Total synthesis of thiostrepton. Assembly of key building blocks and completion of the synthesis

Article abstract of DOI:10.1021/ja052934z

The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target molecule. Thus, the dehydropiperidine peptide core 2

Full text of DOI:10.1021/ja052934z

Published on Web 07/19/2005
Total Synthesis of Thiostrepton. Assembly of Key Building
Blocks and Completion of the Synthesis
K. C. Nicolaou,* Mark Zak, Brian S. Safina, Anthony A. Estrada,
Sang Hyup Lee, and Marta Nevalainen
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received May 4, 2005; E-mail: kcn@scripps.edu
Abstract: The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded
from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target
molecule. Thus, the dehydropiperidine peptide core 2 was, after appropriate manipulation, coupled to the
thiazoline-thiazole fragment 3, and the resulting product was advanced to intermediate 11 possessing the
thiazoline-thiazole macrocycle. The bis-dehydroalanine tail equivalent 4 and the quinaldic acid fragment
5 were then sequentially incorporated, and the products so obtained were further elaborated to forge the
second macrocycle of the molecule. Several roadblocks encountered along the way were systematically
investigated and overcome, finally opening the way, through intermediates 20, 32, 44, 45, and 46, to the
targeted natural product, 1.
Introduction
rocycle 11, a challenge that was met only partially. Thus, under
the best conditions (Me3SnOH in 1,2-dichloroethane at 50 °C),2
In the preceding article1 we described the retrosynthetic
analysis of thiostrepton (1, Figure 1) and the construction of
the key building blocks (2-5) required for its projected total
synthesis. In this paper we discuss the assembly of these
fragments and the elaboration of the resulting advanced
intermediates into the final target (1), including a description
of some of the intriguing setbacks and obstacles that we
encountered, and finally overcame, en route to the destination.
we were able to convert bis-methyl ester 8 to a ca. 2:1 mixture
of monoacids (9 + 9′), in 52% combined yield, accompanied
by 14% of the corresponding diacid and 28% of recovered
starting material (8), both of which were, of course, recyclable.
Even though the two monoacids 9 and 9′ were not separable
by chromatography, nor could the major regioisomer be defined
at this stage, we nevertheless pressed forward in the hope of
achieving a separation at a later stage. Thus, reduction of the
mixture (9 + 9′) with PMe3 in the presence of H2O at 0 °C led
to the corresponding amino acids (10 + 10′), which were sub-
jected to high dilution macrolactamization conditions [HATU,
HOAt, i-Pr2NEt, DMF (0.002 M), 25 °C, 65 h] to afford, in
32% overall yield from acids 9 and 9′, a single macrolactam.
These results indicated that one regiosomer of the amino acid
(10 or 10′) was unable to cyclize upon activation, being instead
consumed during the reaction through polymerization or de-
composition pathways. Although at this juncture we were unable
to definitively establish that the macrocyclic product formed in
this reaction possessed the correct (and desired) regioisomeric
structure, we hoped that an intrinsic preference to form
macrocycle 11 existed due to its presence in the naturally
occurring thiostrepton (1). Indeed, molecular models (manual)
revealed unfavorable strain interactions for the alternative
macrolactamization reaction resulting from amino acid 10′.
Results and Discussion: Assembly of Building Blocks
and Total Synthesis
According to the designed plan, our first order of business
was the coupling of dehydropiperidine peptide fragment 2 with
the thiazoline segment 3 and the forging of the thiazoline-
containing macrocycle 11, a task that proceeded smoothly, as
summarized in Scheme 1. Thus, diastereomerically pure amine
21 was converted to its N-Alloc derivative 6 by reaction with
allyl chloroformate and i-Pr2NEt in the presence of 4-DMAP
as a catalyst (92% yield), and thence to N-Alloc 1,2-amino
alcohol 7 with TFA, whose action caused collapse of both the
N-Boc and acetonide masking devices. This amino alcohol (7)
was then joined to thiazoline building block 31 through an amide
bond-forming reaction promoted by HATU, HOAt, and i-Pr2-
NEt, furnishing peptide bis-methyl ester 8 in 73% overall yield
from N-Boc acetonide 6. The next task called for regioselective
hydrolysis of compound 8 to form the desired precursor
(monoacid 9) to the 26-membered thiazoline-containing mac-
(2) (a) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
Angew. Chem., Int. Ed. 2005, 44, 1378-1382. (b) Furlan, R. L. E.; Mata,
E. G.; Mascaretti, O. A. J. Chem. Soc., Perkin Trans. 1 1998, 355-358.
(c) Furlan, R. L. E.; Mata, E. G.; Mascaretti, O. A.; Pena, C.; Coba, M. P.
Tetrahedron 1998, 54, 13023-13034. (d) Furlan, R. L. E.; Mascaretti, O.
A. Aldrichim. Acta 1997, 30, 55-69. (e) Furlan, R. L. E.; Mata, E. G.;
Mascaretti, O. A. Tetrahedron Lett. 1996, 37, 5229-5232.
(1) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.; Bella,
M.; Estrada, A. A.; Funke, C.; Ze´cri, F. J.; Bulat, S. J. Am. Chem. Soc.
2005, 127, http://dx.doi.org/10.1021/ja0529337.
9
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10.1021/ja052934z CCC: $30.25 © 2005 American Chemical Society

Total Synthesis of Thiostrepton
A R T I C L E S
Figure 1. Thiostrepton (1) and key building blocks (2-5) for its total synthesis.
Scheme 1. Synthesis of Thiazoline-Containing Macrocycle 11a
a Reagents and conditions: (a) AllocCl (5.0 equiv), i-Pr2EtN (10 equiv), 4-DMAP (0.1 equiv), THF, 25 °C, 3 h, 92%; (b) TFA:CH2Cl2 (1:1), 0 °C,
10 min; then 25 °C, 45 min; (c) 7 (1.0 equiv), 3 (1.0 equiv), HATU (1.2 equiv), HOAt (1.2 equiv), i-Pr2NEt (3.0 equiv), DMF, 0 °C, 30 min, 73% (two
steps); (d) Me3SnOH (8.0 equiv), 1,2-dichloroethane, 50 °C, 4 h, 52% (plus 14% diacid and 28% recovered starting material 8); (e) PMe3 (6.0 equiv),
THF:H2O (10:1), 0 °C, 75 min; (f) HATU (5.0 equiv), HOAt (5.0 equiv), i-Pr2NEt (6.0 equiv), DMF (0.002 M), 25 °C, 65 h, 32% (over two steps from
mixture of mono acids 9 and 9′). Abbreviations: Alloc, allyloxy carbonyl; AllocCl, allyl chloroformate; 4-DMAP, 4-dimethylaminopyridine; Boc, tert-
butoxycarbonyl; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; HOAt, 1-hydroxy-7-azabenzotriazole; DMF, N,N-
dimethylformamide; TBS, tert-butyldimethylsilyl; TES, triethylsilyl.
Interestingly (and somewhat worrisomely), it was not until
compound 11 was carried all the way through to the natural
product (1) that this regiochemical ambiguity was resolved.
Having succeeded in forming the thiazoline macrocycle 11,
we then turned our attention to the task of attaching the bis-
dehydroalanine tail as its masked equivalent 41 to the growing
molecule, and then proceeded with the construction of the
remaining quinaldic acid-containing macrocycle (Scheme 2).
Thus, in a remarkable reaction,2 Me3SnOH in 1,2-dichloroethane
at 60 °C accomplished the quantitative hydrolysis of the methyl
ester of macrocycle 11 without epimerization at any of its several
potentially vulnerable stereocenters, leading to carboxylic acid
12. The latter compound (12) was then coupled, through an
amide bond, with bis-phenylseleno dipeptide 41 by the action
of HATU, HOAt, and i-Pr2NEt to furnish, in 83% yield,
advanced intermediate 13. Subsequent esterification of key
quinaldic acid building block 141 with the branching substrate
13 using the latter compound’s secondary hydroxyl group
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A R T I C L E S
Nicolaou et al.
Scheme 2. Synthesis of Advanced Seco Compound 16 and Failed Attempt To Deprotect It to Amino Acid 17a
a Reagents and conditions: (a) Me3SnOH (10 equiv), 1,2-dichloroethane, 60 °C, 2.5 h, 100%; (b) 4 (2.0 equiv), HATU (1.2 equiv), HOAt (1.2 equiv),
i-Pr2NEt (3.0 equiv), DMF, 0 °C, 1.5 h, then 25 °C, 30 min, 83%; (c) 14 (2.0 equiv), 2,4,6-trichlorobenzoyl chloride (4.0 equiv), Et3N (12 equiv), toluene,
25 °C, 16 h; then 13 (1.0 equiv), 4-DMAP (15 equiv), toluene, 35 min, 25 °C, 84%; (d) t-BuOOH (5-6 M in decane):CH2Cl2 (1:10), NaHCO3 (30 equiv),
0 °C, 5 min; then 25 °C, 75 min, 68%; (e) PdCl2(PPh3)2 (0.1 equiv), n-Bu3SnH (50 equiv), CH2Cl2, -45 °C, 5 min; then 0 °C, 1 h. Abbreviations: All, allyl;
Ph, phenyl.
proceeded admirably under modified Yamaguchi conditions3
(2,4,6-trichlorobenzoyl chloride, Et3N, 25 °C; then 4-DMAP,
25 °C) to give ester 15 in 84% yield. The phenylselenium
moieties were then oxidatively removed from 15 by the action
of t-BuOOH at 0-25 °C, furnishing triene 16 in 68% yield.
All that now remained before the total synthesis of 1 could be
declared was the removal of the N-Alloc and allyl ester groups
guarding the amino acid ends, macroring closure, and global
deprotection. That was not to be just yet, for all attempts to
remove the N-Alloc and allyl ester groups from compound 16
(notably with the n-Bu3SnH-PdCl2(PPh3) (cat.) system)4 failed,
leading to decomposition instead.
investigating its cause. To this end, we first exposed the bis-
phenylselenium compound 13 to t-BuOOH, conditions that led
smoothly to bis-dehydroalanine intermediate 18 in 84% yield
(Scheme 3). When this dehydroalanine compound (18) was
subjected to the n-Bu3SnH-PdCl2(PPh3)2 (cat.) N-Alloc lysis
conditions, however, only decomposition was observed. Intrigu-
ingly, though, when the bis-phenylselenium precursor 13 was
subjected to the same conditions, the N-Alloc group was cleanly
removed, affording primary amine 20 in 86% yield and
exposing, at the same time, the bis-dehydroalanine tail as the
culprit of the earlier catastrophic attempts to achieve the desired
deprotection (16f17).
Having encountered the problem of the N-Alloc and ester
group removal from advanced intermediate 16, we began
At this point, and in order to gain a better understanding of
the precise nature of this interference from the dehydroalanine
(3) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993. (b) Nicolaou, K. C.; Patron, A. P.;
Ajito, K.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R. A.;
Tomaszewski, M. J. Chem. Eur. J. 1996, 2, 847-868.
(4) (a) de la Torre, B. G.; Torres, J. L.; Bardaj´ı, E.; Clape´s, P.; Xaus, N.; Jorba,
X.; Calvet, S.; Albericio, F.; Valencia, G. J. Chem. Soc., Chem. Commun.
1990, 965-967. (b) For a review on the use and removal of allylic
protecting groups, see: Guibe´, F. Tetrahedron 1998, 54, 2967-3042.
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Total Synthesis of Thiostrepton
A R T I C L E S
Scheme 3. n-Bu3SnH-PdCl2(PPh3)2 (cat.)-Induced N-Alloc Group Removal in the Presence of Phenylselenium Dehydroalanine Precursors
and Failed Attempt To Remove the N-Alloc Group in the Presence of Dehydroalanine Residuesa
a Reagents and conditions: (a) t-BuOOH (5-6 M in decane):CH2Cl2 (4:10), NaHCO3 (24 equiv), 0 °C, 5 min; then 25 °C, 2 h, 84%; (b) PdCl2(PPh3)2
(0.1 equiv), n-Bu3SnH (50 equiv), CH2Cl2, -45 °C, 5 min; then 0 °C, 30 min; (c) PdCl2(PPh3)2 (0.1 equiv), n-Bu3SnH (50 equiv), CH2Cl2, -45 °C, 5 min;
then 0 °C, 30 min, 86%.
Scheme 4. Synthesis of Bis-dehydroalanine Model System 24a
1
reduction of the most electron-deficient (as suggested by H
NMR spectroscopy) olefin within 24 occurred, providing a ca.
14:1 mixture of regioisomers 25 and 25′ (Scheme 5A). These
observations are reminiscent of the palladium-catalyzed 1,4-
reductions of R,â-unsaturated aldehydes and ketones in which
the olefins are electron-deficient.6 Borrowing from the mech-
anism of these reactions, we propose, in Scheme 5B, a parallel
mechanism for the observed reduction of the dehydroalanine
unit. Thus, n-Bu3SnH and PdCl2(PPh3)2 are assumed to par-
ticipate in a series of reduction and oxidative addition steps,
producing, in situ, the active Pd(II) species 26,4b which engages
the olefinic substrate 24 in a hydropalladation reaction to form
Pd(II)-coordinated intermediate 27. Subsequent reductive elimi-
nation ejects enol stannane 29 and regenerates a Pd(0) species
a Reagents and conditions: (a) Me3SnOH (6.0 equiv), 1,2-dichloroethane,
80 °C, 2 h, 100%; (b) amine 4 (1.0 equiv), HOAt (1.5 equiv), HATU (1.5
(i.e. 28) which re-enters the catalytic cycle with its partnering
reagent n-Bu3SnH. Finally, exposure of enol stannane 29 to
silica gel or aqueous workup conditions affords the reduced
product 25.
equiv), i-Pr2NEt (3.0 equiv), DMF, 0 °C, 20 min; then 25 °C, 2 h, 85%; (c)
t-BuOOH (5-6 M in decane):CH2Cl2 (6:10), 0 °C, 10 min; then 25 °C,
1.5 h, 82%. TBDPS, tert-butyldiphenylsilyl.
tail with the n-Bu3SnH-PdCl2(PPh3)2 (cat.) system, we pro-
ceeded to synthesize and study model system 24 (Scheme 4).
Thus, thiazole ester 215 was hydrolyzed with Me3SnOH,
furnishing carboxylic acid 22, which was coupled with bis-
phenylselenium dipeptide 4 (HATU, HOAt, i-Pr2NEt) to afford
compound 23 in 85% yield. Oxidation of the latter compound
(23) with t-BuOOH caused the desired bis-elimination, providing
bis-dehydroalanine tail system 24 in 82% yield.
After failing to accomplish the liberation of the primary amino
group from its Alloc-protected form within the bis-dehydroala-
nine intermediate 16 (Scheme 2), we proceeded to utilize the
bis-phenylselenium compound 15 (Scheme 6) as the substrate
for the n-Bu3SnH-PdCl2(PPh3)2 (cat.) deprotection step. Having
previously established that both the allyl ester of the quinaldic
acid substrate (138f140, Scheme 12 in the preceding article1)
and the allyl carbamate of the bis-phenylselenium thiazoline
Upon exposure of model compound 24 to the N-Alloc
removal conditions of n-Bu3SnH-PdCl2(PPh3)2 (cat.), selective
(6) (a) Keinan, E.; Gleize, P. A. Tetrahedron Lett. 1982, 23, 477-480. (b)
Four, P.; Guibe´, F. Tetrahedron Lett. 1982, 23, 1825-1828.
(5) Sinha, S. C.; Dutta, S.; Sun, J. Tetrahedron Lett. 2000, 41, 8243-8246.
9
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Scheme 5. (A) Selective Reduction of Bis-dehydroalanine Model System 24 with n-Bu3SnH-PdCl2(PPh3)2 (cat.); (B) Postulated
Mechanisma
a Reagents and conditions: PdCl2(PPh3)2 (0.2 equiv), n-Bu3SnH (50 equiv), CH2Cl2, 0 °C, 10 min; then 25 °C, 110 min, 85%.
Scheme 6. Failed Attempt To Cleave the N-Alloc and Allyl Ester of Bis-phenylselenium-Containing Seco Compound 15a
a Reagents and conditions: (a) PdCl2(PPh3)2 (0.1 equiv), n-Bu3SnH (50 equiv), CH2Cl2, -45 °C, 5 min; then 0 °C, 30 min.
macrocycle (13f20, Scheme 3) could be efficiently dismantled
by n-Bu3SnH-PdCl2(PPh3)2 (cat.) without incident, we had
every confidence that both protecting groups could be removed
from 15 under the same conditions. Much to our dismay,
however, this proved not to be the case since all our attempts
to accomplish the task failed, decomposition being observed
instead. This unfortunate outcome has not, as yet, been
demystified and requires further investigation.
Faced with this intransigence, we opted to change the strategy
for the construction of the final macrocycle. Thus, we adopted
a plan which called for joining the two advanced fragments 20
and 311 via an amide bond, followed by a Yamaguchi-type
macrolactonization3 (Scheme 7). This strategy variant was
supported by the fact that the two fragments (20 + 31)
independently behaved well under the conditions anticipated
for their coupling and further elaboration of the resulting
product. Their good behavior, however, was not to be expressed
when they were in union. Thus, although both the amide bond-
forming reaction between 20 and 31 (HATU, HOAt, i-Pr2NEt,
68% yield) to afford 32 and the oxidative elimination of the
three resident phenylselenium groups (t-BuOOH, 74% yield)
to furnish tris-dehydroalanine derivative 33 proceeded well, the
Fm ester removal step under the required basic conditions7 failed
to produce the desired product. Instead, the carboxylic acid 34,
with a truncated dehydroalanine tail, was formed in 78% yield
by a seemingly mysterious but selective process.
To confirm this unexpected fragmentation, we resorted again
to model system 24 (see Scheme 4 for its preparation) and,
indeed, confirmed its smooth conversion to the truncated
dehydroalanine compound 35 under the Fm ester removal
conditions (i.e. Et2NH),7 as shown in Scheme 8A, and in 93%
yield. Reproducible and consistent as this fragmentation process
(7) Kessler, H.; Siegmeier, R. Tetrahedron Lett. 1983, 24, 281-282.
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Total Synthesis of Thiostrepton
A R T I C L E S
Scheme 7. Synthesis of Advanced Intermediate 33 and Unexpected Bis-dehydroalanine Tail Cleavage under Fluorenylmethyl Ester
Deprotection Conditionsa
a Reagents and conditions: (a) 20 (1.0 equiv), 31 (1.1 equiv), HATU (1.2 equiv), HOAt (1.2 equiv), i-Pr2NEt (3.0 equiv), DMF, 0 °C, 1 h, 68%; (b)
t-BuOOH (5-6 M in decane):CH2Cl2 (1.2:1), 0 °C, 5 min; then 25 °C, 50 min, 74%; (c) Et2NH:CH2Cl2 (1:10), 0 °C, 5 min; then 25 °C, 2.5 h, 78%. Fm,
9-fluorenylmethyl.
was, it begged for an explanation, and our proposed mechanistic
rationale is shown in Scheme 8A. Thus, tautomerization of the
terminal dehydroalanine unit under basic conditions to the
corresponding methyl imine 36 may be followed by nucleophilic
attack of Et2NH to afford intermediate 37, whose collapse, as
shown, may form truncated dehydroalanine 35, ejecting at the
same time ionic species 38, which is presumably hydrolyzed
to the corresponding oxalate upon aqueous workup. The
selectivity of this reaction is consistent with the results
encountered in the n-Bu3SnH-PdCl2(PPh3)2 (cat.) interference
discussed earlier (Scheme 5), whereby the internal olefin, as
the most electron deficient of the two residing on the bis-
dehydroalanine chain, dictates the regiochemical outcome. Thus,
the mechanism shown in Scheme 8A for the cleavage of the
terminal dehydroalanine moiety is presumably not operating in
the case of the internal dehydroalanine unit because of the
electron-withdrawing effect of the carbonyl group conjugated
with the thiazole. This electron-attracting carbonyl group (more
electron-withdrawing than the dehydroalanine carbonyl) could
pull electron density away from the internal dehydroalanine
moiety, as represented by resonance form 40 (Scheme 8B), and
could, under the basic reaction conditions employed (Et2NH),
favor tautomerization to form unreactive iminol 41 at the
expense of the tautomeric form poised to undergo the cleavage
process (i.e. methyl imine 43).8
Having stumbled once more as a result of the idiosyncrasies
of the dehydroalanine units under the basic Fm ester deprotection
conditions, we retreated once again back to the tris-phenylse-
lenium precursor 32, which pleasantly reacted smoothly in the
presence of Et2NH to afford the desired seco hydroxy carboxylic
acid 44 in 87% yield (Scheme 9). This seco acid (44) was then
subjected to the Yamaguchi macrolactonization conditions
(2,4,6-trichlorobenzoyl chloride, Et3N; then 4-DMAP, 25 °C),
leading to the targeted compound 45, boasting the entire ring
skeleton of 1, in 42% yield. Subsequent treatment of the latter
substance (45) with t-BuOOH caused oxidative elimination of
all three phenylseleno groups, generating the penta-silylated
derivative 46 (68% yield) possessing all three dehydroalanine
moieties, but lacking the final olefinic bond adjacent to the
(8) For a study on the structure and chemistry of dehydroamino acids, see:
Crisma, M.; Formaggio, F.; Toniolo, C.; Yoshikawa, T.; Wakamiya, T. J.
Am. Chem. Soc. 1999, 121, 3272-3278.
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A R T I C L E S
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Scheme 8. (A) Regioselective Rupture of Bis-dehydroalanine Tail Model System 24 with Et2NH; (B) Mechanistic Rationale for the Exclusive
Formation of Singly Truncated Product 35 at the Expense of Fully Truncated Product 39a
a Reagents and conditions: (a) Et2NH:CH2Cl2 (1:6.3), 0 °C, 30 min; then 25 °C, 2 h, 93%.
Scheme 9. Completion of the Total Synthesis of Thiostrepton (1)a
a Reagents and conditions: (a) Et2NH:CH2Cl2 (1:6.5), 0 °C, 5 min; then 25 °C, 2.5 h, 87%; (b) 2,4,6-trichlorobenzoyl chloride (30 equiv), Et3N
(40 equiv), 25 °C, 24 h; then 4-DMAP (30 equiv), toluene (0.4 mM), 25 °C, 24 h, 42%; (c) t-BuOOH (5-6 M in decane):CH2Cl2 (1:5), NaHCO3 (33 equiv),
0 °C, 5 min; then 25 °C, 2 h, 68%; (d) HF‚py:THF (1:4), 0 °C, 5 min; then 25 °C, 24 h, 52%.
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Total Synthesis of Thiostrepton
A R T I C L E S
thiazoline ring. Joyfully, that final deprotection step, as suc-
cessfully carried out with HF‚py, not only removed all five
silicon groups but was also accompanied by concomitant anti-
periplanar elimination of the oxygen associated with the TES
group9 to afford the desired Z-trisubstituted double bond,
furnishing in one fell swoop 1. Synthetic 1 exhibited physical
technologies. From the former developments, the hetero-Diels-
Alder dimerization of azadienes10 to dehydropiperidine systems
stands out as a novel synthetic strategy, while from the latter
category the mild hydrolysis of esters with Me3SnOH2 distin-
guishes itself as a selective and remarkably enabling method
for organic synthesis. As such, the thiostrepton project fulfilled
our expectations as an opportunity for discovery and invention
in chemical synthesis.
properties (1H NMR, 13C NMR, TLC, HPLC, IR, [R]32
)
D
identical to those of natural 1, thus marking the end of the
campaign.
Acknowledgment. We thank Drs. D. H. Huang, G. Siuzdak,
and R. Chadha for NMR spectroscopic, mass spectrometric, and
X-ray crystallographic assistance, respectively. Financial support
for this work was provided by The Skaggs Institute for Chemical
Biology, the National Institutes of Health (U.S.A.), fellowships
from The Academy of Finland (to M.N.), The Skaggs Institute
for Research (to M.Z.), and the National Institutes of Health
(to A.A.E.), and grants from Abbott, Amgen, ArrayBiopharma,
Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont,
Merck, Novartis, Pfizer, and Schering Plough.
Conclusion
In this and the preceding article,1 we described our campaign
to synthesize thiostrepton (1), one of nature’s most intriguing
molecules to inspire us in recent years. Lured by its unusual
and complex molecular structure and interesting biological
properties into the adventure, we faced several formidable
challenges on the way, some reasonably predicted, some totally
unexpected. One after the other, these problems were solved in
a pleasing way through rational design and skillful experimenta-
tion. In the end, a body of discovery was generated from which
emerged not only a successful passage from simple starting
materials to 1, but also a number of useful strategies and
Supporting Information Available: Experimental procedures
and compound characterization (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA052934Z
(9) The stereospecific elimination of the TES-protected alcohol to provide the
corresponding Z olefin was expected from the results of a previous model
study. See Scheme 9B in the preceding article.1
(10) Nicolaou, K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S. Angew.
Chem., Int. Ed. 2002, 41, 1941-1945.
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