Total Synthesis of the Boron-Containing Ion Carrier Antibiotic Macrodiolide Tartrolon B

Article abstract of DOI:10.1021/jo035391p

The first total synthesis of the boron-containing macrodiolide antibiotic tartrolon B is reported in full detail. Two convergent approaches to the target compound are described, the first of which eventually failed, due to sensitive functionality. In the

Full text of DOI:10.1021/jo035391p

Tota l Syn th esis of th e Bor on -Con ta in in g Ion Ca r r ier An tibiotic
Ma cr od iolid e Ta r tr olon B
J ohann Mulzer* and Markus Berger
Institut fu¨r Organische Chemie, Universita¨t Wien, Wa¨hringer Strasse 38, A-1090 Wien, Austria
johann.mulzer@univie.ac.at
Received September 24, 2003
The first total synthesis of the boron-containing macrodiolide antibiotic tartrolon B is reported in
full detail. Two convergent approaches to the target compound are described, the first of which
eventually failed, due to sensitive functionality. In the second, successful route the key step was a
stereoselective boron-mediated aldol addition of a bicyclic acetonide protected ketone to a diene-
aldehyde. In this case the synthesis could be completed without major problems, using a Yamaguchi
dimerization macrolactonization endgame.
In tr od u ction
C-2-OHs are shared by both coordination spheres. An-
other interesting feature is the planar conformation of
the E,Z-diene section, which makes the surface of the
molecule lipophilic. All oxygens are turned inside, to
make the core region strongly hydrophilic. In this way
the molecule appears optimized for carrying an ion
through a lipophilic membrane. In fact both tartrolon A
and B act as ion carriers and they are both active against
Gram positive bacteria with MIC values of 1 µg/mL. This
means that the presence of the boron is not required for
the antibiotic activity.
Tartrolon is structurally related to the antibiotics
boromycin,5 aplasmomycin,6 and borophycin7 which are
all feature a very similar C-1-C-7-region, possibly the
pharmacophore of the compounds (Figure 2). In contrast
to tartrolon, these antibiotics all exist only with the boron
core. Boromycin and aplasmomycin were both synthe-
sized a while ago, whereas no attempt toward synthesiz-
ing borophycin has yet been made.
Over the past decade we have been interested in the
total synthesis of structurally complex macrolides for
different reasons.1 One reason was that the molecular
architecture of these compounds poses a challenge to the
synthetic chemist; another reason was the enormous
potential of many of these compounds as potential drugs,
for instance as antibiotics or in tumor therapy. As an
example, we gave a full account of the first total synthesis
of tartrolon A and B,2 which are ion carrier antibiotics
of high activity.
The tartrolons were first isolated in 1994 by Ho¨fle and
Reichenbach from Myxobacterium Sorangium cellulosum
strain So ce678.3 The fermentation furnishes tartrolon
A (2) or B (1) (Figure 1) depending on the fermentation
vessel. Glass vessels provide boron and hence allow the
formation of 1, whereas in steel fermenters the boron-
free compounds 2 are formed as diastereomeric mixtures.
Alternatively, the boron can be incorporated into 2
chemically. This leads to a fixation of the variable
stereogenic center at C2 and forces 1 into a C2-sym-
metrical structure. The absolute and relative configura-
tion of tartrolone B has been clarified by a single-crystal
diffraction analysis4 of the potassium derivative (figure
in the Supporting Information). In this structure the
environment of both the boron and the potassium is
remarkable, as both atoms are close together, in form of
an inner ion pair. Boron forms a tetrahedral and potas-
sium an octahedral complex with macrolide oxygens. The
F ir st-Gen er a tion Retr osyn th esis
In view of the C2-symmetrical overall structure of the
target compounds our first retrosynthetic plan aimed for
a cylodimerization of the monomeric seco acid 3 under
Yamaguchi macrolactonization conditions (Scheme 1).
For the synthesis of 3 an aldol-type addition of ketone 5
to aldehyde 4 was envisaged as the key step. This kind
(5) (a) Hu¨ter, R.; Keller-Schierlein, W.; Knu¨sel, F.; Prelog, V.;
Rodgers, G. C.; Suter, P.; Vogel, G.; Za¨hner, H. J . Antibiot. 1967, 20,
1533. (b) Dunitz, J . D.; Hawley, D. M.; Miklos, D.; White, D. N. J .;
Berlin, Y.; Marusic, R.; Prelog, V. Helv. Chim. Acta 1971, 54, 1709.
Synthesis following that in: White, J . D.; Avery, M. A.; Choudhry, S.
C.; Dhingra, O. P.; Gray, B. D.; Kang, M.-c.; Kuo, S.-c.; Whittle, A. J .
J . Am. Chem. Soc. 1989, 111, 790.
(6) Okami, Y.; Okazaki, T.; Kitahara, T.; Umezawa, H. J . Antibiot.
1976, 29, 1019. Synthesis following that in: (a) Corey, E. J .; Pan, B.-
C.; Hua, D. H.; Deardorff, D. R. J . Am. Chem. Soc. 1982, 104, 6816.
(b) Corey, E. J .; Hua, D. H.; Pan, B.-C.; Seitz, S. P. J . Am. Chem. Soc.
1982, 104, 6818. (c) White, J . D.; Vedananda, T. R.; Kang, M.-c.;
Choudhry, S. C. J . Am. Chem. Soc. 1986, 108, 8105.
* Corresponding author. Phone: +431-4277-52190. Fax: +431-4277-
52189.
(1) Erythronolide B: Mulzer, J .; Kirstein, H. M.; Buschmann, J .;
Lehmann, Ch.; Luger, P. J . Am. Chem. Soc. 1991, 113, 910. Epothilone
B: Mulzer, J . Chem. Mon. 2000, 205. Laulimalide: Mulzer, J .; Oehler,
E. Chem. Rev. 2003, 103, 3753.
(2) Earlier reports: Mulzer, J .; Berger, M. Tetrahedron Lett. 1998,
39, 803-806. Mulzer, J .; Berger, M. J . Am. Chem. Soc. 1999, 121, 8393.
(3) (a) Schummer, D.; Irschik, H.; Reichenbach, H.; Ho¨fle, G. Liebigs
Ann. Chem. 1994, 283. (b) Irschik, H.; Schummer, D.; Gerth, K.; Ho¨fle,
G.; Reichenbach, H. J . Antibiot. 1995, 48, 26.
(4) Schummer, D.; Schomburg, D.; Irschik, H.; Reichenbach, H.;
Ho¨fle, G. Liebigs Ann. Chem. 1996, 965.
(7) Hemscheidt, T.; Puglisi, M. P.; Larsen, L. K.; Patterson, G. M.
L.; Moore, R. E.; Rios, J . L.; Clardy, J . J . Org. Chem. 1994, 59, 3467.
10.1021/jo035391p CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
J . Org. Chem. 2004, 69, 891-898
891

Mulzer and Berger
F IGURE 1. The interconversion of tartrolons A and B.
F IGURE 2. Related boron-containing macrolides.
SCHEME 1. F ir st Gen er a tion Retr osyn th esis
center had yet to be investigated. Following this aldol
addition, a second one has to be used for attaching the
glycol ester unit 6 to a C-3-aldehyde.
The synthesis of aldehyde 4a /b is shown in Scheme
2a. The E/Z-diene moiety was to be generated stereose-
lectively from the corresponding E-ene-yne by a Z-
selective Boland reduction.9 The sequence started with
O-protected lactic ester 7, which was reduced to the
aldehyde and then subjected to a Wadsworth-Horner-
Emmons olefination to generate the enoate. Hydrogena-
tion of the double bond and reduction of the ester led to
aldehyde 8. Corey-Fuchs10 chain elongation generated
alkyne 9, which was deprotonated and after addition of
lithium bromide11 treated with acrolein to furnish enyne-
ol 10. J ohnson-Claisen rearrangement12 occurred exlu-
sively across the olefinic bond and generated the E-enyne-
ester selectively. Cis hydrogenation9 of the alkyne followed
by DIBAL-H reduction delivered aldehyde 4 in high
overall yield (10 steps, ca. 25% overall yield).
In a second approach (Scheme 2b), aiming for the TBS
derivative 4a , aldehyde 8a was subjected to a Z-selective
Wittig reaction13 to furnish vinyl iodide 13. Separately,
3-butyn-1-ol was O-tritylated and then converted to
E-vinylstannane 14 by a free-radical-induced hydrostan-
(9) Boland, W.; Schroer, N.; Sieler, C. Helv. Chim. Acta 1987, 70,
1025.
of aldol addition required a regioselective formation of
the less substituted enolate and had to avoid the forma-
tion of the regioisomeric enolate, which would im-
mediately lead to an elimination of the 7-alkoxy function.
From literature precedence8 it was obvious that enol-
borinates were suited for this purpose; however, the
stereocontrol over the newly created secondary alcohol
(10) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(11) (a) van Rijn, P. E.; Mommers, S.; Visser, R. G.; Verkruijsse, H.
D.; Brandsma, L. Synthesis 1981, 459. (b) Carreira, E. M.; Du Bois, J .
J . Am. Chem. Soc. 1994, 116, 10825. (c) Aerssens, M. H. P. J .; van der
Heiden, R.; Heus, M.; Brandsma, L. Synth. Commun. 1990, 20, 3421.
(12) J ohnson, W. S.; Werthmann, L.; Bartlett, W. R.; Brocksom, T.
J .; Li, T.; Faulkner, D. J .; Petersen, M. R. J . Org. Chem. 1970, 35,
741.
(13) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b)
Bestmann, H. J .; Rippel, H. C.; Dostalek, R. Tetrahedron Lett. 1989,
30, 5261.
(8) Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1.
892 J . Org. Chem., Vol. 69, No. 3, 2004

Tartrolon B Synthesis
SCHEME 2. (a ) Syn th esis of Ald eh yd e 4 (Ser ies a ,
R ) TBS; Ser ies b, R ) TBDP S) a n d (b) a n
Alter n a tive Syn th esis of Ald eh yd e 4a
the second approach is more convergent and turned out
more suitable.
Having secured appropriate quantities of aldehyde
4a /b we turned to the synthesis of the ketone component
5. Again, two alternative approaches were developed,
which both rested on the concept that the stereogenic
centers at C-4 and 8 in 5 be introduced in a configura-
tionally unambiguous way by using commercially avail-
able methyl-2-methyl-3-hydroxypropionate (Roche’s es-
ter) in both the R- and the S-form to generate separate
chiral fragments and join them to the carbon skeleton of
5. In the first approach (Scheme 3a) R-ester 16 was
transformed into the Weinreb amide15 17. On the other
hand S-aldehyde 18 was elaborated into the lithium
acetylide by a Corey-Fuchs protocol. The anion was
immediately trapped with 17 to form alkynone 19 in good
yield. Chiral reduction of the ketone with Alpine-borane16
gave the alcohol 20 with 80% de. After chromatographic
separation the main diastereomer was hydrogenated to
the 1,3-diol-derivative 21 with diimide and protected as
the PMP acetal 22.
Reduction with DIBAL-H shifted the PMB protecting
group to the more hindered 7-position and liberated
primary alcohol 23, which was then converted to the
methyl ketone 5 in three additional steps. Alternatively
(Scheme 3b), the two R- and S-Roche-ester fragments
were connected in the form of aldehyde 18 and phospho-
nate 25 via a Horner-Wadsworth-Emmons olefination17
to form enone 26, which was reduced with the CBS18
reagent to the allylic alcohols 27 and 28 (ratio 9:1).
Unfortunately ketone 29 (24%) was also formed by 1,4-
reduction. Nevertheless, the products were easily sepa-
rated and the overall yield of 27 was 65%. After hydro-
genation of the olefinic bond intermediate 21 was formed
and transformed into ketone 5 as before. Again both
approaches were comparable with respect to selectivity
and overall yield.
At this point we were able to prove the configuration
at the newly created alcohol center (Scheme 4). Hence,
the two diastereomers 27 and 28 were separated and
converted into the cyclic acetals 22 and 30, respectively.
1
The H NMR coupling constants and NOE experiments
indicated chair conformations for both acetals. As the
configuration at C-8 was known, the configuration at C-7
could be concluded from the vicinal 1H-1H-coupling
3
constants. Thus, J H-7,8 was 9.9 Hz for acetal 22 and 2.2
Hz for 30, which indicated a H-H diaxial arrangement
for 22 and an axial-equatorial one for 30.
Reassured by these results we proceeded to the crucial
aldol coupling between ketone 5 and aldehyde 4b (Scheme
5). In the first experiment, ketone 5 was converted into
the enolate with LDA and then treated at -78 °C for 2
min with aldehyde 4b. The aldol addition proceeded in
high yield and regioselectivity, however without any
stereocontrol over the C-11-stereogenic center. We then
turned to the boron-mediated enolization in the chiral
nylation. Components 13 and 14 were connected via a
Stille coupling14 with retention of the double bond
configurations to form ene-yne 15, which was then
converted into aldehyde 4a . Both routes exhibit similar
Z-selectivity (6-7:1) and yield. From the practical view,
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(16) (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano,
A. J . Am. Chem. Soc. 1980, 102, 867. (b) Midland, M. M.; McLoughlin,
J . I.; Gabriel, J . J . Org. Chem. 1989, 54, 153.
(17) Mulzer, J .; Martin, H. J .; List, B. Tetrahedron Lett. 1996, 37,
9177.
(18) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc.
1987, 109, 5551. (b) Review: Corey, E. J .; Helal, C. J . Angew. Chem.,
Int. Ed. 1998, 37, 1986.
(14) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
J . Org. Chem, Vol. 69, No. 3, 2004 893

Mulzer and Berger
SCHEME 4. Str u ctu r a l Assign m en t of 27
SCHEME 3. (a ) Syn th esis of Keton e 5 a n d (b)
Alter n a tive Syn th esis of Keton e 5
SCHEME 5. Mod el Ald ol Ad d ition
894 J . Org. Chem., Vol. 69, No. 3, 2004

Tartrolon B Synthesis
SCHEME 6. In d ep en d en t Syn th esis of 31a
F IGURE 3. Presumable transition states of the aldol addition
of ketone 5 to aldehyde 4b.
version pioneered by Paterson19 and hoped for chiral
induction from the auxiliary applied. To test the influence
of the chiral additive, both enantiomers of diisopinocam-
pheylboron chloride (DIPCl) were used. To our surprise,
aldol adduct 31 was generated with high diastereomeric
excess, however in about the same diastereomeric com-
position in both cases. This means that the reaction is
not auxiliary but substrate (i.e. ketone-enolate) controlled
and that the DIPCl acts via its bulk and not via its
absolute configuration. Inspection of the literature re-
vealed that in our case both the 7-S-alkoxide and the 8-S-
methyl substituents in the ketone obviously cooperate to
induce the 11-S-configuration in the adduct. For example,
Evans’ experiment20 in eq 1 shows the influence of the
methyl group, and Paterson’s experiment19 in eq 2 the
influence of the OPMB group. A rationalization of these
findings is suggested in Figure 3.
For the aldol addition two transition state geometries
I and II may be envisaged, of which I leads to the
observed diastereomer. Both I and II represent trans-
decalin-like geometries, with a Bronsted acid complex
formed between the enolate and the protected side chain
oxygens. Ring A is devoid of the normal 1,3-diaxial
interactions of a cyclohexane ring; thus its stability is
rather determined by the number of syn interactions,
which is one less in I than in II.
Although the configuration at C-11 could be deduced
from the literature precedence19,20 we wanted to be on
the safe side and decided to synthesize aldol adduct 31a
via an alternative stereochemically unambiguous route,
other than the aldol addition (Scheme 6).21 Hence,
glyceraldehyde 32 was converted to aldehyde 33, and
then into E-vinyl iodide 34 via a Takai olefination.22
Castro-Sonogashira coupling23 of 34 with acetylide 9b
led to ene-yne 35, which was hydrogenated Z-selectively
as before9 to form diene 36. Next, the terminal acetonide
was deprotected and transformed into epoxide 37 under
retention of configuration. Separately, aldehyde 24 was
converted into dithiane 38, which was lithiated and
treated with epoxide 37.
(19) Paterson, I.; Yeung, K.-S.; Ward, R. A.; Smith, J . D.; Cumming,
J . G.; Lamboley, S. Tetrahedron 1995, 51, 9467. Paterson, I.; Gibson,
K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585. Paterson, I.; Di
Francesco, M. E; Kuehn, T. Org. Lett. 2003, 5, 599.
(20) Evans, D. A.; Coleman, P. J .; Coˆte´, B. J . Org. Chem. 1997, 62,
788.
(21) For a related strategy see: Smith, A. B., III; Doughty, V. A.;
Lin, Q.; Zhuang, L.; McBriar, M. D.; Boldi, A. M.; Moser, W. M.;
Murase, N.; Nakayama, K.; Sobukawa, M. Angew. Chem., Int. Ed.
2001, 40, 197.
Ring opening occurred selectively at the terminal
position to form adduct 39, which was converted into
ketone 31a . The material obtained was identical in every
respect (NMR, HPLC) with compound 31a , synthesized
earlier.
After this laborious but necessary interlude, the route
to the monoseco acid 3 could be continued with confidence
(Scheme 7).
(22) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(23) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963,
28, 3313.
Thus, intermediate 31a was converted to aldehyde 40
and then subjected to an ester enolate aldol addition with
J . Org. Chem, Vol. 69, No. 3, 2004 895

Mulzer and Berger
SCHEME 7. Syn th esis of th e Mon oseco Acid Ester 42
SCHEME 8. Secon d Gen er a tion Retr osyn th esis
more concise methodology. Hence, “Roche’s ester” was
homologated to known26 ester 45 and reduced to aldehyde
46. A Duthaler-Hafner crotylation27 was used to form
olefin 47 with >95% relative and absolute stereocontrol.
Protecting group manipulation led to 48, which was
oxidized to aldehyde 49 and then treated with the enolate
of 2-OTHP-methyl-glycolate. Aldol adduct 50 was formed
as a mixture of diastereomeric alcohols. Swern oxidation
led to ketone ester 51, which was converted via Wacker
oxidation28 to diketone 52 in high yield. Now the stage
was set for the acetalization, which was efficiently
performed in two steps. First the THP groups were
removed, and then acetone was added under strongly
acidic conditions to generate the desired ketone ester
acetal 44 in acceptable yield. Encouraged by these
findings we performed the aldol addition of ketone 44 to
aldehyde 4a as before and obtained adduct 53 with a 4:1
diastereoselectivity (Scheme 10). This selectivity, which
was significantly lower than the one for the model
system, might be interpreted in terms of the new
complexes I′ and II′ (Figure 4), of which again I′ leads to
the observed adduct. However, compared to the previous
structure I, the annulation of an additional cis-decalin
ring destabilizes I′ and reduces the energy difference
between I′ and II′.
glycolate 6. After Swern oxidation24 diketone 41 was
obtained in 79% overall yield. To arrive at the desired
hydroxy acid 3, the 20-OTBDPS group had to be removed,
and the methyl ester had to be hydrolyzed. The first
operation was successful and provided us with hydroxy
ester 42, whose saponification, however, failed under a
variety of conditions, all of which resulted in extensive
decomposition of the material. In the end, we realized
that this route was not viable, and we decided to
reconsider our overall approach.
Secon d -Gen er a tion Syn th esis
Obviously, the seco acid in its original form suffered
from the lability of its â-keto-ester moiety, which made
it prone to decarboxylation. On looking at the final
functionalization in the tartrolons we realized that a
more appropriate precursor would be a bicyclic acetal
structure25 such as 43, which was very similar to the
correponding section in the natural products (Scheme 8).
To tame the molecule even more we also replaced the
9-carbonyl by a hydroxyl group that could be oxidized in
a later step. So, our new candidate for the seco acid
derivative was 43 in place of the previous intermediate
3. Still, we trusted our aldol strategy for preparing 43,
which meant that we could use aldehyde 4a unchanged,
whereas the ketone component now had to be synthesized
in the form of the diketal derivative 44 (Scheme 9).
Instead of returning to the procedure developed for the
synthesis of 5, we decided to test some new and hopefully
At this point we decided to rely on our earlier prece-
dence for stereochemical assignment and to proceed
without any stringent proof of the configuration at C-11
(Scheme 11). Hence, 53 was protected as the MOM-ether
54, and the problematic 9-ketone was reduced to the
alcohol 55, from which monoseco acid 57 was prepared
by successive desilylation and ester hydrolysis, now
without any problems. The attempt to obtain the diolide
62 from the monomer 57 by a dimerization-cyclization
sequence under Yamaguchi conditions29 in one pot failed.
(26) Andrus, M. B.; Schreiber, S. L. J . Am. Chem. Soc. 1993, 115,
10420.
(27) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit,
P.; Schwarzenbach, F. J . Am. Chem. Soc. 1992, 114, 2321.
(28) Tsuji, J . Synthesis 1984, 369.
(29) Inanaga, I.; Hirata,K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(24) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(25) Cf.: (a) Adams, M. A.; Duggan, A. J .; Smolanoff, J .; Meinwald,
J . J . Am. Chem. Soc. 1979, 101, 5364. (b) Ireland, R. E.; Highsmith,
T. K.; Gegnas, L. D.; Gleason, J . L. J . Org. Chem. 1992, 57, 5071.
896 J . Org. Chem., Vol. 69, No. 3, 2004

Tartrolon B Synthesis
SCHEME 9. Syn th esis of Keton e 44
F IGURE 4. Presumable transition states of the aldol addition
of ketone 44 to aldehyde 4a .
SCHEME 11. Attem p ted
Dim er iza tion -Cycliza tion of Mon oseco Acid 57
(Scheme 12), ester 55 was saponified to the acid, which
was esterified with hydroxyester 56 to obtain dimer 59.
The macrolactonization of 59 to 62 had now to be
performed without touching the ester function already
present. First, the TBS group was removed, and then the
methyl ester was hydrolyzed with barium hydroxyde in
methanol30 to generate seco acid 61, which was macro-
lactonized under Yamaguchi conditions to furnish 62.
SCHEME 10. Ald ol Ad d ition of Ald eh yd e 4a a n d
Keton e 44
Reoxidation of the free 9-OH groups to the ketones and
removal of the acetonide and MOM protective groups
with dimethylboron bromide31 gave a mixture of the
tartrolon A diastereomers, which were converted in
tartrolon B with Borax under the conditions described
Instead the monomacrolactone 58 was obtained in high
yield, along with small amounts of the diolide 62.
Nevertheless, this experiment gave us the information
that the 9-OH was not involved in the macrolactoniza-
tion, and hence did not need to be protected. Therefore
(30) Paterson, I.; Yeung, K.-S.; Ward, J . D.; Cumming, J . G.; Smith,
J . D. J . Am. Chem. Soc. 1994, 116, 9391.
(31) Guindon, Y.; Yoakim, C.; Morton, H. E. J . Org. Chem. 1984,
49, 3912.
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Mulzer and Berger
SCHEME 12. Com p letion of th e Syn th esis of Ta r tr olon B (1)
by Ho¨fle et al.3 To our delight the material obtained
proved to be identical with the authentic compound with
respect to the 1H and 13C NMR spectra (Supporting
Information) as reported by Ho¨fle.32
and failure were closely tied in this synthesis, and we
learned a lesson about the importance of tactics in total
synthesis, once the basic strategy has been fixed.
Ack n ow led gm en t. This paper is dedicated to Pro-
fessor Manfred T. Reetz on the occasion of his 60th
birthday. We thank Prof. G. Ho¨fle for numerous dis-
cussions, Assistant Prof. H.-P. Ka¨hlig for helping us
with the NMR spectra, Prof. A. Nikiforov for recording
the mass spectra, Ing. S. Schneider for HPLC separa-
tions, and the Austrian Science Fund (FWF) for finan-
cial contributions (project P-12677-CHE).
Con clu sion
In the end, we achieved the first total synthesis of
tartrolon B in about 20 steps along the longest linear
route, based on the known ester 45. A key step had been
the aldol addition between ketone 44 and the aldehyde
4a , which proceeded in good yield and reasonable dias-
tereoslectivity. Another interesting point was the ready
formation of the 21-membered macrolide monomer 58
under Yamaguchi lactonization conditions. Apart from
this we were struck by the fact that the first approach
failed so completely. On the other hand, seemingly little
modification was necessary for the second route. Success
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and characterization data for all new compounds, H
and 13C NMR spectra and crystal structure of compound 1,
and 1H NMR spectra of compounds 41 and 54. This material
is available free of charge via the Internet at http://pubs.acs.org.
(32) We thank Prof. G. Ho¨fle for kindly providing us authentic
samples of tartrolon B.
J O035391P
898 J . Org. Chem., Vol. 69, No. 3, 2004