An enantioselective synthesis of the C24-C40 fragment of (-)-pulvomycin

Article abstract of DOI:10.1039/c4cc01338g

The C₂₄-C₄₀ fragment of (-)-pulvomycin was prepared in enantiomerically pure form using a concise synthesis method (15 linear steps from d-fucose, 6.8% overall yield) featuring a diastereoselective addition to an aldehyde, a β-select

Full text of DOI:10.1039/c4cc01338g

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An enantioselective synthesis of the C24–C40
fragment of (À)-pulvomycin†
Cite this: Chem. Commun., 2014,
50, 4901
Sandra Bording and Thorsten Bach*
¨
Received 20th February 2014,
Accepted 21st March 2014
DOI: 10.1039/c4cc01338g
www.rsc.org/chemcomm
The C24–C40 fragment of (À)-pulvomycin was prepared in enantio-
merically pure form using a concise synthesis method (15 linear
steps from D-fucose, 6.8% overall yield) featuring a diastereoselective
addition to an aldehyde, a b-selective glycosylation and a Stille cross-
coupling as the key steps.
The antibiotic pulvomycin was first isolated in 1957 from a
Streptomyces species but due to the limited analytical data no Fig. 1 Structure and compound numbering of (À)-pulvomycin.
structure was assigned to the compound.1 In 1963, Akita et al.
isolated a natural product from Streptomyces albosporeus var.
labilomyceticus,2 which they called labilomycin and which was
later shown to be identical to pulvomycin.3 Extensive analytical
work by Smith et al. revealed the constitution of the natural
product (Fig. 1) as well as the absolute and relative configu-
ration at most stereogenic centers except for C32 and C33.4 The
Scheme 1 Retrosynthetic disconnection of the title compound 1 leading
assignment was confirmed and the complete configuration was
to D-fucose (2) as an appropriate carbohydrate substrate.
eventually proven by a crystal structure (1.4 Å resolution) of
pulvomycin with the bacterial elongation factor Tu (EF-Tu).5
It is well established that pulvomycin is a potent inhibitor of we disclose the enantioselective synthesis of a suitably protected
EF-Tu and it therefore represents a promising lead compound C24–C40 fragment 1 (Scheme 1) of pulvomycin.
for the development of new antibiotics.6
Retrosynthetically, it was envisioned that ketone 1 (TBDPS =
While synthetic reports on pulvomycin are scarce, the bio- tert-butyldiphenylsilyl) could be derived from commercially
synthesis of the pulvomycin aglycone has been elucidated by available D-fucose (2), which shows the correct configuration
labeling experiments.7 Our own interest in pulvomycin was at the stereogenic centers (C36–C39) of the pyranose ring. In
triggered by our previous studies on the synthesis8 and anti- order to establish the desired b-configuration at the glycosidic
biotic activity9 of thiazole peptides, such as the GE factors and center an appropriate neighbouring group, e.g. an acetate, was
the amythiamicins. It has been shown that the EF-Tu binding required (at carbon atom C36)12 and the methyl ether linkage
site of pulvomycin is in close proximity to the binding site of was to be introduced after glycosylation. There was precedence
thiazole peptides.10 The synthesis of pulvomycin and pulvomycin for the differentiation of the two equatorial hydroxy groups at
analogues might consequently help to further investigate the C36 and C37 of D-fucose.13
many facets of EF-Tu activity.11 Apart from its biological activity,
Regarding the C24–C34 fragment, it seemed best to assemble
pulvomycin presents itself as a formidable synthetic challenge the triene14 after the glycosylation step by an appropriate cross-
due to its complex and labile structure. In this communication coupling reaction, e.g. between C29 and C30. The stereogenic
center at C33 appeared to be accessible from the chiral pool, e.g.
from lactic acid, while the adjacent stereogenic center was to be
introduced by a diastereoselective reaction.
¨
¨
¨
Lehrstuhl fur Organische Chemie I, Technische Universitat Munchen,
85747 Garching, Germany. E-mail: thorsten.bach@ch.tum.de;
Fax: +49 89 28913315; Tel: +49 89 28913330
The acetylation of D-fucose (2) (Scheme 2) proceeded quanti-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01338g tatively delivering the tetraacetate as an a/b-mixture (a/b = 95/5)
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Scheme 2 Synthesis of the protected glycosyl donor 5 from D-fucose (2).
DMAP = 4-(N,N-dimethylamino)pyridine, py = pyridine, im = imidazole.
of anomers.13 Conversion to the required thioacetal 3 pro-
ceeded best in our hands with ethanethiol and BF3ÁOEt2 in
CH2Cl2,15 which delivered depending on the reaction condi-
tions and on the reaction scale variable amounts of separable
a/b-isomers (see the ESI† for further details).
Since the relative configuration at the anomeric center was
irrelevant for the desired glycosylation reaction, the a/b-mixture
of 3 was taken into the four-step procedure previously described
for the selective preparation of alcohol b-413 and it furnished
the desired product 4 as an a/b-mixture (a/b D 50/50) in a total
yield of 60% over six steps from D-fucose (2). Conversion of the
equatorial alcohol 4 to silyl ether 5 required elevated tempera-
ture (60 1C) and a prolonged reaction time (3 d).
As mentioned above, it was planned to introduce the stereo-
genic center at C32 by a diastereoselective reaction induced by
the adjacent stereogenic center at the carbon atom C33. Surpris-
ingly, the reduction of a (S)-lactate-derived, para-methoxybenzyl
(PMB) protected alkynyl ketone16 produced the desired alcohol
7 either in low yields or with insufficient diastereoselectivity
(see the ESI† for further details). As an alternative approach,
(S)-lactate-derived aldehyde 617 was alkynylated with TMS-
acetylene under chelation control18 yielding alcohol 7 and its
epimer epi-7 in 81% yield and in a diastereomeric ratio (d.r.) of
87/13 (Scheme 3). The diastereomerically pure product 7 was
isolated in 65% yield.
Protection of the secondary alcohol proceeded smoothly at
ambient temperature and the PMB group was cleaved oxida-
tively with 2,3-dicloro-5,6-dicyanobenzoquinone (DDQ)19 to
deliver alcohol 8. The enantiomeric excess (ee) of alcohol 8 was
established by chiral HPLC analysis and comparison with a racemic
sample (see the ESI† for further details). Gratifyingly, the glyco-
sylation reaction, when performed with N-iodosuccinimide (NIS)
and trifluoromethanesulfonic acid (HOTf) as activating agents,20
delivered a single diastereomerically pure product 9, which was
shown to have the desired b-configuration.21 Reductive removal of
the acetyl groups with diisobutylaluminium hydride (DIBAL-H)22
produced 1,3-diol 10, which was converted into the respective
dimethylether 11 upon treatment with an excess (10 equiv.) of
Meerwein salt and proton sponge [1,8-bis(dimethylamino)-
naphthalene].23 Less electrophilic methylating reagents (MeOTf,
MeI) in combination with appropriate bases failed to react or led
to substrate decomposition. Selective desilylation of the alkyne
was achieved with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).24
With alkyne 12 in hand, various approaches to potential
Scheme 3 Assembly of the C28–C40 fragment via glycosylation of
enantiomerially pure (Z98% ee) alcohol 8 with glycosyl donor 5.
Pd-catalyzed hydrostannylation with Bu3SnH25 can be success-
fully performed with alkyne 12 delivering stannane 13 in 44%
yield (Scheme 4). Iodide 14 was obtained from stannane 13
upon treatment with iodine in dichloromethane (85% yield).26
The alkyne hept-3-en-1-yne-5-ol27 seemed to be the most suit-
able precursor for iodide 15 and stannane 16. The compound
was available from bis-1,4-(trimethylsilyl)buta-1,3-diyne in four
steps and an overall yield of 53% (see the ESI† for further
details). Stannylation of hept-3-en-1-yne-5-ol with Bu3SnH was
readily achieved employing the Cu-based protocol of Betzer
et al.28 to deliver stannane 16 in 79% yield. As for 14, iodide 15
was generated by iodo-de-stannylation employing iodine in
dichloromethane (79% yield).
While attempted Stille cross-coupling reactions29 of stannane
13 and iodide 15 failed, the desired C–C bond formation
proceeded smoothly, when performed with the carbohydrate
building block as the electrophile. Iodide 14 and stannane 16
underwent a clean cross-coupling employing Pd(MeCN)2Cl2
Scheme 4 Stille cross-coupling of building blocks 13 and 15 as key step
cross-coupling substrates were pursued. It was found that the for the assembly of the title compound.
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(10 mol%) as the catalyst.30 Alcohol 17 was obtained in 87%
yield and was immediately further oxidized to the desired
ketone by treatment with an excess (30 equiv.) of MnO2. Despite
a pronounced long wavelength absorption (lmax = 308 nm,
e = 28 035 MÀ1 cmÀ1 in MeCN), trienone 1 appears to be more
stable than alcohol 17 (lmax = 271 nm, e = 39 350 MÀ1 cmÀ1 in
MeCN; shoulder at lmax = 282 nm, e = 31 180 MÀ1 cmÀ1) and
could be stored for one week at À25 1C in the dark.
13 D. Comegna, E. Bedini and M. Parrilli, Tetrahedron, 2008, 64,
3381–3391.
14 For selected recent total syntheses of naturally occurring conjugated
(E,E,E)-trienes, see: (a) D. J. Del Valle and M. J. Krische, J. Am.
Chem. Soc., 2013, 135, 10986–10989; (b) C. Jahns, T. Hoffmann,
¨
S. Mu¨ller, K. Gerth, P. Washausen, G. Hofle, H. Reichenbach,
M. Kalesse and R. Mu¨ller, Angew. Chem., Int. Ed., 2012, 51,
5239–5243; (c) M. Yoshino, K. Eto, K. Takahashi, J. Ishihara and
S. Hatakeyama, Org. Biomol. Chem., 2012, 10, 8164–8174; (d) P. G. E.
Craven and R. J. K. Taylor, Tetrahedron Lett., 2012, 53, 5422–5425;
(e) H. J. Jessen, A. Schumacher, F. Schmid, A. Pfaltz and
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In summary, the enantiomerically pure western fragment 1
of (À)-pulvomycin was synthesized in 15 linear steps. The
fragment comprises the carbohydrate part (labilose, C35–C40
)
of the natural product and one of its three triene components
(C24–C34). Should an aldol-type reaction of fragment 1 with a
suitable Eastern fragment not be successful, stannane 13 and
iodide 14 offer suitable options to connect the protected glyco-
side fragment to the rest of the molecule.
This project was supported by the Deutsche Forschungs-
gemeinschaft (Ba 1372-18/1), by the TUM Graduate School, and
by the Fonds der Chemischen Industrie. Olaf Ackermann and
Florian Mayr are acknowledged for help with the HPLC analyses.
¨
15 P. Sjolin, S. K. George, K.-E. Bergquist, S. Roy, A. Svensson and
J. Kihlberg, J. Chem. Soc., Perkin Trans. 1, 1999, 1731–1742.
16 The ketone was prepared from literature known Weinreb amide
(V. Convertino, P. Manini, W. B. Schweizer and F. Diederich,
Org. Biomol. Chem., 2006, 4, 1206–1208) by substitution with the
respective magnesium acetylide (see the ESI† for further details).
17 W. Yu, Y. Zhang and Z. Jin, Org. Lett., 2001, 3, 1447–1450.
18 K. T. Mead, Tetrahedron Lett., 1987, 28, 1019–1022.
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21 1H-NMR data of glycoside 9 (500 MHz, CDCl3): d (ppm) = 0.09 [s, 9H;
Si(CH3)3], 0.97 [s, 9H; C(CH3)3], 0.96–0.99 (m, 3H; H3-40), 1.05 [s, 9H;
C(CH3)3], 1.30 (d, 3J = 6.3 Hz, 3H; H3-34), 1.46 (s, 3H; C(O)CH3-36),
2.12 [s, 3H; C(O)CH3-38], 3.05 (q, 3J = 6.4 Hz, 1H; H-39), 3.41
(qd, 3J = 6.3, 3.9 Hz, 1 H; H-33), 3.44 (d, 3J = 8.1 Hz, 1 H; Hb-35),
3.60 (dd, 3J = 9.8, 3.3 Hz, 1H; H-37), 4.19 (d, 3J = 3.9 Hz, 1H; H-32),
4.79 (d, 3J = 3.3 Hz, 1H; H-38), 5.06 (dd, 3J = 9.8, 8.1 Hz, 1H;
H-36), 7.23–7.27 (m, 4H; Harom), 7.30–7.48 (m, 10H; Harom),
7.55–7.58 (m, 2H; Harom), 7.60–7.65 (m, 4H; Harom), 7.69–7.73
(m, 2H; Harom).
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