Total synthesis of antibiotics GE2270A and GE2270T

Article abstract of DOI:10.1002/anie.200602798

(Chemical Equation Presented) Beat the bugs: Total syntheses of the thiopeptide antibiotics GE2270A (X-Y = CH₂-CH) and GE2270T (X-Y = CH= C) have been accomplished. The modular approach featured a hetero-Diels-Alder dimerization Circled latin capital letter A to construct the trithiazolyl pyridine domain, and highly regioselective macrolactamizations Circled latin capital letter B to furnish the macrocyclic core.

Full text of DOI:10.1002/anie.200602798

Communications
Thiopeptide Antibiotics
DOI: 10.1002/anie.200602798
Total Synthesis of Antibiotics GE2270A and
GE2270T**
K. C. Nicolaou,* Bin Zou, Dattatraya H. Dethe,
Dong Bo Li, and David Y.-K. Chen*
Among the thiopeptide antibiotics, GE2270A (1) and
GE2270T (2, Scheme 1) occupy a commanding position, not
only because of their novel molecular architectures but also as
a result of their potent activities against Gram positive
bacteria.[1] These thiazolyl peptide antibiotics isolated from
Planobispora rosea ATCC53773 exert their selective anti-
[*] Prof. Dr. K. C. Nicolaou, Dr. B. Zou, Dr. D. H. Dethe, Dr. D. B. Li,
Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology, and Research (A*STAR)
11 Biopolis Way, The Helios Block, Nos. 03–08
Singapore 138667 (Singapore)
E-mail: david_chen@ices.a-star.edu.sg
Prof. Dr. K. C. Nicolaou
Department of Chemistry and
The Skaggs Institute for Chemical Biology,
The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry,
University of California, San Diego,
9500 Gilman Drive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
[**] We thank Dr. J. Lim (Institute of Bioengineering and Nanotechnol-
ogy, A*STAR) for assistance in obtaining the 13C NMR spectra of
GE2270A (1) and GE2270T (2), and D. Tan (ICES) for assistance
with high resolution mass spectrometry (HRMS). Financial support
for this work was provided by A*STAR, Singapore.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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methyl ester 11 (84% yield) by simple ester
exchange.[8] Removal of the Boc-acetonide pro-
tecting group from methyl ester thiazole deriva-
tive 11 with TFA provided the amino thiol 12.
Engagement of 12 with aldehyde 13 (prepared by
adaptation of a literature procedure)[7a] pro-
ceeded smoothly in the presence of KHCO3 to
afford thiazolidine 14 (82% yield for the two
steps), an intermediate that served admirably as a
precursor to heterodiene 15 (Ag2CO3, DBU,
pyridine, BnNH2).[7a] The latter species 15
proved quite fleeting and furnished under the
reaction conditions, and after hydrolysis, the
intended [4+2]-cycloaddition/dimerization prod-
uct, the amino dehydropiperidine fragment 16 in
60% yield as a 1:1 mixture of trans diastereoiso-
mers.[7a] Finally, heating a solution of 16 with
DBU in EtOAc to reflux gave the desired
trisubstituted pyridine core 4 in 50% yield
through aromatization, which involved expulsion
of ammonia and dehydrogenation.
Scheme 1. Retrosynthetic analysis of antibiotics GE2270A (1) and GE2270T (2)
leading to key fragments 3–9. B oc=tert-butyloxycarbonyl, TBS=tert-butyldimethyl-
silyl.
bacterial properties through inhibition of the bacterial
elongation factor Tu, but not the eukaryote elongation
factor-1 alpha.[2] The complete structure of GE2270A (1)
has been fully established through the notable efforts of
Tavecchia and co-workers,[3] and of Heckmann and Bach.[4]
Furthermore, synthetic studies toward the GE2270 factors
were also reported by the research groups of Bach[4,5] and
Shin.[6] Herein, we report the total synthesis of GE2270A (1)
and GE2270T (2) through a convergent strategy that features
a hetero-Diels–Alder/dimerization process[7] to construct the
trithiazolyl pyridine core of the molecule.
Inspection of the structures of GE2270A (1) and
GE2270T (2) reveals, in addition to the 29-membered macro-
cycle, the presence of one pyridine, one phenyl, one proline,
and six thiazole rings, as well as one oxazoline system in the
case of 1, or one oxazole moiety in the case of 2. A convergent
strategy towards 2 that would provide the oxazoline inter-
mediate en route should additionally provide access to 1, and
therefore was preferred. Furthermore, the introduction of the
proline-containing tail in the final stages of the synthesis
would allow a convenient entry into a range of designed
analogues of these naturally occurring antibiotics for struc-
ture–activity-relationship (SAR) studies.[2b] Scheme 1 shows
the seven key building blocks 3–9 required for such a strategy,
as derived from the indicated retrosynthetic analysis. The
assembly of 3–9 into the final structures 1 and 2 would
demand the construction of the remaining three rings, namely
one thiazole, one oxazoline- or oxazole-ring system, and the
macrocycle. The latter ring could, in principle, be conve-
niently closed at any of the five indicated sites through amide
bond formation (ꢀ–ꢀ, Scheme 1).
Scheme 2. Synthesis of trithiazole-substituted pyridine 4. Reagents and
conditions: a) nBu2SnO, MeOH, reflux, 6 h, 84%; b) TFA/CH2Cl2 (1:1),
258C, 4 h; then MeOH/H2O (1:1), 258C, concentration in vacuo;
c) 12·TFA (1.0 equiv), 13 (1.0 equiv), KHCO3 (3.0 equiv), MeOH/H2O
(1:1), 258C, 16 h, 82% for the two steps; d) Ag2CO3 (1.1 equiv),
BnNH2 (1.0 equiv), DBU (0.25 equiv), py, À158C, 1 h; then H2O/
EtOAc (1:1), 1 h, 60%; e) DBU (5.0 equiv), EtOAc, reflux, 5 h, 50%.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, py=pyridine, TFA=tri-
fluoroacetic acid.
1
5
Scheme 2 summarizes the construction of the pyridine
core 4, which is the central scaffold equipped with suitable
functionalities for extension in three directions as required for
the target molecules. Thus, the thiazole derivative 10, which
had been previously synthesized,[7a] was converted into its
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Scheme 4. Synthesis of bisthiazole subunits 30 and 32. Reagents and
conditions: a) LiOH (3.5 equiv), MeOH, 258C, 16 h; b) TFA/CH2Cl2
(1:4), 258C, 1 h; c) HATU (1.1 equiv), iPr2NEt (2.0 equiv), CH2Cl2,
258C, 3 h, 80% for the two steps from 5; d) LiOH (3.5 equiv), MeOH,
258C, 16 h; e) KHCO3 (3.0 equiv), allyl bromide (2.0 equiv), DMF,
258C, 3 h, 70% for the two steps; f) TFA/CH2Cl2 (1:4), 258C, 1 h,
90%.
Scheme 3. Synthesis of trisubstituted thiazole 6. Reagents and con-
ditions: a) LDA (2.5 equiv), methoxyacetyl chloride (1.2 equiv), THF,
À78 to 258C, 16 h, 59%; b) LiBH4 (1.0 equiv), THF/CH2Cl2/MeOH
(4:2:1), À788C, 5 min; c) TFA/CH2Cl2 (1:4), 08C, 1 h; d) Boc-valine
(1.1 equiv), HATU (1.5 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 3 h,
71% for the three steps; e) TBSCl (1.1 equiv), imidazole (1.5 equiv),
DMF, 208C, 16 h, 77%; f) Lawesson reagent (1.5 equiv), THF, reflux,
16 h, 66%; g) TBAF (1.1 equiv), THF, 5 h, 93%; h) DAST (1.5 equiv),
CH2Cl2, À788C, 1 h; i) BrCCl3 (1.1 equiv), DBU (2.2 equiv), CH2Cl2,
08C, 1 h, 84% for the two steps. DAST=N,N’-diethylaminosulfur
trifluoride, HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-
uronium hexafluorophosphate, LDA=lithium diisopropylamide,
TBAF=tetrabutylammonium fluoride.
ing amide bond ꢀ (Scheme 1). To this end, the carboxylic
1
acid 27 (generated by saponification of methyl ester 5,[11]
Scheme 4) was coupled with amine 28 (generated by removal
of the Boc group from 6) under the influence of HATU and
iPr2NEt to afford peptide 29 in 80% overall yield from 5
Scheme 3 summarizes the synthesis of the
thiazole derivative 6 from the Boc-glycine
methyl ester 17. Thus, C-acylation of 17 with
methoxyacetyl chloride (18) as facilitated by
LDA at À788C produced the Boc derivative 19
(59% yield). Sequential exposure of 19 to
LiBH4 and TFA reduced the ketone moiety
and liberated the amine, which provided amino
alcohol 21 via intermediate 20. Reaction of 21
with Boc-valine in the presence of HATU and
iPr2NEt afforded the hydroxy dipeptide 22 in
71% yield over the three steps. Protection of
the hydroxy group of 22 as a TBS ether
furnished derivative 23 (77% yield). Exposure
of 23 to Lawesson reagent in refluxing THF led
to thioamide 24 in 66% yield. Removal of the
TBS group gave 25 (93% yield) and subsequent
treatment first with DAST,[9] and then with
BrCCl3 and DBU,[10] furnished the thiazole
intermediate 6, through the intermediacy of
compound 26, in 84% overall yield for the two
steps.
With all seven required fragments 3–9 now
available, their assembly into the target mole-
cules 1 and 2 became our next task. From all the
possible strategies, we chose first to pursue the
one involving macrocycle construction by form-
Scheme 5. Synthesis of tetrathiazole 40. Reagents and conditions: a) TFA/H2O (3:1),
258C, 1 h; b) 8 (1.1 equiv), HATU (1.2 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 3 h,
85% for the two steps from 4; c) TBSCl (2.0 equiv), imidazole (3.0 equiv), DMF,
258C, 16 h, 82%; d) Lawesson reagent (1.5 equiv), benzene, reflux, 16 h, 80%;
e) HF·py (10 equiv), pyridine/THF (1:8), 258C, 2 h, 92%; f) DAST (1.5 equiv), CH2Cl2,
À788C, 1 h; g) BrCCl3 (1.5 equiv), DBU (3.0 equiv), CH2Cl2, 08C, 1 h, 69% for the two
steps from 36; h) TFA/CH2Cl2 (1:4), 258C, 1 h; i) Boc-glycine (1.1 equiv), HATU
(1.2 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 24 h, 90% for the two steps; j) TFA/
CH2Cl2 (1:4), 258C, 1 h.
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(Scheme 4). Basic hydrolysis of the
methyl ester of compound 29 then led to
carboxylic acid 30. Next to be targeted
was the hexacyclic system 40, whose
construction from the pyridine core struc-
ture 4 is summarized in Scheme 5. Thus, 4
was exposed to acidic conditions (TFA/
H2O) which led to the collapse of the Boc-
acetonide protecting group, thereby gen-
erating the corresponding amino alcohol.
This amino alcohol was then coupled with
the carboxylic acid derivative 8 (prepared
through a modification of a literature
procedure)[12] in the presence of HATU
and iPr2NEt to afford the hydroxy dipep-
tide 33 in 85% yield over the two steps. In
preparation for the construction of the
fourth thiazole system required in the
growing fragment, compound 33 was
sequentially converted into the TBS-
ether derivative 34 (TBSC1, 82% yield),
thioamide 35 (Lawesson reagent, 80%
yield), and hydroxy thioamide 36 (HF·py,
92% yield). Conversion of 36 into tetra-
thiazole 37 was carried out by sequential
exposure to DAST[9] and BrCCl3/DBU[10]
in 69% overall yield. The Boc group was
then cleaved off this intermediate (TFA/
CH2Cl2), which allowed its elongation to
the glycine derivative 40 through
a
sequence that involved liberation of the
amine to afford 38 (TFA), coupling with
the Boc-glycine (HATU/iPr2NEt) to give
39 (90% overall yield) and cleavage of the
newly introduced Boc group (TFA).
The resulting amine 40 was coupled
with the dithiazole-containing carboxylic
acid 30 (Scheme 6) through the action of
HATU and iPr2NEt to afford peptide 41
(66% overall yield from 39), which was
further elaborated to the macrocycle 46 as
indicated in Scheme 6. Thus, treatment of
Scheme 6. Construction of macrocycle 46 (ring closure ꢀ1 , Scheme 1). Reagents and
conditions: a) 30 (1.1 equiv), HATU (1.5 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 24 h,
66% for the two steps from 39; b) Me3SnOH (1.0 equiv), 1,2-dichloroethane, 608C, 16 h,
42: 20% and 43: 20% (90% based on recovered starting material); c) TFA/CH2Cl2 (1:4),
258C, 1 h; d) FDPP (5.0 equiv), DMF/CH2Cl2 (1:4), 0.0003m, 24 h, 20% for the two steps.
FDPP=pentafluorophenyl diphenylphosphinate.
diester 41 with 1.0 equivof Me SnOH[13]
3
resulted in the formation of the two
monoacids 42 and 43 in 40% combined
yield and in around a 1:1 ratio (90% based
on recovered starting material). Chroma-
tographic separation of the two regioisomers gave the pure
carboxylic acids 42 and 43, each of which was separately
subjected to Boc removal (TFA) and macrocyclization
conditions. While the amino acid 45 derived from the less
polar isomer 43 (Rf = 0.58, silica gel, EtOAc/MeOH 1:1)
underwent smooth ring closure (verified by LC-MS analysis)
to furnish macrocycle 46, the regioisomeric amino acid 44,
derived from the more polar isomer 42 (Rf = 0.47, silica gel,
EtOAc/MeOH 1:1), failed to cyclize. In light of these
observations, subsequent cyclizations were carried out with
the mixture of amino acids 44 and 45 (FDPP/iPr2NEt, CH2Cl2/
DMF 4:1, 0.0003m), a practice that proved more convenient
and efficient, and which led to the isolation of macrocycle 46
in 20% overall yield from 42/43.
The identical macrocycle 46 was obtained through a
modified route in which the macrocycle was formed by ring
closure ꢀ (see Scheme 1) as shown in Scheme 7. Thus,
4
compound 39 was hydrolyzed with Me3SnOH[13] to afford a
mixture of inseparable monocarboxylic acids 47 and 48 (ca.
1:1 ratio, 45% along with 50% recovered starting material).
Acids 47 and 48 were then coupled with amine 32, which was
obtained from 30 by allylation (KHCO3/allyl bromide, 70%
from 29 via intermediate 31) and TFA-induced removal of the
Boc group (90%, Scheme 4), in the presence of HATU and
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Scheme 7. Alternative construction of macrocycle 46 (ring closure ꢀ4 , Scheme 1). Reagents and conditions: a) Me3SnOH (1.0 equiv), 1,2-
dichloroethane, 608C, 20 h, 47/48 (ca. 1:1 ratio) 45% (90% based on 50% recovered starting material); b) 32 (1.1 equiv), HATU (1.5 equiv),
iPr2NEt (3.0 equiv), CH2Cl2, 258C, 16 h, 70%; c) [Pd(PPh3)4] (20 mol%), NMA (2.0 equiv), THF, 258C, 1 h; d) TFA/CH2Cl2 (1:4), 258C, 1 h;
e) FDPP (5.0 equiv), iPr2NEt (10 equiv), CH2Cl2/DMF (1:4, 0.30mm), 258C, 24 h, 30% for the three steps. NMA=N-methylaniline.
iPr2NEt, to afford the coupling products 49 and 50. The
mixture of 49/50 was converted into cyclization precursors 53
and 54 by deallylation with [Pd(PPh3)4] and Boc removal
(TFA). Exposure of the mixture of 53 and 54 to the
macrolactamization conditions (FDPP/iPr2NEt, CH2Cl2/
DMF 4:1, 0.0003m) again furnished only one macrocycle 46
(30% overall yield from 49/50 for the three steps), which was
proven from chromatographic and spectroscopic data to be
identical to the one obtained from 43 or 42/43, as described
earlier (Scheme 6). Again, the formation of a single regioiso-
mer 46 in this cyclization reaction points to a unique structural
feature of these systems. The structural identity of the formed
macrocycle and the precise reasons for its preference in these
reactions were not known at this stage. While the tentatively
assigned structure 46 was later proven by its eventual
conversion to the natural products 1 and 2 (described
below), the rationale for its formation in preference to its
regioisomer remains to be elucidated.
Macrolactamizations were also performed at sites ꢀ and
3
ꢀ (see Scheme 1) using amino acid precursors prepared by
5
modifications of the chemistry described above.[14] Interest-
ingly, while ring closure at site ꢀ proceeded smoothly and
5
again furnished the same macrocycle 46 (15% overall yield
for the last three steps involving deprotection of the amino
acid and formation of the peptide bond) as from the ring
closures at ꢀ and ꢀ, macrolactamization at site ꢀ was not
1
4
3
feasible because of the reluctance of fragments longer than
glycine to couple with the amino group of that site.
The final stages of the total synthesis of GE2270A (1) are
shown in Scheme 8. Thus, the methyl ester of advanced
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Scheme 8. Completion of the total synthesis of GE2270A (1). Reagents and conditions: a) Me3SnOH (10 equiv), 1,2-dichloroethane, 808C, 5 h;
b) l-serine methyl ester (1.1 equiv), HATU (1.5 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 16 h, 55% for the two steps; c) DAST (1.5 equiv),
CH2Cl2, À258C, 1 h, 85%; d) TBAF (1.2 equiv), THF, 258C, 80%; e) Me3SnOH (10 equiv), 1,2-dichloroethane, 808C, 1 h; f) l-proline amide
(1.1 equiv), HATU (1.2 equiv), iPr2NEt (2.0 equiv), CH2Cl2, 258C, 3 h, 60% for the two steps.
macrocycle 46 was hydrolyzed with Me3SnOH,[13,15] affording
carboxylic acid 55. The convergent strategy for the introduc-
tion of the required dipeptide fragment (l-serine-l-prolin-
amide) was unsuccessful. A stepwise approach was adopted
whereby attachment of the l-serine moiety was carried out
first, thereby yielding hydroxy methyl ester 56 in 55% overall
yield for the two steps. Generation of the desired oxazoline
moiety was then carried out by exposing hydroxy amide 56 to
DAST[9] in CH2Cl2 at À258C to furnish ester silyl ether 57 in
85% yield. Sequential treatment of the latter compound with
TBAF followed by Me3SnOH[13,15] led, through the interme-
diacy of hydroxy methyl ester 58 (80% yield), to hydroxy
carboxylic acid 59, which was set for the final coupling.
Indeed, reaction of 59 with l-proline amide 9 in the presence
of HATU and iPr2NEt furnished GE2270A (1) in 60%
overall yield from 58. Synthetic 1 exhibited identical physical
nature from natural amino acids, as previously suggested by
degradation studies.[3]
Advanced intermediate oxazoline 58 encountered along
the way to 1 was also converted into GE2270T (2) as shown in
Scheme 9. Thus, exposure of oxazoline 58 to the action of
BrCCl3 and DBU[10] gave oxazole methyl ester 60. Hydrolysis
of 60 to give carboxylic acid 61 was smoothly accomplished by
Me3SnOH.[13,15] Finally, coupling of 61 with l-proline amide 9,
facilitated by HATU and iPr2NEt as described above,
furnished GE2270T (2) in 40% overall yield from 58 (three
steps). The physical properties of synthetic 2 were in
accordance with its assigned structure and the literature
data.[1c]
The chemistry described herein demonstrates the applic-
ability of the [4+2]-cycloaddition/dimerization cascade
involving heterodienes[7] in complex molecule construction,
and the exquisite regioselective preferences of the ring-
closing reactions in thiopeptide-like substrates. Furthermore,
the high convergency associated with this route renders this
strategy particularly suited for analogue synthesis and SAR
1
properties (in H and 13C NMR spectra, and MS) to those
reported[1c] for the naturally occurring substance. Although
no specific optical rotation has been reported for GE2270A
(1), we assumed that 1 and its congeners were derived in
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[3] P. Tavecchia, P. Gentili, M. Kurz, C.
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Scheme 9. Completion of the total synthesis of GE2270T (2). Reagents and conditions:
a) BrCCl3 (1.5 equiv), DBU (3.0 equiv), CH2Cl2, 0 to 258C, 16 h; b) Me3SnOH (10 equiv), 1,2-
dichloroethane, 808C, 6 h; c) l-proline amide (1.1 equiv), HATU (1.2 equiv), iPr2NEt (1.5 equiv),
CH2Cl2, 258C, 5 h, 40% for the three steps.
[12] a) D. B. Hansen, M. M. JoulliØ, Tetrahedron: Asymmetry 2005,
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studies, especially at the proline–oxazole tail end[2b] of the
molecule, with an advanced intermediate serving as a
common precursor to a wide variety of designed molecules
as potential new antibacterial agents.
[13] K. C. Nicolaou, A. A. Estrada, M. Zak, S. H. Lee, B. S. Safina,
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Received: July 13, 2006
Published online: October 24, 2006
[14] Details of these experiments will be described in the full account
of this work.
[15] K. C. Nicolaou, M. Zak, B. S. Safina, A. A. Estrada, S. H. Lee,
M. Nevalainen, J. Am. Chem. Soc. 2005, 127, 11176 – 11183.
Keywords: antibiotics · hetero-Diels–Alder reaction ·
macrocycles · natural products · total synthesis
.
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