Synthesis of (4R,12S,15S,16S,19R,20R,34S)-muricatetrocin and (4R,12R,15S,16S,19R,20R,34S)-muricatetrocin, two potent inhibitors of mitochondrial complex I

Article abstract of DOI:10.1002/1099-0690(200006)2000:12<2207::AID-EJOC2207>3.0.CO;2-C

(4R,12S,15S,16S,19R,20R,34S)-Muricatetrocin (1) and (4R,12R,15S,16S,19R,20R,34S)-muricatetrocin (2) were synthesized by a modular synthetic strategy. Both compounds act as potent inhibitors of mitochondrial complex I. Compound 1 showed analytical data in agreement with howiicin E and a fit with the data for muricatetrocin A if one reassigns the reported ¹³C signals for C(13) and C(14). Compound 2 matched muricatetrocin B in respect to all NMR data. However, a lower optical rotation was found for 2 ([α](D)/²⁸ = +6.7) than was reported for the natural product ([α](D)/²⁵ = +15.0).

Full text of DOI:10.1002/1099-0690(200006)2000:12<2207::AID-EJOC2207>3.0.CO;2-C

FULL PAPER
Synthesis of (4R,12S,15S,16S,19R,20R,34S)-Muricatetrocin and
(4R,12R,15S,16S,19R,20R,34S)-Muricatetrocin, Two Potent Inhibitors of
Mitochondrial Complex I
Stefan Bäurle,[a] Ulf Peters,[a] Thorsten Friedrich,[b] and Ulrich Koert*[a]
Keywords: Natural products / Complex I inhibitors / Muricatetrocin / Howiicin E / Synthetic methods / Total synthesis
(4R,12S,15S,16S,19R,20R,34S)-Muricatetrocin
(1)
and
E and a fit with the data for muricatetrocin A if one reassigns
the reported 13C signals for C(13) and C(14). Compound 2
matched muricatetrocin B in respect to all NMR data. How-
ever, a lower optical rotation was found for 2 ([α]2D8 = +6.7)
than was reported for the natural product ([α]2D5 = +15.0).
(4R,12R,15S,16S,19R,20R,34S)-muricatetrocin (2) were syn-
thesized by a modular synthetic strategy. Both compounds
act as potent inhibitors of mitochondrial complex I. Com-
pound 1 showed analytical data in agreement with howiicin
Introduction
muricata.[10] They were named muricatetrocin A and B.
Structure 1 was proposed for muricatetrocin A and struc-
ture 2 for muricatetrocin B. In 1994 Yang et al. published
analytical data for howiicin E isolated from Goniothalamus
howii, which indicated a constitutional identity and a ste-
reochemical match for muricatetrocin A and howiicin E.[11]
All three natural products have a C35 skeleton, three hy-
droxyl groups in the left side chain (C-16, C-19, C-20), one
hydroxyl group in the right side chain (C-4) and a butenol-
ide moiety at the right end of the molecule. The assignment
of the relative and absolute configuration of the seven ste-
reocentres of muricatetrocin A and B was based on NMR
measurements including Mosher ester methodology.[10] The
relative configuration of the 2,5-disubstituted THF ring was
proposed to be cis for muricatetrocin A and trans for mur-
icatetrocin B. Here we report on the total synthesis of com-
pounds 1 and 2 and the comparison of their analytical data
with the data reported for muricatetrocin A, howiicin E and
muricatetrocin B.
Over 250 acetogenins from Annonaceae have been isol-
ated and characterized so far.[1] This class of natural prod-
ucts shows remarkable biological properties, e.g. as antitu-
mour agents, immunosuppressants or pesticides.[1] The in-
hibition of mitochondrial complex I is discussed as one
mode of action.[2] Complex I, also known as NADH:
ubiquinone oxido reductase, transfers electrons from
NADH to ubiquinone and links this process with transloca-
tion of protons across the inner membrane. Numerous syn-
thetic routes to the different subtypes of Annonaceae aceto-
genins have been elaborated over the last decade.[3Ϫ9]
In 1993 McLaughlin et al. reported on the isolation of
two new monotetrahydrofuran acetogenins from Annona
1
Results and Discussion
Our retrosynthesis of 1 (Scheme 1) disconnects between
C-15 and C-16, and so leads to the addition of an organo-
metallic reagent 3 to the aldehyde 4. A related coupling has
already successfully been used in the total synthesis of muc-
ocin.[4c] The THF aldehyde 4 can be prepared via a Wittig
reaction of the ylide 5 and the butenolide aldehyde 6.
The synthesis of the right half of the target molecule 1 is
summarized in Scheme 2. The cis THF alcohol 7 was pre-
pared following a known route, using the enantioselective
addition of a diorganozinc reagent to an aldehyde following
Knochel’s procedure.[12] Protection of the primary hydroxyl
group in 7 as a triethylsilyl (TES) ether followed by reduct-
ive cleavage of the pivalate gave the alcohol 8. The latter
was converted via the corresponding iodide into the phos-
phonium salt 9. A Wittig reaction of 9 with the aldehyde
10[4c] afforded the olefin 11 in 65% yield as a mixture of
Figure 1. Structures of the target molecules 1 and 2
[a]
Institut für Chemie der Humboldt-Universität zu Berlin,
Hessische Strasse 1Ϫ2, D-10115 Berlin, Germany
Fax: (internat.) ϩ 49-(0)30/2093-7266
E-mail: koert@lyapunov.chemie.hu-berlin.de
Institut für Biochemie, Heinrich-Heine Universität,
[b]
Universitätstrasse 1, 40225 Düsseldorf, Germany
Eur. J. Org. Chem. 2000, 2207Ϫ2217
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0612Ϫ2207 $ 17.50ϩ.50/0
2207

S. Bäurle, U. Peters, T. Friedrich, U. Koert
FULL PAPER
Scheme 3. Preparation of the trans THF aldehyde 15 from the trans
THF alcohol 14; details are given in ref. [4c]
Scheme 1. Retrosynthetic analysis of 1
Scheme 4. a) 3-butyn-1-ol (2.6 equiv.), nBuLi (5.0 equiv.), NH3/
THF/DMPU, rfx., 10 h, 50%; b) LiAlH4 (5.8 equiv.), diglyme, 100
°C, 14 h, 83%; c) BnBr (1.3 equiv.), NaH (3.0 equiv.), DMF, 90 °C,
24 h, 91%; d) AD-mix β, MeSO2NH2 (1.0 equiv.), H2O/tBuOH 1:1
0 °C Ǟ room temp., 20 h, 90%, ee ϭ 98%; e) 2,2-dimethoxypropane
(10 equiv.), CSA (cat.), CH2Cl2, room temp., 1 h, 95%; f) H2 (1
atm), Pd-C (0.5 mol-% Pd), EtOAc, room temp., 20 h, 95%; g) I2
(1.2 equiv.), PPh3 (1.1 equiv.), imidazole (3.0 equiv.), CH2Cl2, 0 °C
Ǟ room temp., 5 h, 66%
moiety. A chemoselective hydrogenation, using Wilkinson’s
catalyst,[13] of the isolated double bond in 11, followed by
TES-deprotection, gave the alcohol 12. The Swern oxida-
tion of 12 provided the aldehyde 13.
Following the same route, the trans THF alcohol 14 was
converted into the trans THF aldehyde 15 (Scheme 3). This
reaction sequence was used for the first time in the context
of the mucocin synthesis and is described in ref. 4c.
Scheme 2. a) TESCl (2.5 equiv.), imidazole (3.0 equiv.), CH2Cl2,
room temp., 2 h, 95%; b) DIBAH (2.5 equiv.), THF, Ϫ40 °C Ǟ
Ϫ15 °C, 1 h, 86%; c) I2 (1.2 equiv.), PPh3 (1.1 equiv.), imidazole
(3.0 equiv.), CH2Cl2, 0 °C Ǟ room temp., 1.5 h, 74%; d) PPh3 (5.0
equiv.), CH3CN/toluene 1:1, 70 °C, 20 h; e) NaHMDS (1.0 equiv.),
THF, 0 °C, 30 min, then 10, Ϫ70 °C Ǟ 0 °C, 20 min, 65%;
f) [(PPh3)3RhCl] (0.15 equiv.), H2 (1 atm), benzene, room temp.,
3 h, 83%; g) CSA (0.03 equiv.), CH2Cl2/MeOH 5:1, Ϫ20 °C,
10 min, 75%; h) (COCl)2 (2.5 equiv.), DMSO (5.0 equiv.), NEt3 (7.0
equiv.), CH2Cl2, Ϫ70 °C Ǟ 0 °C, 1.5 h, 87%. TES ϭ triethylsilyl,
TBDMS ϭ tert-butyldimethylsilyl, NaHMDS ϭ sodium hexa-
methyldisilazide, CSA ϭ camphorsulfonic acid
The synthesis of the left side chain, containing the two
stereocentres at C-19 and C-20, was addressed next
(Scheme 4). To this end, the bromide 16 was allowed to re-
act with the dianion of 3-butyn-1-ol to give the alkylation
product 17 in 50% yield. An (E)-selective reduction of the
triple bond to the corresponding alkene followed by benzyl-
ation of the primary hydroxyl function resulted in com-
pound 18. The Sharpless dihydroxylation[14] of 18 with AD-
mix β gave the diol 19 with an ee ϭ 98% as determined
by HPLC. The vicinal diol was protected as an acetonide.
(E)/(Z) isomers. Aldehyde 10 was prepared in 10 steps from Hydrogenolytic cleavage of the benzyl ether afforded the
acetoacetic acid methyl ester. Key steps were a Noyori hy- alcohol 20, which could be transformed into the iodide 21.
drogenation to establish the sterogenic centre at C-4 and an
The final part of the synthesis of 1 required the chelation-
alkylation with (S)-propylene oxide leading to the lactone controlled addition of an organometallic reagent prepared
2208
Eur. J. Org. Chem. 2000, 2207Ϫ2217

Synthesis of Muricatetrocin
FULL PAPER
from the iodide 21 to the cis THF aldehyde 13. Organomag-
nesium compounds form the chelation-controlled product
with the related trans THF aldehyde 15.[4c] Due to the small
scale of the coupling reaction (Ͻ 1 mmol), heterogeneous
Grignard-type chemistry with magnesium turnings was not
very suitable. Instead, the homogeneous generation of the
corresponding organolithium compound followed by trans-
metallation to magnesium was used. The iodide 21 was sub-
jected to an iodine-lithium exchange[15] in Et2O at Ϫ 105
°C and subsequently treated with magnesium bromide in
Et2O at Ϫ 100 °C. Addition of the aldehyde 13 gave the
two secondary alcohols 22 and 23 as coupling products
(60%) with a 1:1 stereoselectivity. Both epimers could be
separated by chromatography. The stereochemical assign-
ment[16] was based on 13C NMR data (new chiral centre:
δ ϭ 74.5 for 22 and 72.1 for 23). It should be pointed out
that no stereocontrol could be achieved in the addition of
the organomagnesium compound to the cis THF aldehyde.
This stands in contrast to the results obtained in the trans
Scheme 6. a) 21 (1.3 equiv.), tBuLi (1.9 equiv.), Et2O, Ϫ105 °C,
4 min, then MgBr2 Et2O (3.9 equiv.), Ϫ100 Ǟ Ϫ30 °C, 2 h, Ǟ Ϫ75
°C, 15 (1.0 equiv.), Ǟ Ϫ10 °C, 2 h, 34% (single isomer), 10% of
aldehyde 15 reisolated; b) HF/CH3CN (3.0 equiv.), CH2Cl2, room
temp., 30 min, then CSA (0.5 equiv.), MeOH, room temp., 1 h, 84%
Addition of the organomagnesium compound prepared
case (ref.[4c] and vide infra). Deprotection of the TBDMS from 21 to the trans THF aldehyde 15 gave the chelation-
group in 22 with HF in CH3CN and subsequent cleavage controlled coupling product 25 in 34% yield as a single iso-
of the acetonide function provided compound 1 in 68% mer (Scheme 6). The epimeric product, which in the cis
yield. The epimeric coupling product 23 yielded the C-16 series was formed in equimolar amounts, was not observed.
epimer 24 in 63% yield after the same deprotection se- TBDMS deprotection and cleavage of the acetonide af-
quence (Scheme 5).
forded compound 2.
Compound 1 was isolated as a waxy solid with [α]D33
ϭ
ϩ12.5 (c ϭ 1.1 in CHCl3). The reported optical rotation for
muricatetrocin A is [α]2D5 ϭ ϩ10.3 (c ϭ 0.15 in CHCl3). The
reported optical rotation for howiicin E is [α]1D8.5 ϭ ϩ15.79
(c ϭ 0.8 in CHCl3). The MS and IR data for 1 are in agree-
ment with the reported data for muricatetrocin A. Based on
the synthesis we assign the following absolute configuration
to the seven stereocentres of 1: 4R,12S,15S,
1
16S,19R,20R,34S. A comparison of the H- and 13C-NMR
data for the synthetic compound 1 and the natural products
muricatetrocin A and howiicin E is shown in Table 1 and
Table 2.
There is a good match for all 1H- and 13C signals of com-
pound 1 and the reported data for howiicin E. A compar-
ison of the NMR data for muricatetrocin A and compound
1 shows differences for the CH2 groups in the THF ring at
C(13) and C(14). McLaughlin et al. report a 13C resonance
for C(13) at 28.43 and for C(14) at 32.43. For compound
1 we see no 13C resonance around 28.43. Based on 2D-
experiments (HH and HC COSY) we assign the signal at
27.79 to C(14) and one of the signals in the overlap region
between 25 and 30 ppm to C(13) (probably at 26.11 ppm).
In the original publication,[10] the same 13C resonances were
reported at C(13) and C(14) for muricatetrocin A and mur-
icatetrocin B. Because both natural products differ in their
relative configuration at the THF ring one might expect
differences for the resonances at C(13) and C(14). Inspec-
tion of copies of the NMR spectra of muricatetrocin A,
kindly provided by Prof. McLaughlin, allowed no closer
analysis of the 13C region between 24 and 34 ppm.[17] Based
on the present data it can be stated that howiicin E has the
structure of 1 and that after reassignment of the C(13)/
C(14) NMR data of muricatetrocin A it is possible that mu-
Scheme 5. a) 21 (1.3 equiv.), tBuLi (2.0 equiv.), Et2O, Ϫ105 °C,
4 min, then MgBr2 Et2O (4.2 equiv.), Ϫ100 Ǟ Ϫ25 °C, 2 h, Ǟ Ϫ78
°C, 13 (1.0 equiv.), Ǟ Ϫ5 °C, 2 h, 60% (1:1 mixture of 22 and 23,
separated by FCC), 28% of aldehyde 13 reisolated; b) HF CH3CN
(3.0 equiv.), CH2Cl2, room temp., 1 h, then CSA (0.5 equiv.),
MeOH, room temp., 1 h, 68%; c) HF CH3CN (3.0 equiv.), CH2Cl2,
room temp., 1 h, then CSA (0.5 equiv.), MeOH, room temp., 1 h,
63%
Eur. J. Org. Chem. 2000, 2207Ϫ2217
2209

S. Bäurle, U. Peters, T. Friedrich, U. Koert
FULL PAPER
1
Table 1. H resonances and assignments for compound 1 (600 MHz), muricatetrocin A[10] (500 MHz) and howiicin E[11] (400 MHz)
δ 1
δ Muricatetrocin A
δ Howiicin E
HaϪC(3)
HbϪC(3)
2.38
2.38
2.38
(ddt, J ϭ 15.2, 8.4, 0.9 Hz)
2.51
(ddt, J ϭ 15.1, 8.0, 1.4 Hz)
2.51
(dd, J ϭ 14.5, 8.1 Hz)
2.50
(ddt, J ϭ 15.2, 3.1, 1.5 Hz)
3.77Ϫ3.92 (m)
1.2Ϫ1.7 (m)
1.2Ϫ1.7 (m)
3.77Ϫ3.92 (m)
(ddt, J ϭ 15.1, 4.0, 1.4 Hz)
3.82 (m)
(dd, J ϭ 14.5, 3.1 Hz)
3.88 (m)
HϪC(4)
CH2(5)
CH2(6Ϫ11)
HϪC(12)
1.45 (m)
1.45 (m)
1.2Ϫ1.5
1.2Ϫ1.6
3.85
3.76 (m)
(dt, J ϭ 5.9, 6.7 Hz)
1.96 (m)
HaϪC(13)
HbϪC(13)
HaϪC(14)
HbϪC(14)
HϪC(15)
1.3Ϫ1.9 (m)
1.3Ϫ1.9 (m)
1.9 (m)
1.6 (m)
3.70
1.97 (m)[a]
1.69 (m)[a]
3.88 (m)
1.65 (m)
1.91 (m)
1.72 (m)
3.70
(q, J ϭ 6.8 Hz)
3.34Ϫ3.48 (m)
1.2Ϫ1.7 (m)
1.2Ϫ1.7 (m)
3.34Ϫ3.48 (m)
3.34Ϫ3.48 (m)
1.2Ϫ1.7 (m)
1.2Ϫ1.7 (m)
0.86
(q, J ϭ 7.0 Hz)
3.39 (m)
HϪC(16)
CH2(17)
CH2(18)
HϪC(19)
HϪC(20)
CH2(21)
CH2(22Ϫ31)
CH3(32)
3.43 (m)
1.54 (m)
1.4Ϫ1.6 (m)
1.4Ϫ1.6 (m)
3.43 (m)
1.56 (m)
3.42 (m)
3.39 (m)
3.43 (m)
1.57 (m)
1.4Ϫ1.6 (m)
1.2Ϫ1.6
1.2Ϫ1.5
0.85
0.88
(t, J ϭ 7.0 Hz)
7.16
(t, J ϭ 7.0 Hz)
7.17
(t, J ϭ 7.7 Hz)
7.18 (br. s)
HϪC(33)
HϪC(34)
CH3(35)
(d, J ϭ 1.1 Hz)
5.04
(d, J ϭ 1.4 Hz)
5.04
5.05
(dq, J ϭ 7.1, 1.3 Hz)
1.41
(dq, J ϭ 7.1, 1.4 Hz)
1.41
(q, J ϭ 6.7 Hz)
1.41
(d, J ϭ 6.8 Hz)
(d, J ϭ 7.1 Hz)
(d, J ϭ 6.8 Hz)
[a]
Signals may be interchanged.
Table 2. 13C-NMR resonances and assignments for compound 1 the following absolute configuration to the seven ste-
(75 MHz), muricatetrocin A[10] (125 MHz) and howiicin E[11]
(100 MHz)
reocentres of 2: 4R,12R,15S,16S,19R,20R,34S. A compar-
1
ison of the H- and 13C-NMR data for the synthetic com-
pound 2 and the natural product muricatetrocin A is shown
in Table 3.
δ 1
δ Muricatetrocin A
δ Howiicin E
There is a good match for all 1H and 13C signals of com-
pound 2 and the reported data for muricatetrocin B. Based
on the NMR data it is likely that muricatetrocin B has the
4R,12R,15S,16S,19R,20R,34S configuration. However,
there is a discrepancy in the magnitude of the optical rota-
tion for the natural product and compound 2, which pre-
vents us from unequivocally stating that muricatetrocin B
and compound 2 are identical.[17]
C(1)
174.62
131.16
33.35
69.92
37.37
25Ϫ29
80.02
26.11
27.79
82.05
74.25
35.94
33.46
74.57
74.88
31.35
25Ϫ30
22.97
14.10
151.82
77.89
19.10
174.53
131.10
33.39
69.94
37.41
25Ϫ29
80.03
28.43
32.43
82.01
74.90
35.99
33.48
74.62
74.39
29.95
25Ϫ29
22.71
14.18
151.81
77.99
19.16
174.63
131.19
33.37
69.94
37.41
25Ϫ29
80.05
26.14
27.83
82.12
74.29
35.55
33.52
74.57
74.91
31.38
25Ϫ30
22.70
14.10
151.86
78.00
19.13
C(2)
C(3)
C(4)
C(5)
C(6Ϫ11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
C(20)
C(21)
C(22Ϫ30)
C(31)
C(32)
C(33)
HϪC(34)
CH3(35)
Biological Evaluation
Compounds 1, 2, and 24 were tested as inhibitors of bo-
vine-heart mitochondrial complex I. Bovine-heart mito-
chondria were prepared as described before.[18] The inhibi-
tion of oxygen uptake was measured. The respiratory activ-
ricatetrocin
A
has the configuration 4R,12S,15S, ities were analyzed with a Clark-type oxygen electrode
(100 m sodium phosphate pH 7.4, 1 m EDTA, 1 m
16S,19R,20R,34S.
Compound 2 was isolated as a waxy solid with [α]D28
ϭ
MgCl2, 0.2 mg/mL protein).[13] All three compounds exhib-
ϩ6.7 (c ϭ 0.4 in CHCl3). The reported optical rotation for ited very high activities (1: Ki50 ϭ 1.6 n, 2: Ki50 ϭ 3.3 n,
muricatetrocin B is [α]2D5 ϭ ϩ15.0 (c ϭ 0.43 in CHCl3). The 24: Ki50 ϭ 1.5 n). These results show that compounds 1,
MS and IR data for 2 are in agreement with the reported 2, and 24 have similar activities in comparison with the
data for muricatetrocin B. Based on the synthesis we assign known strong inhibitor rotenon (rotenon: Ki50 ϭ 1.0 n).[2]
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Eur. J. Org. Chem. 2000, 2207Ϫ2217

Synthesis of Muricatetrocin
FULL PAPER
Table 3. 1H and 13C NMR resonances and assignments for compound 2 (300 MHz, 75 MHz) and muricatetrocin B[10] (500 MHz,
125 MHz)
δ(H) 2
δ(C) 2
δ(H) Muricatetrocin B
δ(C) Muricatetrocin B
C(1)
174.64
131.12
33.35
174.53
131.04
33.39
C(2)
HaϪC(3)
2.32 (m)
2.46 (m)
2.38
(ddt, J ϭ 15.1, 8.0, 1.4 Hz)
2.51
HbϪC(3)
(ddt, J ϭ 15.1, 4.0, 1.4 Hz)
3.82 (m)
HϪC(4)
CH2(5)
CH2(6Ϫ11)
HϪC(12)
3.75Ϫ3.93 (m)
1.21Ϫ1.78 (m)
1.21Ϫ1.78 (m)
3.75Ϫ3.93 (m)
69.93
37.36
25Ϫ29
79.3
69.88
37.28
25Ϫ29
79.27
1.45 (m)
1.2Ϫ1.5
3.85
(dt, J ϭ 5.9, 6.7 Hz)
2.00 (m)
HaϪC(13)
HbϪC(13)
HaϪC(14)
HbϪC(14)
HϪC(15)
1.90Ϫ2.08 (m)
1.21Ϫ1.78 (m)
1.90Ϫ2.08 (m)
1.21Ϫ1.78 (m)
3.75Ϫ3.93 (m)
28.39
32.39
81.72
28.43
32.43
81.73
1.63 (m)
1.97 (m)
1.71 (m)
3.78
(q, J ϭ 7.0 Hz)
3.40 (m)
HϪC(16)
CH2(17)
CH2(18)
HϪC(19)
HϪC(20)
CH2(21)
CH2(22Ϫ30)
CH3(32)
3.35Ϫ3.51 (m)
1.21Ϫ1.78 (m)
1.21Ϫ1.78 (m)
3.35Ϫ3.51 (m)
3.35Ϫ3.51 (m)
1.21Ϫ1.78 (m)
1.21Ϫ1.78 (m)
0.86
74.43
35.49
33.44
74.58
74.24
29.92
25Ϫ29
14.12
74.43
35.43
33.48
74.56
74.23
29.95
25Ϫ29
14.17
1.40 (m)
1.57 (m)
3.42 (m)
3.40 (m)
1.57 (m)
1.2Ϫ1.5
0.85
(t, J ϭ 7.0 Hz)
7.16
(t, J ϭ 7.0 Hz)
7.17
HϪC(33)
HϪC(34)
CH3(35)
151.85
77.99
19.10
151.81
77.99
19.14
(d, J ϭ 1.1 Hz)
5.04
(d, J ϭ 1.4 Hz)
5.04
(dq, J ϭ 6.8, 1.5 Hz)
1.41
(dq, J ϭ 7.1, 1.4 Hz)
1.41
(d, J ϭ 6.8 Hz)
(d, J ϭ 7.1 Hz)
It should be noticed that all three different stereoisomers for compound 2 and muricatetrocin B are identical except
display comparable activity. This observation is in agree- for a difference in the magnitude of the optical rotation.
ment with recent results from Miyoshi et al., who found
that the stereochemistry around the THF rings was of
minor importance.[2b] It has been stated that bis-THF
Experimental Section
acetogenins like bullatacin and squamocin A are more po-
tent complex I inhibitors than mono-THF acetogenins.[1c]
General: All b.p.s and m.p.s are uncorrected values. Ϫ IR:
Our data for the mono-THF acetogenins 1, 2, and 24 are
comparable with the data for the bis-THF acetogenin squa-
mocin A (Ki50 ϭ 1.0 n). Therefore, we see no remarkable
difference in complex I inhibition for both groups of com-
pounds. The high selectivities reported for the cytotoxicity
of Annonaceae acetogenins in different cancer cell lines
may reflect the different degrees of uptake and transport by
the tumor cells. Once the acetogenins reach complex I, most
of them strongly inhibit the enzyme.
PerkinϪElmer FT-IR 1600, Biorad FTS 3000MX. Ϫ NMR:
Bruker AC-300, DPX-300, and AMX-600. For H NMR, CHCl3
1
impurity in CDCl3 solvent δH ϭ 7.24; for 13C NMR, CDCl3 as
solvent δC ϭ 77.0. Ϫ Elemental analysis: CHNS-932 Analysator
(Leco). Ϫ HRMS: Finnigan MAT 95. All reactions were performed
under an Ar-atmosphere in oven- or flame-dried glassware except
where otherwise stated. Ϫ HPLC: Rainin-Dynamax, SD-200 and
SD-1, PDA1. Dry solvents: THF, Et2O, benzene, and xylene were
distilled from sodium benzophenone. Pyridine, triethylamine, and
CH2Cl2 were distilled from CaH2. All commercially available re-
agents were used without purification unless otherwise noted. All
reactions were monitored by thin-layer chromatography (TLC) car-
ried out on Merck F-254 silica glass plates visualized with UV light
and/or heat-gun treatment with 5% phosphomolybdic acid in eth-
anol. Column chromatography (CC) and flash column chromato-
graphy (FCC) were performed with Merck silica gel 60 (70Ϫ200
mesh and 230Ϫ400 mesh). Ϫ PE: light petroleum ether, b.p. 40Ϫ60
°C. MTBE: methyl tert-butyl ether. DMPU: N,NЈ-Dimethylpropy-
leneurea.
Conclusion
A modular synthetic strategy was used for the stereose-
lective synthesis of (4R,12S,15S,16S,19R,20R,34S)-murica-
tetrocin 1 and (4R,12R,15S,16S,19R,20R,34S)-muricatetro-
cin 2. Both compounds are very strong inhibitors of bovine
heart mitochondrial complex I. Based on the present data
we can suggest the identity of howiicin E and compound 1.
In the case of muricatetrocin A a reassignment of NMR
5-[(2ЈS,5ЈS)-5Ј-(Hydroxymethyl)tetrahydrofuran-2Ј-yl]pentyl Pival-
ate (7): For the preparation of 7 see ref.[12] Rf ϭ 0.19 (n-hexane/
data at C(13) and C(14) is proposed. The analytical data MTBE 1:1); HPLC: Rt ϭ 22.9 min (Superspher Si 60, n-hexane/
Eur. J. Org. Chem. 2000, 2207Ϫ2217 2211

S. Bäurle, U. Peters, T. Friedrich, U. Koert
FULL PAPER
iPrOH 96/4, 1.0 mL minϪ1); [α]2D0ϭ Ϫ6.5, (c ϭ 0.94, CHCl3, pure
Phosphonium Salt 9. ؊ 1. Iodination: To a solution of imidazole
cis-isomer). Ϫ IR (film): ν˜ ϭ 3445 m br (OH), 2937/2864 s (CH), (283 mg, 4.16 mmol) and PPh3 (399 mg, 1.52 mmol) in CH2Cl2
1728 s (CϭO), 1481 m, 1398/1366 w (tBu), 1285 s, 1159 s, 1058 s, (15 mL) at 0 °C was added first a solution of iodine (421 mg,
1038 w. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.13 (s, 9 H, tBu),
1.24Ϫ1.48 and 1.49Ϫ1.70 and 1.77Ϫ1.97 (m, 12 H, 3Ј-H2, 4Ј-H2,
1.66 mmol) in CH2Cl2 (7 mL) and then a solution of alcohol 8
(419 mg, 1.39 mmol) in CH2Cl2 (3 mL). The reaction mixture was
2-H2, 3-H2, 4-H2, 5-H2), 2.28 (s, br, 1 H, OH), 3.42 (dd, J ϭ 11.3/ stirred at room temp. for 1.5 h, Na2S2O3 solution (5% in water,
5.7 Hz, 1 H, 1ЈЈ-Ha), 3.61 (dd, J ϭ 11.5/3.6 Hz, 1 H, 1ЈЈ-Hb), 30 mL) was then added and the mixture was stirred until the brown
3.64Ϫ3.75 (m, 1 H, 2Ј-H), 3.85Ϫ4.00 (m, 1 H, 5Ј-H),3.99 (t, J ϭ colour disappeared. The phases were separated and the aqueous
6.6 Hz, 2 H, 1-H2). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 25.76, layer was extracted with MTBE (3ϫ 15 mL). The combined or-
25.84, 27.0, 28.5, 31.3, 35.7 (C-3Ј,4Ј,2Ϫ5), 27.1 [C(CH3)3], 38.6 ganic layers were washed with sat. aqueous NaCl (2ϫ 20 mL) and
[C(CH3)3], 64.2 (C-1), 65.2 (C-1ЈЈ), 79.2 (C-5Ј), 79.9 (C-2Ј), 178.5 dried with MgSO4. The solvents were evaporated in vacuo and the
(COOtBu). Ϫ C15H28O4 (272.38): calcd. C 66.14, H 10.36; found
C 66.22, H 10.71.
residue was purified by CC (45 g silica gel, PE/MTBE 1:1) to yield
the iodide as a colourless oil (420 mg, 74%). (2S,5S)-2-(5Ј-Iodopen-
tyl)-5-(triethylsilyloxymethyl)tetrahydrofuran: Rf ϭ 0.72 (n-hexane/
MTBE 1:1); [α]2D2 ϭ Ϫ4.1 (c ϭ 0.48, CHCl3). Ϫ IR (film): ν˜ ϭ
2953/2935/2911/2875 s (CH), 1460 w, 1238 w, 1094 m, 1012 w, 798
5-[(2ЈS,5ЈS)-5Ј-(Triethylsilyloxymethyl)tetrahydrofuran-2Ј-yl]-
pentan1-ol (8). ؊ 1. TES Protection: To a solution of the alcohol
7 (488 mg, 1.79 mmol) in CH2Cl2 (20 mL) were added imidazole
1
w, 744/728 s. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.52Ϫ0.63 (m,
˚
(366 mg, 5.37 mmol) and powdered molecular sieves (4 A, 50 mg).
6 H, 3ϫ SiCH2CH3), 0.88Ϫ0.97 (m, 9 H, 3ϫ Si CH2CH3),
1.23Ϫ1.93 (m, 12 H, 6ϫ alkyl-CH2), 3.16 (t, J ϭ 7.2 Hz, 2 H,
5Ј-H2), 3.44Ϫ3.52 (m, 1 H, 1ЈЈ-Ha), 3.55Ϫ3.64 (m, 1 H, 1ЈЈ-Hb),
3.75Ϫ3.86 (m, 1 H, 2-H), 3.87Ϫ3.97 (m, 1 H, 5-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 4.4 (SiCH2CH3)3, 6.7 (SiCH2CH3)3, 7.1 (C-
5Ј), 25.2, 27.9, 30.58, 30.9, 33.5, 35.7 (C-3,4,1Ј-4Ј), 65.8 (C-1ЈЈ),
79.5 (C-5), 79.8 (C-2). Ϫ C16H33IO2Si (412.42). Ϫ 2. Preparation
of the Triphenylphosphonium Salt 9: The iodide (293 mg,
0.71 mmol) and PPh3 (932 mg, 3.5 mmol) were dissolved in toluene
(1 mL) and CH3CN (4 mL). The solution was stirred at 70 °C for
48 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 9 was dried in vacuo (ca.
0.1 mbar) and was used for the Wittig reaction without further
purification.
The mixture was treated with TESCl (0.75 mL, 4.48 mmol) at 0 °C.
After stirring at room temp. for 2 h, the reaction mixture was fil-
tered 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 (3ϫ 7 mL) and the combined or-
ganic layers were washed with sat. aqueous NaCl (2ϫ 20 mL) and
dried with MgSO4. The solvents were evaporated and the residue
was purified by CC (25 g silica, PE/MTBE 2:1) to yield the TES-
protected alcohol (657 mg, 95%) as
a colourless liquid. Ϫ
5-[(2ЈS,5ЈS)-5Ј-(Triethylsilyloxymethyl)tetrahydrofuran-2Ј-yl]pentyl
Pivalate: Rf ϭ 0.68 (n-hexane/MTBE 1:1); [α]2D0 ϭ Ϫ3.6 (c ϭ 1.0,
CHCl3). Ϫ IR (film): ν˜ ϭ 2956/2938/2912/2876 s (CH), 1731 s (Cϭ
O), 1285 m, 1156 s, 1100 m, 744 m. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.57 (q, J ϭ 7.9 Hz, 6 H, 3ϫ SiCH2CH3), 0.93 (t, J ϭ
7.7 Hz, 9 H, 3ϫ SiCH2CH3), 1.16 (s, 9 H, tBu), 1.28Ϫ1.49 (m, 6
H, 3ϫ alkyl-CH2), 1.50Ϫ1.75 (m, 4 H, 2ϫ alkyl-CH2), 1.81Ϫ1.95
(m, 2 H, alkyl-CH2), 3.48 (dd, J ϭ 10.4/5.8 Hz, 1 H, 1ЈЈ-Ha), 3.60
(dd, J ϭ 10.5/4.9 Hz, 1 H, 1ЈЈ-Hb), 3.75Ϫ3.84 (m, 1 H, 2Ј-H),
(5S)-3-{(2ЈR,4ЈΘ)-tert-Butyldimethylsilyloxy-9Ј-{(2ЈЈS,5ЈЈS)-5ЈЈ-
[(triethylsilyl)oxymethyl]tetrahydrofuran-2ЈЈ-yl}non-4Ј-enyl}-5-
methylfuran-2(5H)-one (11): The phosphonium salt 9 was dissolved
3.86Ϫ3.95 (m, 1 H, 5Ј-H), 4.01 (t, J ϭ 6.6 Hz, 2 H, 1-H2). Ϫ 13C in THF (5 mL) and treated with NaHMDS (0.55 mL 1  in THF,
NMR (75 MHz, CDCl3): δ ϭ 4.4 (SiCH2CH3)3, 6.7 (SiCH2CH3)3, 0.55 mmol) at 0 °C. The orange solution was stirred at 0 °C for
25.9, 26.1, 28.0, 28.6, 30.9, 35.8 (C-3Ј,4Ј,2Ϫ5), 27.2 [C(CH3)3], 38.7 30 min, and was then cooled to Ϫ70 °C and a solution of aldehyde
[C(CH3)3], 64.3 (C-1), 65.8 (C-1ЈЈ), 79.4 (C-5Ј), 79.8 (C-2Ј), 178.6 10 (165 mg, 0.55 mmol) in THF (3 mL) was added dropwise. The
(COOtBu). Ϫ C21H42O4Si (386.64): calcd. C 65.23, H 10.95; found
C 65.15, H 10.97. Ϫ 2. Cleavage of the Pivalate: A solution of
cooling bath was replaced by an ice bath and the now light brown-
yellow solution was stirred 20 min at 0 °C. The reaction was
the pivalate (651 mg, 1.68 mmol) in THF (20 mL) was treated with quenched by the addition of phosphate buffer solution (1 , pH 7,
DIBAH (4.21 mL, 4.21 mmol, 1  in hexanes) at Ϫ40 °C. The reac-
tion mixture was allowed to warm up to Ϫ15 °C during 1 h. The
reaction was quenched by addition of MeOH (2 mL), sat. aqueous
NaHCO3 (4 mL), and ethyl acetate (15 mL). The mixture was
stirred 30 min at room temp., solid Na2SO4 (10 g) was then 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/
7 mL). The mixture was diluted with MTBE (10 mL) and water
(8 mL). The aqueous layer was extracted with MTBE (3ϫ 7 mL)
and the combined organic layers were washed with sat. aqueous
NaCl (2ϫ 10 mL) and dried with MgSO4. The solvents were re-
moved in vacuo and the residue was purified by FCC (35 g silica
gel, cHexH/MTBE 5:1) to yield olefin 11 (200 mg, 65%) as a col-
ourless oil. 11: Rf ϭ 0.61 (n-hexane/MTBE 1:1). Ϫ IR (film): ν˜ ϭ
2954/2933 s (CH), 2876/2858 m (CH), 1761 m (CϭO), 1463 w,
1
MTBE 2:1) to obtain alcohol 8 (438 mg, 86%) as a colourless oil. 1373/ 1357 w (tBu), 1252 w, 1079 m, 1005 w, 836 w, 775 w. Ϫ H
8: Rf ϭ 0.19 (n-hexane/MTBE 1:1); [α]2D3 ϭ Ϫ5.7, (c ϭ 0.28,
CHCl3). Ϫ IR (film): ν˜ ϭ 3429 m br (OH), 2936/2913/2875 s (CH), SiCH3), 0.58 (q, J ϭ 8.2 Hz, 6 H, 3ϫ SiCH2CH3), 0.84 [s, 9 H,
NMR (300 MHz, CDCl3): δ ϭ Ϫ0.01 (s, 3 H, SiCH3), 0.03 (s, 3 H,
1
1673 w, 1458 w, 1096 m, 1015 w, 742 m. Ϫ H NMR (300 MHz,
SiC(CH3)3], 0.93 (t, J ϭ 7.7 Hz, 9 H, 3ϫ SiCH2CH3), 1.39 (d, J ϭ
CDCl3): δ ϭ 0.58 (q, J ϭ 8.2 Hz, 6 H, 3ϫ SiCH2CH3), 0.93 (t, J ϭ 6.4 Hz, 3 H, CH3), 1.24Ϫ1.76 (m, 8 H, 4ϫ alkyl-CH2), 1.81Ϫ2.03
7.7 Hz, 9 H, 3ϫ SiCH2CH3), 1.27Ϫ1.76 (m, 11 H, OH and 5ϫ (m, 4 H, 2ϫ alkyl-CH2), 2.09Ϫ2.29 (m, 2 H, alkyl-CH2), 2.30Ϫ2.50
alkyl-CH2), 1.83Ϫ1.95 (m, 2 H, alkyl-CH2), 3.48 (dd, J ϭ 10.4/ (m, 2 H, alkyl-CH2), 3.48 (dd, J ϭ 10.4/5.8 Hz, 1 H, 1ЈЈЈ-Ha), 3.60
5.8 Hz, 1 H, 1ЈЈ-Ha), 3.55Ϫ3.66 (m, 3 H, 1ЈЈ-Hb, 1-H2), 3.75Ϫ3.86 (dd, J ϭ 10.4/5.1 Hz, 1 H, 1ЈЈЈ-Hb), 3.74Ϫ3.84 (m, 1 H, 2ЈЈ-H),
(m, 1 H, 2Ј-H), 3.87Ϫ3.97 (m, 1 H, 5Ј-H). Ϫ 13C NMR (75 MHz, 3.84Ϫ4.08 (m, 2 H, 4-H, 5ЈЈ-H), 4.97 (dq, J ϭ 6.8/1.1 Hz, 1 H, 5-
CDCl3): δ ϭ 4.4 (SiCH2CH3)3, 6.7 (SiCH2CH3)3, 25.8, 26.1, 28.0, H), 5.27Ϫ5.52 (m, 2 H, 4Ј-H, 5Ј-H), 7.09 (d, J ϭ 1.5 Hz, 1 H, 4-
30.9, 32.7, 36.9 (C-3Ј,4Ј,2Ϫ5), 62.9 (C-1), 65.8 (C-1ЈЈ), 79.4 (C-5Ј),
79.9 (C-2Ј). Ϫ C16H34O3Si (302.52): calcd. C 63.52, H 11.33; found
C 63.20, H 11.26.
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.6, Ϫ4.4 (2 SiCH3), 4.4
(2 SiCH2CH3), 6.7 (2 SiCH2CH3), 18.0 [SiC(CH3)3], 18.9 (CH3),
25.8 [SiC(CH3)3], 26.0, 27.5, 27.9, 29.7, 31.8, 32.6, 35.0, 35.9 (C-
2212
Eur. J. Org. Chem. 2000, 2207Ϫ2217

Synthesis of Muricatetrocin
FULL PAPER
1Ј,3Ј,6Ј-9Ј,3ЈЈ,4ЈЈ), 65.8 (C-1ЈЈЈ), 70.00 (C-2Ј), 77.4 (C-5), 79.4 (C-
5ЈЈ), 79.9 (C-2ЈЈ), 124.8 (C-5Ј), 130.9 (C-3), 132.1 (C-4Ј), 151.5 (C-
4), 173.9 (C-2). Ϫ HRMS (EI): C31H58O5Si2 calcd. 567.3901, found
567.3909 ([M ϩ H]ϩ).
of alcohol 12 (116 mg, 255 µmol) in CH2Cl2 (1 mL) was added at
Ϫ65 °C. After another 20 min of stirring, the solution was treated
at Ϫ50 °C with NEt3 (0.25 mL, 1.79 mmol). The mixture was
stirred for 30 min at Ϫ50 °C and a further 60 min at 0 °C. Then the
reaction was quenched by the addition of phosphate buffer solution
(2 mL, 1 , pH 7), water (3 mL) and CH2Cl2 (5 mL). The phases
were separated and the aqueous layer was extracted with CH2Cl2
(3ϫ 4 mL). The combined organic layers were washed with water
(2ϫ 5 mL) and dried with MgSO4. The solution was concentrated
in vacuo and the residue was purified by FCC (20 g silica gel, cyclo-
hexane/MTBE 1:1) to afford aldehyde 13 (101 mg, 87%) as a col-
ourless oil. Rf ϭ 0.33 (n-hexane/MTBE 1:2); [α]2D7 ϭ Ϫ9.7 (c ϭ
0.98, CHCl3). Ϫ IR (film): ν˜ ϭ 2930/2857 s (CH), 1757 s (CϭO),
1735 m (CϭO) 1463 w, 1258 w, 1076 m, 836 m, 775 w. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ Ϫ0.03Ϫ0.04 (m, 6 H, 2ϫ SiCH3), 0.84 [s,
9 H, SiC(CH3)3], 1.39 (d, J ϭ 6.8 Hz, 3 H, CH3), 1.20Ϫ2.24 (m,
18 H, 3,4,1Ј-7Ј-CH2), 2.39 (d, J ϭ 5.7 Hz, 2 H, 9Ј-H2), 3.88Ϫ4.04
(m, 2 H, 5-H, 8Ј-H), 4.21 (ddd, J ϭ 8.5/5.5/1.7 Hz, 1 H, 2-H),
4.93Ϫ5.02 (m, 1 H, 5ЈЈ-H), 7.09 (d, J ϭ 1.1 Hz, 1 H, 4ЈЈ-H), 9.65
(d, J ϭ 1.9 Hz, 1 H, CHO). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
Ϫ4.5 (2 SiCH3), 18.0 [SiC(CH3)3], 18.9 (CH3), 25.8 [SiC(CH3)3],
25.1, 26.1, 27.8, 29.46, 29.51, 29.6, 31.0, 32.7, 35.6, 36.9 (C-3,C-
4,C-1Ј-7Ј,C-9Ј), 70.1 (C-8Ј), 77.4 (C-5ЈЈ), 81.5 (C-2), 82.9 (C-5),
130.8 (C-3ЈЈ), 151.5 (C-4ЈЈ), 174.0 (C-2ЈЈ), 203.3 (CHO). Ϫ HRMS
(EI): C25H44O5Si calcd. 453.3036, found 453.3038 ([M ϩ H]ϩ).
(5S)-3-{(2ЈR)-tert-Butyldimethylsilyloxy-9Ј-{(2ЈЈS,5ЈЈS)-5ЈЈ-
(hydroxymethyl)tetrahydrofuran-2ЈЈ-yl}nonyl}-5-methylfuran-2(5H)-
one (12). ؊ 1. Wilkinson Hydrogenation: A solution of (PPh3)3RhCl
(61 mg, 0.07 mmol) in benzene (4 mL, spectroscopy grade) was de-
gassed and stirred under hydrogen for 15 min. A solution of olefin
11 (258 mg, 0.44 mmol) in benzene (2 mL) was added and the mix-
ture was stirred under hydrogen (1 atm) for 3 h at room temp. The
solution was concentrated in vacuo and the residue was purified by
FCC (18 g silica gel, cyclohexane/MTBE 2:1) to yield the hydro-
genation product as a light brown oil (207 mg, 83%). Ϫ (5S)-
3-{(2ЈR)-tert-Butyldimethylsilyloxy-9Ј-[(2ЈЈS,5ЈЈS)-5ЈЈ-{(triethyl-
silyl)oxymethyl}tetrahydrofuran-2ЈЈ-yl]nonyl}-5-methyl-
furan-2(5H)-one: Rf ϭ 0.46 (silica gel, treated with 1  AgNO3, n-
hexane/MTBE 2:1); [α]2D2 ϭ 7.2, (c ϭ 0.16, CHCl3). Ϫ IR (film):
ν˜ ϭ 2953/2931 s (CH), 2877/2857 m (CH), 1759 s (CϭO), 1462 w,
1253 w, 1075 m, 836 w, 776 w. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ Ϫ0.03Ϫ0.09 (m, 6 H, 2ϫ SiCH3), 0.58 (q, J ϭ 7.8 Hz, 6 H,
3ϫ SiCH2CH3), 0.85 (s, 9 H, SiC(CH3)3), 0.93 (t, J ϭ 7.9 Hz, 9 H,
3ϫ SiCH2CH3), 1.39 (d, J ϭ 7.2 Hz, 3 H, CH3), 1.17Ϫ1.76 (m, 16
H, 8ϫ alkyl-CH2), 1.81Ϫ2.02 (m,2 H, alkyl-CH2), 2.37Ϫ2.43 (m,
2 H,1Ј-H2), 3.48 (dd, J ϭ 10.4/5.8 Hz, 1 H, 1ЈЈЈ-Ha), 3.61 (dd, J ϭ
10.4/5.1 Hz, 1 H, 1ЈЈЈ-Hb), 3.67Ϫ4.06 (m, 3 H, 2Ј-H, 2ЈЈ-H, 5ЈЈ-H),
4.93Ϫ5.03 (m, 1 H, 5-H), 7.09 (d, J ϭ 1.5 Hz, 1 H, 4-H). Ϫ 13C
Hexadec-3-yn-1-ol (17): Ammonia (50 mL, predried with sodium)
was condensed in a 150 mL three-neck flask at Ϫ78 °C under argon
NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5 (2 SiCH3), 4.4 (2 SiCH2CH3), atmosphere. A solution of nBuLi (13 mL, 32 mmol, 2.46  in hex-
6.7 (2 SiCH2CH3), 18.0 [SiC(CH3)3], 19.0 (CH3), 26.9 [SiC(CH3)3],
25.1, 25.8, 26.2, 28.0, 29.5, 29.6, 30.8, 32.7, 36.0, 36.9 (C-1Ј,3Ј-
anes) was added. The obtained suspension was stirred for 15 min,
then it was treated with a solution of butynol (1.17 g, 16.7 mmol)
9Ј,3ЈЈ,4ЈЈ), 65.8 (C-1ЈЈЈ), 70.2 (C-2Ј), 77.4 (C-5), 79.4 (C-5ЈЈ), 80.0 in THF (25 mL). The cooling bath was removed and the mixture
(C-2ЈЈ), 130.8 (C-3), 151.5 (C-4), 174.0 (C-2). Ϫ HRMS (EI): was allowed to reflux for 30 min. After the addition of bromodode-
C31H60O5Si2 calcd. 569.4058, found 569.4057 ([M ϩ H]ϩ). Ϫ 2. cane (1.60 g, 6.42 mmol) in THF (25 mL) and a further 15 min of
TES-Deprotection: At Ϫ20 °C a solution of camphorsulfonic acid
(CSA) (2.4 mg, 10 µmol) in MeOH (1 mL) was added to a solution
of the protected alcohol (194 mg, 340 µmol) in CH2Cl2 (5 mL). The
mixture was stirred at Ϫ20 °C for 10 min, and then phosphate buf-
fer solution (1 , pH 7) (3 mL) and water (2 mL) were added. The
aqueous layer was extracted with MTBE (4ϫ 5 mL) and the com-
stirring, DMPU (20 mL, freshly distilled) was added. The mixture
was allowed to reflux for another 15 min, then kept at Ϫ40 °C
overnight (cryostat) and then refluxed for further 8 h. The reaction
was quenched by the addition of solid NH4Cl. The ammonia was
allowed to evaporate and then water (50 mL) and MTBE (50 mL)
were added and the phases were separated. The aqueous layer was
bined organic layers were washed with sat. aqueous NaCl (2ϫ extracted with MTBE (3ϫ 50 mL) and the combined organic layers
7 mL) and dried with MgSO4. The solvents were evaporated in va-
cuo and the residue was purified by FCC (12 g silica gel, MTBE)
to yield the primary alcohol 12 (117 mg, 75%) as a colourless li-
were washed with sat. aqueous NaCl (100 mL) and dried with
MgSO4. The solvents were removed in vacuo and the residue was
purified by CC (100 g silica gel, hexane/MTBE 1:1) to afford
quid. Rf ϭ 0.48 (MTBE); [α]2D4 ϭ 12.4 (c ϭ 1.2, CHCl3). Ϫ IR 771 mg (50%) of alkynol 17 as a white waxy solid. 17: Rf ϭ 0.38
(film): ν˜ ϭ 3455 w br (OH), 2930 s (CH), 2857 m (CH), 1756 m (n-hexane/MTBE 1:1). Ϫ IR (film): ν˜ ϭ 3221 br m (OH), 2953 m/
(CϭO), 1464 w, 1373 w, 1318 w, 1255 w, 1204 w, 1078 m, 837 m,
2917/2849 s (CH), 1468 m (CH2), 1044 w, 720 w. Ϫ 1H NMR
1
775 w. Ϫ H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.04Ϫ0.04 (m, 6 H, (300 MHz, CDCl3): δ ϭ 0.68 (t, J ϭ 6.2 Hz, 3 H, 16-H3), 1.18Ϫ1.40
2ϫ SiCH3), 0.84 [s, 9 H, SiC(CH3)3], 1.38 (d, J ϭ 6.8 Hz, 3 H, (m, 18 H, 7Ϫ15-H2), 1.78 (t, J ϭ 6.2 Hz, 2 H, OH), 1.39Ϫ1.51 (m,
CH3), 1.18Ϫ2.04 (m, 18 H, 9ϫ alkyl-CH2), 2.39 (d, J ϭ 5.6 Hz, 2
2 H), 2.10Ϫ2.16 (m, 2 H), 2.37Ϫ2.43 (m, 2 H) (2,5,6-H2), 3.65 (dt,
H, 1Ј-H2), 3.39Ϫ3.50 (m, 1 H, 1ЈЈЈ-Ha), 3.61Ϫ3.70 (m, 1 H, 1ЈЈЈ- J ϭ 6.2 Hz, 1-H2). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.1 (C-
Hb), 3.77Ϫ4.02 (m, 3 H, 4-H, 12-H, 5ЈЈ-H), 4.92Ϫ5.02 (m, 1 H, 5-
H), 7.09 (d, J ϭ 1.1 Hz, 1 H, 4-H). Ϫ 13C NMR (75 MHz, CDCl3):
16), 18.7, 22.7, 23.2, 28.9, 29.0, 29.2, 29.3, 29.5, 29.6, 29.7, 31.9 (C-
2, 5Ϫ15), 61.4 (C-1), 76.2, 82.8 (C-3, C-4). Ϫ C16H30O (238.41):
calcd. C 80.61, H 12.68; found C 80.77, H 12.40.
δ
ϭ Ϫ4.5 (2 SiCH3), 18.0 [SiC(CH3)3], 18.9 (CH3), 25.8
[SiC(CH3)3], 25.1, 26.2, 26.9, 27.0, 29.5, 29.6, 31.4, 32.7, 35.9, 36.9
(C-1Ј,3Ј-9Ј,3ЈЈ,4ЈЈ), 65.3 (C-1ЈЈЈ), 70.1 (C-2Ј), 77.4 (C-5), 79.8 (C-
5ЈЈ), 80.2 (C-2ЈЈ), 130.8 (C-3), 151.5 (C-4), 174.0 (C-2). Ϫ HRMS
(EI): C25H46O5Si calcd. 455.3193, found 455.3194 ([M ϩ H]ϩ).
O-Benzyl-(E)-hexadec-3-en-1-ol (18). ؊ 1. (E)-Selective Reduction:
Alkynol 17 (771 mg, 6.42 mmol), dissolved in diglyme (8 mL), was
treated with LiAlH4 (350 mg, 9.22 mmol). The mixture was stirred
for 14 h at 100 °C. After cooling to 0 °C, MTBE (25 mL) was
added and then water (0.35 mL), NaOH (0.35 mL, 15% in water),
(2S,5S)-5-{(8ЈR)-8Ј-tert-Butyldimethylsilyloxy-9Ј-[{(5ЈЈS)-5ЈЈ-
methyl-2ЈЈ-oxo-2ЈЈ,5ЈЈ-dihydrofuran-3ЈЈ-yl}nonyl]tetrahydrofuran}-2- and again water (1 mL) were added dropwise. After 1 h of stirring
carbaldehyde (13): To a solution of oxalyl chloride (0.06 mL, at 50 °C the precipitate was removed by filtration through a pad
0.64 mmol) in CH2Cl2 (6 mL) was added DMSO (0.09 mL, of celite. The precipitate was washed with MTBE and water. The
1.28 mmol) dropwise at Ϫ70 °C. After 15 min of stirring a solution
phases of the filtrate were separated and the aqueous layer was
Eur. J. Org. Chem. 2000, 2207Ϫ2217
2213

S. Bäurle, U. Peters, T. Friedrich, U. Koert
extracted with MTBE (3ϫ 30 mL). The combined organic layers 3.34Ϫ3.47 (m, 1 H), 3.59Ϫ3.79 (m, 3 H) (1-H2, 2-H2, 3-H, 4-H),
FULL PAPER
were washed with sat. aqueous NaCl (50 mL) and dried with
MgSO4. The solvents were removed in vacuo. The precipitate was
dissolved with hydrochloric acid (2 , 20 mL), the solution was
extracted with MTBE (3ϫ 20 mL) and the combined organic layers
were washed with sat. aqueous NaHCO3 (20 mL) and dried with
MgSO4. The solvents were removed in vacuo. The combined crude
products were purified by CC (90 g silica gel, PE/MTBE 1:1) to
afford 649 mg (83%) of the desired (E)-alkenol as a white waxy
solid. Ϫ (E)-Hexadec-3-en-1-ol: Rf ϭ 0.38 (n-hexane/MTBE 1:1).
Ϫ IR (film): ν˜ ϭ 3336 br m (OH), 2956 m/ 2921 s/2852 s (CH),
1467 w, 1049 w, 966 w, 721 w. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
0.86 (t, J ϭ 6.6 Hz, 3 H, 16-H3), 1.15Ϫ1.60 (m, 20 H, 6Ϫ15-H2),
1.95Ϫ2.02 (m, 2 H), 2.20Ϫ2.27 (m, 2 H) (2,5-H2), 3.53Ϫ3.68 (m, 2
H, 1-H2), 5.29Ϫ5.40 (m, 1 H), 5.48Ϫ5.59 (m, 1 H), (3,4-H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 14.1 (C-16), 22.7, 29.2, 29.3, 29.5,
29.5, 29.6, 29.6, 29.7, 29.7, 31.9, 32.7 (C-5Ϫ15), 36.0 (C-2), 62.0
(C-1), 125.6 (C-4), 134.5 (C-3). Ϫ C16H32O (240.42). Ϫ 2. Benzyl
Protection: (E)-Hexadec-3-en-1-ol (630 mg, 2.62 mmol) was dis-
solved in DMF (25 mL) and treated with NaH (190 mg, 7.9 mmol).
Two drops of DMSO were added and the mixture was stirred for
30 min at 50 °C. Then benzyl bromide (590 mg, 3.4 mmol) was ad-
ded dropwise and the suspension was stirred for another 24 h at 90
°C. After cooling to room temp., solid NH4Cl and water (30 mL)
were added and after 10 min stirring the phases were separated.
The aqueous layer was extracted with MTBE (3ϫ 20 mL) and the
combined organic layers were washed with sat. aqueous NaCl (2ϫ
25 mL) and dried with MgSO4. The solvents were removed in va-
cuo and the crude product was purified by CC (50 g silica gel,
cHexH/MTBE 20:1) to obtain 789 mg (91%) of benzyl ether 18 as
a colourless oil. Rf ϭ 0.40 (cHexH/MTBE 20:1). Ϫ IR (film): ν˜ ϭ
2925/2854 s (CH), 1362 w, 1101 m (COC), 909 m, 734 s/697 m (Ar).
4.51 (s, 2 H, PhCH2O), 7.20Ϫ7.39 (m, 5 H, Ph). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1 (C-16), 22.7, 25.8, 29.3 29.6, 29.6, 29.6,
29.7, 29.7, 31.9, 33.2, 33.5 (C-2, 5Ϫ15), 68.6 (C-1), 73.4 (PhCH2),
73.7, 74.3 (C-3, C-4), 127.7, 127.9, 128.5, 137.7 (Ph). Ϫ C23H40O3
(364.56): calcd. C 75.77, H 11.06; found C 75.69, H 11.30.
(3R,4R)-3,4-O-Isopropylidenehexadecane-1,3,4-triol (20). ؊ 1. Ace-
tonide Protection: Compound 19 (152 mg, 0.42 mmol) was dis-
solved in CH2Cl2 (10 mL) and 2,2-dimethoxypropane (152 mg,
0.42 mmol) and CSA (ca. 5 mg) was added at room temp. After
50 min of stirring, phosphate buffer solution (5 mL, pH 7, 1 )
and water (5 mL) were added and the phases were separated. The
aqueous layer was extracted with MTBE (3ϫ 10 mL) and the com-
bined organic layers were washed with sat. aqueous NaCl (2ϫ
15 mL) and dried with MgSO4. The solvents were removed in va-
cuo and the residue was filtered with cHexH/MTBE 20:1 over silica
gel to afford 161 mg (95%) of the protected triol as a colourless oil.
Ϫ (3R,4R)-1-O-Benzyl-3,4-O-isopropylidenehexadecane-1,3,4-triol:
Rf ϭ 0.33 (cHexH/MTBE 20:1); [α]2D9 ϭ 23.6 (c ϭ 1.0, CHCl3). Ϫ
IR (film): ν˜ ϭ 2926/2855 s, 1456 m, 1368 m, 1241 m, 1171 w, 1094
s, 1029 w, 872 w, 734 m/697 w. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 0.87 (t, J ϭ 6.9 Hz, 3 H, 16-H3), 1.20Ϫ1.34 (m, 20 H, 6Ϫ15-
H2), 1.36 (d, J ϭ 2.3 Hz, 6 H, acetonide-CH3), 1.37Ϫ1.58 (m, 2 H,
5-H2), 1.72Ϫ1.95 (m, 2 H, 2-H2), 3.53Ϫ3.69 (m, 3 H, 1-Ha, 3,4-H),
3.73 (dt, J ϭ 8.1/3.8 Hz, 1 H, 1-Hb), 4.50 (s, 2 H, PhCH2O),
7.21Ϫ7.35 (m, 5 H, Ph). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.1
(C-16), 22.7, 26.1, 27.2, 27.3, 29.3, 29.5, 29.6, 29.7, 29.7, 29.8, 31.9,
32.7, 33.2 (C-2, 5Ϫ15, acetonide-CH3), 67.3 (C-1), 73.0 (PhCH2),
78.1, 81.0 (C-3, C-4), 107.9 (OCO), 127.5, 127.6, 128.3, 138.4 (Ph).
Ϫ C26H44O3 (404.63): calcd. C 77.18, H 10.96; found C 77.06, H
10.98. Ϫ 2. Cleavage of the Benzyl Ether: Palladium on activated
carbon (15 mg, 10% Pd) was suspended in a solution of the benzyl-
protected alcohol (132 mg, 0.33 mmol) in EtOAc (20 mL, HPLC-
grade). The mixture was degassed at 0 °C and then vigorously
stirred under hydrogen (1 atm) for 20 h at room temp. Then the
suspension was filtered through a pad of celite and the solvent was
evaporated in vacuo. The alcohol 20 was obtained in 95% yield
(98 mg) as a colourless oil which needed no further purification.
20: Rf ϭ 0.29 (n-hexane/MTBE 2:1); [α]2D3 ϭ 20.5 (c ϭ 1.0, CHCl3).
Ϫ IR (film): ν˜ ϭ 3430 br. m (OH), 1056 s, 874 w. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 6.9 Hz, 3 H, 16-H3), 1.15Ϫ1.23
(m, 20 H, 6Ϫ15-H2), 1.36 (s, 6 H, acetonide-CH3), 1.40Ϫ1.58 (m,
2 H, 5-H2), 1.64Ϫ1.87 (m, 2 H, 2-H2), 2.46 (br. s, 1 H, OH),
3.59Ϫ3.74 (m, 2 H, 3,4-H), 3.78 (t, J ϭ 5.7 Hz, 2 H, 1-H2). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 14.1 (C-16), 22.7, 26.0, 27.2, 27.3,
29.3, 29.5, 29.5, 29.6, 29.6, 29.7, 31.9, 32.5, 34.7 (C-2, 5Ϫ15, ace-
tonide-CH3), 60.9 (C-1), 80.2, 81.0 (C-3, C-4), 108.3 (OCO). Ϫ
C19H38O3 (314.50): calcd. C 72.56, H 12.18; found C 72.41, H
12.35.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.87 (t, J ϭ 6.8 Hz, 3 H, 16-
H3), 1.13Ϫ1.39 (m, 20 H, 6Ϫ15-H2),1.97 (dt, J ϭ 6.7 Hz, 6.7 Hz,
2 H, 5-H2), 2.31 (dt, J ϭ 6.6 Hz, 6.6 Hz, 2 H, 2-H2), 3.47 (t, J ϭ
7.0 Hz, 2 H, 1-H2), 4.51 (s, 2 H, PhCH2O), 5.33Ϫ5.58 (m, 2 H, 3,4-
H), 7.17Ϫ7.47 (m, 5 H, Ar). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
14.1 (C-16), 22.7, 29.2, 29.4, 29.5, 29.5, 29.6, 29.7, 29.7, 29.7, 31.9,
32.7, 33.1 (C-2, C-5Ϫ15), 70.3 (C-1), 72.8 (PhCH2), 126.1 (C-4),
127.5, 127.6, 128.2, 128.3, 128.7, 138.6 (Ph), 132.7 (C-3). Ϫ
C23H38O (330.55): calcd. C 83.57, H 11.59; found C 83.77, H 11.61.
(3R,4R)-1-O-Benzylhexadecane-1,3,4-triol (19): Alkene 18 (789 mg,
2.38 mmol) was dissolved in tBuOH/H2O 1:1 (20 mL), cooled to 0
°C and treated with AD-mix β (3.34 g) and methanesulfonamide
(226 mg, 2.38 mmol). The mixture was allowed to warm to room
temp. and was stirred for 20 h. The colour changed from orange
to yellow. The reaction was quenched by the addition of sodium
thiosulfate pentahydrate (3.48 g, 14 mmol). After 15 min, MTBE
(20 mL) was added and the phases were separated. The aqueous
layer was extracted with MTBE (3ϫ 15 mL), the combined organic
layers were washed with sat. aqueous NaCl (2ϫ 15 mL) and dried
with MgSO4. The solvents were evaporated in vacuo and the res-
idue was purified by CC (80 g silica gel, PE/MTBE 3:1) to yield
782 mg (90%) of the dihydroxylated product 19 as a colourless
solid. The enantiomeric ratio was determined by chiral HPLC to
(3R,4R)-1-Iodo-3,4-O-isopropylidenehexadecane-3,4-diol (21): To a
solution of imidazole (58 mg, 0.84 mmol) and PPh3 (81 mg,
0.31 mmol) in CH2Cl2 (7 mL) at 0 °C was added first a solution of
iodine (87 mg, 0.34 mmol) in CH2Cl2 (3 mL) and then a solution
be 98:2. m.p.: 62 °C; Rf ϭ 0.34 (n-hexane/MTBE 1:3); HPLC: Rt of alcohol 20 (89 mg, 0.28 mmol) in CH2Cl2 (1.5 mL). The reaction
(R,R-isomer) ϭ 11.2 min, Rt (S,S-isomer) ϭ 14.8 min, (Chiralcel-
OD-H, n-hexane/iPrOH 96:4, 1.0 mL minϪ1); [α]2D1 ϭ 7.5 (c ϭ 1.0,
CHCl3). Ϫ IR (film): ν˜ ϭ 3414/3032 br. s (OH), 2957 w/2919/2850
mixture was stirred at room temp. for 5 h, and then sat. aqueous
Na2S2O3 was added dropwise until the brown colour disappeared.
The phases were separated and the aqueous layer was extracted
s (CH), 1471 m, 1372 m, 1105 m, 1072 m, 859 w, 729 m/695 w. Ϫ with MTBE (3ϫ 10 mL). The combined organic layers were
1H NMR (300 MHz, CDCl3): δ ϭ 0.86 (t, J ϭ 6.6 Hz, 3 H, 16-
H3), 1.11Ϫ1.45 (m, 22 H, 5Ϫ15-H2), 2.42 (d, 1 H, J ϭ 5.7 Hz, 1
washed with sat. aqueous NaCl (2ϫ 15 mL) and dried with
MgSO4. The solvents were evaporated in vacuo and the residue was
H, OH), 3.12 (d, 1 H, J ϭ 3.8 Hz, 1 H, OH), 1.70Ϫ1.96 (m, 2 H), purified by CC (30 g silica gel, PE/MTBE 2:1) to yield iodide 21
2214 Eur. J. Org. Chem. 2000, 2207Ϫ2217

Synthesis of Muricatetrocin
FULL PAPER
(79 mg, 66%) as a colourless oil. 21: Rf ϭ 0.67 (n-hexane/MTBE
27.2, 27.3, 29.3, 29.5, 29.5, 29.6, 29.7, 29.8, 31.3, 31.9, 32.7, 32.8
2:1). Ϫ IR (film): ν˜ ϭ 2986 w/2925 s/2854 s, 1466 w, 1378 m, 1369 (C-3,5Ϫ11,13,14,17,18,21Ϫ31, acetonide-CH3), 70.1 (C-4), 72.1 (C-
1
m, 1237 m, 1173 w, 1088 w, 857 w, 563 w. Ϫ H NMR (300 MHz,
16), 77.4 (C-34), 79.7 (C-15), 80.8 (C-12), 80.9, 82.1 (C-19, C-20),
CDCl3): δ ϭ 0.83Ϫ0.89 (m, 3 H, 16-H3), 1.17Ϫ1.34 (m, 20 H, 107.9 (OCO), 130.8 (C-2), 151.5 (C-33), 174.0 (C-1). Ϫ HRMS
6Ϫ15-H2), 1.35 (d, J ϭ 5.3 Hz, 6 H, acetonide-CH3), 1.43Ϫ1.61 (EI): C44H82O7Si calcd. 750.5830, found 750.5823 ([M]ϩ).
(m, 2 H, 5-H2), 1.96Ϫ2.11 (m, 2 H, 2-H2), 3.16Ϫ3.37 (m, 2 H, 3,4-
H), 3.57Ϫ3.72 (m, 2 H, 1-H2). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
1.8 (C-1), 14.1 (C-16), 22.7, 26.0, 27.2, 27.3, 29.3, 29.5, 29.6, 29.6,
(4R,12S,15S,16S,19R,20R,34S)-Muricatetrocin (1): The protected
compound 22 (20 mg, 26.6 µmol) was dissolved in CH2Cl2 (1 mL)
29.7, 29.7, 31.9, 32.8 (C-5Ϫ15, acetonide-CH3), 37.5 (C-2), 80.3,
and HF CH3CN (0.24 mL, 80 µmol) was added dropwise at room
80.6 (C-3, C-4), 108.4 (OCO). Ϫ C19H37IO2 (424.40): calcd. C
temp. After 1 h of stirring, a solution of CSA (3 mg, 12 µmol) in
53.77, H 8.79; found C 53.92, H 9.10.
MeOH (0.5 mL) was added and the solution was stirred for a fur-
ther 60 min. Then phosphate buffer solution (pH 7, 1 , 0.5 mL),
water (2 mL) and CH2Cl2 (3 mL) were added. The aqueous layer
(4R,12S,15S,16S,19R,20R,34S)-4-O-(tert-Butyldimethylsilyl)-19,20-
was extracted with CH2Cl2 (4ϫ 2 mL) and CHCl3/iPrOH 1:1 (2ϫ
O-isopropylidenemuricatetrocin (22) and (4R,12S,15S,16R,19R,
2 mL). The combined organic layers were dried with MgSO4. The
20R,34S)-4-O-(tert-butyldimethylsilyl)-19,20-O-isopropylidene-
muricatetrocin (23): In a 10-mL Schlenk tube a solution of iodide
solvents were evaporated in vacuo and the residue was purified by
FCC (8 g silica gel, first n-hexane/MTBE 1:2, then CHCl3/MeOH
21 (73 mg, 172 µmol) in Et2O (3 mL) was cooled to Ϫ105 °C and
10:1) to yield 10.8 mg (68%) of the product 1 as a colourless solid.
treated with tert-butyllithium (0.23 mL, 1.48  in pentane, 422
Final impurities were removed by preparative HPLC (Rainin Si 60,
µmol). After 4 min at Ϫ100 °C, MgBr2 Et2O (0.14 mL, 543 µmol)
was added. The formation of a colourless solid was observed. The
reaction mixture was allowed to warm up to Ϫ25 °C over 2 h. Then
21.4 ϫ 250 mm, n-hexane/iPrOH 80:20, 20 mL minϪ1). Rf ϭ 0.31
(CHCl3/MeOH 10:1); Rt ϭ 18.4 min (Superspher Si 60, n-hexane/
iPrOH 75:25, 1.0 mL minϪ1); UV: λmax ϭ 215 nm; [α]3D2 ϭ 12.5 (c ϭ
the mixture was cooled to Ϫ78 °C and a solution of aldehyde 13
1.1, CHCl3). Ϫ IR (film): ν˜ ϭ 3408 m br (OH), 2919 s /2850 m
(60 mg, 133 µmol) in cold Et2O (2 mL) was added. The solution
was allowed to warm up to Ϫ5 °C over 2 h. The reaction was
quenched by the addition of phosphate buffer solution (1 , pH
7, 2 mL). The mixture was diluted with water (5 mL) and MTBE
(CH), 1746 m (CϭO), 1467 w, 1322 w, 1202 w, 1067 w, 1025 w,
1
853 w. Ϫ H NMR (300 MHz, CDCl3): see Table 1. Ϫ 13C NMR
(75 MHz, CDCl3): see Table 2. Ϫ MS (EI): m/z ϭ 597 [M ϩ H]ϩ,
379 [M Ϫ (C-20Ϫ32) Ϫ H2O]ϩ, 361 [M Ϫ (C-20Ϫ32) Ϫ 2 H2O]ϩ,
(10 mL). The aqueous layer was extracted with MTBE (4ϫ 5 mL)
309 [M Ϫ (C-16Ϫ32)]ϩ, 291 [M Ϫ (C-16Ϫ32) Ϫ H2O]ϩ, 269 [(C-
and CH2Cl2 (1ϫ 5 mL). The combined organic layers were washed
16Ϫ32) Ϫ H2O]ϩ, 141 [(C-1Ϫ4/C-33Ϫ35)]ϩ. Ϫ HRMS (EI):
with sat. aqueous NaCl (2ϫ 6 mL) and dried with MgSO4. The
solvents were removed in vacuo and the residue was purified by
C35H64O7 calcd. 597.4730, found 597.4736 ([M ϩ H]ϩ).
FCC (20 g silica gel, gradient PE/MTBE 1:1 to 1:2) to yield the
coupling products 22 and 23 (60 mg, 60%) as a colourless oil. Alde-
hyde 13 (28%, 17 mg) was reisolated. The 1:1 mixture (13C NMR) compound 23 (20 mg, 26.6 µmol) was dissolved in CH2Cl2 (1 mL)
of the C-16 epimers 22 and 23 was separated by optimized flash and HF CH3CN (0.24 mL, 80 µmol) was added dropwise at room
chromatography (40 g silica gel, PE/MTBE 2:1 to MTBE). Ϫ 22: temp. After 1 h of stirring, a solution of CSA (3 mg, 12 µmol) in
Rf ϭ 0.50 (n-hexane/MTBE 1:2); [α]2D2 ϭ 10.7 (c ϭ 0.37, CHCl3).
MeOH (0.5 mL) was added and the solution was stirred for a fur-
(4R,12S,15S,16R,19R,20R,34S)-Muricatetrocin (24): The protected
Ϫ IR (film): ν˜ ϭ 3501 w br (OH), 2928 s/2856 m (CH), 1760 m ther 60 min. Then phosphate buffer solution (pH 7, 1 , 0.5 mL),
(CϭO), 1463 w, 1376 w, 1251 w, 1073 m, 836 w, 775 w. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ Ϫ0.02Ϫ0.06 [m, 6 H, Si(CH3)], 0.81Ϫ0.90
water (2 mL) and CH2Cl2 (3 mL) were added. The aqueous layer
was extracted with CH2Cl2 (4 ϫ 2 mL) and CHCl3/iPrOH 1:1 (2
[m, 12 H, SiC(CH3)3, 32-H3], 1.19Ϫ2.12 (m, 44 H, alkyl), 1.39 (d, ϫ 2 mL). The combined organic layers were dried with MgSO4.
J ϭ 6.8 Hz, 3 H, 35-H3), 2.36Ϫ2.43 (m, 2 H, 3-H2), 2.51 (d, J ϭ The solvents were evaporated in vacuo and the residue was purified
4.1 Hz, 1 H, OH), 3.31Ϫ3.42 (m, 1 H), 3.51Ϫ3.62 (m, 2 H),
by FCC (8 g silica gel, first n-hexane/MTBE 1:2, then CHCl3/
3.62Ϫ3.75 (m, 1 H), 3.76Ϫ3.88 (m, 1 H), 3.88Ϫ4.06 (m, 1 H) MeOH 10:1) to yield 10.0 mg (63%) of 24 as a colourless solid
(4,12,15,16,19,20-H), 4.98 (dq, J ϭ 6.8/1.3 Hz, 1 H, 34-H), 7.10 (d,
which needed no further purification. Rf ϭ 0.28 (CHCl3/MeOH
J ϭ 1.1 Hz, 1 H, 33-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5, 10:1); Rt ϭ 16.4 min (Superspher Si 60, n-hexane/iPrOH 75:25,
(2 SiCH3), 14.1 (C-32), 18.0 [SiC(CH3)3], 19.0 (C-35), 29.6 1.0 mL minϪ1); UV: λmax ϭ 216 nm; [α]3D2 ϭ 12.4 (c ϭ 0.5, CHCl3).
[SiC(CH3)3], 22.7, 25.1, 25.9, 26.1, 26.2, 27.3, 27.8, 29.3, 29.5,
29.6, 29.7, 29.8, 31.3, 31.9, 32.7, 36.0, 36.9 (C-
3,5Ϫ11,13,14,17,18,21Ϫ31, acetonide-CH3), 70.2 (C-4), 74.5 (C-
16), 77.5 (C-34), 79.9 (C-15), 81.2, 81.3, 82.3 (C-12, C-19, C-20),
Ϫ IR (film): ν˜ ϭ 3395 m br (OH), 2922 s /2853 m (CH), 1744 m
(CϭO), 1453 w, 1322 w, 1205 w, 1076 w, 1028 w. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 6.8 Hz, 3 H, 32-H3), 1.41 (d,
J ϭ 6.8 Hz, 3 H, 35-H3), 1.21Ϫ1.34, 1.35Ϫ2.07 (m, 44 H, alkyl),
107.8 (OCO), 130.8 (C-2), 151.5 (C-33), 174.0 (C-1). Ϫ HRMS 2.28Ϫ2.58 (m, 2 H, 3-H2), 3.30Ϫ3.50 (m, 3 H, 19,20-H), 3.70Ϫ3.92
(EI): C44H82O7Si calcd. 750.5830, found 750.5834 ([M]ϩ). Ϫ 23:
(m, 4 H, 4,12,15,16-H), 5.03 (dq, J ϭ 6.8/1.4 Hz, 1 H, 34-H), 7.16
Rf ϭ 0.46 (n-hexane/MTBE 1:2); [α]2D2 ϭ 11.9 (0.42, CHCl3). Ϫ IR (d, J ϭ 1.5 Hz, 1 H, 33-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
(film): ν˜ ϭ 3488 w br (OH), 2927 s/2856 m (CH), 1761 s (CϭO), 14.1 (C-32), 19.1 (C-35), 22.7 (C-31), 24.4, 25.5, 25.7, 26.1, 27.0,
1464 w, 1376 w, 1254 w, 1076 m, 836 w, 775 w. Ϫ 1H NMR 29.32, 29.35, 29.37, 29.5, 29.60, 29.62, 29.64, 29.66, 29.70, 31.0,
(300 MHz, CDCl3): δ ϭ Ϫ0.02Ϫ0.05 [m, 6 H, Si(CH3)], 0.82Ϫ0.90
31.2, 33.7, 35.7 (C-6Ϫ11,13,14,17,18,21Ϫ30), 33.3 (C-3), 37.4 (C-
[m, 12 H, SiC(CH3)3, 32-H3], 1.18Ϫ2.07 (m, 44 H, alkyl), 1.39 (d, 5), 69.9 (C-4), 72.3 (C-16), 74.5, 74.8 (C-19, C-20), 78.0 (C-34),
J ϭ 6.8 Hz, 3 H, 35-H3), 2.40 (d, J ϭ 5.7 Hz, 2 H, 3-H2), 2.65 (br. 79.7 (C-12), 82.0 (C-15), 131.2 (C-2), 151.8 (C-33), 174.6 (C-1). Ϫ
s, 1 H, OH), 3.53Ϫ3.63 (m, 2 H), 3.65Ϫ3.87 (m, 3 H), 3.87Ϫ4.02 MS (EI): m/z ϭ 597 [M ϩ H]ϩ, 379 [M Ϫ (C-20Ϫ32) Ϫ H2O]ϩ,
(m, 1 H) (4,12,15,16,19,20-H), 4.98 (dq, J ϭ 6.8/1.2 Hz, 1 H, 34-
361 [M Ϫ (C-20Ϫ32) Ϫ 2H2O]ϩ, 309 [M Ϫ (C-16Ϫ32)]ϩ, 291 [M
Ϫ (C-16Ϫ32) Ϫ H2O]ϩ, 269 [(C-16Ϫ32) Ϫ H2O]ϩ, 199 [(C-
H), 7. 90 (d, J ϭ 1.1 Hz, 1 H, 33-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ4.6, (2 SiCH3), 14.1 (C-32), 18.0 [SiC(CH3)3], 19.0 20Ϫ32)]ϩ, 141 [(C-1Ϫ4/C-33Ϫ35)]ϩ. Ϫ HRMS (EI): C35H64O7
(C-35), 29.6 [SiC(CH3)3], 22.7, 24.8, 25.1, 25.8, 25.9, 26.1, 26.2, calcd. 597.4730, found 597.4736 ([M ϩ H]ϩ).
Eur. J. Org. Chem. 2000, 2207Ϫ2217
2215

S. Bäurle, U. Peters, T. Friedrich, U. Koert
FULL PAPER
(4R,12R,15S,16S,19R,20R,34S)-4-O-(tert-Butyldimethylsilyl)-
19,20-O-isopropylidenemuricatetrocin (25): In a 10-mL Schlenk
tube a solution of iodide 21 (27 mg, 63.2 µmol) in Et2O (1 mL) was
cooled to Ϫ105 °C and treated with tert-butyllithium (0.08 mL,
1.48  in pentane, 120 µmol). After 4 min at Ϫ100 °C, MgBr2 Et2O
(0.05 mL, 190 µmol) was added. The formation of a colourless
solid was observed. The reaction mixture was allowed to warm up
to Ϫ30 °C over 2 h. The precipitate redissolved at that temperature.
Then the mixture was cooled to Ϫ75 °C and a solution of aldehyde
14 (22 mg, 48.6 µmol) in cold Et2O (1 mL) was added. The solution
was allowed to warm up to Ϫ10 °C over 2 h. The reaction was
quenched by the addition of phosphate buffer solution (1 , pH 7,
1 mL). The mixture was diluted with water (5 mL) and MTBE
(10 mL). The aqueous layer was extracted with MTBE (4ϫ 5 mL)
and CH2Cl2 (1ϫ 5 mL). The combined organic layers were washed
with sat. aqueous NaCl (2ϫ 6 mL) and dried with MgSO4. The
solvents were removed in vacuo and the residue was fractionated
by FCC (15 g silica gel, gradient PE/MTBE 1:1 to 1:2) to afford a
crude coupling product (25 mg), which was purified by optimized
flash chromatography (18 g silica gel, gradient PE/MTBE 1:1 to
1:2) to yield 12.3 mg (34%) of the desired product 25 as a colourless
solid. The C-16-epimer was not observed. Aldehyde 14 (2.1 mg,
10%) was reisolated. Rf ϭ 0.52 (n-hexane/MTBE 1:2); [α]2D4 ϭ 4.5
(c ϭ 0.25 (CHCl3). Ϫ IR (film): ν˜ ϭ 3480 w br (OH), 2928 s/2856
m (CH), 1760 m (CϭO), 1463 w, 1373 w, 1251 w, 1071 m, 836 w,
777 w. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.03Ϫ0.07 (m, 6 H,
Si(CH3)), 0.80Ϫ0.90 (m, 12 H, SiC(CH3)3, 32-H3), 1.18Ϫ2.10 (m,
44 H, alkyl), 1.39 (d, J ϭ 6.8 Hz, 3 H, 35-H3), 2.40 (d, J ϭ 5.7 Hz,
2 H, 3-H2), 2.57 (d, J ϭ 3.4 Hz, 1 H, OH), 3.32Ϫ3.43 (m, 1 H),
3.50Ϫ3.62 (m, 2 H), 3.66Ϫ3.80 (m, 1 H), 3.76 (m, 1 H, 15-H),
3.81Ϫ3.98 (m, 1 H) (4,12,15,16,19,20-H), 4.98 (dq, J ϭ 6.8/1.3 Hz,
1 H, 34-H), 7.10 (d, J ϭ 1.1 Hz, 1 H, 33-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ4.5, (2 SiCH3), 14.1 (C-32), 19.0 [SiC(CH3)3], 19.2
(C-35), 29.6 [SiC(CH3)3], 22.7, 25.1, 25.8, 25.8, 25.9, 26.1, 27.0,
27.3, 28.4, 29.3, 29.5, 29.6, 29.7, 29.8, 30.3, 31.9, 32.4, 32.8, 35.6
(C-3,5Ϫ11,13,14,17,18,21Ϫ31, acetonide-CH3), 70.1 (C-4), 74.2 (C-
16), 77.5 (C-34), 79.3 (C-15), 81.2, 81.3, 82.0 (C-12, C-19, C-20),
107.9 (OCO), 130.8 (C-2), 151.5 (C-33), 174.0 (C-1). Ϫ HRMS
(EI): C44H82O7Si calcd. 751.5908, found 751.5911 ([M ϩ H]ϩ).
Acknowledgments
This work was supported by the Deutsche Forschungsgemein-
schaft, Fonds der Chemischen Industrie and ASTA-Medica AG.
We thank Prof. J. L. McLaughlin for sending us copies of the NMR
spectra of muricatetrocin A and muricatetrocin B.
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Nonadjacent THFϪTHP:
S. Takahashi, T. Nakata, Tetra-
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[5a]
Tris-THF:
S. C. Sinha, A. Sinha, S. C. Sinha, E. Keinan, J.
[5b]
Am. Chem. Soc. 1997, 119, 12014Ϫ12015. Ϫ
S. C. Sinha,
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[6a]
Adjacent bis-THF:
J. A. Marshall, H. Jiang, J. Nat. Prod.
1999, 62, 1123Ϫ1127. Ϫ [6b] S. C. Sinha, S. C. Sinha, E. Keinan,
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A. Sinha, S. C.
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2381Ϫ2386. Ϫ [6d] J. A. Marshall, H. Jiang, J. Org. Chem. 1999,
(4R,12R,15S,16S,19R,20R,34S)-Muricatetrocin (2): The protected
compound 25 (12 mg, 16 µmol) was dissolved in CH2Cl2 (1 mL)
and HF CH3CN (0.14 mL, 48 µmol) was added dropwise at room
temp. After 30 min of stirring, a solution of CSA (2 mg, 8 µmol)
in MeOH (0.5 mL) was added and the solution was stirred for a
further 60 min. Then phosphate buffer solution (pH 7, 1 ,
0.5 mL), water (2 mL) and CH2Cl2 (3 mL) were added. The aque-
ous layer was extracted with CH2Cl2 (4ϫ 2 mL) and CHCl3/iPrOH
1:1 (2ϫ 2 mL). The combined organic layers were dried with
MgSO4. The solvents were evaporated in vacuo and the residue
was purified by FCC (6 g silica gel, first n-hexane/MTBE 1:2, then
CHCl3/MeOH 10:1) to yield 8.0 mg (84%) of the product 2 as a
colourless solid. Final impurities were removed by preparative
HPLC (Rainin Si 60, 21.4 ϫ 250 mm, n-hexane/iPrOH 80:20, 20
mL minϪ1). Rf ϭ 0.24 (CHCl3/MeOH 10:1); Rt ϭ 17.6 min (Su-
perspher Si 60, n-hexane/iPrOH 75:25, 1.0 mL minϪ1); UV: λmax ϭ
214 nm; [α]2D8 ϭ 6.7 (c ϭ 0.4, CHCl3). Ϫ IR (film): ν˜ ϭ 3449/3305
m br (OH), 2954 w/ 2919 vs/2849 s (CH), 1742 m (CϭO), 1066 m,
1026 w, 853 w. Ϫ 1H NMR (300 MHz, CDCl3): see Table 3. Ϫ 13C
NMR (75 MHz, CDCl3): see Table 3. Ϫ MS (EI): m/z ϭ 597 [M
ϩ H]ϩ, 397 [M Ϫ (C-20Ϫ32)]ϩ, 379 [M Ϫ (C-20Ϫ32) Ϫ H2O]ϩ,
361 [M Ϫ (C-20Ϫ32) Ϫ 2 H2O]ϩ, 343 [M Ϫ (C-20Ϫ32) Ϫ 3 H2O]ϩ,
309 [M Ϫ (C-16Ϫ32)]ϩ, 291 [M Ϫ (C-16Ϫ32) Ϫ H2O]ϩ. Ϫ HRMS
(EI): C35H64O7 calcd. 597.4730, found 597.4736 ([M ϩ H]ϩ).
64, 971Ϫ975. Ϫ [6e] U. Emde, U. Koert, Tetrahedron Lett. 1999,
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40, 5979Ϫ5982. Ϫ
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[6h]
A. Yaz-
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5863Ϫ5868. Ϫ
B. M. Trost, T. L. Calkins, C. G. Bochet,
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61, 7640Ϫ7641. Ϫ
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[8]
[7a]
Nonadjacent bisϪTHF:
J. A. Marshall, H. Jiang, J. Org.
[7b]
Chem. 1998, 63, 7066Ϫ7071. Ϫ
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Oritani, Tetrahedron Lett. 1997, 38, 4247Ϫ4250.
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Mono-THF:
T.-S. Hu, Q. Yu, Q. Lin, Y.-L. Wu, Y. Wu,
[8b]
Org. Lett. 1999, 1, 399Ϫ401. Ϫ
Q. Wu, Z.-J. Yao, X.-G.
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Ϫ
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[8e]
1493Ϫ1496. Ϫ
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H. Makabe, H. Tanimoto, A. Tanaka, T.
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Other acetogenins:
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H. Konno,
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2216
Eur. J. Org. Chem. 2000, 2207Ϫ2217

Synthesis of Muricatetrocin
FULL PAPER
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2217