Total Synthesis of Macroviracin D (BA-2836-4)

Article abstract of DOI:10.1002/chem.200305588

The first total synthesis of the complex glycolipid macroviracin D (BA-2836-4) (1) is described. This antivirally active metabolite isolated from the mycelium extracts of Streptomyces sp. BA-2836 incorporates a unique 46-membered macrodilactone motif deco

Full text of DOI:10.1002/chem.200305588

FULL PAPER
Total Synthesis of Macroviracin D (BA-2836-4)
Jacek Mlynarski, Juliana Ruiz-Caro, and Alois F¸rstner*[a]
Abstract: The first total synthesis of
the complex glycolipid macroviracin D
(BA-2836-4) (1) is described. This anti-
virally active metabolite isolated from
the mycelium extracts of Streptomyces
sp. BA-2836 incorporates a unique 46-
membered macrodilactone motif deco-
rated with glycosylated fatty acid ap-
pendices. Compound 1 consists of three
identical subunits which are closely re-
lated to one of the segments found in
cycloviracin B1 (2), another antiviral
glycoconjugate previously synthesized
in our laboratory. Key steps of the syn-
thesis route to 1 involve the stereose-
lective, ligand-controlled addition of
the functionalized diorganozinc deriva-
tive 9 to aldehydes 8a,b, a series of b-
selective glycosidation reactions using
appropriately protected trichloroacet-
imidate donors, and three esterifica-
tions via the Yamaguchi method; one
of them is performed intramolecularly
to forge the macrocyclic lactone ring of
the target in 89% isolated yield. This
total synthesis also firmly establishes
the absolute configuration of the sub-
units of compound 1 as 3R,17S,23R.
Keywords: antiviral
carbohydrates
agents
glycolipids
¥
¥
¥
macrocycles ¥ natural products
Introduction
with respect to their core structures. While the ester linkages
in 2 are attached to the proximal 2-O-methyl-glucoside resi-
dues, they extend to the distal sugar entities in the macrovir-
acin series thus forming a 46-membered ring. This analysis
was corroborated by a recent model study[3] which proved
that the constitutive acid component 3 in 1 has in fact the
same stereochemistry as the right wing of 2. Since the latter
had been unambiguously shown to be (3R,17S,23R)-config-
ured by our total synthesis,[10,11] a viable plan for the con-
quest of 1 emerged. Outlined below is the successful reduc-
tion of this blueprint to practice.
The quest for novel antiviral agents has recently led to the
discovery of a new family of structurally rather intriguing
glycolipids isolated from the mycelium of Streptomyces sp.
BA 2836, which exhibit surprisingly strong and selective ac-
tivity against various human pathogens including herpes
simplex-, human immunodeficiency- and varicella-zoster
virus.[1,2] The homologous series of amphiphilic natural prod-
ucts was originally called ™BA-2836 compound(s)∫ after the
producing strain, but may be better termed ™macrovira-
cins∫[3] in view of their remarkable macrocyclic dilactone
core structure. Macroviracin D (BA-2836-4) 1 is a prototype
member of this family, differing from its congeners only in
the length of the fatty acid chains forming the central lactide
ring and the appendices attached to it.
Results and Discussion
Only three closely related synthons representing the individ-
ual subunits of macroviracin D (1) are required for the as-
sembly of this target. They merely differ in the chosen pro-
tecting groups which must be orthogonal to ensure selective
formations of the different ester linkages. Therefore all
building blocks can be derived from alcohol 4 which is
easily prepared from pentadecanolide as the starting materi-
Our keen interest in bioactive glycoconjugates[4 let us to
8]
recognize a subtle relationship between 1 and cyclovira-
cin B1 (2),[9] yet another antivirally active dilactone deriva-
tive of bacterial origin which was subject to intense prepara-
tive and biological studies in this laboratory.[10,11] Specifical-
ly, the three subunits forming compound 1 closely resemble
one of the inequivalent sectors of 2 (see Scheme 1). This
then suggests that the macroviracins and the cycloviracins–
while differing in their periphery–are constitutional isomers
al on
a
multigram scale as previously outlined
(Scheme 2).[10,11]
Glycosidation of 4 with the known trichloroacetimidates
5a[12] and 5b[10,11] promoted by TMSOTf in a mixed solvent
system comprising CH2Cl2 and MeCN afforded the corre-
sponding b-glycosides 6a and 6b, respectively, in excellent
yields.[13] It is noteworthy, however, that the O-6 protecting
group of the donor exerts a subtle influence on the stereo-
chemical course of the reaction. While the perbenzylated
[a] Dr. J. Mlynarski, Dr. J. Ruiz-Caro, Prof. A. F¸rstner
Max-Planck-Institut f¸r Kohlenforschung
45470 M¸lheim/Ruhr (Germany)
Fax : (+49)208-3062994
E-mail: fuerstner@mpi-muelheim.mpg.de
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DOI: 10.1002/chem.200305588
Chem. Eur. J. 2004, 10, 2214 2222

2214 2222
formed with F3CCOOH fur-
nished acid 17, whereas its ana-
logue 18 was deacetylated in
87% yield on treatment with
NH3 in MeOH/THF without af-
fecting the tert-butyl ester
moiety.
Along similar lines, the glyco-
sidation of 11b with donor 20[17]
bearing a 6-O-TBDPS group
also leads to a mixture of both
anomers of 21, which could
only be separated by prepara-
tive HPLC. Treatment of the
major b-anomer with trifluoro-
acetic acid in CH2Cl2 resulted
in a selective cleavage of the
tert-butyl ester group while
leaving the silylether moiety
intact. Attempts to esterify the
resulting acid 22 with alcohol
19 in the presence of DIC and
DMAP were unrewarding;
gratifyingly, however, applica-
tion of the Yonemitsu variant[18]
of the Yamaguchi esterifica-
tion[19] procedure delivered
ester 23 in 86% isolated yield
(Scheme 5). Subsequent cleav-
age of the residual O-TBDPS
ether with TBAF followed by
deprotection of the tert-butyl
ester group in the resulting
Scheme 1. Structure of macroviracin D (1) and comparison with cycloviracin B1 (2).
product 24 was carried out in
™one pot∫ in 67% overall yield.
derivative 5a led to an exclusive formation of the desired
product 6a, its analogue 5b bearing a 6-O-acetyl group
reacts less selectively and afforded 15% of the a-anomer in
addition to the required b-glycoside 6b. The isomers, howev-
er, can be separated by conventional flash chromatography.
The terminal O-TBDPS-group was then cleaved by means
of TBAF, thus liberating alcohols 7a,b which were oxidized
with PCC to the corresponding aldehydes 8a and 8b. Subse-
quent exposure of these compounds to the functionalized di-
organozinc derivative 9 (prepared from iodide 15 by a CuI-
catalyzed halogen/zinc exchange reaction[14] as shown in
Scheme 3)[11] in the presence of a catalyst formed in situ
from Ti(OiPr)4 and (S,S)-bistriflate 10 as the stereochemical
determinant[15,16] provided the secondary alcohols 11a,b in
excellent yields and thereby set the stage for the next glyco-
sidation event.
To ensure the proper orthogonal protecting group regime
required in the assembly stages, the perbenzylated deriva-
tive 11a was independently glycosylated with 5a and 5b to
give products 16 and 18 (Scheme 4). A comparison of the
selectivities observed in these transformations reveals again
the proclivity of the 6-O-acetylated donor 5b for competing
a-glycoside formation, while the perbenzylated donor 5a
does not show this bias. Treatment of compound 16 thus
Hydroxy acid 25 thus formed constitutes the key com-
pound for the envisaged macrolactonization step. This trans-
formation worked exquisitely well under standard Yamagu-
chi conditions,[19] providing the 46-membered dilactone de-
rivative 26 in 89% isolated yield. We were pleased to find
that its lactone linkages remained intact during the subse-
quent cleavage of the peripheral 6-O-acetyl group by solvol-
ysis with NH3 in MeOH, despite the very long reaction time
necessary to drive this reaction to completion. The liberated
primary hydroxyl function in 27 was then esterified with
acid 17, again by taking recourse to Yamaguchi×s mixed an-
hydride methodology,[19] which furnished product 28 as the
fully protected surrogate of macroviracin D in 74% yield
(Scheme 6).
In contrast to our expectations, however, the ultimate de-
protection step turned out to be particularly difficult.
Benzyl ethers were chosen as protecting groups for all hy-
droxyl functions not involved in any of the esterification re-
actions to be carried out en route to 1, not least because
they can be cleaved under neutral conditions via standard
hydrogenolysis. Moreover, benzyl ethers were successfully
employed and removed without difficulty during our previ-
ous total synthesis of cycloviracin B1 (2) and several related
products.[10,11,20] Unfortunately, however, attempts to run the
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A. F¸rstner et al.
FULL PAPER
ester 29a formed by exhaustive solvolysis of the trimeric
construct. Similar degradations were observed using isopro-
panol, CHCl3/MeOH/H2O, or CHCl3/acetone as solvents in
the presence or absence of NH4OAc as a buffer. After con-
siderable experimentation it was found that the hydrogenol-
ysis of 28 can be performed using Pd(OH)2 as the precata-
lyst in rigorously dried EtOH which had to be directly distil-
led from Mg into a flame dried reaction flask prior to use.
The reaction time is also critical and must not exceed 12 h.
Under these conditions, macroviracin D (1) has been ob-
tained in virtually quantitative yield. Its spectroscopic and
analytical data are in agreement with those reported in the
literature.[1] Particularly diagnostic is the direct comparison
1
of the pattern signature in the H and 13C NMR spectra re-
corded at 600 and 150 MHz, respectively, with those depict-
ed in reference [1]. Moreover, the high resolution ESI-MS
of the sample is consistent with the intact trimeric structure.
In contrast to the difficulties encountered during the at-
tempted deprotection reactions in various solvent systems
we found that pure 1, when kept in freshly distilled and
carefully dried [D4]MeOH, is stable for days and does not
show any noticeable degradation. Trace impurities, however,
may suffice to change this situation and can result in metha-
nolysis with formation of the monomeric ester 29b within
less than 24 h. This sensitivity–which is in striking contrast
to the resistance of the fully protected macrocycle 26 to-
wards solvolysis in MeOH even in the presence of excess
NH3 (see above)–must be taken into account in any further
evaluation of this lead compound in the search for novel an-
tiviral agents.[21]
Experimental Section
General: All reactions were carried out under Ar in carefully dried glass-
ware. The solvents used were purified by distillation over the drying
agents indicated and were transferred under Ar: THF, Et2O (Mg/anthra-
cene), CH2Cl2 (P4O10), MeCN, Et3N (CaH2), MeOH (Mg), DMF, DMA
(Desmodur, dibutyltin dilaurate), hexane, toluene (Na/K). Flash chroma-
tography: Merck silica gel 60 (230 400 mesh). IR: Nicolet FT-7199 spec-
trometer, wave numbers in cmÀ1. MS (EI): Finnigan MAT 8200 (70 eV),
HRMS: Finnigan MAT 95 or Bruker APEX III FT-ICR-MS (7 T
magnet). Melting points: Gallenkamp melting point apparatus (uncor-
rected). Optical rotation: Perkin Elmer 343 at l=589 nm (Na D-line).
Elemental analyses: H. Kolbe, M¸lheim/Ruhr. All commercially avail-
able compounds (Lancaster, Aldrich) were used as received. NMR: Spec-
tra were recorded on Bruker DPX 300, AV 400, or DMX 600 spectrome-
ters in the solvents indicated; chemical shifts (d) are given in ppm rela-
tive to TMS, coupling constants (J) in Hz.
Scheme 2. Preparation of the key glycolipidic fragment: a) donor 5a,
TMSOTf, CH2Cl2/MeCN, 91% (6a); or: donor 5b, TMSOTf, CH2Cl2/
MeCN, 74% (6b, +15% of the a-anomer); b) TBAF, THF, 90% (7a),
92% (7b); c) PCC, CH2Cl2; d) compound 9, Ti(OiPr)4, ligand 10, toluene,
73% (11a, over both steps), 77% (11b, over both steps).
(3R)-tert-Butyl [17-tert-butyldiphenylsilyloxy-3-(2,3,4,6-tetra-O-benzyl-b-
d-glucopyranosyl)oxy]heptadecanoate (6a): TMSOTf (20 mL) was added
to a solution of alcohol 4 (1.0 g, 1.67 mmol) and trichloroacetimidate 5a
(1.37 g, 2.0 mmol) in CH2Cl2 and CH3CN (1:1, 50 mL) at À508C and the
resulting mixture was stirred for 30 min before it was allowed to reach
ambient temperature. After neutralization with triethylamine and evapo-
ration of the solvents, the residue was purified by chromatography
(hexane/ethyl acetate 9:1) delivering the desired b-glycoside 6a as a col-
orless syrup (1.7 g, 91%). [a]=+4.5 (c=1.10, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.16 7.41 and 7.64 7.69 (2m, 30H), 4.96 4.52
(4AB, 8H), 4.49 (d, 1H, J=7.8 Hz), 4.09 (m, 1H), 3.73 3.58 (m, 6H),
3.44 3.38 (m, 2H), 2.80 (dd, 1H, J=5.3, 15.1 Hz), 2.45 (dd, 1H, J=7.9,
15.1 Hz), 1.42 (s, 9H), 1.15 1.62 (m, 26H), 1.04 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=170.7, 138.7, 138.5, 138.3, 135.6, 129.4, 128.3
127.4, 103.1, 84.8, 82.4, 80.3, 77.9, 76.9, 75.7, 74.9, 74.8, 74.8, 73.4, 69.0,
Scheme 3. Preparation of the functionalized diorganozinc reagent:
a) i) Mg, THF; ii) cat. CuCl(COD), (R)-propene oxide, 70%; b) BnBr,
NaH, 73%; c) TBAF, THF, 93%; d) I2, imidazole, PPh3, 89%; e) Et2Zn
(excess), cat. CuCN.
deprotection of 28 under the conditions successfully em-
ployed in the cycloviracin series using either MeOH or
EtOH/EtOAc as the reaction medium resulted only in a col-
lapse of the macrocyclic structure, giving rise to the methyl
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Macroviracin D
2214 2222
1235, 1071 cmÀ1
;
elemental analysis
calcd (%) for C66H90O10Si: C 73.98, H
8.47; found: C 74.12, H 8.40.
The second fraction contained the cor-
responding a-anomer (160 mg, 15%)
which showed the following proper-
ties: colorless syrup; [a]=+26.5 (c=
1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.67 7.24 (m, 25H), 4.96
(d, 1H, J=2.5 Hz), 4.99 4.54 (3AB,
6H), 4.29 (dd, 1H, J=4.6, 11.9 Hz),
4.20 (dd, 1H, J=2.1, 11.9 Hz), 4.04
3.93 (m, 3H), 3.65 (t, 2H, J=6.6 Hz),
3.50 (dd, 1H, J=3.7, 9.7 Hz), 3.46 (dd,
1H, J=9.0 Hz), 2.53 (dd, 1H, J=5.6,
15.5 Hz), 2.38 (dd, 1H, J=6.9,
15.5 Hz), 2.01 (s, 3H), 1.65 1.24 (m,
26H), 1.43 (s, 9H), 1.04 (s, 9H);
13C NMR (100 MHz, CDCl3): d=
170.7, 170.6, 138.7, 138.12, 137.8, 135.5,
134.2, 129.4, 128.4 127.5, 95.7, 81.8,
80.5, 79.7, 77.5, 75.6, 75.1, 75.0, 72.9,
69.1, 64.0, 63.2, 40.7, 35.1, 32.6, 29.7
29.4, 28.1, 26.9, 25.8, 25.5, 20.8; ele-
mental analysis calcd (%) for
C66H90O10Si: C 73.98, H 8.47; found: C
73.88, H 8.55.
(3R)-tert-Butyl
[3-(2,3,4,6-tetra-O-
benzyl-b-d-glucopyranosyl)-oxy]hepta-
decanoate (7a): A solution of com-
pound 6a (1.7 g, 1.52 mmol) and tetra-
butylammonium fluoride trihydrate
(505 mg, 1.6 mmol) in THF (10 mL)
was stirred at ambient temperature
until TLC analysis showed complete
conversion (ca. 2 h). Evaporation of
the solvent gave a viscous oil which
was purified by flash chromatography
(hexane/ethyl acetate 7:3) to yield al-
cohol 7a as
a colorless oil (1.2 g,
90%). [a]=+6.2 (c=1.20, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.20
7.15 (m, 20H), 4.95 4.51 (4AB, 8H),
4.49 (d, 1H, J=7.8 Hz), 4.09 (m, 1H),
3.72 3.57 (m, 6H), 3.43 2.38 (m, 2H),
2.80 (dd, 1H, J=5.3, 15.1 Hz), 2.45
(dd, 1H, J=8.0, 15.1 Hz), 1.60 1.19
(m, 26H), 1.42 (s, 9H); 13C NMR
= 170.7, 138.7, 138.5, 138.3, 138.2, 128.3 127.4,
Scheme 4. Preparation of the three required building blocks differing only in the lateral pattern of orthogonal
protecting groups: a) donor 5a, TMSOTf, CH2Cl2/MeCN, 88%; b) F3CCOOH, CH2Cl2, 97%; c) donor 5b,
TMSOTf, CH2Cl2/MeCN, 58% (18
+ 22% of the a-anomer); d) NH3, MeOH/THF, 87%; e) donor 20,
TMSOTf, CH2Cl2/MeCN, 79% (a:b 1:2.8); f) F3CCOOH, CH2Cl2, 85%.
64.0, 42.3, 32.6, 28.8, 29.7 29.5, 29.4, 28.1, 26.9, 25.8, 25.0, 19.2; IR: n˜ =
3030, 2928, 2855, 1728, 1365, 1110, 1071 cmÀ1; MS (ESI): m/z: 1141
[M+Na]+ ; elemental analysis calcd (%) for C71H94O9Si: C 76.17, H 8.46;
found: C 76.04, H 8.37.
(100 MHz, CDCl3): d
103.0, 84.8, 82.4, 80.3, 77.9, 76.9, 75.7, 74.9, 74.8, 74.8, 73.4, 68.9, 63.0,
42.3, 34.5, 32.8, 29.8, 29.6 29.4, 28.1, 25.7, 25.0; IR: n˜ = 3439, 2924, 2853,
1728, 1071 cmÀ1; HRMS (ESI): m/z: calcd for C55H76O9+Na: 903.5387;
found: 903.5394 [M+Na]+.
(3R)-tert-Butyl [17-tert-butyldiphenylsilyloxy-3-(2,3,4-tri-O-benzyl-6-O-
acetyl-b-d-glucopyranosyl)oxy]heptadecanoate (6b): TMSOTf (15 mL)
was added to a solution of alcohol 4 (500 mg, 0.83 mmol) and trichloro-
acetimidate 5b (800 mg, 1.25 mmol) in CH2Cl2 and CH3CN (1:1, 40 mL)
at À508C and the resulting mixture was stirred for 30 min before it was
allowed to reach ambient temperature. After neutralization with triethyl-
amine and evaporation of the solvents, the residue was purified by flash
chromatography (hexane/ethyl acetate 15:1). The first product to be
eluted was the desired b-anomer 6b. Colorless syrup (660 mg, 74%);
[a]=+8.1 (c=2.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.80 7.15
(m, 25H), 4.96 4.53 (3AB, 6H), 4.49 0(d, 1H, J=7.8 Hz), 4.30 (d, 1H,
J=11.1 Hz), 4.20 (dd, 1H, J=4.8, 11.7 Hz), 4.04 (m, 1H), 3.65 (t, 2H,
J=6.6 Hz), 3.62 (m, 1H), 3.49 (m, 2H), 3.39 (dd, 1H, J=7.8, 9.1 Hz),
2.56 (dd, 1H, J=5.3, 15.1 Hz), 2.41 (dd, 1H, J=8.0, 15.1 Hz), 2.02 (s,
3H), 1.60 1.24 (m, 26H), 1.43 (s, 9H), 1.04 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=170.7, 170.6, 138.4, 137.8, 135.6, 129.4, 128.4 127.5, 103.1,
84.8, 82.2, 80.3, 77.6, 77.4, 75.7, 74.9, 72.7, 64.0, 63.3, 42.2, 34.6, 32.6, 29.8
29.4, 28.1, 26.9, 25.8, 25.1, 20.8; IR: n˜ = 2928, 2855, 1744, 1731, 1454,
(3R)-tert-Butyl
[3-(6-O-acetyl-2,3,4-tri-O-benzyl-b-d-glucopyranosyl)-
oxy]heptadecanoate (7b): A solution of compound 6b (1.0 g, 1.30 mmol)
and tetrabutylammonium fluoride trihydrate (440 mg, 1.40 mmol) in THF
(10 mL) was stirred at ambient temperature until TLC analysis showed
complete conversion (ca. 2 h). Evaporation of the solvent gave a viscous
oil which was purified by flash chromatography (hexane/ethyl acetate
4:1) to yield alcohol 7b as a colorless syrup (1.0 g, 92%). [a]=+12.2
(c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.28 7.20 (m, 15H),
4.96 4.53 (3AB, 6H), 4.49 (d, 1H, J=7.8 Hz), 2.28 (d, 1H, J=10.8 Hz),
4.20 (dd, 1H, J=4.5, 11.6 Hz), 4.04 (m, 1H), 3.65 (m, 1H), 3.63 (t, 2H,
J=6.6 Hz), 3.48 (m, 2H), 3.40 (dd, 1H, J=7.9, 9.1 Hz), 2.74 (dd, 1H, J=
5.4, 15.1 Hz), 2.42 (dd, 1H, J=8.0, 15.2 Hz), 2.02 (s, 3H), 1.65 1.15 (m,
26H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): d=170.7, 138.4, 138.3,
137.8, 128.4 127.6, 103.1, 84.8, 82.2, 80.3, 77.6, 77.4, 75.7, 74.9, 74.8, 72.7,
63.3, 63.1, 42.2, 34.6, 32.8, 29.7 29.4, 28.1, 25.7, 25.1, 20.8; IR: n˜ = 3438,
2926, 2854, 1744, 1728, 1367, 1070 cmÀ1; MS (ESI): m/z: 855 [M+Na]+
elemental analysis calcd (%) for C50H72O10: C 72.08, H 8.71; found: C
72.14, H 8.63.
;
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A. F¸rstner et al.
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water and brine. The organic phase
was dried (Na2SO4) and evaporated,
and the residue was purified by flash
chromatography (hexane/ethyl acetate
4:1) to yield alcohol 11a as a colorless
syrup (350 mg, 73% over both steps).
[a]=+1.1 (c=1.10, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.25 7.15 (m,
25H), 4.82 4.43 (5AB, 10H), 4.49 (d,
1H, J=7.8 Hz), 4.08 (m, 1H), 3.75
3.35 (m, 8H), 2.80 (dd, 1H, J=5.4,
15.1 Hz), 2.45 (dd, 1H, J=8.0,
15.1 Hz), 1.62 1.15 (m, 36H), 1.42 (s,
9H), 1.18 (d, 3H, J=6.1 Hz);
13C NMR (100 MHz, CDCl3): d=
170.7, 139.1, 138.6, 138.5, 138.3, 138.2,
128.3 127.3, 103.1, 84.3, 82.4, 80.3,
77.9, 76.9, 75.7, 74.9, 74.9, 74.8, 73.4,
72.0, 70.2, 69.0, 42.3, 37.5, 37.4, 36.6,
34.5, 29.8 29.5, 28.1, 25.7, 25.6, 25.5,
25.0, 19.6; IR: n˜ = 3476, 2927, 2854,
1727, 1070 cmÀ1; MS (ESI): m/z: 1107
[M+Na]+
; elemental analysis calcd
(%) for C69H96O10: C 76.35, H 8.91;
found: C 76.33, H 8.79.
Compound 11b: A mixture of PCC
(430 mg, 2.0 mmol) and alcohol 7b
(830 mg, 1.0 mmol) in dichlorome-
thane (20 mL) was stirred at room
temperature for 1.5 h before being
poured onto a silica gel column. Elu-
tion with hexane/EtOAc (4:1) gave
the crude aldehyde 8b (770 mg, 98%)
which was directly used in the next
step. Characteristic data of 8b: [a]=
+13.0 (c=0.60, CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.75 (t, 1H,
J=1.9 Hz), 7.30 7.20 (m, 15H), 4.96
4.53 (3AB, 6H), 4.49 (d, 1H, J=
7.8 Hz), 4.30 (d, 1H, J=11.8 Hz), 4.21
(dd, 1H, J=4.5, 11.5 Hz), 4.04 (m,
1H), 3.65 (m, 1H), 3.49 (m, 2H), 3.40
(dd, 1H, J=7.9, 9.1 Hz), 2.73 (dd, 1H,
J=5.4, 15.1 Hz), 2.44 2.34 (m, 3H),
2.02 (s, 3H), 1.65 1.15 (m, 24H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3):
d=202.9, 170.7, 170.6, 138.4, 137.7,
128.4 127.6, 103.1, 84.8, 82.2, 80.4,
77.7, 77.4, 77.3, 75.7, 74.9, 74.8, 72.7,
63.3, 43.9, 42.2, 34.6, 28.8 29.2, 28.1,
Scheme 5. Formation of the macrocyclic core: a) Et3N, 2,4,6-trichlorobenzoyl chloride, toluene, DMAP, 86%;
b) TBAF, THF; c) F3CCOOH, CH2Cl2, 82% (over both steps); d)i) Et3N, THF, 2,4,6-trichlorobenzoyl chlo-
ride; ii) slow addition to DMAP, toluene, 89%; e) NH3 in MeOH, THF, 86%.
Compound 11a: A mixture of PCC (215 mg, 1.0 mmol) and alcohol 7a
(440 mg, 0.5 mmol) in dichloromethane (10 mL) was stirred at room tem-
perature for 1.5 h before it was poured on top of a short silica gel
column. Elution with hexane/ethyl acetate (4:1) gave crude aldehyde 8a
(920 mg, 96%) which was used directly in the next step. Characteristic
data of 8a: [a]2D0 =+6.3 (c=1.15, CHCl3); 1H NMR (400 MHz, CDCl3):
d=9.75 (t, 1H, J=1.9 Hz), 7.10 7.35 (m, 20H), 4.96 4.52 (4AB, 8H),
4.49 (d, 1H, J=7.8 Hz), 4.08 (m, 1H), 3.75 3.57 (m, 4H), 3.47 3.36 (m,
2H), 2.80 (dd, 1H, J=5.3, 15.1 Hz), 2.45 (dd, 1H, J=8.0, 15.1 Hz), 2.40
(td, 2H, J=1.9, 7.4 Hz), 1.65 1.15 (m, 24H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=202.8, 170.7, 138.6, 138.5, 138.3, 138.2, 128.3
127.5, 103.1, 84.8, 82.4, 80.3, 77.9, 76.9, 75.7, 74.9, 74.8, 74.8, 73.4, 68.9,
43.9, 42.3, 34.5, 29.8, 29.6 29.1, 28.1, 25.0, 22.1; IR: n˜ =2926, 2854, 2717,
1726, 1071 cmÀ1; MS (ESI): m/z: 901 [M+Na]+.
25.1, 22.1, 20.8; IR: n˜ = 2926, 2854, 2717, 1743, 1727, 1070; MS (ESI):
m/z: 853 [M+Na]+.
A solution of bis-triflate 10 (113 mg, 0.3 mmol) and Ti(OiPr)4 (700 mL,
3.0 mmol) in toluene (4 mL) was stirred at 408C for 30 min. After the
solution was cooled to À508C, the zinc reagent 9 (3 mmol, 3 equiv) was
added to this mixture prior to the addition of a solution of the crude al-
dehyde 8b (1 mmol) in toluene (2 mL). The mixture was slowly (1 h)
warmed to À208C, the reaction was quenched with sat. aq. NH4Cl and di-
luted with tert-butyl methyl ether, and the organic phase was successively
washed with 1m HCl, water and brine. The organic phase was dried
(Na2SO4) and evaporated, and the residue was purified by flash chroma-
tography (hexane/ethyl acetate 7:3) to yield alcohol 11b as a colorless
syrup (810 mg, 77% over both steps). [a]=+5.3 (c=1.10, CHCl3).
1H NMR (400 MHz, CDCl3): d=7.28 7.15 (m, 20H), 4.96 4.43 (4AB,
8H), 4.48 (d, 1H, J=7.7 Hz), 4.29 (d, 1H, J=10.7 Hz), 4.20 (dd, 1H, J=
4.5, 11.7 Hz), 4.01 (m, 1H), 3.69 3.44 (m, 5H), 3.40 (dd, 1H, J=7.8,
9.1 Hz), 2.74 (dd, 1H, J=5.4, 15.1 Hz), 2.40 (dd, 1H, J=8.0, 15.1 Hz),
2.02 (s, 3H), 1.62 1.17 (m, 36H), 1.43 (s, 9H), 1.18 (d, 3H, J=6.1 Hz);
13C NMR (100 MHz, CDCl3): d=170.6, 138.4, 138.3, 137.8, 128.4 127.3,
103.1, 84.8, 82.3, 80.3, 77.7, 77.4, 75.7, 74.9, 74.9, 74.8, 72.7, 72.2, 70.3,
63.3, 42.2, 37.5, 37.4, 36.6, 34.6, 29.8 29.4, 28.1, 25.6, 25.6, 25.5, 25.1, 20.8,
A solution of bis-triflate 10 (50 mg, 0.13 mmol) and Ti(OiPr)4 (350 mL,
1.5 mmol) in toluene (2 mL) was stirred at 408C for 30 min. After being
cooled to À508C, the zinc reagent 9 (1.5 mmol, 3 equiv)[11] was intro-
duced prior to the addition of a solution of the crude aldehyde 8a (ca.
0.5 mmol) in toluene (2 mL). The resulting mixture was slowly (1 h)
warmed to À208C, the reaction was quenched with sat. aq. NH4Cl, dilut-
ed with tert-butyl methyl ether, and consecutively washed with 1m HCl,
2218
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2214 2222

Macroviracin D
2214 2222
17 as an amorphous solid (880 mg,
97%). [a]=+11.0 (c=0.80, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.40
7.15 (m, 45H), 4.97 4.42 (9AB, 18H),
4.46 (d, 1H, J=7.9 Hz), 4.42 (d, 1H,
J=7.8 Hz), 4.04 (quint., 1H, J=
5.7 Hz), 3.73 3.55 (m, 8H), 3.48 3.40
(m, 6H), 2.66 (dd, 1H, J=6.5,
15.4 Hz), 2.60 (dd, 1H, J=4.7,
15.3 Hz), 1.70 1.15 (m, 36H), 1.15 (d,
3H, J=6.1 Hz); 13C NMR (100 MHz,
CDCl3): d=172.9, 138.7, 138.6, 138.4,
128.5 127.4, 103.9, 102.6, 84.9, 84.7,
82.4, 82.0, 79.9, 78.8, 78.0, 77.7, 77.2,
75.7, 75.6, 74.9 74.8, 74.7, 74.4, 73.5,
73.4, 70.2, 96.2, 69.1, 41.2, 36.6, 35.3,
34.9, 34.0, 30.1, 29.9, 29.7 29.6, 29.5,
25.4, 25.3, 25.3, 25.1, 19.6; IR: n˜
=
3088, 3063, 3030, 2926, 2854, 1732,
1709, 1070 cmÀ1; MS (ESI): m/z: 1574
[M+Na]+
; elemental analysis calcd
(%) for C99H122O15: C 76.61, H 7.92;
found: C 76.54, H 8.07.
Compound 18: TMSOTf (10 mL) was
added to a solution of alcohol 11a
(600 mg, 0.55 mmol) and trichloroacet-
imidate 5b (530 mg, 0.83 mmol) in
CH2Cl2 and CH3CN (1:1, 20 mL) at
À508C and the resulting mixture was
stirred for 30 min before being
warmed to ambient temperature.
After neutralization with triethylamine
and evaporation of the solvents, the
residue was purified by flash chroma-
tography (hexane/ethyl acetate 4:1).
The first fraction to be eluted con-
tained the desired b-anomer 18 as a
colorless solid (500 mg, 58%). M.p.
46 478C; [a]=+7.8 (c=1.10, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.15
7.25 (m, 40H), 4.97 4.41 (8AB, 16H),
4.49 (d, 1H, J=7.8 Hz), 4.42 (d, 1H,
J=8.1 Hz), 4.31 (dd, 1H, J=2.0,
11.9 Hz), 4.17 (dd, 1H, J=5.0,
11.7 Hz), 4.08 (m, 1H), 3.70 3.58 (m,
Scheme 6. Completion of the total synthesis of macroviracin D: a) Et3N, 2,4,6-trichlorobenzoyl chloride, tolu-
ene, DMAP, 74%; b) H2 (1 atm), cat. Pd(OH)2, anhydrous EtOH, quant.; c) H2 (1 atm), Pd/C, MeOH, quant.
19.6; IR: n˜ = 3477, 2927, 2854, 1744, 1728, 1070 cmÀ1; MS (ESI): m/z:
6H), 3.52 3.38 (m, 6H), 2.80 (dd, 1H, J=5.4, 15.1 Hz), 2.45 (dd, 1H, J=
8.0, 15.1 Hz), 2.01 (s, 3H), 1.68 1.18 (m, 36H), 1.42 (s, 9H), 1.15 (d, 3H,
J=6.1 Hz); 13C NMR (100 MHz, CDCl3): d=170.7, 170.6, 138.6 137.8,
128.4 127.3, 103.0, 102.6, 84.9, 84.8, 82.3, 82.3, 80.3, 80.2, 77.8, 77.7, 76.9,
75.7, 76.6, 74.9, 74.8, 74.8, 74.8, 74.7, 73.4, 72.6, 70.2, 68.9, 63.3, 42.2, 36.6,
34.8, 34.5, 34.1, 30.0, 29.8 29.7, 29.5, 28.1, 25.4, 25.2, 25.2, 25.0, 20.8, 19.6;
IR: n˜ = 3030, 2928, 2855, 1743, 1728, 1070 cmÀ1; MS (ESI): m/z: 1582
[M+Na]+ ; elemental analysis calcd (%) for C98H126O16: C 75.45, H 8.14;
found: C 75.28, H 8.15.
1059 [M+Na]+ ; elemental analysis calcd (%) for C64H92O11 (MW
=
1037.36): C 74.10, H 8.94; found: C 73.86, H 8.89.
Compound 16: TMSOTf (10 mL) was added to a solution of alcohol 11a
(350 mg, 0.32 mmol) and trichloroacetimidate 5a (330 mg, 0.48 mmol) in
CH2Cl2 and CH3CN (1:1, 10 mL) at À508C and the resulting mixture was
stirred for 30 min before it was warmed to À308C. After neutralization
at that temperature with triethylamine and evaporation of the solvents,
the residue was purified by flash chromatography (hexane/ethyl acetate
9:1) to give b-glycoside 16 as an oil (450 mg, 88%). [a]=+4.0 (c=0.90,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.40 7.15 (m, 45H), 4.98 4.42
(9AB, 18H), 4.49 (d, 1H, J=7.8 Hz), 4.42 (d, 1H, J=8.1 Hz), 4.08 (m,
1H), 3.73 3.55 (m, 9H), 3.49 3.38 (m, 5H), 2.80 (dd, 1H, J=5.4,
15.1 Hz), 2.45 (dd, 1H, J=7.9, 15.1 Hz), 1.65 1.15 (m, 36H), 1.43 (s, 9H),
1.15 (d, 3H, J=6.1 Hz); 13C NMR (100 MHz, CDCl3): d=170.7, 139.1,
138.7 138.2, 128.3 127.3, 103.1, 102.6, 84.9, 84.8, 82.4, 82.3, 80.3, 79.9,
78.0, 77.8, 76.9, 75.7, 75.6, 74.9 74.8, 73.6, 73.4, 70.2, 69.2, 68.9, 42.3, 36.6,
34.9, 34.5, 34.1, 30.1 29.5, 28.1, 25.5, 25.3, 25.2, 25.0, 19.6; IR: n˜ = 3080,
2926, 2854, 1727, 1070 cmÀ1; MS (ESI): m/z: 1630 [M+Na]+ ; elemental
analysis calcd (%) for C103H130O15: C 76.61, H 7.92; found: C 76.48, H
7.89.
The second fraction contained the corresponding a-anomer (190 mg,
22%) which showed the following analytical and spectroscopic proper-
ties: m.p. 57 588C; [a]=+26.4 (c=0.70, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.33 7.15 (m, 40H), 4.93 (m, 1H), 5.02 4.43 (8AB, 16H),
4.49 (d, 1H, J=7.8 Hz), 4.30 (dd, 1H, J=4.4, 12.0 Hz), 4.20 (dd, 1H, J=
2.1, 11.9 Hz), 4.09 (m, 1H), 3.73 3.38 (m, 12H), 2.80 (dd, 1H, J=5.4,
15.1 Hz), 2.45 (dd, 1H, J=8.0, 15.1 Hz), 2.00 (s, 3H), 1.65 1.15 (m, 36H),
1.43 (s, 9H), 1.17 (d, 3H, J=6.1 Hz); 13C NMR (100 MHz, CDCl3): d=
170.7, 170.7, 138.6 137.8, 128.4 127.4, 103.0, 95.5, 84.8, 82.3, 82.0, 80.3,
80.0, 78.3, 77.8, 77.5, 76.9, 75.7, 75.6, 75.0, 74.9, 74.9, 74.8, 74.7, 73.4, 73.2,
70.2, 68.9, 68.8, 63.2, 42.2, 36.6, 34.5, 34.4, 33.1, 30.0, 29.9 29.7, 29.5, 28.1,
25.8, 25.4, 25.0, 24.9, 20.8, 19.6; IR: n˜ = 3030, 2927, 2855, 1742, 1089,
1071 cmÀ1; MS (ESI): m/z: 1582 [M+Na]+ ; elemental analysis calcd (%)
for C98H126O16: C 75.45, H 8.14; found: C 75.54, H 7.99.
Compound 17: A solution of ester 16 (300 mg, 0.19 mmol) in CH2Cl2
(5 mL) and trifluoroacetic acid (0.5 mL) was stirred for 30 min. For work
up, the solvent was evaporated and the residual trifluoroacetic acid was
removed by repeated azeotropic distillation with toluene. Purification of
the residue by flash chromatography (hexane/acetone 4:1) yielded acid
Compound 19: A saturated methanolic solution of ammonia (5 mL) was
added to a solution of glycoside 18 (400 mg, 0.26 mmol) in THF (2 mL)
and the resulting mixture was stirred for 4 d before it was concentrated
2219
Chem. Eur. J. 2004, 10, 2214 2222
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. F¸rstner et al.
FULL PAPER
to dryness. The residue was purified by flash chromatography (hexane/
ethyl acetate 4:1) to give alcohol 19 (340 mg, 87%). [a]=+3.5 (c=1.05,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.40 7.15 (m, 40H), 4.96 4.41
(8AB, 16H), 4.48 (d, 1H, J=7.8 Hz), 4.45 (d, 1H, J=7.9 Hz), 4.09
(quint., 1H, J=5.7 Hz), 3.83 (dd, 1H, J=2.5, 11.8 Hz), 3.73 3.59 (m,
6H), 3.53 (t, 1H, J=9.5 Hz), 3.49 3.32 (m, 6H), 2.79 (dd, 1H, J=5.4,
15.1 Hz), 2.45 (dd, 1H, J=8.0, 15.1 Hz), 1.61 1.15 (m, 37H), 1.42 (s, 9H),
1.15 (d, 3H, J=6.1 Hz); 13C NMR (100 MHz, CDCl3): d=170.7, 138.7
138.0, 128.4 127.3, 103.1, 102.5, 84.8, 84.7, 82.4, 82.3, 80.3, 80.1, 77.9, 77.8,
75.6, 75.6, 75.0, 74.9, 74.8, 73.4, 70.2, 69.0, 62.3, 42.3, 36.7, 34.9, 34.5, 34.2,
30.1, 29.8 29.5, 28.1, 25.4, 25.3, 25.2, 25.0, 19.6; IR: n˜ = 3479, 2926, 2855,
1728, 1497, 1070 cmÀ1; MS (ESI): m/z: 1540 [M+Na]+ ; elemental analysis
calcd (%) for C96H124O15: C 75.96, H 8.23; found: C 76.11, H 8.15.
pos.): m/z: 1674 [M+Na]+
;
elemental analysis calcd (%) for
C
103H130O16Si: C 74.87, H 7.93; found: C 75.00, H 8.04.
Compound 23: Triethylamine (35 mL, 0.225 mmol) and 2,4,6-trichloroben-
zoyl chloride (16 mL, 0.103 mmol) were added to a solution of acid 22
(140 mg, 0.085 mmol) in toluene (5 mL). The resulting mixture was stir-
red for 1.5 h before a solution of alcohol 19 (140 mg, 0.10 mmol) and
DMAP (5 mg, 0.043 mmol) in toluene (3 mL) was introduced. After 1 h,
the mixture was concentrated and the residue was purified by flash chro-
matography (hexane/acetone 9:1) to give ester 23 (230 mg, 86%) as a
colorless syrup. [a]=+5.1 (c=1.70, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.75 7.15 (m, 85H), 5.02 4.41 (m, 32H), 4.49 (d, 1H, J=
7.7 Hz), 4.48 (d, 1H, J=7.9 Hz), 4.47 (d, 1H, J=7.7 Hz), 4.35 4.15 (m,
3H), 4.08 (m, 1H), 3.93 (d, 1H, J=11.1 Hz), 3.86 (dd, 1H, J=4.4,
11.1 Hz), 3.75 (quint., 1H, J=5.6 Hz), 3.74 3.57 (m, 10H), 3.50 3.30 (m,
12H), 2.90 (dd, 1H, J=5.1, 16.0 Hz), 2.80 (dd, 1H, J=5.4, 15.1 Hz), 2.51
(dd, 1H, J=7.8, 16.0 Hz), 2.47 (dd, 1H, J=7.9, 15.1 Hz), 1.99 (s, 3H),
1.70 1.10 (m, 72H), 1.42 (s, 9H), 1.15 (d, 6H, J=6.1 Hz), 1.06 (s, 9H),
13C NMR (100 MHz, CDCl3): d=171.0, 170.7, 170.6, 138.6 138.2, 137.8,
135.8, 135.5, 133.6, 133.2, 129.5, 128.4 127.3, 103.7, 103.0, 102.4, 102.1,
85.0, 84.8, 84.7, 84.7, 82.6, 82.3, 82.3, 82.2, 80.3, 80.8, 78.9, 78.0, 77.8, 77.7,
77.6, 77.2, 75.7 75.6, 74.9 74.8, 74.7, 73.3, 72.6, 70.2, 68.9, 63.3, 63.1, 62.9,
42.2, 40.8, 36.6, 35.1, 34.9, 34.7, 34.5, 33.8, 33.4, 30.1 29.6, 28.1, 26.8, 25.5
25.4, 25.1 25.0, 20.8, 19.6, 19.2; IR: n˜ =3031, 2928, 2855, 1740, 1454,
1360, 1070 cmÀ1; HRMS (ESI-pos.): m/z: calcd for C199H252O30Si: 3149.22
Compound 21: TMSOTf (10 mL) was added to a solution of alcohol 11b
(500 mg, 0.48 mmol) and trichloroacetimidate 20 (520 mg, 0.62 mmol) in
CH2Cl2 and CH3CN (1:1, 10 mL) at À508C, and the resulting mixture
was stirred for 30 min before being warmed to À108C. After neutraliza-
tion at that temperature with triethylamine and evaporation of the sol-
vents, the residue was purified by flash chromatography (hexane/ethyl
acetate 9:1) to give a mixture of both anomers of product 21 (650 mg,
79%, a/b 1:2.8). These compounds were separated by preparative HPLC
(Nucleosil-7-100-C18/A, acetonitrile/2-propanol 85:15). a-Anomer: syrup
(112 mg, 14%). [a]=+19.2 (c=2.20, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.65 7.14 (m, 45H), 4.99 4.45 (7AB, 14H), 4.75 (d, 1H, J=
3.7 Hz), 4.50 (d, 1H, J=7.9 Hz), 4.29 (d, 1H, J=10.7 Hz), 4.20 (m, 1H),
4.08 4.00 (m, 1H), 3.95 3.78 (m, 3H), 3.59 (brquint., 1H, J=5.7 Hz),
3.69 3.35 (m, 8H), 2.75 (dd, 1H, J=5.4, 15.1 Hz), 2.41 (dd, 1H, J=7.9,
15.1 Hz), 2.02 (s, 3H), 1.62 1.16 (m, 36H), 1.42 (s, 9H), 1.10 (d, 3H, J=
6.1 Hz), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3): d=170.7, 170.6,
138.5, 138.4, 138.3, 137.8, 135.8, 135.6, 133.7, 133.3, 129.5, 129.4, 128.4
127.2, 103.1, 95.0, 84.8, 82.3, 82.2, 80.6, 80.3, 78.1, 77.6, 77.4, 77.3, 75.7,
75.1, 74.9, 74.9, 73.2, 72.7, 71.8, 70.2, 63.3, 62.9, 42.2, 36.6, 34.6, 34.4, 32.9,
30.1, 29.8 29.7, 29.5, 28.1, 26.8, 25.7, 25.4, 25.1, 25.0, 20.8, 19.6, 19.3; IR:
found: 1613.86 [M+2K]2+
.
Compound 25: A solution of compound 23 (200 mg, 0.063 mmol) and tet-
rabutylammonium fluoride trihydrate (22 mg, 0.07 mmol) in THF (3 mL)
was stirred at ambient temperature overnight. Evaporation of the solvent
gave product 24 as a viscous oil which was dissolved in CH2Cl2 (5 mL)
and treated with trifluoroacetic acid (0.5 mL) at ambient temperature for
30 min. For work up, the trifluoroacetic acid was removed by repeated
azeotropic distillation with toluene. Purification of the residue by flash
chromatography (hexane/acetone 4:1) yielded hydroxy acid 25 as a color-
less oil (147 mg, 82%). [a]=+10.2 (c=1.74, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.35 7.15 (m, 75H), 4.97 4.41 (m, 35H), 4.33 (d,
1H, J=11.2 Hz), 4.27 (brd, 1H, J=11.3 Hz), 4.20 (m, 1H), 4.05 (m, 2H),
3.84 (dd, 1H, J=2.8, 11.8 Hz), 3.70 3.56 (m, 8H), 3.54 (t, 1H, J=
9.5 Hz), 3.42 3.32 (m, 14H), 2.88 (dd, 1H, J=5.0, 16.0 Hz), 2.68 (dd, 1H,
J=6.6, 15.3 Hz), 2.59 (dd, 1H, J=4.8, 15.3 Hz), 2.52 (dd, 1H, J=7.8,
16.0 Hz), 1.99 (s, 3H), 1.64 1.10 (m, 72H), 1.15 (d, 6H, J=6.1 Hz);
13C NMR (100 MHz, CDCl3): d=173.1, 170.9, 170.6, 139.0, 138.5 137.7,
137.5, 128.4, 127.2, 103.9, 103.7, 102.4, 84.7, 84.6, 82.3, 82.2, 82.1, 82.0,
80.1, 80.0, 78.7, 77.9, 77.7, 77.6, 77.5, 72.2, 75.7 75.6, 74.9 74.7, 74.6, 74.4,
73.4, 72.6, 70.1, 69.2, 63.2, 63.0, 62.2, 41.2, 40.8, 36.6, 35.3, 35.1, 34.8, 34.7,
34.1, 33.8, 30.0 29.7, 29.5, 25.4, 25.4, 25.3, 25.1, 20.8, 19.5; IR: n˜ = 3437,
3030, 2920, 2851, 1732, 1709, 1071 cmÀ1; HRMS (ESI-pos.): m/z: calcd for
n˜ = 2928, 2855, 1742, 1240, 1071 cmÀ1; MS (ESI): m/z: 1730 [M+Na]+
;
elemental analysis calcd (%) for C107H138O16Si: C 75.23, H 8.14; found: C
75.08, H 8.12.
The second fraction consists of the desired b-anomer 21: syrup (270 mg,
32%). [a]=+4.4 (c=1.50, CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.75 7.10 (m, 45H), 5.05 4.42 (7AB, 14H), 4.50 (d, 1H, J=7.8 Hz), 4.48
(d, 1H, J=7.7 Hz), 4.29 (d, 1H, J=10.8 Hz), 4.21 (m, 1H), 4.03
(brquint., 1H, J=5.4 Hz), 3.95 (dd, 1H, J=2.3, 10.9 Hz), 3.87 (dd, 1H,
J=4.5, 11.1 Hz), 3.73 (quint., 1H, J=5.7 Hz), 3.70 3.60 (m, 3H), 3.42
3.30 (m, 6H), 2.75 (dd, 1H, J=5.4, 15.1 Hz), 2.41 (dd, 1H, J=7.9,
15.1 Hz), 2.01 (s, 3H), 1.70 1.16 (m, 36H), 1.43 (s, 9H), 1.15 (d, 3H, J=
6.1 Hz), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3): d=170.7, 170.6,
138.7, 138.7, 138.4, 138.3, 138.2, 138.8, 135.8, 135.5, 133.7, 133.2, 129.5,
128.4 127.3, 103.1, 102.1, 85.0, 84.8, 82.7. 82.3, 80.3, 78.9, 77.8, 77.6, 77.4,
77.2, 75.8, 75.7, 75.6, 74.9, 74.8, 74.8, 74.8, 72.7, 70.2, 63.3, 63.0, 42.2, 36.6,
34.9, 34.6, 33.5, 30.0, 30.0, 29.8 29.7, 29.5, 28.1, 26.8, 25.5, 25.4, 25.1, 25.0,
20.7, 19.6, 19.3; IR: n˜ = 3031, 2928, 2855, 1743, 1070 cmÀ1; MS (ESI):
m/z: 1730 [M+Na]+ ; elemental analysis calcd (%) for C107H138O16Si: C
75.23, H 8.14; found: C 75.48, H 8.04.
C
179H225O30+K (potassium salt of the acid): 2893.50; found: 1485.74
[M+2K]2+
.
Compound 26: Triethylamine (26 mL, 0.19 mmol) was added to a solution
of compound 25 (180 mg, 0.063 mmol) in THF (3 mL). After 10 min, the
mixture was treated with 2,4,6-trichlorobenzoyl chloride (12 mL,
0.08 mmol) and stirring was continued for 2 h. The mixture was then di-
luted with anhydrous toluene (20 mL) and added over a period of 3 h via
syringe pump to a refluxing solution of DMAP (118 mg, 0.9 mmol) in tol-
uene (50 mL). After the addition was complete, reflux was continued for
1 h before the solvent was evaporated and the residue was purified by
flash chromatography (hexane/ethyl acetate 4:1) to give macrolactone 26
Compound 22: A solution of ester 21 (220 mg, 0.128 mmol) in CH2Cl2
(5 mL) and trifluoroacetic acid (0.5 mL) was stirred at ambient tempera-
ture for 30 min. The mixture was diluted with toluene, the solvent was
distilled off, and residual trifluoroacetic acid was removed by repeated
azeotropic distillation with toluene. Purification of the residue by flash
chromatography (hexane/acetone 4:1) yielded acid 22 (180 mg, 85%) as
an amorphous solid. [a]=+12.7 (c=0.60, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.70 7.10 (m, 45H), 5.01 4.42 (7AB, 14H), 4.49 (d, 1H, J=
7.8 Hz), 4.48 (d, 1H, J=7.7 Hz), 4.44 4.42 (m, 1H), 4.14 (dd, 1H, J=4.4,
11.9 Hz), 4.03 (quint., 1H, J=5.2 Hz), 3.92 (dd, 1H, J=2.0, 10.1 Hz),
3.85 (dd, 1H, J=4.4, 11.1 Hz), 3.73 (quint., 1H, J=5.8 Hz), 3.69 3.62 (m,
3H), 3.51 (t, 1H, J=9.8 Hz), 3.47 3.40 (m, 4H), 3.32 (m, 1H), 2.68 (dd,
1H, J=6.7, 15.3 Hz), 2.55 (dd, 1H, J=4.9, 15.3 Hz), 2.04 (s, 3H), 1.70
1.11 (m, 36H), 1.15 (d, 3H, J=6.1 Hz), 1.08 (s, 9H); 13C NMR
(400 MHz, CDCl3): d=173.5, 171.5, 139.1, 138.7, 138.7, 138.4, 137.7,
135.8, 135.6, 129.5, 128.4 127.3, 103.7, 102.1, 85.0, 84.6, 82.7, 82.1, 79.0,
78.2, 77.8, 77.3, 75.75, 75.71, 74.99, 74.83, 72.8, 70.2, 62.9, 62.6, 41.0, 36.7,
35.5, 34.9, 33.4, 30.1, 30.0, 29.7, 29.7, 29.5, 26.8, 25.5, 25.4, 25.3, 25.0, 20.9,
19.6, 19.3; IR: n˜ =3065, 2927, 2855, 1735, 1704, 1068 cmÀ1; MS (ESI-
as
a colorless syrup (160 mg, 89%). [a]=+10.6 (c=0.65, CHCl3);
1H NMR (600 MHz, CDCl3): d=7.35 7.20 (m, 75H), 4.96 4.42 (m, 32H),
4.40 (d, 1H, J=7.9 Hz), 4.38 (d, 1H, J=7.8 Hz), 4.36 4.32 (m, 2H), 4.25
(d, 1H, J=10.6 Hz), 4.17 (dd, 1H, J=4.5, 11.7 Hz), 4.11 (m, 3H), 4.06
(quint., 1H, J=6.3 Hz), 3.68 3.55 (m, 9H), 3.52 3.34 (m, 13H), 2.92 (dd,
1H, J=5.6, 16.1 Hz), 2.85 (dd, 1H, J=5.4, 16.1 Hz), 2.52 (dd, 1H, J=7.0,
16.1 Hz), 2.48 (dd, 1H, J=7.3, 16.1 Hz), 1.93 (s, 3H), 1.65 1.10 (m, 72H),
1.15 (d, 3H, J=6.1 Hz), 1.14 (d, 3H, J=6.1 Hz); 13C NMR (150 MHz,
CDCl3): d=171.1, 171.0, 170.6, 139.1, 138.7, 138.5 138.3, 137.8, 137.7,
128.4, 128.4 127.5, 127.3, 103.8, 103.7, 102.9, 102.8, 84.9, 84.8, 84.7, 82.4,
82.3, 82.2, 80.7, 80.6, 78.2, 77.7, 77.6, 77.6, 75.7 75.6, 75.0 74.8, 74.7, 73.3,
72.7, 72.7, 70.2, 68.7, 63.6, 63.5, 63.1, 40.9, 40.8, 36.7, 35.3, 35.2, 35.1, 35.0,
34.5, 34.4, 30.1 29.7, 25.5, 25.4, 25.3, 25.3, 25.2, 20.8, 19.6; IR: n˜ = 2921,
2220
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2214 2222

Macroviracin D
2214 2222
2851, 1731, 1071 cmÀ1; HRMS (ESI-pos.): m/z: calcd for C179H224O29
:
Acknowledgement
2837.54; found: 1457.77 [M+2K]2+
.
Generous financial support by the Deutsche Forschungsgemeinschaft
(Leibniz award to A.F.) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. J.M. thanks the Alexander-von-Humboldt Founda-
tion for a fellowship. We are grateful to Dr. M. Albert for bringing the
macroviracins to our attention, to Mr. A. Deege and his team for per-
forming the preparative HPLC separation, to Dr. R. Mynott and Mrs. P.
Philipps for their help with the high field NMR spectra, and to Dr. W.
Schrader and Mr. H. W. Klein for the HRMS service.
Compound 27: Lactone 26 (40 mg) was dissolved in THF (3 mL) and
treated with a saturated methanolic solution of ammonia (3 mL). The re-
sulting mixture was stirred for 8 d at ambient temperature and then
evaporated to dryness. The residue was purified by flash chromatography
(hexane/ethyl acetate 4:1) to give alcohol 27 as a colorless syrup (34 mg,
86%). [a]=+4.5 (c=1.70, CHCl3); 1H NMR (600 MHz, CDCl3) d=
7.35 7.10 (m, 75H), 4.93 4.32 (m, 36H), 4.15 4.05 (m, 4H), 3.68 3.30 (m,
24H), 2.92 (dd, 1H, J=5.6, 16.2 Hz), 2.65 (dd, 1H, J=8.3, 15.5 Hz), 2.52
(dd, 1H, J=7.0, 16.1 Hz), 2.43 (dd, 1H, J=3.6, 15.4 Hz), 1.60 1.15 (m,
72H), 1.15 (d, 3H, J=6.1 Hz), 1.14 (d, 3H, J=6.1 Hz); 13C NMR
(150 MHz, CDCl3): d=172.1, 171.1, 139.2, 138.7, 138.6 137.7, 128.3
127.6, 103.8, 103.3, 103.2, 102.9, 84.9, 84.8, 84.8, 84.7, 82.5, 82.4, 82.3, 82.3,
81.4, 80.7, 78.4, 78.3, 78.2, 77.8, 77.7, 77.7, 75.6, 75.6, 75.1 73.3, 72.7, 70.2,
68.7, 64.2, 63.5, 62.5, 41.2, 40.9, 36.7, 35.9, 35.1, 35.0, 34.6, 30.1 29.7, 25.5
25.3, 19.6.
[1] T. Hyoda, Y. Tsuchiya, A. Semine, T. Amano, Jpn. Kokai Tokkyo
Koho Jpn. Pat. 11246587 (Sept. 14, 1999) [Chem. Abstr. 1999, 131,
227743].
[2] The potency of these compounds is reported to exceed that of acy-
clovir by a factor of 10.
[3] S. Takahashi, M. Hosoya, H. Koshino, T. Nakata, Org. Lett. 2003, 5,
1555 1558.
[4] a) A. F¸rstner, T. M¸ller, J. Org. Chem. 1998, 63, 424 425; b) A.
F¸rstner, T. M¸ller, J. Am. Chem. Soc. 1999, 121, 7814 7821;
c) C. W. Lehmann, A. F¸rstner, T. M¸ller, Z. Kristallogr. 2000, 215,
114 117.
[5] a) A. F¸rstner, F. Jeanjean, P. Razon, Angew. Chem. 2002, 114,
2203 2206; Angew. Chem. Int. Ed. 2002, 41, 2097 2101; b) A.
F¸rstner, F. Jeanjean, P. Razon, C. Wirtz, R. Mynott, Chem. Eur. J.
2003, 9, 307 319; c) A. F¸rstner, F. Jeanjean, P. Razon, C. Wirtz, R.
Mynott, Chem. Eur. J. 2003, 9, 320 326.
[6] A. F¸rstner, K. Radkowski, J. Grabowski, C. Wirtz, R. Mynott, J.
Org. Chem. 2000, 65, 8758 8762.
[7] a) A. F¸rstner, I. Konetzki, J. Org. Chem. 1998, 63, 3072 3080;
b) A. F¸rstner, I. Konetzki, Tetrahedron 1996, 52, 15071 15078;
c) A. F¸rstner, I. Konetzki, Tetrahedron Lett. 1998, 39, 5721
5724.
[8] For recent studies on the use of carbohydrate building blocks for
the synthesis of lipidic products see: a) A. F¸rstner, K. Radkowski,
C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem.
Soc. 2002, 124, 7061 7069; b) A. F¸rstner, M. Schlede, Adv. Synth.
Catal. 2002, 344, 657 665.
[9] a) M. Tsunakawa, N. Komiyama, O. Tenmyo, K. Tomita, K.
Kawano, C. Kotake, M. Konishi, T. Oki, J. Antibiot. 1992, 45, 1467
1471; b) M. Tsunakawa, C. Kotake, T. Yamasaki, T. Moriyama, M.
Konishi, T. Oki, J. Antibiot. 1992, 45, 1472 1480.
[10] a) A. F¸rstner, M. Albert, J. Mlynarski, M. Matheu, J. Am. Chem.
Soc. 2002, 124, 1168 1169; b) A. F¸rstner, J. Mlynarski, M. Albert,
J. Am. Chem. Soc. 2002, 124, 10274 10275.
[11] A. F¸rstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J.
Am. Chem. Soc. 2003, 125, 13132 13142.
Compound 28: Triethylamine (4 mL, 0.03 mmol) and 2,4,6-trichlorobenzo-
yl chloride (2 mL, 0.012 mmol) were added to a solution of acid 17
(16 mg, 0.01 mmol) in toluene (2 mL). The resulting mixture was stirred
for 1.5 h before a solution of alcohol 27 (15 mg, 0.005 mmol) and DMAP
(0.6 mg, 0.005 mmol) in toluene (1 mL) was introduced. After stirring for
1 h, the mixture was concentrated and the residue was purified by flash
chromatography (hexane/ethyl acetate 4:1) to give ester 28 as a colorless
syrup (17 mg, 74%). [a]=+7.3 (c=1.70, CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.32 7.24 (m, 120H), 4.95 4.39 (24AB+m, 54H), 4.32 (m,
1H), 4.28 (m, 2H), 4.15 4.05 (m, 6H), 3.72 3.32 (m, 36H), 2.93 (dd, 2H,
J=5.5, 16.3 Hz), 2.83 (dd, 1H, J=5.3, 15.9 Hz), 2.59 (dd, 1H, J=7.5,
15.8 Hz), 2.53 (dd, 1H, J=6.9, 16.1 Hz), 2.45 (dd, 1H, J=7.2, 16.1 Hz),
1.60 1.15 (m, 108H), 1.15 (d, 6H, J=6.1 Hz), 1.14 (d, 3H, J=6.1 Hz);
13C NMR (150 MHz, CDCl3): d=171.1, 171.0, 170.9, 139.1, 138.7 138.2,
137.8, 137.7, 128.4 127.5, 127.4, 103.8, 103.7, 103.6, 102.8, 102.7, 102.6,
85.0, 84.9, 84.8, 84.7, 84.6, 82.4, 82.3, 82.3, 82.2, 82.2, 80.6, 80.4, 79.9, 78.2,
78.1, 78.0, 77.8, 77.7, 77.5, 75.6 75.5, 75.1 74.6, 73.6, 73.4, 73.3, 72.8, 72.7,
70.2, 69.2, 68.8, 68.7, 63.6, 63.5, 62.8, 40.9, 40.8, 36.7, 36.6, 36.0, 35.2, 35.0,
34.9, 34.4, 34.3, 34.1, 30.1 29.6, 25.5 25.1, 19.6; HRMS (ESI-pos.): m/z:
calcd for C276H342O42: 4328.4626; found: 1465.8091 [M+3Na]3+
.
Compound 1: Pd(OH)2 (5 mg) was added to a solution of compound 28
(8.1 mg, 1.87 mmol) in carefully dried EtOH (6 mL) and the resulting
suspension was stirred under H2 (1 atm) for 12 h at ambient temperature.
The catalyst was filtered off through a short pad of Celite, the Celite was
rinsed with anhydrous EtOH, and the combined filtrates were evaporat-
ed giving compound 1 as an analytically pure white solid (4 mg, 100%).
1
[a]2D5 = À21 (c=0.36, CH3OH) [lit.:[1] À27.2 (c=1)]; H NMR (600 MHz,
CD3OD): d=4.55 (brs, 24H), 4.44 (dd, 1H, J=1.9, 11.6 Hz), 4.43 (dd,
1H, J=1.9, 11.6 Hz), 4.39 (dd, 1H, J=1.9, 11.7 Hz), 4.35 (d, 1H, J=
7.9 Hz), 4.34 (d, 1H, J=7.8 Hz), 4.33 (d, 1H, J=7.8 Hz), 4.31 (d, 1H, J=
7.7 Hz), 4.27 (d, 1H, J=7.8 Hz), 4.33 4.25 (m, 2H), 4.21 (dd, 1H, J=5.8,
11.7 Hz), 4.15 (dd, 1H, J=7.6, 11.8 Hz), 4.13 (dd, 1H, J=7.5, 11.8 Hz),
4.12 4.03 (m, 10H), 3.85 3.57 (m, 27H), 2.82 (dd, 1H, J=6.2, 15.8 Hz),
2.81 (m, 2H), 2.57 (dd, 1H, J=5.9, 15.3 Hz), 2.49 (dd, 1H, J=5.6,
15.6 Hz), 2.45 (dd, 1H, J=6.5, 15.7 Hz), 1.63 1.25 (m, 108H), 1.14 (d,
9H, J=6.1 Hz); 13C NMR (150 MHz, CD3OD): d=173.6, 173.4, 172.9,
104.7, 104.3, 104.3, 103.9, 103.9, 103.8, 103.4, 81.3, 81.2, 81.1, 80.5, 78.4,
78.2, 78.1, 78.0, 77.9, 77.7, 77.7, 75.3, 75.3, 75.2, 75.2, 75.1, 72.1, 71.8, 71.5,
71.4, 68.6, 65.4, 65.3, 64.8, 64.7, 63.0, 62.9, 62.8, 42.2, 40.2, 36.4, 36.2, 36.2,
36.0, 35.5, 34.9, 31.1 30.8, 26.9, 26.8, 26.6 26.1, 26.0, 23.6, 23.5; HMRS
[12] H. Rathore, T. Hashimoto, K. Igarashi, H. Nukaya, D. S. Fullerton,
Tetrahedron 1985, 41, 5427 5438.
[13] For reviews on the trichloroacetimidate method see: a) R. R.
Schmidt, Angew. Chem. 1986, 98, 213 236; Angew. Chem. Int. Ed.
Engl. 1986, 25, 212 235; b) R. R. Schmidt, W. Kinzy, Adv. Carbo-
hydr. Chem. Biochem. 1994, 50, 21 123; c) R. R. Schmidt, K.-H.
Jung, in Preparative Carbohydrate Chemistry (Ed.: S. Hanessian),
Marcel Dekker, New York, 1997, pp. 283 312.
[14] M. J. Rozema, C. Eisenberg, H. L¸tjens, R. Ostwald, K. Belyk, P.
Knochel, Tetrahedron Lett. 1993, 34, 3115 3118.
[15] H. Takahashi, T. Kawakita, M. Ohno, M. Yoshioka, S. Kobayashi,
Tetrahedron 1992, 48, 5691 5700.
[16] Reviews: a) P. Knochel, in Active Metals: Preparation, Characteriza-
tion, Applications (Ed.: A. F¸rstner), VCH, Weinheim, 1996,
pp. 191 236; b) P. Knochel, Synlett 1995, 393 403; c) R. Noyori,
in Asymmetric Catalysis in Organic Synthesis, Wiley, New York,
1994, pp. 255 297; d) K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833
856.
[17] W. Xu, S. A. Springfield, J. T. Koh, Carbohydr. Res. 2000, 325, 169
176.
[18] M. Hikota, Y. Sakurai, K. Horita, O. Yonemitsu, Tetrahedron Lett.
1990, 31, 6367 6370.
(ESI-pos.): calcd for
C
108H198O42
:
2167.33577; found: 1106.67026
[M+2Na2+].
Compound 29a: 1H NMR (600 MHz, CD3OD): d=4.32 (d, 1H, J=
8.0 Hz), 4.30 (d, 1H, J=8.0 Hz), 4.08 (m, 1H), 3.84 (dd, 1H, J=2.5,
11.8 Hz), 3.81 (dd, 1H, J=2.1, 11.8 Hz), 3.72 3.68 (m, 2H), 3.67 (dd, 1H,
J=5.5, 11.8 Hz), 3.63 (s, 3H), 3.63 (dd, 1H, J=5.5, 11.8 Hz), 3.34 (t, 1H,
J=8.9 Hz), 3.33 (t, 1H, J=8.8 Hz), 3.32 3.20 (m, 4H), 3.15 (dd, 1H, J=
7.8, 9.0 Hz), 3.12 (dd, 1H, J=7.8, 9.2 Hz), 2.71 (dd, 1H, J=7.1, 15.4 Hz),
2.51 (dd, 1H, J=5.5, 15.4 Hz), 1.66 1.26 (m, 36H), 1.13 (d, 3H, J=
6.1 Hz); 13C NMR (150 MHz, CD3OD): d=174.4, 104.2, 103.4, 80.5, 78.2,
78.1, 78.0, 77.97, 77.7, 77.68, 75.3, 75.2, 71.8, 71.7, 68.6, 62.9, 49.3, 41.9,
40.1, 35.93, 35.90, 34.8, 31.0, 30.8, 30.75, 30.73, 30.72, 30.71, 30.6, 26.8,
26.3, 26.1, 26.0, 23.5.
2221
Chem. Eur. J. 2004, 10, 2214 2222
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. F¸rstner et al.
FULL PAPER
[19] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 1993.
[20] A. F¸rstner, J. Ruiz-Caro, H. Prinz, H. Waldmann, J. Org. Chem.
2004, 69, 459 467.
[21] For detailed biochemical and biological evaluations of various glyco-
lipids see refs. [11,20]. For a recent review see: A. F¸rstner, Eur. J.
Org. Chem. 2004, 943 958.
Received: September 30, 2003 [F5588]
2222
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 2214 2222