Total synthesis of (+)-11/11'-Dideoxyverticillin A

Article abstract of DOI:10.1126/science.1170777

The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natura

Full text of DOI:10.1126/science.1170777

REPORTS
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The mechanism we have described requires
only a few general materials characteristics, in
particular that at temperatures where a liquidus
exists, the more slowly evaporating component
accumulates as a liquid on the surface. Therefore,
comparable behavior is expected in other III-V
semiconductors such as InAs (23) and perhaps in
many other systems. Evaporation is used in the
cleaning of GaAs, and Ga droplets are central to
droplet epitaxy (15–18). The intrinsic droplet mo-
tion observed here may therefore have important
technological consequences and may open up
new extensions for the droplet epitaxy technique.
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Supporting Online Material
www.sciencemag.org/cgi/content/full/324/5924/236/DC1
Materials and Methods
SOM Text
Fig. S1
Movies S1 and S2
References
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References and Notes
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9 December 2008; accepted 10 February 2009
10.1126/science.1169546
acid feeding experiments and his hypothesis
for gliotoxin biosynthesis (10) prompted us to
consider the possibility that the epidisulfides of
(+)-1 are assembled by enzymes that exploit the
inherent chemistry of dimeric diketopiperazines.
Our retrosynthetic analysis of (+)-1 imitates a plau-
sible biosynthetic sequence of events linking
dimeric epidithiodiketopiperazines to common
a-amino acid precursors (Fig. 2). We envisioned
preparation of (+)-1 by mild oxidation of the
tetrathiol 5, which could be accessed via stereo-
selective tetrathiolation of an octacyclic tetraol 6.
In contrast to a previous biosynthetic hypothesis
for monomeric epidithiodiketopiperazines invoking
thiolation via an N-hydroxylation–dehydration se-
quence (11), we speculated that a postdimerization
Ca-hydroxylation would enable substrate-directed
hemiaminal thiolation through the intermediacy of
an acyliminium ion. Intermediate 7, which we hy-
Total Synthesis of
(+)-11,11'-Dideoxyverticillin A
Justin Kim, James A. Ashenhurst, Mohammad Movassaghi*
The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine
Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically
complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric
epidithiodiketopiperazines have been known for nearly 4 decades, none has succumbed to total
synthesis. We report a concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A
via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and
chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a
mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were
developed to address this highly sensitive substructure. Our rapid functionalization of the advanced
molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for
the chemical synthesis of other members of this family of alkaloids.
he fungal metabolite (+)-11,11'- and tetrathiolation reactions, providing a general- pothesized to arise from a dimerization event,
dideoxyverticillin A (1, Fig. 1) (1) is a izable solution to the epidithiodiketopiperazine could be assembled from the readily available
member of the epidithiodiketopiperazine substructure found in the broader family of these cyclo-dipeptide 8 by using the concise cobalt-
T
alkaloids, a large family of natural products that alkaloids.
mediated dimerization strategy reported from
has received substantial attention from the scien-
At the outset of our synthetic studies, struc- our laboratories (12, 13). The imposing chal-
tific community for its rich biological activity and tural similarities among members of this alkaloid lenges associated with quadruple Ca-methine
complex molecular architecture (2–7). The dimer- family combined with Kirby’s radio-labeled amino hydroxylation of 7 and the tetrathiolation of inter-
ic subset of alkaloids to which the title compound
belongs has been known for nearly 4 decades with
the isolation of (+)-chaetocin A (2) (8) and (+)-
verticillin A (3) (9). Reflective of the daunting
challenges posed by molecular structures replete
with sterically congested stereogenic centers and
highly acid-, base-, and redox-sensitive functional
groupings (5), no dimeric epidithiodiketopipera-
zine alkaloid has yet succumbed to total synthesis.
Herein we describe a concise strategy for the
enantioselective total synthesis of the dimeric
epidithiodiketopiperazine alkaloid (+)-1. Our bio-
synthetically inspired synthesis features stereo- and
chemoselective advanced-stage tetrahydroxylation
H
N
H
N
O
O
H
H
Me
Me
O
O
N
HO
Me
N
S
S
S
S
Me
Me
Me
N
N
N
N
S
S
S
S
N
N
OH
O
O
N
N
H
H
O
O
H
H
(+)-11,11'-dideoxyverticillin A (1)
(+)-chaetocin A (2)
H
O
H
Me
O
H
H
N
N
Me
Me
N
Me
Me
N
S
S
S
S
O
O
N
HO
N
HO
OH
Me
Me
Me
OH
N
N
S
S
S
S
O
O
N
N
Me
Me
N
H
N
H
H
O
O
H
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
(+)-verticillin A (3)
(+)-leptosin K (4)
Fig. 1. The molecular structure of (+)-11,11'-dideoxyverticillin A (1) and representative dimeric
epidithiodiketopiperazine alkaloids.
*To whom correspondence should be addressed. E-mail:
movassag@mit.edu
238
10 APRIL 2009 VOL 324 SCIENCE www.sciencemag.org

REPORTS
mediate 6 notwithstanding, the need for abso- the introduction of the C3 and the C3′ vicinal cent of Seebach’s self-reproduction of chirality
lute and relative stereochemical control (Fig. 2) quaternary stereocenters as a prelude to stereo- (14). Such a final-stage tetrathiolation followed
of the six tetrasubstituted carbons of (+)-1 posed chemical control of the four thiolated-carbon by immediate disulfide formation would obvi-
noteworthy strategic concerns. We envisioned stereogenic centers of (+)-1 in a strategy reminis- ate the need to mask the notoriously sensitive
epidithiodiketopiperazine functional grouping
in the early stages of the synthesis.
H
H
N
O
O
The dimeric diketopiperazine (+)-13 was as-
sembled in six steps from commercially available
amino acid derivatives (Fig. 3) [supporting on-
line material (SOM) text]. The sequential treat-
ment of amide (–)-9 with trifluoroacetic acid
followed by cyclization with morpholine readily
afforded access to the desired cis-diketopiperazine
(–)-10 in 84% yield (>20 g). Exposure of cyclo-L-
tryptophan-L-alanine (–)-10 to molecular bro-
mine in acetonitrile at 0°C furnished the desired
monomeric tetracyclic bromide (+)-11 in 76%
isolated yield (SOM text). Treatment of tetra-
cyclic bromide (+)-11 with methyl iodide and
potassium carbonate gave the base-sensitive di-
merization precursor (+)-12 in 77% yield (15).
H
N
H
Me
HS
Me
HO
disulfide
N
N
tetrathiolation
Me
formation
O
O
O
HS
N
HO
N
(+)-1
Me
Me
Me
OH
N
N
SH
OH
O
O
6
5
N
H
SH
Me
N
H
Me
N
N
H
O
O
O
H
tetrahydroxylation
Me
OH
H
N
O
H
Me
H
NH2
L-alanine
O
condensation
O
dimerization
N
3'
NH
N
H
Me
Me
H
HN
N
H
HN
Me
OH
O
3
8
N
H
7
O
NH2
L-tryptophan
HN
Me
N
H
O
Fig. 2. Retrosynthetic analysis of (+)-11,11'-dideoxyverticillin A (1) based on a biosynthetic hypothesis. Reductive dimerization of the tertiary benzylic bro-
O
O
O
Me
CO2Me
R
a. TFA;
Br
N
NH
Me
b. Br2
(+)-11, R = H
(+)-12, R = Me
morpholine
c. MeI
77%
HN
N
HN
(–)-10
PhSO2N
Me
76%
84%
H
O
N
O
(–)-9
SO2Ph
>10g-scale
NHBoc
PhSO2N
Me
d. CoCl(PPh3)3 46%
SO2Ph
SO2Ph
N
SO2Ph
N
O
O
O
H
N
H
Me
HO
H
Me
Me
O
N
3'
N
TBSO
N
f. TBSCl
O
e. Py2AgMnO4
O
Me
Me
N
HO
N
N
HO
N
Me
Me
OH
Me
Me
PPY
55%
N
OH
63%
3
N
OH
N
O
O
O
15
N
N
OTBS
Me
1
H
N
2g-scale
O
Me
H
SO2Ph
N
H
(+)-15
N
(+)-14
(+)-13
O
SO2Ph
O
SO2Ph
g. Na(Hg) 87%
S
H
N
O
H
O
H
Me
S
SH
H
N
Me
TBSO
O
S S
O
Me
N
H
TBSO
N
N
–
HN
NH
O
S
N
O
Me
N
HO
Me
N
N
h. K2CS3
N
Me
Me
Me
Me
H
N
OH
Me
O
N
OH
S S
O
O
O
TFA
56%
N
OTBS
Me
N
+
OTBS
N
H
S
Me
N
H
O
17
(+)-16
(+)-18
H
O
H
i. ethanolamine
H2N
H
O
O
H
N
Me
S
HS
HS
N
S
O
O
Me
Me
KI3
H
O
O
HN
NH
N
HS
N
N
Me
Me
Me
SH
N
N
pyridine
62%
N
SH
O
S
H
Me
O
S S
O
N
HN
O
Me
N
H
H
S
(+)-11,11'-dideoxyverticillin A (1)
5
20
19
Fig. 3. Concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A (1). manganate (Py2AgMnO4), CH2Cl2, 23°C, 2 hours. (f) tert-butyl(chloro)dimethylsilane
Isolated yields are given for each step. Reaction conditions are as follows: (a) trifluoro- (TBSCl), PPY 5 mole %, triethylamine (Et3N), N,N-dimethyl formamide (DMF),
acetic acid (TFA), dichloromethane (CH2Cl2), 23°C, 4 hours; tert-butanol (tBuOH), 23°C, 30 min. (g) 5% Na(Hg), NaH2PO4, methanol (MeOH), 23°C. (h) K2CS3, TFA,
morpholine, 23°C, 48 hours. (b) Br2, acetonitrile (MeCN), 0°C, 5 min. (c) methyl CH2Cl2, 23°C, 28 min. (i) ethanolamine, acetone, 23°C; KI3, pyridine, CH2Cl2, 23°C.
iodide (MeI), K2CO3, acetone, 23°C, 5 days. (d) tris(triphenylphosphine)cobalt(I) The thermal ellipsoid representation of synthetic (+)-1 from x-ray crystallographic
chloride [CoCl(PPh3)3], acetone, 23°C, 30 min. (e) bis(pyridine)silver(I) per- analysis is shown with most hydrogens omitted for clarity.
www.sciencemag.org SCIENCE VOL 324 10 APRIL 2009
239

REPORTS
mide (+)-12 with tris(triphenylphosphine)cobalt(I) atom abstraction from formyl groups became a
The dimeric octacyclic tetraol (+)-14 proved
chloride in acetone provided the key dimeric focus of our efforts in pursuit of an effective strat- highly acid- and base-sensitive. Its treatment with
octacyclic intermediate (+)-13 in 46% yield (16). egy for single-step tetrahydroxylation of dimeric Brønsted acids led to formation of tetraene 26
Preference for cis-fusion on 5,5-ring systems made octacycle (+)-13. After extensive experimentation, (Fig. 4B) (22), whereas its exposure to base re-
this an effective strategy for simultaneously se- we found that the treatment of the diketopiperazine sulted in either decomposition or conversion to
curing the two vicinal C3 and C3′ quaternary 21 with tetra-n-butylammonium permanganate hemiaminal diastereomers (SOM text). The high
stereocenters (12). This chemistry is amenable to (3.0 equiv) (18) in pyridine at 23°C for 2 hours sensitivity of tetraol (+)-14 to base may be at-
multigram scale synthesis of (+)-13 (e.g., 43% provided the desired tetracyclic diol 22 in 78% tributed to reversible ring opening at the C15-
yield on 8 g scale).
yield primarily as one diastereomer. Application aminal, allowing deleterious side reactions of the
Guided by our biosynthetic hypothesis for of these conditions to the oxidation of the more- alpha-keto amide derivative 27 (Fig. 4B). Unex-
late-stage functionalization of the diketopipera- challenging dimeric octacycle (+)-13 resulted in pectedly, even dissolution of (+)-14 in methanol at
zines (i.e., 7→5, Fig. 2), we sought methods for 40% yield of the desired tetraol as a complex mix- ambient temperature led to slow decomposition.
Ca-oxidation of the dimeric octacycle (+)-13. ture of hemiaminal diastereomers. Because this
With multigram access to dimeric octacyclic
Initially, we focused on the oxidation of the read- tetrahydroxylation was fraught with competing tetraol (+)-14, we focused on its conversion to
ily accessible enol tautomers or corresponding epimerization of Ca-methines and incomplete oxi- alkaloid (+)-1. Removal of the benzenesulfonyl
enolates of (+)-13 (SOM text). Unfortunately, dation leading to complex product mixtures (SOM groups with sodium amalgam in methanol buf-
these strategies were plagued by formation of text), we sought to refine this reaction.
fered with dibasic sodium phosphate unveiled an
partially oxidized and diastereomeric products Further studies revealed that bis(pyridine)- unstable diaminotetrahemiaminal 28 (Fig. 4C).
in addition to substantial competing decom- silver(I) permanganate (Py2AgMnO4) (19) oxi- Immediate exposure of this labile compound to
position. Likewise, a variety of soft-enolization dized dimeric octacycle (+)-13 selectively and condensed hydrogen sulfide at –78°C with a Lewis
and electrophilic amide activation strategies failed efficiently. Under optimal conditions, treatment acid (6), followed by warming, resulted in forma-
to provide the necessary Ca-methine oxidation. of dimer (+)-13 with Py2AgMnO4 (4.8 equiv) in tion of the corresponding tetrathiol 29 as a mixture
Although we ultimately developed conditions dichloromethane at 23°C for 2 hours afforded of hemithioaminal diastereomers. Oxidation of
for dihydroxylation (or didehydrogenation) of the desired dimeric octacyclic tetraol (+)-14 in the crude mixture of tetrathiols with potassium
a model monomeric tetracyclic diketopiper- 63% yield as a single diastereomer (Fig. 3). The triiodide resulted in (+)-11,11'-dideoxyverticillin
azine 21 (Fig. 4A) along with its conversion to high level of diastereoselection (SOM text) is A (1), albeit in low overall yields (2 to 15%, three
the corresponding monomeric epidithiodike- consistent with a fast abstraction-rebound mech- steps) from tetraol (+)-14.
topiperazine 23 (SOM text), none of these meth- anism (20, 21), as suggested by hydroxylation of
The fragility of tetraol (+)-14 and derivatives
odologies proved effective when applied to the the radical-clock hydantoin 24 (74%) (Fig. 4A) 28 and 29, the poor mass balance of this capricious
more-challenging dimeric octacyclic bisdiketo- and x-ray diffraction analysis of tetraol (+)-14. three-step sequence, and our preference to avoid
piperazine (+)-13, likely because of additional Oxidation of the corresponding cyclo-D-Trp-L-Ala the use of pressurized toxic hydrogen sulfide led
modes of C3–C3′ bond fragmentation and/or derivatives under these conditions resulted only us to seek a superior strategy for the synthesis of
unfavorable interactions between the tetracyclic in oxidation at the alanine Ca(L-Ala)-methines, the epidithiodiketopiperazine substructure of this
subunits.
leaving the Ca(D-Trp)-methines unchanged (SOM family of alkaloids. After substantial experimen-
Careful analysis of the bond dissociation ener- text). This observation, which has important con- tation, we realized that a simple tactical conver-
gies (17) involved in our successful radical-based sequences for the choice of natural or unnatural sion of the tetraol (+)-14 to the diol (+)-15 (Fig. 3)
abstraction of Ca-methines in the model tetracycle amino acid precursors, is attributed to a nonoptimal imparted considerable stability to this structure,
21 (SOM text) suggested weak Ca–H bonds re- conformation of the C–H bond for abstraction consistent with prevention of an undesired diketo-
sulting from stabilization of the ensuing Ca- and/or the sterically disfavored approach of the piperazine ring opening. The use of Fu’s (R)-(+)-4-
radicals in diketopiperazines. Thus, the use of oxidant from the concave face of the 5,5-ring pyrrolidinopyridinyl(pentamethylcyclopentadienyl)-
mild oxidants typically reserved for hydrogen system.
iron (PPY) catalyst (5 mole %) (23) was optimal
SO2Ph
O
acidic
A
Me
B
SO2Ph
N
conditions
H
N
O
O
Me
HO
O
H
R
N
O
R
N
H2C
Me
R
O
O
O
N
N
(+)-14
N
HO
Me
NPh
Me
N
N
MeN
NHMe
O
Me
OH
O
Me
H
N
N
basic
conditions
N
H
O
O
CH2
SO2Ph
26
27
H
N
15
N
21, R = H
22, R = OH
23, R,R = S–S
24, R = H
25, R = OH
SO2Ph
oxidation
thiolation
Me
SO2Ph
decomposition or isomerization
O
C
H
H
O
O
H
N
H N
Me
HO
Me
HS
N
N
O
O
O
b. H2S
a. Na(Hg)
c. KI3
N
HO
N
HS
Me
Me
Me
Me
SH
(+)-1
N
N
OH
SH
Hf(OTf)4
O
O
N
H
OH
Me
N
H
Me
N
N
(+)-14
28
29
O
H
H
Fig. 4. Key observations enabling our first-generation synthesis of (+)-11,11'- alkaloid (+)-1 from dimeric tetraol (+)-14. Conditions: (a) 5% Na(Hg),
dideoxyverticillin A (1). (A) Functionalization of exploratory models. (B) Na2HPO4, MeOH, 23°C. (b) H2S, CH2Cl2, hafnium(IV) trifluoromethane-
Sensitivity of dimeric octacyclic tetraol (+)-14 to both acidic and basic sulfonate [Hf(OTf)4], –78→23°C, 14 hours. (c) KI3, pyridine, CH2Cl2, 23°C,
conditions. (C) Thermal ellipsoid representation of (+)-14. Synthesis of 2 to 15% for three steps.
240
10 APRIL 2009 VOL 324 SCIENCE www.sciencemag.org

REPORTS
11. J. D. Herscheid, R. J. Nivard, M. W. Tijhuis, H. P. Scholten,
for the selective derivatization of both alanine- merization (vide supra). Furthermore, thiola-
derived hemiaminals of (+)-14 (SOM text). Treat- tion of the oxidized diketopiperazines at an
ment of a methanolic solution of diol (+)-15 earlier stage led to substantial reductive cleav-
containing monobasic sodium phosphate with age or elimination of the sensitive carbon-sulfur
sodium amalgam cleanly unveiled the stable dia- bonds during subsequent transformations. These
minodiol (+)-16 in 87% yield as a surrogate for our key insights guided our described strategy,
H. C. Ottenheijm, J. Org. Chem. 45, 1880 (1980).
12. M. Movassaghi, M. A. Schmidt, Angew. Chem. Int. Ed. 46,
3725 (2007).
13. M. Movassaghi, M. A. Schmidt, J. A. Ashenhurst,
Angew. Chem. Int. Ed. 47, 1485 (2008).
14. D. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am.
Chem. Soc. 105, 5390 (1983).
hypothetical biosynthetic intermediate 6 (Fig. 2).
whereby the conversion of diaminodiol (+)-16
15. Sensitivity of diketopiperazine (+)-11 to epimerization at the
tryptophan-derived Ca-methine is highlighted by isolation
of the corresponding diastereomer of 12 in 11% yield.
16. The major isolable side product is the C3-reduction
product. Although the use of tetrahydrofuran (THF) as
solvent provided a higher yield of dimer (+)-13
(52%) on <1 g scale, the yields of larger scale
reactions (>1 g scale) in THF were lower (40%).
17. A. Rauk et al., Biochemistry 38, 9089 (1999).
18. T. Sala, M. V. Sargent, J. Chem. Soc. Chem. Commun.
1978, 253 (1978).
At this juncture, we envisioned that coor- to dimeric dithiepanethione (+)-18 enabled tetra-
dinating the introduction of the two sulfur atoms on thiolation with concomitant inversion of all four
each diketopiperazine ring would provide greater Ca-stereocenters, allowing rapid epidithiodiketo-
stereochemical control and structural stability. In- piperazine formation.
spired by the Woodward-Prévost cis-dihydroxylation
Collectively, our observations on the in-
of alkenes with carboxylate ions (24) and cog- herent reactivity of these structures hint at a
nizant of the observation from Kishi’s seminal plausible biosynthetic sequence for alkaloid
synthesis of gliotoxin that epidithiodiketopiper- (+)-1 (Fig. 2). Whereas the viability of the pro-
azines are acutely sensitive toward basic, re- posed biosynthetic intermediates is supported
ductive, oxidative, and strongly acidic conditions through chemical synthesis, the successful im-
(5), we reasoned that the use of a trithiocarbonate plementation of our synthetic strategy offers a
(25) would deliver a sulfurated product poised potential roadmap to the function of enzymes
for mild unveiling of the targeted tetrathiol at involved in the biosynthesis of epidithiodike-
an advanced stage. In the event, treatment of topiperazine alkaloids. For instance, Howlett’s
diaminodiol (+)-16 with potassium trithiocar- studies of the epidithiodiketopiperazine bio-
bonate and trifluoroacetic acid in dichlorometh- synthetic gene clusters (28, 29) have identified
ane resulted in rapid formation and isolation of genes encoding proteins with unassigned func-
the desired dimeric bisdithiepanethione (+)-18 in tion that have sequence homology to cytochrome
56% yield (26) (SOM text), likely via kinetic P450 mono-oxygenases. The mechanistic sem-
trapping of iminium ion 17 followed by intramo- blance of our permanganate diketopiperazine
lecular dithiepanethione formation. In this single hydroxylation to the well-studied C–H abstraction-
operation, four carbon-oxygen bonds are ex- hydroxylation of substrates by P450 oxygenases
changed for four carbon-sulfur bonds, the stereo- (30, 31) prompts consideration of the involve-
chemistry at all four tertiary thiols is secured, and ment of these genes in the Ca-oxidation of the
the targeted cis-dithiodiketopiperazine substruc- diketopiperazine core.
19. H. Firouzabadi, B. Vessal, M. Naderi, Tetrahedron Lett.
23, 1847 (1982).
20. K. A. Gardner, J. M. Mayer, Science 269, 1849 (1995).
21. T. Strassner, K. N. Houk, J. Am. Chem. Soc. 122, 7821
(2000).
22. All attempts at the conversion of tetraene 26 to 1 based
on the chemistry developed (fig. S5) in the synthesis of
23 failed, highlighting the additional challenges of the
dimeric series.
23. J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 120, 11532 (1998).
24. R. B. Woodward, F. V. Brutcher, J. Am. Chem. Soc. 80,
209 (1958).
25. E. Cuthbertson, D. D. MacNicol, P. R. Mallinson,
Tetrahedron Lett. 16, 1345 (1975).
26. In addition to the desired (+)-(11S,11'S,15S,15'S)-18,
the corresponding (11R,11'S,15R,15'S)-18a and
(11R,11'R,15R,15'R)-18b diastereomers were also
isolated (18:18a:18b, 25:7:1). Exposure of any
diastereomer to the reaction conditions does not result
in equilibration.
27. The expected 1,3-oxazolidine-2-thione (20) was observed
ture of 5 is attained.
Alkaloid (+)-1 potently inhibits the tyrosine
in the product mixture.
Addition of ethanolamine to a solution of kinase activity of the epidermal growth factor
bisdithiepanethione (+)-18 at 23°C rapidly af- receptor (median inhibitory concentration =
forded the proposed biosynthetic precursor di- 0.14 nM), exhibits antiangiogenic activity, and
aminotetrathiol 5 (27), which is subject to mild has efficacy against several cancer cell lines
oxidation to (+)-1 upon exposure to air (SOM text). (32–34). The strategy and methodologies de-
Under optimized conditions, after the formation of scribed here are expected to yield ready access
diaminotetrathiol 5, partitioning of the reaction to related compounds and provide an inroad to
mixture between aqueous hydrochloric acid further biological studies. In this report, we have
and dichloromethane and immediate addition of attempted to capture the power of biosynthetic
potassium triiodide to the organic layer provided considerations as a guiding principle for synthetic
28. E. M. Fox, B. J. Howlett, Mycol. Res. 112, 162 (2008).
29. D. M. Gardiner, B. J. Howlett, FEMS Microbiol. Lett. 248,
241 (2005).
30. H. Chen, B. K. Hubbard, S. E. O’Connor, C. T. Walsh,
Chem. Biol. 9, 103 (2002).
31. A. Schoendorf, C. D. Rithner, R. M. Williams, R. B.
Croteau, Proc. Natl. Acad. Sci. U.S.A. 98, 1501 (2001).
32. Y.-X. Zhang et al., Anticancer Drugs 16, 515 (2005).
33. Y. Chen et al., Biochem. Biophys. Res. Commun. 329,
1334 (2005).
34. Y. Chen, Z. Miao, W. Zhao, J. Ding, FEBS Lett. 579, 3683
(2005).
21
35. L. E. Overman, T. Sato, Org. Lett. 9, 5267 (2007).
36. Z. Wu, L. J. Williams, S. J. Danishefsky, Angew. Chem. Int.
Ed. 39, 3866 (2000).
(+)-11,11'-dideoxyverticillin A {½aꢀD ¼ þ590 planning and as an inspiration for the develop-
21
(c 0.30, CHCl3); for lit. ½aꢀD ¼ þ624:1 (c 0.3, ment of new reactions.
CHCl3); where a is the specific rotation and c is
37. M.M. is an Alfred P. Sloan Research Fellow and a
Beckman Young Investigator. J.K. and J.A.A. acknowledge
predoctoral (National Defense Science and Engineering
Graduate) and postdoctoral [Fonds québécois de la
recherche sur la nature et les technologies (FQRNT)]
fellowships, respectively. We thank P. Müller for
assistance with x-ray structures of (+)-1 and (+)-14.
We acknowledge generous support from Amgen,
AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,
Merck, and Lilly. Structural parameters for (+)-1 and
(+)-14 are freely available from the Cambridge
Crystallographic Data Centre under CCDC-719219 and
CCDC-719218, respectively.
concentration in g/100 ml} in 62% yield as a
References and Notes
colorless solid. All spectroscopic data for (+)-1
matched those reported in the literature (1).
Furthermore, we unambiguously secured the
structure of synthetic (+)-1 by crystallographic
analysis.
1. B. W. Son, P. R. Jensen, C. A. Kauffman, W. Fenical,
Nat. Prod. Res. 13, 213 (1999).
2. D. M. Gardiner, P. Waring, B. J. Howlett, Microbiology
151, 1021 (2005).
3. Y. Kishi, T. Fukuyama, S. Nakatsuka, J. Am. Chem. Soc.
95, 6490 (1973).
4. R. M. Williams, W. H. Rastetter, J. Org. Chem. 45, 2625
(1980).
This concise strategy for the synthesis of
(+)-1 required a carefully choreographed se-
quence of events. In this sequence, the inherent
chemistry of intermediates was maximally used
in generation of chemical complexity and stereo-
chemical control. For example, unveiling of the
aniline nitrogen (N1) of (+)-13 followed by at-
tempted tetrahydroxylation led to complete de-
composition under a variety of conditions. The
challenges associated with the high sensitivity
of (+)-13 toward epimerization at the L-amino
acid–derived Ca-stereocenters was compounded
by the requirement for oxidation before epi-
5. T. Fukuyama, S. Nakatsuka, Y. Kishi, Tetrahedron 37,
2045 (1981).
6. For other representative syntheses of epidithiodiketo-
piperazines, see (35) and references cited therein.
7. For a recent total synthesis of a sulfur containing
diketopiperazine, see (36).
Supporting Online Material
www.sciencemag.org/cgi/content/full/324/5924/238/DC1
8. D. Hauser, H. P. Weber, H. P. Sigg, Helv. Chim. Acta 53,
1061 (1970).
Materials and Methods
SOM Text
Figs. S1 to S5
Tables S1 to S14
References
9. K. Katagiri, K. Sato, S. Hayakawa, T. Matsushima,
H. Minato, J. Antibiot. (Tokyo) 23, 420 (1970).
10. G. W. Kirby, D. J. Robins, in The Biosynthesis of
Mycotoxins: A Study in Secondary Metabolism,
P. S. Steyn, Ed. (Academic Press, New York, 1980),
p. 301.
12 January 2009; accepted 23 February 2009
10.1126/science.1170777
www.sciencemag.org SCIENCE VOL 324 10 APRIL 2009
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