sat. aq. NaCl solution (2 Â 20 mL), and dried with
MgSO4. The solvents were evaporated and the residue was filtered through
silica gel (70 g, PE/MTBE 10:1) to afford tosylate (3.73 g, 88%) as a
colorless oil.
(373 mg, 93%) as a colorless oil. Rf ˆ 0.33 (n-hexane/MTBE 1:1); [a]D25
ˆ
À4.1 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3407 (OH), 2935/2877 s (CH), 1008 w,
743 w; 1H NMR (300 MHz, CDCl3): d ˆ 0.57 (q, J ˆ 7.4 Hz, 6H, 3 Â
SiCH2CH3), 0.92 (t, J ˆ 7.7 Hz, 9H, 3  SiCH2CH3), 1.22 ± 1.76 (m, 11H,
OH, 5  alkyl-CH2), 1.90 ± 2.02 (m, 2H, alkyl-CH2), 3.50 (dd, J ˆ 10.4,
5.5 Hz, 1H, 1''-Ha), 3.56 ± 3.64 (m, 3H, 1''-Hb, 1-H2), 3.83 ± 3.94 (m, 1H, 2'-
H), 3.97 ± 4.07 (m, 1H, 5'-H); 13C NMR (75 MHz, CDCl3): d ˆ 4.4
(SiCH2CH3)3, 6.7 (SiCH2CH3)3, 25.8, 26.0, 28.3, 31.8, 32.7, 35.7 (C-3',4',2 ±
5), 62.9 (C-1), 65.7 (C-1''), 79.0 (C-5'), 79.4 (C-2'); C16H34O3Si (302.52):
calcd C 63.52, H 11.33; found C 63.37, H 11.06.
(6S,9S)-6-(p-Toluenesulfonyloxy)-9,10-bis(triisopropyl-silyloxy)decyl piva-
late: Rf ˆ 0.26 (n-hexane/MTBE 10:1); 1H NMR (300 MHz, CDCl3): d ˆ
0.96 ± 1.04 (m, 42H, 2 Â TIPS), 1.16 (s, 9H, tBu), 1.19 ± 1.74 (m, 12H,
3,4,6,7,8,9-H2), 2.40 (s, 3H, Ar-CH3), 3.36 (dd, J ˆ 9.4, 8.7 Hz, 1H, 1-Ha),
3.62 (dd, J ˆ 9.4, 4.9 Hz, 1H, 1-Hb), 3.70 ± 3.80 (m, 1H, 2-H), 3.96 (t, J ˆ
6.4 Hz, 2H, 10-H2), 4.48 ± 4.58 (m, 1H, 5-H), 7.27 (d, J ˆ 8.1 Hz, 2H, Ar-H),
7.75 (d, J ˆ 8.1 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d ˆ 11.8, 12.4
(2 Â SiCH(CH3)2), 17.9, 18.0, 18.1 (2 Â SiCH(CH3)2), 21.6 (Ar-CH3), 24.2,
25.7, 28.3, 28.4, 29.3, 34.0 (C-3,4,6 ± 9), 27.2 (C(CH3)3), 38.7 (C(CH3)3), 64.2
(C-10), 66.1 (C-1), 72.0 (C-2), 72.5 (C-5), 84.5 (C-5), 127.6, 129.6, 134.7,
144.2 (Ar), 178.5 (COOtBu).
Phosphonium salt 39: 1. Iodation: To a solution of imidazole (271 mg,
3.98 mmol) and PPh3 (383 mg, 1.46 mmol) in CH2Cl2 (15 mL) was added at
08C first a solution of iodine (404 mg, 1.59 mmol) in CH2Cl2 (7 mL) and
then a solution of alcohol 38 (401 mg, 1.33 mmol) in CH2Cl2 (3 mL). The
reaction mixture was stirred at rt for 1.5 h, then Na2S2O3 solution (5% in
water, 30 mL) was added and the mixture was stirred until the brown color
disappeared. The phases were separated and the aqueous layer was
extracted with MTBE (3 Â 15 mL). The combined organic layers were
washed with sat. aq. NaCl solution (2 Â 20 mL) and dried with MgSO4. The
Compound 37: 2. Deprotection and ring closure: A solution of the tosylate
(2.51 g, 3.31 mmol) in THF (20 mL) was treated with a solution of TBAF
(3.15 g, 10.0 mmol) in THF (7 mL) at rt. The reaction mixture was stirred
Chem. Eur. J. 2000, 6, No. 13
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2391

U. Koert et al.
FULL PAPER
solvents were evaporated in vacuo and the residue was purified by CC (45 g
silica gel, PE/MTBE 1:1) to yield the iodide (460 mg, 84%) as a colorless
oil.
ester 41 (1.0 g, 4.0 mmol) in THF (10 mL) was treated at rt with borane/
dimethyl sulfide complex (0.9 mL, 8.8 mmol). Dimethyl sulfide was distilled
off at 608C with a light argon flow. After 30 min the Claisen bridge was
removed. The mixture was cooled to 08C and water (8 mL) was added
carefully. After addition of solid K2CO3 (500 mg) and MTBE (10 mL) the
phases were separated. The aqueous layer was extracted with MTBE (2 Â
20 mL) and the combined organic layers were washed with sat. aq. NaCl
solution (2 Â 15 mL) and dried with MgSO4. The solvents were removed in
vacuo and the residue was purified by FCC (60 g silica gel, MTBE) to yield
the benzyl protected triol (740 mg, 83%) as a colorless liquid.
(3S)-6-(Benzyloxy)hexane-1,3-diol: Rf ˆ 0.16 (MTBE); [a]1D9 ˆ À6.6 (c ˆ
1.1, CHCl3); IR (film): nÄ ˆ 3382 s (OH), 3087/3063/3030 w, 2941/2861 s
(CH), 1453 m, 1363 m, 1204 m, 1098 s, 734/698 m; 1H NMR (300 MHz,
CDCl3): d ˆ 1.45 ± 1.80 (m, 6H, 2,4,5-H2), 3.40 ± 3.55 (m, 4H, 1-H2, 2  OH),
3.60 ± 3.70 (m, 3H, 3-H, 6-H2), 4.50 (s, 2H, OCH2Ph), 7.20 ± 7.37 (m, 5H,
Ph); 13C NMR (75 MHz, CDCl3): d ˆ 26.0 (C-5), 34.9 (C-4), 38.3 (C-2), 61.3
(C-1), 70.4 (C-3), 71.4 (C-6), 72.9 (OCH2Ph), 127.6, 127.7, 128.3, 137.9 (Ph);
C13H20O3 (224.30): calcd C 69.61, H 8.99; found C 69.51, H 9.18.
(2R,5S)-2-(5'-Iodopentyl)-5-(triethylsilyloxymethyl)-tetrahydrofuran:
Rf ˆ 0.79 (n-hexane/MTBE 1:1); IR (film): nÄ ˆ 2953/2935 s (CH), 2911 m,
2875 s, 1460 w, 1088 m, 1005 m, 800 w, 744/728 s; 1H NMR (300 MHz,
CDCl3): d ˆ 0.51 ± 0.63 (m, 6H, 3  SiCH2CH3), 0.93 (t, J ˆ 7.9 Hz, 9H, 3 Â
SiCH2CH3), 1.20 ± 1.86 (m, 10H, 5 Â alkyl-CH2), 1.89 ± 2.03 (m, 2H, alkyl-
CH2), 3.16 (t, J ˆ 7.0 Hz, 2H, 5'-H2), 3.47 ± 3.55 (m, 1H, 1''-Ha), 3.55 ± 3.63
(m, 1H, 1''-Hb), 3.82 ± 3.94 (m, 1H, 2-H), 3.97 ± 4.07 (m, 1H, 5-H); 13C NMR
(75 MHz, CDCl3): d ˆ 4.4 (SiCH2CH3)3, 6.7 (SiCH2CH3)3, 7.1 (C-5'), 25.2,
28.3, 30.6, 31.8, 33.5, 35.6 (C-3,4,1'-4'), 65.7 (C-1''), 79.0 (C-5), 79.3 (C-2);
‡
HR-MS (EI): C16H33IO2Si calcd 411.1216; found 411.1212 [M À H] .
2. Preparation of the triphenyl-phosphonium salt 39: The iodide (205 mg,
0.50 mmol) and PPh3 (656 mg, 2.5 mmol) were dissolved in toluene (3 mL)
and CH3CN (5 mL). The solution was stirred at 708C for 24 h. The mixture
was concentrated in vacuo and washed with Et2O several times until the
rinsing liquid was free of PPh3 (checked by TLC). The phosphonium salt 39
was dried in vacuo (ca. 0.1 mbar) and was introduced in the Wittig reaction
without further purification.
2. TBDMS-protection: Imidazole (1.00 g, 14.7 mmol), DMAP (60 mg,
0.49 mmol), and powdered molecular sieves (4 Š, 50 mg) were added to a
solution of the unprotected diol (1.10 g, 4.90 mmol) in CH2Cl2 (20 mL). The
mixture was treated with TBDMSCl (3.56 g, 11.8 mmol, 50% in toluene) at
08C. After stirring at rt for 16 h, the reaction mixture was filtered through a
pad of Celite and diluted with MTBE (30 mL) and half sat. aq. NH4Cl
solution (30 mL). The aqueous layer was extracted with MTBE (3 Â
15 mL) and the combined organic layers were washed with sat. aq. NH4Cl
solution (20 mL), sat. aq. NaCl solution (20 mL) and dried with MgSO4.
The solvents were removed in vacuo and the product was purified by FCC
(100 g silica gel, PE/MTBE 2:1) to yield the fully protected triol 42 (1.96 g,
88%) as a colorless liquid. Rf ˆ 0.50 (n-hexane/MTBE 10:1); [a]2D0 ˆ 8.6
(c ˆ 2.0, CHCl3); IR (film): nÄ ˆ 2954/2929/2857 s, 1472 m, 1361 w, 1256 m,
1099 s, 836 s, 775 s, 734/697 w; 1H NMR (300 MHz, CDCl3): d ˆ 0.03 (s, 12H,
4 Â SiCH3), 0.87 (s, 18H, 2 Â SiC(CH3)3), 1.41 ± 1.57 (m, 2H, 5-H2), 1.57 ±
1.72 (m, 4H, 2,4-H2), 3.45 (t, J ˆ 6.4 Hz, 2H, 1-H2), 3.65 (t, J ˆ 6.6 Hz, 2H,
6-H2), 3.84 (quint, J ˆ 5.6 Hz, 1H, 3-H), 4.49 (s, 2H, OCH2Ph), 7.24 ± 7.35
(m, 5H, Ph); 13C NMR (75 MHz, CDCl3): d ˆ À5.3 (2  SiCH3), À4.6,
À4.4 (2 Â SiCH3), 18.1, 18.3 (2 Â Si(C(CH3)3), 25.4 (C-5), 25.9, 25.9 (2 Â
Si(C(CH3)3), 33.9 (C-4), 40.9 (C-2), 59.9 (C-1), 69.1 (C-3), 70.6 (C-6), 72.8
(OCH2Ph), 127.4, 127.6, 128.3, 138.7 (Ph); C25H48O3Si2 (452.82): calcd C
66.31, H 10.68; found C 66.34, H 10.48.
Methyl (3S)-6-(benzyloxy)-3-hydroxyhexanoate (41): 1. Alkylation: So-
dium hydride (80% in mineral oil, 4.5 g, 150 mmol) was suspended in THF
(200 mL) and cooled to À308C (internal temperature). The b-ketoester 40
(13.9 g, 120 mmol) dissolved in THF (50 mL) was added dropwise, keeping
the temperature below À258C and stirred for 15 min. Then n-butyllithium
(68.8 mL, 2.18m in hexane, 150 mmol) was added (T< 258C). After 15 min
stirring, O-benzyl-2-bromoethanol (21.5 g, 100 mmol), diluted with THF
(50 mL), was added dropwise (T< 108C). The mixture was stirred for 2 h
(T< 08C) and then kept at À258C for further 15 h. The reaction was
quenched by the addition of conc. HCl (30 mL), MTBE (150 mL) and
water (50 mL). The aqueous layer was extracted with MTBE (3 Â 50 mL).
The combined organic layers were washed with sat. aq. NaHCO3 solution
(2 Â 50 mL) and sat. aq. NaCl solution (2 Â 50 mL) and were dried with
MgSO4. The solvents were removed in vacuo and the residue was purified
by FCC (350 g silica gel, gradient PE/MTBE 8:1 to 1:2) to yield the desired
b-keto ester (18.0 g, 72%) as a pale yellow oil.
Methyl 6-(benzyloxy)-3-oxohexanoate: Rf ˆ 0.40 (n-hexane/MTBE 1:1);
ˆ
IR (film): nÄ ˆ 2953/2862 s (CH), 1747/1716 s (C O), 1453 m, 1437 m, 1322
1
m, 1261 m, 1104 m (COC), 739/699 m (Ar); H NMR (300 MHz, CDCl3):
d ˆ 1.90 (quint, J ˆ 6.2 Hz, 2H, 5-H2), 2.64 (t, J ˆ 6.6 Hz, 2H, 4-H2), 3.44 (s,
2H, 2-H2), 3.48 (t, J ˆ 6.0 Hz, 2H, 6-H2), 3.70 (s, 3H, OCH3), 4.35 (s, 2H,
OCH2Ph), 7.25 ± 7.36 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): d ˆ 23.6 (C-
5), 39.7 (C-4), 48.9 (C-2), 52.2 (OCH3), 68.9 (C-6), 72.8 (OCH2Ph), 126.9,
127.5, 127.6, 128.3, 128.4, 138.2 (Ph), 167.6 (C-1), 202.4 (C-3); C14H18O4
(250.29): calcd C 67.18, H 7.25; found C 67.13, H 7.34.
(4S)-4,6-Bis(tert-butyldimethylsilyloxy)-hexan-1-ol (43): 10% Pd on acti-
vated carbon (ca. 0.4 mol%) (120 mg) was suspended in ethyl acetate
(75 mL, HPLC grade). The mixture was degassed and stirred under a
hydrogen atmosphere for 15 min. A solution of the benzyl ether 42 (13.0 g,
28.7 mmol) in ethyl acetate (20 mL) was added and the mixture was
vigorously stirred at rt for 20 h under hydrogen atmosphere (1 atm). The
suspension was filtered through a pad of Celite and the solvent was
removed in vacuo to yield 43 (10.1 g, 97%) as a colorless oil. The product
2. Asymmetric hydrogenation: For the preparation of the catalyst complex
[RuCl2(PhH)2]2 (94.3 mg, 0.145 mmol) and (S)-(À)-BINAP (200 mg,
0.32 mmol) were dissolved in DMF (5 mL) and stirred at 1108C for
20 min. A solution of 6-benzyloxy-3-oxo-hexanoic acid methylester (12.0 g,
47.9 mmol) in degassed methanol (20 mL) was added to the catalyst
solution and this mixture was transferred to the hydrogenation reactor
(Premex) through a PTFE tube. The solution was treated with 4.5 bar
hydrogen at 958C and vigorous stirring for 18 h. After cooling to rt the dark
red solution was concentrated in vacuo and purified by FCC (400 g silica
gel, PE/MTBE 3:1 to 1:3) to afford b-hydroxy ester 41 (10.58 g, 88%) as a
pale yellow liquid. The enantioselectivity was determined by chiral HPLC
and found to be 98:2 favoring the desired isomer. Rf ˆ 0.25 (n-hexane/
MTBE 1:1); HPLC: tR (S enantiomer) ˆ 14.2 min, tR (R enantiomer) ˆ
required no further purification. Rf ˆ 0.38 (n-hexane/MTBE 2:1); [a]D22
ˆ
9.5 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3348 br (OH), 2954/2858 s (CH), 1463 w,
1339 w, 1255 m, 1096 m, 1054 m, 836 m, 774 w; 1H NMR (300 MHz, CDCl3):
d ˆ 0.02 (s, 6H, 2  SiCH3), 0.04 (s, 6H, 2  SiCH3), 0.87 (s, 18H, 2 Â
SiC(CH3)3), 1.50 ± 1.76 (m, 6H, 2,3,5-H2), 2.09 (brs, 1H, OH), 3.56 ± 3.68
(m, 4H, 1,6-H2), 3.91 (quint, J ˆ 5.7 Hz, 1H, 4-H); 13C NMR (75 MHz,
CDCl3): d ˆ À5.3 (2  SiCH3), À4.7, À4.5 (2  SiCH3), 18.1, 18.2 (2 Â
SiC(CH3)3), 25.9, 25.9 (2 Â SiC(CH3)3), 28.1 (C-2), 33.7 (C-3), 39.5 (C-5),
59.8 (C-6), 63.1 (C-1), 69.0 (C-4); C18H42O3Si2 (362.70): calcd C 59.61, H
11.67; found C 59.55, H 11.61.
(4S)-4,6-Bis(tert-butyldimethylsilyloxy)-hexanoic acid (44): 1. Swern oxi-
dation: DMSO (9.86 mL, 139 mmol) was added at À758C to a solution of
oxalyl chloride (6.07 mL, 69.6 mmol) in CH2Cl2 (200 mL). After 15 min
stirring, a solution of the alcohol 43 (10.1 g, 27.8 mmol) in CH2Cl2 (20 mL)
was added dropwise at À708C. After stirring for 20 min, NEt3 (27 mL,
195 mmol) was added dropwise at À508C. The mixture was stirred at
À508C for 30 min and at 08C for 60 min. The reaction was quenched by the
addition of water (100 mL). The phases were separated and the aqueous
layer was extracted with CH2Cl2 (3 Â 30 mL). The combined organic layers
were washed with water (2 Â 30 mL) and dried with MgSO4. The solvent
was removed in vacuo and the residue was filtered by FCC (100 g silica gel,
PE/MTBE 2:1) to yield the aldehyde (9.75 g, 97%) as a yellow oil which
was oxidized to the carboxylic acid immediately.
10.6 min (Chiralcel OD-H, n-hexane/iPrOH 90:10, 1.0 mLminÀ1); [a]D22
ˆ
23.7 (96:4 mixture of the enantiomers, c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 3444
ˆ
br (OH), 2950/2858 m (CH), 1737 vs (C O), 1438 m, 1201 m, 1166 m, 1098 s,
739/699 m; 1H NMR (300 MHz, CDCl3): d ˆ 1.41 ± 1.60 (m, 2H, 5-H2),
1.60 ± 1.79 (m, 2H, 4-H2), 2.36 ± 2.43 (m, 2H, 2-H2), 3.26 (d, J ˆ 3.4 Hz, 1H,
OH), 3.43 (t, J ˆ 6.0 Hz, 2H, 6-H2), 3.62 (s, 3H, OCH3), 3.91 ± 4.00 (m, 1H,
3-H), 4.43 (s, 2H, OCH2Ph), 7.17 ± 7.29 (m, 5H, Ph); 13C NMR (75 MHz,
CDCl3): d ˆ 25.8 (C-5), 33.6 (C-4), 41.3 (C-2), 51.2 (OCH3), 67.7 (C-3), 70.1
(C-6), 72.9 (OCH2Ph), 127.5, 2 Â 127.6, 2 Â 128.3, 138.2 (Ph), 173.1 (C-1);
C14H20O4 (252.31): calcd C 66.65, H 7.99; found C 66.66, H 7.79.
(3S)-1,3-Bis(tert-butyldimethylsilyloxy)-6-benzyloxy-hexane (42): 1. Ester
reduction: In a two-necked flask equipped with a Claisen bridge, methyl
2392
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2392 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 13

(À)-Mucocin
2382±2396
(4S)-4,6-Bis(tert-butyldimethylsilyloxy)-hexanal: Rf ˆ 0.62 (n-hexane/
THF (15 mL) at À208C. The yellow mixture was warmed up to 08C and
stirred for 30 min. A solution of PhSeCl (2.36 g, 12.4 mmol) in THF
(10 mL) was added and the reaction mixture was stirred at 08C for 1 h and
additional 20 min at rt. The reaction was quenched by the addition of
phosphate buffer solution (1m, pH 7) (30 mL), water (30 mL) and MTBE
(30 mL). The aqueous layer was extracted with MTBE (3 Â 20 mL) and the
combined organic layers were washed with sat. aq. NaCl solution (2 Â
30 mL) and dried with MgSO4. The mixture was concentrated in vacuo and
the crude selenium compound 46 was redissolved in THF/MeOH (20 mL/
20 mL). At 08C MMPP (purity 85%, 9.5 g, 16.5 mmol) was added. The
solution was stirred at rt for 20 min, then phosphate buffer solution (1m,
pH 7) (15 mL), water (25 mL), and MTBE (40 mL) were added. The
aqueous layer was extracted with MTBE (2 Â 20 mL) and CH2Cl2 (15 mL).
The combined organic layers were washed with sat. aq. NaCl solution (2 Â
30 mL) and dried with MgSO4. The solvents were removed in vacuo and
the residue was purified by FCC (60 g silica gel, PE/MTBE 5:1) to yield the
unsaturated lactone 47 (1.51 g, 87%) as a colorless liquid. Rf ˆ 0.20 (n-
hexane/MTBE 5:1); [a]2D2 ˆ 31.7 (c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 2956/2930
MTBE 2:1); [a]2D3
ˆ
4.1 (c ˆ 0.56, CHCl3); IR (film): nÄ ˆ 2956/2930 s
ˆ
(CH), 2889 m/2858 s (CH), 2822/2712 w (aldehyde-CH), 1730 s (C O),
1473 m, 1389/1361 w (tBu), 1257 s, 1099 s, 1048 m, 836 s, 775 s; H NMR
1
(300 MHz, CDCl3): d ˆ 0.00 ± 0.04 (m, 12H, 2  SiCH3), 0.84 ± 0.88 (m,
18H, 2  SiC(CH3)3), 1.51 ± 1.92 (m, 4H, 3,5-H2), 2.47 (dt, J ˆ 7.5, 1.5 Hz,
2H, 2-H2), 3.63 (t, J ˆ 6.4 Hz, 2H, 6-H2), 3.88 (quint, J ˆ 5.5 Hz, 1H, 4-H),
9.76 (t, J ˆ 1.5 Hz, 1H, 1-H); 13C NMR (75 MHz, CDCl3): d ˆ À5.4 (2 Â
SiCH3), À4.6, À4.5 (2 Â SiCH3), 18.0, 18.2 (2 Â Si(C(CH3)3), 25.8, 25.9 (2 Â
Si(C(CH3)3), 29.2 (C-5), 39.6 (C-3), 39.8 (C-2), 59.6 (C-6), 68.2 (C-4), 202.5
(C-1).
2. Chlorite oxidation: A solution of the aldehyde (9.75 g, 27 mmol) in
tBuOH (100 mL, p.A.) and 2-methyl-2-butene (25 mL) was treated with a
solution of NaClO2 (purity 80%, 9.4 g, 83.4 mmol) and NaHPO4 Â 2H2O
(17.3 g, 111 mmol) in water (120 mL) at 08C. The mixture was stirred
vigorously at rt for 2 h, then the phases were separated. The aqueous layer
was extracted with MTBE (2 Â 30 mL) and the combined organic layers
were washed with sat. aq. NaCl solution (2 Â 40 mL) and dried with
MgSO4. The solvents were evaporated and the residue was purified by CC
(100 g silica gel, CHCl3/MeOH 19:1) to afford the carboxylic acid 44
(9.84 g, 97%) as a colorless oil. Rf ˆ 0.25 (CHCl3/MeOH 19:1); [a]2D1 ˆ 1.6
ˆ
s (CH), 2858 m, 2762 s (C O), 1473 m, 1257 m, 1097 s, 1030 m, 837 s, 775 s;
1H NMR (300 MHz, CDCl3): d ˆ 0.00 ± 0.06 (m, 12H, 2  SiCH3), 0.83 ±
0.88 (m, 18H, 2  SiC(CH3)3), 1.38 (d, J ˆ 6.8 Hz, CH3), 1.58 ± 1.68 (m, 2H,
3'-H2), 2.42 ± 2.47 (m, 2H, 1'-H2), 3.58 ± 3.72 (m, 2H, 4'-H2), 4.05 ± 4.15 (m,
1H, 2'-H), 4.93 ± 5.02 (m, 1H, 5-H), 7.10 ± 7.13 (m, 1H, 4-H); 13C NMR
(75 MHz, CDCl3): d ˆ À5.4 (2  SiCH3), À4.7, À4.5 (2  SiCH3), 18.0, 18.2
(2 Â SiC(CH3)3), 19.0 (CH3), 25.8, 25.9 (2 Â SiC(CH3)3), 32.9 (C-1'), 39.6 (C-
3'), 59.5 (C-4'), 67.3 (C-2'), 77.5 (C-5), 130.6 (C-3), 151.5 (C-4), 174.0 (C-2);
C21H42O4Si2 (414.73): calcd C 60.82, H 10.21; found C 60.57, H 10.15.
ˆ
(c ˆ 1.0, CHCl3); IR (film): nÄ ˆ 2956/2930/2858 m, 1712 m (C O), 1473 w,
1
1257 w, 1098 w, 836 w, 775 w; H NMR (300 MHz, CDCl3): d ˆ 0.00 ± 0.04
(m, 12H, 2 Â SiCH3), 0.84 ± 0.88 (m, 18H, 2 Â SiC(CH3)3), 1.51 ± 1.92 (m,
4H, 3,5-H2), 2.40 (t, J ˆ 7.7 Hz, 2H, 2-H2), 3.63 (t, J ˆ 6.4 Hz, 2H, 6-H2),
3.88 (quint, J ˆ 5.7 Hz, 1H, 4-H); 13C NMR (75 MHz, CDCl3): d ˆ À5.4
(2 Â SiCH3), À4.6 (2 Â SiCH3), 18.0, 18.2 (2 Â SiC(CH3)3), 25.8, 25.9 (2 Â
SiC(CH3)3), 29.6 (C-5), 31.7 (C-3), 39.8 (C-2), 59.6 (C-6), 68.2 (C-4), 179.7
(C-1); C18H40O4Si2 (376.68): calcd C 57.40, H 10.70; found C 57.19, H 10.24.
(5S)-3-[(2'S)-2'-(tert-Butyldimethylsilyloxy)-4'-hydroxy-butyl]-5-methyl-
furan-2(5H)-one (48): At 08C a solution of CSA (188 mg, 0.81 mmol) in
MeOH (20 mL) was added to a solution of the protected alcohol 47 (1.35 g,
3.26 mmol) in CH2Cl2 (20 mL). The mixture was stirred at 08C for 30 min,
then phosphate buffer solution (1m, pH 7) (5 mL) and water (10 mL) were
added. The aqueous layer was extracted with MTBE (4 Â 10 mL) and the
combined organic layers were washed with sat. aq. NaHCO3 solution
(pH 8, 10 mL), H2O (10 mL), sat. aq. NaCl solution (2 Â 15 mL), and dried
with MgSO4. The solvents were evaporated in vacuo and the residue was
purified by FCC (60 g silica gel, PE/MTBE 1:2) to yield the primary alcohol
48 (772 mg, 79%) as a colorless liquid. 11% starting material 47 (155 mg)
(3V,5S)-3-[(2'S)-2',4'-Bis(tert-butyldimethylsilyloxy)-butyl]-5-methyl-di-
hydrofuran-2(3H)-one (45): A solution of diisopropylamine (4.34 mL,
31.9 mmol) in THF (90 mL) was treated with n-butyllithium (10.6 mL, 2.5m
in hexanes, 26.6 mmol). The temperature was allowed to rise to 08C during
30 min. At 08C a solution of the carboxylic acid 44 in THF (20 mL) was
added dropwise. The dark yellow solution was stirred for 40 min at 08C.
Then a solution of (S)-propylene oxide in THF (10 mL) was added. The
cooling bath was removed and the mixture was stirred at rt for 3 h. The
reaction was quenched by the addition of sat. aq. NH4Cl solution (20 mL),
water (20 mL) and MTBE (30 mL). The aqueous layer was extracted with
MTBE (2 Â 30 mL), acidified to pH 3 with HCl (2m), and extracted with
MTBE (2 Â 20 mL) again. The combined organic layers were washed with a
sat. aq. NaCl solution (3 Â 40 mL) and dried with MgSO4. The mixture was
concentrated in vacuo and redissolved in CH2Cl2 (50 mL). At 08C NEt3
(2.9 mL, 21.2 mmol) and pivaloyl chloride (1.4 g, 11.7 mmol) were added.
The mixture was stirred at rt for 30 min. The reaction was quenched by
addition of water (40 mL), the phases were separated and the aqueous
layer was extracted with MTBE (3 Â 20 mL). The combined organic layers
were washed with sat. aq. NaCl solution (2 Â 30 mL) and dried with
MgSO4. The solvents were removed under reduced pressure and the
residue was purified by FCC (120 g silica gel, PE/MTBE 5:1) to afford a 2:1
mixture (1H NMR) of the epimeric lactones 45 (2.94 g, 67%) as a colorless
oil. Rf ˆ 0.63 (n-hexane/MTBE 1:1); IR (film): nÄ ˆ 2956/2930 s (CH), 2896/
was recovered. Rf ˆ 0.16 (n-hexane/MTBE 1:2); [a]D22
ˆ 40.5 (c ˆ 1.3,
CHCl3); IR (film): nÄ ˆ 3443 br (OH), 2955/2931 s, 2887/2858 m, 1752 s
(C O), 1256 m, 1085 m, 1028 m, 837 m, 776 m; 1H NMR (300 MHz,
ˆ
CDCl3): d ˆ 0.05 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3), 0.86 (s, 9H,
SiC(CH3)3), 1.39 (d, J ˆ 6.8 Hz, CH3), 1.59 ± 1.81 (m, 2H, 3'-H2), 2.21 (brs,
OH), 2.42 ± 2.58 (m, 2H, 1'-H2), 3.66 ± 3.84 (m, 2H, 4'-H2), 4.14 ± 4.24 (m,
1H, 2'-H), 4.95 ± 5.04 (m, 1H, 5-H), 7.09 ± 7.13 (m, 1H, 4-H); 13C NMR
(75 MHz, CDCl3): d ˆ À4.8, À4.5 (2  SiCH3), 17.9 (SiC(CH3)3), 18.9
(CH3), 25.8 (SiC(CH3)3), 32.9 (C-1'), 38.1 (C-3'), 59.7 (C-4'), 68.9 (C-2'), 77.6
(C-5), 130.4 (C-3), 151.9 (C-4), 173.9 (C-2); C15H28O4Si (300.47): calcd C
59.96, H 9.39; found C 59.86, H 9.01.
(3S)-3-(tert-Butyldimethylsilyloxy)-4-[(5'S)-5'-methyl-2'-oxo-2',5'-dihydro-
furan-3'-yl]-butanal (49): Dess ± Martin periodinane (2.12 g, 5.0 mmol) was
added to a solution of alcohol 48 (500 mg, 1.66 mmol) in CH2Cl2 (20 mL)
and pyridine (1.34 mL, 16.6 mmol). The solution was stirred at rt for 4.5 h,
then phosphate buffer solution (1m, pH 7, 15 mL) and water (10 mL) were
added. The aqueous layer was extracted with MTBE (3 Â 15 mL) and the
combined organic layers were washed with sat. aq. NaCl solution (2 Â
20 mL) and dried with MgSO4. The solution was concentrated in vacuo and
the residue was purified by FCC (40 g silica gel, PE/MTBE 1:1) to afford
aldehyde 49 (446 mg, 90%) as a colorless oil. Rf ˆ 0.30 (n-hexane/MTBE
1:1); [a]2D3 ˆ 27.8 (c ˆ 0.36, CHCl3); IR (film): nÄ ˆ 2956/2932 s (CH), 2858
1
ˆ
2886 m, 2858 s, 1774 s (C O), 1257 m, 836 m, 775 s; H NMR (300 MHz,
CDCl3): major epimer: d ˆ 0.00 ± 0.06 (m, 12H, 2  SiCH3), 0.86 (s, 18H,
2  SiC(CH3)3), 1.33 (d, J ˆ 6.4 Hz, CH3), 1.42 ± 1.82 (m, 4H, 1'-H2, 3'-H2),
1.98 ± 2.15 (m, 2H, 4-H2), 2.65 ± 2.85 (m, 1H, 3-H), 3.56 ± 3.71 (m, 2H, 4'-
H2), 3.96 ± 4.07 (m, 1H, 2'-H), 4.57 ± 4.69 (m, 1H, 5-H); minor epimer: d ˆ
0.00 ± 0.06 (m, 12H, 2  SiCH3), 0.86 (s, 18H, 2  SiC(CH3)3), 1.39 (d, J ˆ
6.4 Hz, CH3), 1.42 ± 1.82 (m, 4H, 1'-H2, 3'-H2), 1.98 ± 2.15 (m, 2H, 4-H2),
2.44 ± 2.55 (m, 1H, 3-H), 3.56 ± 3.71 (m, 2H, 4'-H2), 3.87 ± 3.97 (m, 1H, 2'-
H), 4.37 ± 4.50 (m, 1H, 5-H); 13C NMR (75 MHz, CDCl3): major epimer:
d ˆ À5.4 (2  SiCH3), À4.6, À4.5 (2  SiCH3), 18.0, 18.2 (2  Si(C(CH3)3),
21.0 (CH3), 25.8 (2 Â Si(C(CH3)3), 35.5 (C-3), 36.3 (C-4), 38.5 (C-1'), 40.3
(C-3'), 59.4 (C-4'), 67.7 (C-2'), 74.6 (C-5), 179.3 (C-2); minor epimer: d ˆ
À5.4 (2 Â SiCH3), À4.6, À4.5 (2 Â SiCH3), 18.0, 18.2 (2 Â SiC(CH3)3), 20.9
(CH3), 25.8 (2 Â SiC(CH3)3), 37.7, 38.0, 38.2 (C-3,4,1'), 40.0 (C-3'), 59.4 (C-
4'), 67.4 (C-2'), 75.2 (C-5), 179.4 (C-2); C21H44O4Si2 (416.74): calcd C 60.52,
H 10.64; found C 60.63, H 10.48.
1
ˆ
m, 1755/1728 s (C O), 1405 m, 1085 m, 938 m; H NMR (300 MHz, CDCl3):
d ˆ 0.03 ± 0.07 (m, 6H, 2  SiCH3), 0.81 ± 0.86 (m, 9H, SiC(CH3)3), 1.40 (d,
J ˆ 6.8 Hz, 3H, CH3), 2.43 ± 2.61 (m, 4H, 2,4-H2), 4.45 ± 4.55 (m, 1H, 3-H),
4.95 ± 5.05 (m, 1H, 5'-H), 7.11 ± 7.16 (m, 1H, 4'-H), 9.77 (t, J ˆ 2.3 Hz, 1H,
1-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.8, À4.6 (2  SiCH3), 17.9
(Si(C(CH3)3), 18.7 (CH3), 25.6 (Si(C(CH3)3), 33.4 (C-4), 50.2 (C-2), 65.9
(C-3), 77.6 (C-5'), 129.7 (C-3'), 152.4 (C-4'), 173.6 (C-2'), 201.2 (C-1);
C15H26O4Si (298.45): calcd C 60.37, H 8.78; found C 60.33, H 9.11.
(5S)-3-[(2'S)-2',4'-Bis(tert-butyldimethylsilyloxy)-butyl]-5-methylfuran-
2(5H)-one (47): A solution of lactone 45 (1.72 g, 4.12 mmol) in THF
(40 mL) was treated with a suspension of KHMDS (2.46 g, 12.4 mmol) in
(5S)-3-{(2'R,4'V)-2'-tert-Butyldimethylsilyloxy-9'-[(2''R,5''S)-5''-(triethyl-
silyloxy)methyl-tetrahydrofuran-2''-yl}-non-4'-enyl]-5-methylfuran-2(5H)-
one (50): The phosphonium salt 39 was dissolved in THF (5 mL) and
Chem. Eur. J. 2000, 6, No. 13
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2393 $ 17.50+.50/0
2393

U. Koert et al.
FULL PAPER
treated with NaHMDS (0.4 mL 1m in THF, 0.4 mmol) at 08C. The orange
solution was stirred at 08C for 30 min, then it was cooled to À708C and a
solution of aldehyde 49 (120 mg, 0.4 mmol) in THF (3 mL) was added
dropwise. The cooling bath was replaced by an ice bath and the now light
brown-yellow solution was stirred 20 min at 08C. The reaction was
quenched by the addition of phosphate buffer solution (1m, pH 7, 7 mL).
The mixture was diluted with MTBE (10 mL) and water (8 mL). The
aqueous layer was extracted with MTBE (3 Â 7 mL) and the combined
organic layers were washed with sat. aq. NaCl solution (2 Â 10 mL) and
dried with MgSO4. The solvents were removed in vacuo and the residue
was purified by FCC (35 g silica gel, PE/MTBE 2:1) to yield olefin 50
(138 mg, 60%) as a colorless oil. Rf ˆ 0.65 (n-hexane/MTBE 1:1); IR (film):
4.09 (m, 1H, 5''-H), 4.90 ± 5.00 (m, 1H, 5-H), 7.04 ± 7.09 (m, 1H, 4-H);
13C NMR (75 MHz, CDCl3): d ˆ À4.6 (2  SiCH3), 17.9 (SiC(CH3)3), 18.9
(CH3), 25.8 (SiC(CH3)3), 25.0, 26.1, 27.4, 29.4, 29.5 (2 Â), 31.9, 32.6, 35.6,
36.8 (C-1',3'-9',3'',4''), 64.9 (C-1'''), 70.1 (C-2'), 77.4 (C-5), 78.8 (C-5''), 79.4
(C-2''), 130.7 (C-3), 151.5 (C-4), 174.0 (C-2); HR-MS (EI): C25H46O5Si calcd
455.3193; found 455.3191 [M‡H] .
(2S,5R)-5-{(8'R)-8'-tert-Butyldimethylsilyloxy-9'-[(5''S)-5''-methyl-2''-oxo-
‡
2'',5''-dihydrofuran-3''-yl]nonyl}-tetrahydrofuran-2-carbaldehyde
(52):
Dess ± Martin periodinane (145 mg, 340 mmol) was added to a solution of
alcohol 51 (78 mg, 170 mmol) in CH2Cl2 (6 mL) and pyridine (0.14 mL,
1.7 mmol). The solution was allowed to warm up to rt and was stirred for
4.5 h, then phosphate buffer solution (1m, pH 7, 5 mL), water (3 mL) and
MTBE (6 mL) were added. The aqueous layer was extracted with MTBE
(4 Â 7 mL) and the combined organic layers were washed with sat. aq. NaCl
solution (2 Â 10 mL) and dried with MgSO4. The solution was concentrated
in vacuo and the residue was purified by FCC (8 g silica gel, PE/MTBE 1:2)
to afford aldehyde 52 (70 mg, 91%) as a colorless oil. Rf ˆ 0.38 (n-hexane/
ˆ
nÄ ˆ 2954/2929 s (CH), 2876/2857 m (CH), 1767 m (C O), 1462 w, 1377/1361
w (tBu), 1252 w, 1083 m, 1005 w, 837 w, 776 w; 1H NMR (300 MHz, CDCl3):
d ˆ À0.01 (s, 3H, SiCH3), 0.03 (s, 3H, SiCH3), 0.58 (q, J ˆ 8.0 Hz, 6H, 3 Â
SiCH2CH3), 0.85 (s, 9H, SiC(CH3)3), 0.93 (t, J ˆ 8.1 Hz, 9H, 3 Â
SiCH2CH3), 1.39 (d, J ˆ 7.2 Hz, 3H, CH3), 1.22 ± 1.76 (m, 8H, 4  alkyl-
CH2), 1.90 ± 2.04 (m, 4H, 2 Â alkyl-CH2), 2.09 ± 2.48 (m, 4H, 2 Â alkyl-CH2),
3.50 (dd, J ˆ 10.4, 5.5 Hz, 1H, 1'''-Ha), 3.60 (dd, J ˆ 10.4, 5.1 Hz, 1H, 1'''-
Hb), 3.82 ± 3.93 (m, 1H, 2''-H), 3.93 ± 4.08 (m, 2H, 4-H, 5''-H), 4.98 (dq, J ˆ
6.7, 1.0 Hz, 1H, 5-H), 5.27 ± 5.53 (m, 2H, 4'-H, 5'-H), 7.09 (d, J ˆ 1.5 Hz, 1H,
4-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.6, À4.4 (2  SiCH3), 4.4 (2 Â
SiCH2CH3), 6.7 (2 Â SiCH2CH3), 18.0 (SiC(CH3)3), 18.9 (CH3), 25.8
(SiC(CH3)3), 26.0, 27.5, 28.3, 29.7, 31.8, 32.6, 35.1, 35.7 (C-1',3',6'-9',3'',4''),
66.7 (C-1'''), 70.0 (C-2'), 77.2 (C-5), 79.0 (C-5''), 79.4 (C-2''), 124.8 (C-5'),
130.9 (C-3), 132.1 (C-4'), 151.5 (C-4), 173.9 (C-2); C31H58O5Si2 (566.96):
calcd C 65.67, H 10.31; found C 66.11, H 10.19; HR-MS (EI): calcd 567.3901;
ˆ
MTBE 1:2); IR (film): nÄ ˆ 2930/2857 s (CH), 1757 s (C O), 1405 w, 1255 w,
1076 m, 837 m, 776 w; 1H NMR (300 MHz, CDCl3): d ˆ À0.02 (s, 3H,
SiCH3), 0.00 (s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3), 1.37 (d, J ˆ 6.8 Hz,
3H, CH3), 1.15 ± 2.21 (m, 18H, 1'-7',3,4-CH2), 2.37 (d, J ˆ 5.6 Hz, 2H, 9'-
H2), 3.84 ± 4.01 (m, 2H, 5-H, 8'-H), 4.24 ± 4.31 (m, 1H, 2-H), 4.96 (dq, J ˆ
6.8, 0.9 Hz, 1H, 5''-H), 7.05 ± 7.10 (m, 1H, 4''-H), 9.61 (d, J ˆ 1.9 Hz, 1H,
CHO); 13C NMR (75 MHz, CDCl3): d ˆ À4.5 (2  SiCH3), 18.0
(SiC(CH3)3), 18. 9 (CH3), 25.8 (SiC(CH3)3), 25.0, 26.0, 27.1, 29.4, 29.5,
29.5, 31.1, 32.6, 35.3, 36.9 (C-3,4,1'-7',9'), 70.1 (C-8'), 77.4 (C-5''), 81.2 (C-2),
82.3 (C-5), 130.7 (C-3''), 151.5 (C-4''), 174.0 (C-2''), 203.2 (CHO); HR-MS
‡
found 567.3902 [M‡H] .
‡
(EI): C25H44O5Si calcd 452.2958; found 452.2959 [M] .
(5S)-3-{(2'R)-tert-Butyldimethylsilyloxy-9'-[(2''R,5''S)-5''-(hydroxymeth-
yl)-tetrahydrofuran-2''-yl]-nonyl}-5-methylfuran-2(5H)-one (51): 1. Wilkin-
son hydrogenation: A solution of [(PPh3)3RhCl] (85 mg, 0.09 mmol) in
benzene (4 mL, spectroscopy grade) was degassed and stirred under
(2S,5S,1''R,4''R)-tert-Butyldiphenylsilyloxymethyl-5-(1''-hydroxy-4''-tert-
butyldimethylsilyloxy)-pentyl-tetrahydrofuran (57): tBuLi (0.35 mL,
0.59 mmol, 1.68m in pentane) was added to a solution of iodide 55
(101 mg, 0.32 mmol) in Et2O (7 mL) at À1058C. After 10 min magnesium
bromide etherate (0.27 mL, 0.64 mmol, 2.35m in Et2O) was added and the
solution was stirred for 1.5 h (À1008C ! À258C). Then the mixture was
cooled to À788C and a solution of aldehyde 56 (118 mg, 0.32 mmol) in
Et2O (2 mL) was added. The solution was allowed to warm up to À108C
during 1.5 h. The reaction was quenched by the addition of water (2 mL).
The mixture was diluted with water (5 mL) and MTBE (10 mL). The
aqueous layer was extracted with MTBE (3 Â 5 mL) and the combined
organic layers were washed with a sat. aq. NaCl solution (5 mL) and dried
with MgSO4. The solvents were removed in vacuo and the residue was
purified by FCC (20 g silica gel, PE/MTBE 5:1) to yield the coupling
products 57 and 58 (131 mg, 0.235 mmol, 73%) as colorless oils. The
diastereomers could be separated by FCC (6:1 mixture): 57 (major isomer,
chelate product): Rf ˆ 0.46 (n-hexane/MTBE 5:1); 58 (minor isomer): Rf ˆ
0.33 (n-hexane/MTBE 5:1); 57 (major isomer): 1H NMR (300 MHz,
CDCl3): d ˆ 0.05 (s, 6H, SiCH3), 0.89 (s, 9H, SiC(CH3)3), 1.06 (s, 9H,
SiC(CH3)3), 1.13 ± 1.19 (m, 3H, 5''-H3), 1.45 ± 1.54 (m, 2H, 2''-H2), 1.60 ± 1.72
(m, 2H, 3''-H2), 1.77 ± 1.90 (m, 2H, 3,4-H2), 1.91 ± 2.51 (m, 2H, 3,4-H2), 2.40
(m, 1H, 1''-OH), 3.33 ± 3.44 (m, 1H, 1''-H), 3.62 ± 3.71 (m, 2H, 1'-H2), 3.79 ±
3.90 (m, 2H, 4'', 5-H), 4.08 ± 4.17 (m, 1H, 2-H), 7.37 ± 7.40 (m, 6H, SiPh),
7.67 ± 7.71 (m, 4H, SiPh); 13C NMR (75 MHz, CDCl3): d ˆ À4.7, À4.4
(SiCH3), 18.1, 19.2 [SiC(CH3)], 23.7 (C-5''), 25.9, 26.7 [C(CH3)], 28.2, 28.4
(C-3, C-4), 29.2 (C-2''), 35.2 (C-3''), 66.4 (C-1'), 68.3 (C-4''), 73.8 (C-1''), 79.5
(C-2), 82.6 (C-5), 127.6, 129.6, 133.6, 135.6 (SiPh); HR-MS (C32H52O4Si2):
hydrogen atmosphere for 15 min.
A solution of olefin 50 (340 mg,
0.60 mmol) in benzene (2 mL) was added and the mixture was stirred
under hydrogen atmosphere (1 atm) for 3 h at rt. The solution was
concentrated in vacuo and the residue was purified by FCC (18 g silica gel,
cyclohexane/MTBE 2:1) to yield the desired compound (325 mg, 95%) as a
light brown oil.
(5S)-3-{(2'R)-tert-Butyldimethylsilyloxy-9'-{(2''R,5''S)-5''-[(triethylsilyl-
oxy)methyl]-tetrahydrofuran-2''-yl}-nonyl}-5-methyl-furan-2(5H)-one:
Rf ˆ 0.55 (silica gel treated with 1m AgNO3, n-hexane/MTBE 2:1); [a]D22
ˆ
5.6 (c ˆ 1.1, CHCl3); IR (film): nÄ ˆ 2953/2930 s (CH), 2876/2857 m (CH),
1766 s (C O), 1463 w, 1385 w, 1253 w, 1084 m, 1005 w, 836 w; 1H NMR
ˆ
(300 MHz, CDCl3): d ˆ À0.01± À0.06 (m, 6H, 2  SiCH3), 0.58 (q, J ˆ
7.9 Hz, 6H, 3  SiCH2CH3), 0.85 (s, 9H, SiC(CH3)3), 0.93 (t, J ˆ 7.9 Hz,
9H, 3  SiCH2CH3), 1.39 (d, J ˆ 7.2 Hz, 3H, CH3), 1.15 ± 1.75 (m, 16H, 8 Â
alkyl-CH2), 1.90 ± 2.03 (m, 2H, alkyl-CH2), 2.37 ± 2.43 (m, 2H, 1'-H2), 3.50
(dd, J ˆ 10.4, 5.5 Hz, 1H, 1'''-Ha), 3.61 (dd, J ˆ 10.6, 4.9 Hz, 1H, 1'''-Hb),
3.61 ± 3.97 (m, 2H, 12-H, 2'-H), 3.97 ± 4.07 (m, 1H, 5''-H), 4.98 (dq, J ˆ 6.7,
1.4 Hz, 1H, 5-H), 7.09 (d, J ˆ 1.1 Hz, 1H, 4-H); 13C NMR (75 MHz, CDCl3):
d ˆ À4.5 (2  SiCH3), 4.4 (2  SiCH2CH3), 6.7 (2  SiCH2CH3), 18.0
(SiC(CH3)3), 19.0 (CH3), 25.9 (SiC(CH3)3), 25.1, 26.2, 27.0, 28.3, 29.5,
29.6, 31.8, 32.7, 35.8, 36.9 (C-1',3'-9',3'',4''), 65.8 (C-1'''), 70.1 (C-2'), 77.4 (C-
5), 79.0 (C-5''), 79.5 (C-2''), 130.8 (C-3), 151.4 (C-4), 174.0 (C-2); HR-MS
‡
(EI): C31H60O5Si2 calcd 569.4058; found 569.4055 [M‡H] .
2. TES-deprotection: At À208C a solution of CSA (10 mg, 43 mmol) in
MeOH (1 mL) was added to a solution of the protected alcohol (307 mg,
540 mmol) in CH2Cl2 (5 mL). The mixture was stirred at À208C for 10 min,
then phosphate buffer solution (1m, pH 7, 3 mL) and water (2 mL) were
added. The aqueous layer was extracted with MTBE (4 Â 5 mL) and the
combined organic layers were washed with sat. aq. NaCl solution (2 Â
7 mL) and dried with MgSO4. The solvents were evaporated in vacuo and
the residue was purified by FCC (15 g silica gel, MTBE) to yield the
primary alcohol 51 (187 mg, 76%) as a light orange liquid. Rf ˆ 0.44
(MTBE); [a]2D0 ˆ 3.5 (c ˆ 0.6, CHCl3); IR (film): nÄ ˆ 3433 br (OH), 2929 s
‡
1
calcd 499.2700; found 499.2698 [M À C4H9] . 58 (minor isomer): H NMR
(300 MHz, CDCl3): d ˆ 0.05 (s, 6H, SiCH3), 0.89 (s, 9H, SiC(CH3)3), 1.05 (s,
9H, SiC(CH3)3), 1.13 ± 1.19 (m, 3H, 5''-H3), 1.42 ± 2.14 (m, 8H, 2'',3'',3,4-
H2), 2.51 (d, J ˆ 2.4 Hz, 1H, 1''-OH), 3.67 ± 3.76 (m, 3H, 1''-H, 1'-H2), 3.79 ±
3.89 (m, 2H, 4'', 5-H), 4.08 ± 4.18 (m, 1H, 2-H), 7.37 ± 7.40 (m, 6H, SiPh),
7.67 ± 7.72 (m, 4H, SiPh); 13C NMR (75 MHz, CDCl3): d ˆ À4.7, À4.4
(SiCH3), 18.1, 19.2 [SiC(CH3)], 23.7 (C-5''), 25.9, 26.7 [C(CH3)], 28.2, 28.3
(C-3, C-4), 29.2 (C-2''), 35.2 (C-3''), 66.0 (C-1'), 67.6 (C-4''), 72.1 (C-1''), 79.9
(C-2), 83.4 (C-5), 127.6, 129.6, 133.6, 135.6 (SiPh).
ˆ
(CH), 2857 m (CH), 1757 m (C O), 1462 w, 1377 w, 1361 w, 1254 w, 1196 w,
Protected mucocin fragment without butenolide 59: Iodide 20 (230 mg,
0.35 mmol) was dissolved in Et2O (10 mL) at À1058C. tBuLi (0.40 mL,
0.67 mmol, 1.68m in pentane) and, after 10 min, magnesium bromide
etherate (0.29 mL, 0.68 mmol, 2.3m in Et2O) were added and the solution
was allowed to warm up to À108C during 1.5 h. Then the mixture was
cooled to À788C and a solution of aldehyde 56 (104 mg, 0.28 mmol) in
1976 m, 836 m, 775 w; 1H NMR (300 MHz, CDCl3): d ˆ À0.04 (s, 3H,
SiCH3), À0.01 (s, 3H, SiCH3), 0.81 (s, 9H, SiC(CH3)3), 1.36 (d, J ˆ 6.8 Hz,
3H, CH3), 1.14 ± 1.69 (m, 16H, 8 Â alkyl-CH2), 1.84 ± 2.03 (m, 2H, alkyl-
CH2), 1.36 (brs, 1H, OH), 2.36 (d, J ˆ 5.3 Hz, 2H, 1'-H2), 3.37 ± 3.48 (m, 1H,
1'''-Ha), 3.51 ± 3.62 (m, 1H, 1'''-Hb), 3.81 ± 3.95 (m, 2H, 2''-H, 2'-H), 3.99 ±
2394
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0947-6539/00/0613-2394 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 13

(À)-Mucocin
2382±2396
Et2O (2 mL) was added. The mixture was stirred for 1.5 h (À788C !
À108C). The reaction was quenched by the addition of sat. aq. sodium
bicarbonate solution (10 mL). The aqueous layer was extracted with
MTBE (3 Â 5 mL) and the combined organic layers were washed with sat.
aq. NaCl solution (5 mL) and dried with MgSO4. The solvents were
removed in vacuo and the residue was purified by FCC (100 g silica gel, PE/
MTBE 10:1) to yield the coupling products 59 and 60 (124 mg, 0.139 mmol,
50%) as colorless oils. The diasteromers could be separated by FCC (4.5:1
mixture): 59 (major isomer, chelate product): Rf ˆ 0.34 (n-hexane/MTBE
10:1); 60 (minor isomer): Rf ˆ 0.31 (n-hexane/MTBE 10:1); 59 (major
11), 70.5 (C-23), 73.5 (C-19), 73.8 (C-16), 79.7 (C-12), 80.1 (C-20), 82.0 (C-
24), 82.9 (C-15); HR-MS (C24H47O6): calcd 431.3373; found 431.3369.
4,19,23-O-Tris(tert-butyldimethylsilyl)-mucocin (64) and 16-epi-4,19,23-O-
tris(tert-butyldimethylsilyl)-mucocin (65): In a 10 mL Schlenk tube a
solution of iodide 20 (200 mg, 0.305 mmol) in Et2O (5 mL) was cooled to
À1058C and treated with tert-butyllithium (0.37 mL, 1.482m in pentane,
0.559 mmol). After 4 min at À1008C MgBr2 ´ Et2O (0.2 mL, 0.61 mmol)
was added. The reaction mixture was allowed to warm up to À358C during
1.5 h. Then the mixture was cooled to À788C and a solution of aldehyde 52
(113 mg, 0.25 mmol) in Et2O (2 mL) was added. The solution was allowed
to warm up to À158C during 1.5 h. The reaction was quenched by the
addition of phosphate buffer solution (1m, pH 7, 2 mL). The mixture was
diluted with water (5 mL) and MTBE (10 mL). The aqueous layer was
extracted with MTBE (5 Â 5 mL) and the combined organic layers were
washed with sat. aq. NaCl solution (2 Â 6 mL) and dried with MgSO4. The
solvents were removed in vacuo and the residue was purified by FCC (20 g
silica gel, gradient PE/MTBE 3:1 ! MTBE) to yield the coupling products
64 and 65 (136 mg, 56%) as a colorless oil and to recover unconsumed
aldehyde 52 (33 mg, 34%). The 4:1 mixture (HPLC) of the C-16 epimers
were separated by preparative HPLC (Rainin Si 60, 21.4 mm  250 mm, n-
hexane/iPrOH 99:1, 20 mLminÀ1). Major isomer 64: Rf ˆ 0.30 (n-hexane/
MTBE 2:1); HPLC: tR ˆ 10.34 min (Rainin Si 60, n-hexane/iPrOH 99:1,
1.0 mLminÀ1); [a]D22 ˆ À19.2 (c ˆ 0.60, CHCl3); IR (film): nÄ ˆ 3123 brs
1
isomer): H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 12H, Si(CH3)), 0.88 (m,
21H, SiC(CH3)3, 34-H3), 1.06 (s, 9H, SiC(CH3)3), 1.31 ± 2.10 (m, 30H, 13,
14, 17, 18, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33-H2), 2.39 (m, 1H, 16-OH),
2.99 ± 3.04 (m, 1H, 24-H), 3.21 ± 3.30 (m, 2H, 20-H, 23-H), 3.31 ± 3.40 (m,
1H, 16-H) 3.61 ± 3.70 (m, 3H, 11-H2, 19-H), 3.78 ± 3.86 (m, 1H, 15-H),
4.07 ± 4.16 (m, 1H, 12-H), 7.37 ± 7.40 (m, 6H, SiPh), 7.67 ± 7.71 (m, 4H,
SiPh); 13C NMR (75 MHz, CDCl3): d ˆ À4.8, À4.6, À4.4, À4.0 (SiCH3),
14.1 (C-34), 18.0, 18.2, 19.2 (SiC(CH3)3), 25.8, 25.9, (SiC(CH3)3), 22.7, 25.1,
26.8, 28.3, 28.4, 29.1, 29.3, 29.6, 29.7, 29.8, 31.9, 33.5 (C-13, 14, 17, 18, 21, 22,
25 ± 33), 66.4 (C-11), 71.0 (C-23), 74.1 (C-19), 74.5 (C-16), 79.5 (C-12), 80.0
(C-20), 82.4 (C-24), 82.8 (C-15), 127.6, 129.6, 133.6, 135.6 (SiPh); 60 (minor
1
isomer): H NMR (300 MHz, CDCl3): d ˆ 0.05 (s, 12H, Si(CH3)), 0.88 (m,
21H, SiC(CH3)3, 34-H3), 1.06 (s, 9H, SiC(CH3)3), 1.31 ± 2.10 (m, 30H,
13,14,17,18,21,22,25,26,27,28,29,30,31,32,33-H2), 2.43 (m, 1H, 16-OH),
2.97 ± 3.04 (m, 1H, 24-H), 3.19 ± 3.27 (m, 2H, 20,23-H), 3.61 ± 3.74 (m,
4H, 11-H2, 16,19-H), 3.78 ± 3.90 (m, 1H, 15-H), 4.09 ± 4.16 (m, 1H, 12-H),
7.37 ± 7.40 (m, 6H, SiPh), 7.67 ± 7.71 (m, 4H, SiPh); 13C NMR (75 MHz,
CDCl3): d ˆ À4.8, À4.6, À4.4, À4.0 (SiCH3), 14.1 (C-34), 18.0, 18.2, 19.2
(SiC(CH3)3), 25.8, 25.9, (SiC(CH3)3), 22.7, 25.1, 25.2, 26.8, 28.2, 29.1, 29.4,
29.6, 29.6, 29.7, 29.8, 31.9, 33.5, (C-13, 14, 17, 18, 21, 22, 25 ± 33), 66.6 (C-11),
70.9 (C-23), 72.4 (C-16), 74.4 (C-19), 79.8 (C-12), 80.0 (C-20), 82.3 (C-24),
82.4 (C-15), 127.6, 129.6, 133.6, 135.6 (SiPh).
ˆ
(OH), 2929 s (CH), 2856 s, 1760 m (C O), 1255 w, 1095 m, 836 m, 776 m;
1H NMR (300 MHz, CDCl3): d ˆ 0.02 (brs, 18H, 6  SiCH3), 0.85 (brs,
30H, 3  SiC(CH3)3, 34-H3), 1.39 (d, J ˆ 6.8 Hz, 3H, 37-H3), 1.15 ± 2.04 (m,
44H, alkyl), 2.40 (d, J ˆ 5.3 Hz, 2H, 3-H2), 2.43 (d, J ˆ 2.7 Hz, 1H, OH),
2.98 (m, 1H, 24-H), 3.14 ± 3.27 (m, 2H, 20-H, 23-H), 3.27 ± 3.38 (m, 1H, 16-
H), 3.62 (dt, J ˆ10.5, 5.3 Hz, 1H, 19-H), 3.75 (dt, J ˆ 14.2, 6.7 Hz, 1H, 15-
H), 3.79 ± 3.88 (m, 1H, 12-H), 3.89 ± 3.94 (m, 1H, 4-H), 4.98 (dq, J ˆ 6.8,
1.1 Hz, 1H, 36-H), 7.09 (d, J ˆ 1.1 Hz, 1H, 35-H); 13C NMR (75 MHz,
CDCl3): d ˆ À4.8, À4.6, À4.5, À4.4, À4.0 (SiCH3), 14.1 (C-34), 17.9, 18.0,
18.2 (3 Â SiC(CH3)3), 19.0 (C-35), 25.8, 25.85, 25.9 (3 Â SiC(CH3)3), 22.7,
25.1, 25.6, 26.2, 28.4, 28.7, 28.8, 29.3, 29.5, 29.6, 29.7, 29.8, 31.9, 32.4, 32.7,
33.5, 35.7, 36.9 (C-3,5 ± 11,13,14,17,18,21,22,25 ± 33), 70.1 (C-4), 71.0 (C-23),
74.1 (C-19), 74.6 (C-16), 77.4 (C-36), 79.2 (C-12), 79.9 (C-20), 82.0 (C-15),
82.4 (C-24), 130.8 (C-2), 151.5 (C-35), 174.0 (C-1); HR-MS (EI):
(2S,3R,6S,1'S)-2-Decyl-3-tert-butyldimethylsilyloxy-6-(1'-tert-butyldime-
thylsilyloxy)-propyl-tetrahydropyran (61): 1H NMR (300 MHz, CDCl3):
d ˆ 0.03 (s, 12H, SiCH3), 0.86 ± 0.87 (m, 21H, SiC(CH3)3, 10''-H3), 1.23 ±
1.77 (m, 25H, 1'',2'',3'',4'',5'',6'',7'',8'',9'',2',3',4,5-H2), 1.93 ± 2.02 (m, 1H,
4-H2), 2.96 ± 3.04 (m, 1H, 2-H), 3.17 ± 3.26 (m, 2H, 3,6-H), 3.43 ± 3.55 (m,
1H, 1'-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.7, À4.6, À4.4, À4.0
(SiCH3), 10.1 (C-3'), 14.1 (C-10''), 17.9, 18.2 [C(CH3)], 22.7 (C-9''), 25.8,
25.9 [C(CH3)], 25.0, 25.2, 25.4, 26.0, 29.4, 29.7, 29.7, 29.8, 31.9, 33.6 (C-4,
C-5, C-2', C-1'', C-2'', C-3'', C-4'', C-5'', C-6'', C-7'', C-8''), 71.1 (C-3), 75.5 (C-
1'), 79.9 (C-6), 82.4 (C-2); HR-MS (C30H64O3Si2): calcd 471.3690; found
‡
C55H108O8Si3 calcd 981.7430; found 981.7441 [M‡H] ; minor isomer 65:
Rf ˆ 0.30 (n-hexane/MTBE 2:1); HPLC: tR ˆ 13.66 min (Rainin Si 60, n-
hexane/iPrOH 99:1, 1.0 mLminÀ1); [a]D22 ˆ À21.7 (c ˆ 0.18, CHCl3); IR
ˆ
(film): nÄ ˆ 3127 brs (OH), 2929 m (CH), 2857 w, 1760 w (C O), 1255 w,
1096 m, 836 w, 775 w; 1H NMR (300 MHz, CDCl3): d ˆ 0.00 ± 0.06 (m, 18H,
6  Si(CH3)), 0.82 ± 0.90 (m, 30H, 3  SiC(CH3)3, 34-H3), 1.39 (d, J ˆ
6.8 Hz, 3H, 37-H3), 1.18 ± 2.09 (m, 44H, alkyl), 2.37 ± 2.43 (m, 3H, 3-H2,
OH), 2.94 ± 3.04 (m, 1H, 24-H), 3.16 ± 3.27 (m, 2H, 20,23-H), 3.57 ± 3.73 (m,
2H, 16, 19-H), 3.80 ± 3.97 (m, 3H, 4,12,15-H), 4.94 ± 5.04 (m, 1H, 36-H), 7.10
(d, J ˆ 1.5 Hz, 1H, 35-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.8, À4.6,
À4.5, À4.3, À4.0 (6SiCH3), 14.1 (C-34), 18.0, 18.0, 18.2 (3 Â SiC(CH3)3),
19.0 (C-35), 25.8, 25.9, 25.9 (3 Â SiC(CH3)3), 22.7, 25.1, 25.1, 25.3, 25.5, 26.1,
29.0, 29.1, 29.4, 29.5, 29.6, 29.7, 29.7, 29.8, 31.9, 32.3, 32.7, 33.5, 36.1, 37.0 (C-
3,5 ± 11,13,14,17,18,21,22,25 ± 33), 70.2 (C-4), 70.9 (C-23), 72.6 (C-16), 74.3
(C-19), 77.2 (C-36), 80.0, 80.1 (C-12, C-20), 81.4 (C-15), 82.4 (C-24), 130.9
(C-2), 151.5 (C-35), 174.0 (C-1); HR-MS (EI): C55H108O8Si3 calcd 981.7430;
‡
471.3689 [M À tBu] .
(2S,3R,6S,1'S)-2-Decyl-3-tert-butyldimethylsilyloxy-6-(1'-hydroxy-3'-tert-
butyldimethylsilyl)-propyl-tetrahydropyran (62): 1H NMR (300 MHz,
CDCl3): d ˆ 0.01 (s, 6H, SiCH3), 0.03 (s, 12H, SiCH3), 0.33 ± 0.75 (m, 2H,
3'-H2), 0.85 ± 0.87 (m, 21H, SiC(CH3)3, 10''-H3), 1.23 ± 1.77 (m, 23H,
1'',2'',3'',4'',5'',6'',7'',8'',9'',2',4,5-H2), 1.93 ± 2.02 (m, 1H, 4-H2), 2.48 ± 2.53
(m, 1H, OH), 2.96 ± 3.04 (m, 1H, 2-H), 3.17 ± 3.33 (m, 3H, 3,6,1'-H);
13C NMR (75 MHz, CDCl3): d ˆ À6.6, À6.3, À4.7, À4.0 (SiCH3), 7.5 (C-3'),
14.1 (C-10''), 16.2, 18.2 [SiC(CH3)], 22.7 (C-9''), 25.5, 25.8 [SiC(CH3)], 25.2,
25.4, 26.6, 27.1, 27.6, 29.4, 29.7, 29.7, 31.9, 32.0, 33.2 (C-4, C-5, C-2', C-1'',
C-2'', C-3'', C-4'', C-5'', C-6'', C-7'', C-8''), 71.3 (C-3), 76.1 (C-1'), 79.2 (C-6),
82.2 (C-2); HR-MS (C30H64O3Si2): calcd 471.3690; found 471.3682 [M À
‡
found 981.7443 [M‡H] .
(À)-Mucocin: A solution of tris-silyl ether 64 (22 mg, 24.4 mmol) in CH2Cl2
(1 mL) was treated with HF/acetonitrile (0.4 mL, ca. 0.12 mmol, 5% HF in
CH3CN). The mixture was stirred at rt for 1 h, then phosphate buffer
solution (1m, pH 7, 1 mL) and water (1 mL) were added. The aqueous layer
was extracted with CHCl3/iPrOH 1:1 (6 Â 5 mL) and the combined organic
layers were dried with MgSO4. The solvents were removed in vacuo and the
residue was purified by FCC (8 g silica gel, hexane/MTBE 2:1 then CHCl3/
MeOH 10:1) to afford (À)-mucocin (13 mg, 91%) as a colorless oil. Rf ˆ
0.36 (CHCl3/MeOH 10:1); HPLC: tR ˆ 8.9 min (Rainin Si 60, n-hexane/
‡
tBu] .
Mucocin fragment without butenolide 63: Compound 59 (73 mg,
0.082 mmol) was dissolved in THF (5 mL) and treated with HF (1 mL,
5% in CH3CN) at 08C. After 6 h the reaction was quenched by addition of
sat. aq. NH4Cl solution (5 mL). The aqueous phase was extracted with ethyl
acetate (4 Â 10 mL). Washing of the combined organic layers with sat. aq.
NaCl solution (5 mL), drying with MgSO4, evaporation of the solvent and
purification by FCC (1 g silica gel, MTBE/acetone 1:1) provided 63 (26 mg,
0.061 mmol, 74%) as a colorless oil. Rf ˆ 0.43 (acetone/MTBE 1:1);
1H NMR (300 MHz, CDCl3): d ˆ 0.85 (t, 3H, 34-H3), 1.21 ± 2.10 (m, 30H,
13,14,17,18,21,22,25,26,27,28,29,30,31,32,33-H2), 2.30 ± 2.60 (brs, 1H, OH),
2.77 ± 2.94 (brs, 2H, OH), 2.98 ± 3.05 (m, 1H, 24-H), 3.08 ± 3.20 (m, 1H, 20-
H), 3.21 ± 3.28 (m, 1H, 23-H), 3.36 ± 3.54 (m, 3H, 11-H2, 16,19-H), 3.61 ±
3.68 (m, 1H, 11-H2), 3.78 ± 3.86 (m, 1H, 15-H), 4.07 ± 4.15 (m, 1H, 12-H);
13C NMR (75 MHz, CDCl3): d ˆ 14.1 (C-34), 22.7, 25.5, 26.9, 27.8, 28.5, 28.7,
28.9, 29.3, 29.6, 29.7, 31.9, 32.0, 32.6 (C-13, 14, 17, 18, 21, 22, 25 ± 33), 64.8 (C-
25
25
iPrOH 70:30, 1.5 mLminÀ1); [a]2D5 ˆ À12.7, [a] ˆ À13.1, [a] ˆ À14.9,
578
546
25
25
[a] ˆ À26.5, [a] ˆ À40.3 (c ˆ 0.27, CH2Cl2); IR (film): nÄ ˆ 3124 brs
436
365
(OH), 2926 s (CH), 2854 w, 1740 w (C O), 1094 w, 1072 w; 1H NMR
(300 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 6.8 Hz, 3H, 34-H3), 1.41 (d, J ˆ 6.8 Hz,
3H, 37-H3), 1.13 ± 1.75 (m, 41H, alkyl), 1.76 ± 1.88 (m, 1H), 1.89 ± 2.05 (m,
2H, 13,14-H2), 2.05 ± 2.14 (m, 1H, 22-H2), 2.30 (brs, 1H, OH), 2.37 (dd, J ˆ
15.1, 8.3 Hz, 1H, 3-H2), 2.50 (d, J ˆ 15.1 Hz, 1H, 3-H2), 2.71 (brs, 1H, OH),
2.84 (brs, 1H, OH), 3.02 (dt, J ˆ 8.8, 2.2 Hz, 1H, 24-H), 3.08 ± 3.18 (m, 1H,
ˆ
Chem. Eur. J. 2000, 6, No. 13
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0613-2395 $ 17.50+.50/0
2395

U. Koert et al.
FULL PAPER
20-H), 3.18 ± 3.32 (m, 1H, 23-H), 3.34 ± 3.52 (m, 2H, 16,19-H), 3.67 ± 3.95
(m, 3H, 4,12,15-H), 5.04 (dq, J ˆ 6.8, 1.5 Hz, 1H, 36-H), 7.16 (d, J ˆ 1.5 Hz,
1H, 35-H); 13C NMR (75 MHz, CDCl3): d ˆ 14.11 (C-34), 19.10 (C-35),
22.67, 25.47, 25.52, 26.15, 26.90, 28.33, 28.69, 28.76, 29.32, 29.40, 29.45, 29.53,
29.63, 29.72, 31.89, 31.96, 32.39, 32.62, 33.34, 35.58, 37.37 (C-3,5 ±
11,13,14,17,18,21,22,25 ± 33), 69.95 (C-4), 70.55 (C-23), 73.48 (C-19), 73.77
(C-16), 77.97 (C-36), 79.30 (C-12), 80.14 (C-20), 81.90 (C-15), 82.00 (C-24),
131.17 (C-2), 151.80 (C-35), 174.61 (C-1); HR-MS (EI): C37H66O8 calcd
Chem. 1999, 64, 2381 ± 2386; e) P. Li, J. Yang, K. Zhao, J. Org. Chem.
1999, 64, 2259 ± 2263; f) J. A. Marshall, H. Jiang, J. Org. Chem. 1999,
64, 971 ± 975; g) Z.-M. Wang, S.-K. Tian, M. Shi, Tetrahedron Lett.
1999, 40, 977 ± 980; h) T.-S. Hu, Q. Yu, Q. Lin, Y.-L. Wu, Y. Wu, Org.
Lett. 1999, 1, 399 ± 401; i) J. A. Marshall, H. Jiang, J. Org. Chem. 1998,
63, 7066 ± 7071; j) S. Hanessian, T. A. Grillo, J. Org. Chem. 1998, 63,
1049 ± 1057; k) S. C. Sinha, A. Sinha, S. C. Sinha, E. Keinan, J. Am.
Chem. Soc. 1997, 119, 12014 ± 12015; l) B. M. Trost, T. L. Calkins,
C. G. Bochet, Angew. Chem. 1997, 109, 2746 ± 2748; Angew. Chem. Int.
Ed. Engl. 1997, 36, 2632 ± 2634; m) J. A. Marshall, K. W. Hinkle, J.
Org. Chem. 1997, 62, 5989 ± 5995; n) J. A. Marshall, M. Chen, J. Org.
Chem. 1997, 62, 5996 ± 6000; p) T. R. Hoye, L. Tan, J. Am. Chem. Soc.
1996, 118, 1801 ± 1802; q) S. C. Sinha, A. Sinha, A. Yazbak, E. Keinan,
J. Org. Chem. 1996, 61, 7640 ± 7641; r) I. Wöhrle, A. Claûen, M.
Peterek, H.-D. Scharf, Tetrahedron Lett. 1996, 37, 7001 ± 7004; s) X.
‡
639.4836; found 639.4838 [M‡H] .
16-epi-Mucocin: A solution of tris-silyl ether 65 (9 mg, 9.17 mmol) in
CH2Cl2 (1 mL) was treated with HF/acetonitrile (0.20 mL, ca. 0.06 mmol,
5% HF in CH3CN). The mixture was stirred at rt for 2 h, then phosphate
buffer solution (1m, pH 7, 1 mL) and water (1 mL) were added. The
aqueous layer was extracted with CHCl3/iPrOH 1:1 (6 Â 5 mL) and the
combined organic layers were dried with MgSO4. The solvents were
removed in vacuo and the residue was purified by FCC (8 g silica gel,
hexane/MTBE 1:2, then CHCl3/MeOH 10:1) to afford 16-epi-mucocin
(4 mg, 75%) as a colorless oil. Rf ˆ 0.36; [a]2D5 ˆ À4.5 (c ˆ 0.09, CHCl3); IR
Á
Â
Frank, B. Figadere, A. Cave, Tetrahedron Lett. 1996, 37, 1593 ± 1594;
t) H. Konno, H. Makabe, A. Tanaka, T. Oritani, Tetrahedron 1996, 52,
9399 ± 9408; for work prior to 1996 see ref. [1].
[6] G. Shi, D. Alfonso, M. O. Fatope, L. Zeng, Z.-M. Gu, K. He, J. M.
MacDougal, J. L. McLaughlin, J. Am. Chem. Soc. 1995, 117, 10409 ±
10410.
[7] a) G. Shi, J. F. Kozlowski, J. T. Schwedler, K. V. Wood, J. M. Mac-
Dougal, J. L. McLaughlin, J. Org. Chem. 1996, 61, 7988 ± 7989; b) Total
synthesis of muconin: S. E. Schaus, J. Branalt, E. N. Jacobsen, J. Org.
Chem. 1998, 63, 4876 ± 4877; W.-Q. Yang, T. Kitahara, Tetrahedron
Lett. 1999, 40, 7827 ± 7830.
ˆ
(film): nÄ ˆ 3411/3140 brm (OH), 2926 s (CH), 2855 m, 1745 w (C O), 1094
w, 1082 w; 1H NMR (300 MHz, CDCl3): d ˆ 0.86 (t, J ˆ 6.8 Hz, 3H, 34-H3),
1.43 (d, J ˆ 6.8 Hz, 3H, 37-H3), 1.13 ± 1.65 (m, 41H, alkyl), 1.76 ± 1.88 (m,
1H), 1.89 ± 2.05 (m, 2H, 13,14-H2), 1.98 ± 2.14 (m, 1H, 22-H2), 2.25 (brs, 1H,
OH), 2.37 (dd, J ˆ 15.1, 8.3 Hz, 1H, 3-H2), 2.52 (d, J ˆ 15.1 Hz, 1H, 3-H2),
2.79 (brs, 1H, OH), 2.98 ± 3.07 (m, 1H, 24-H), 3.08 ± 3.17 (m, 1H, 20-H),
3.18 ± 3.31 (m, 1H, 23-H), 3.39 ± 3.50 (m, 2H, 19-H), 3.69 ± 3.72 (m, 1H, 16-
H), 3.75 ± 3.98 (m, 3H, 4,12,15-H), 5.04 (dq, J ˆ 6.8, 1.5 Hz, 1H, 36-H), 7.16
(d, J ˆ 1.5 Hz, 1H, 35-H); 13C NMR (75 MHz, CDCl3): d ˆ 14.11 (C-34),
19.11 (C-35), 22.68, 25.46, 25.54, 25.71, 26.11, 26.97, 27.01, 28.86, 29.32, 29.42,
29.48, 29.58, 29.62, 29.72, 31.91, 31.96, 32.23, 32.58, 33.37, 35.99, 37.39 (C-
3,5 ± 11,13,14,17,18,21,22,25 ± 33), 69.97 (C-4), 70.53 (C-23), 72.51 (C-16),
74.15 (C-19), 77.97 (C-36), 80.08 (C-12), 80.21 (C-20), 81.47 (C-15), 81.99
(C-24), 131.17 (C-2), 151.79 (C-35), 174.60 (C-1); HR-MS (EI): C37H66O8
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‡
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Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft, Fonds
der Chemischen Industrie, Schering AG and Asta-Medica. We thank
Wacker AG for gifts of chemicals. Ms. Dipl. Chem. S. Fietz-Razavian is
acknowledged for support in the beginning of this project.
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Received: October 25, 1999 [F2103]
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