孕妇感冒吃什么药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 miconductors such as InAs(23)and perhaps in many other systems.Evaporation is ud in the cleaning of GaAs,and Ga droplets are central to droplet epitaxy(15–18).The intrinsic droplet mo-tion obrved here may therefore have important technological conquences and may open up new extensions for the droplet epitaxy technique.
References and Notes
1.C.D.Bain,G.D.Burnett-Hall,R.R.Montgomerie,Nature
372,414(1994).
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(1995).
3.A.K.Schmid,N.C.Bartelt,R.Q.Hwang,Science290,
1561(2000).
4.Y.Sumino,N.Magome,T.Hamada,K.Yoshikawa,
Phys.Rev.Lett.94,068301(2005).
5.M.K.Chaudhury,G.M.Whitesides,Science256,1539(1992).
6.K.Ichimura,S.-K.Oh,M.Nakagawa,Science288,1624
(2000).
7.K.Iizuka et al.,J.Cryst.Growth150,13(1995).
8.N.Isomura,S.Tsukamoto,K.Iizuka,Y.Arakawa,
J.Cryst.Growth301-302,26(2007).
9.J.R.Arthur,J.Phys.Chem.Solids28,2257(1967).
10.J.Y.Tsao,Materials Fundamentals of Molecular Beam
Epitaxy(Academic Press,San Diego,CA,1993).
11.M.Zinke-Allmang,L.C.Feldman,W.van Saarloos,
Phys.Rev.Lett.68,2358(1992).
12.C.T.Foxon,J.A.Harvey,B.A.Joyce,J.Phys.Chem.Solids
34,1693(1973).
13.T.D.Lowes,M.Zinke-Allmang,J.Appl.Phys.73,4937(1993).
14.C.Chatillon,D.Chatain,J.Cryst.Growth151,91(1995).
15.T.Mano et al.,Nano Lett.5,425(2005).
16.S.Huang et al.,Appl.Phys.Lett.89,031921(2006).
17.M.Yamagiwa et al.,Appl.Phys.Lett.89,113115(2006).
18.Ch.Heyn et al.,Phys.Rev.B76,075317(2007).
19.S.A.Nepijko,N.N.Sedov,G.Schönhen,J.Microsc.
203,269(2001).
20.See supporting material on Science Online.
21.E.Kaxiras,Y.Bar-Yam,J.D.Joannopoulos,K.C.Pandey,
Phys.Rev.B35,9625(1987).
22.G.-X.Qian,R.M.Martin,D.J.Chadi,Phys.Rev.B38,
7649(1988).
23.J.-Y.Shen,C.Chatillon,J.Cryst.Growth106,543(1990).
24.We thank R.Mackie for technical support.Supported by
Australian Rearch Council grants DP0556492and
DP0985290(D.E.J.,W.X.T.).
Supporting Online Material
www.sciencemag/cgi/content/full/324/5924/236/DC1
Materials and Methods
SOM Text
Fig.S1
Movies S1and S2
References
9December2008;accepted10February2009
10.1126/science.1169546
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 denly functionalized,stereochemically complex,and intricate dimeric epidithiodiketopiperazine natural products.Although the dimeric epidithiodiketopiperazines have been known for nearly4decades,none has succumbed to total synthesis.We report a conci enantiolective total synthesis of(+)-11,11'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid.Highly stereo-and chemolective 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 nsitive 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.
T he fungal metabolite(+)-11,11'-dideoxyverticillin A(1,Fig.1)(1)is a
member of the epidithiodiketopiperazine alkaloids,a large family of natural products that has received substantial attention from the scien-tific community for its rich biological activity and complex molecular architecture(2–7).The dimer-ic subt of alkaloids to which the title compound belongs has been known for nearly4decades with the isolation of(+)-chaetocin A(2)(8)and(+)-verticilli
n A(3)(9).Reflective of the daunting challenges pod by molecular structures replete with sterically congested stereogenic centers and highly acid-,ba-,and redox-nsitive functional groupings(5),no dimeric epidithiodiketopipera-zine alkaloid has yet succumbed to total synthesis. Herein we describe a conci strategy for the enantiolective total synthesis of the dimeric epidithiodiketopiperazine alkaloid(+)-1.Our bio-synthetically inspired synthesis features stereo-and chemolective advanced-stage tetrahydroxylation and tetrathiolation reactions,providing a general-
izable solution to the epidithiodiketopiperazine
substructure found in the broader family of the
alkaloids.
At the outt of our synthetic studies,struc-
tural similarities among members of this alkaloid
family combined with Kirby’s radio-labeled amino
acid feeding experiments and his hypothesis
for gliotoxin biosynthesis(10)prompted us to
consider the possibility that the epidisulfides of
(+)-1are asmbled by enzymes that exploit the
inherent chemistry of dimeric diketopiperazines.
Our retrosynthetic analysis of(+)-1imitates a plau-
sible biosynthetic quence of events linking
dimeric epidithiodiketopiperazines to common
a-amino acid precursors(Fig.2).We envisioned
preparation of(+)-1by mild oxidation of the
tetrathiol5,which could be accesd via stereo-
lective tetrathiolation of an octacyclic tetraol6.
In contrast to a previous biosynthetic hypothesis
for monomeric epidithiodiketopiperazines invoking
thiolation via an N-hydroxylation–dehydration -
quence(11),we speculated that a postdimerization
C a-hydroxylation would enable substrate-directed
hemiaminal thiolation through the intermediacy of
an acyliminium ion.Intermediate7,which we hy-
pothesized to ari from a dimerization event,
could be asmbled from the readily available
cyclo-dipeptide8by using the conci cobalt-
mediated dimerization strategy reported from
our laboratories(12,13).The imposing chal-
lenges associated with quadruple C a-methine
hydroxylation of7and the tetrathiolation of inter-
Department of Chemistry,Massachutts Institute of Technology, Cambridge,MA02139,USA.
*To whom correspondence should be addresd.E-mail: movassag@mit.edu
(+)-11,11'-dideoxyverticillin A(1)
(+)-verticillin A(3)(+)-leptosin K(4)
(+)-chaetocin A(2)
Fig.1.The molecular structure of(+)-11,11'-dideoxyverticillin A(1)and reprentative dimeric epidithiodiketopiperazine alkaloids.
mediate 6notwithstanding,the need for abso-lute and relative stereochemical control (Fig.2)of the six tetrasubstituted carbons of (+)-1pod noteworthy strategic concerns.We envisioned
the introduction of the C3and the C3′vicinal quaternary stereocenters as a prelude to stereo-chemical control of the four thiolated-carbon stereogenic centers of (+)-1in a strategy reminis-
cent of Seebach ’s lf-reproduction of chirality (14).Such a final-stage tetrathiolation followed by im
mediate disulfide formation would obvi-ate the need to mask the notoriously nsitive epidithiodiketopiperazine functional grouping in the early stages of the synthesis.
The dimeric diketopiperazine (+)-13was as-mbled in six steps from commercially available amino acid derivatives (Fig.3)[supporting on-line material (SOM)text].The quential treat-ment of amide (–)-9with trifluoroacetic acid followed by cyclization with morpholine readily afforded access to the desired cis -diketopiperazine (–)-10in 84%yield (>20g).Exposure of cyclo -L -tryptophan-L -alanine (–)-10to molecular bro-mine in acetonitrile at 0°C furnished the desired monomeric tetracyclic bromide (+)-11in 76%isolated yield (SOM text).Treatment of tetra-cyclic bromide (+)-11with methyl iodide and potassium carbonate gave the ba-nsitive di-merization precursor (+)-12in 77%yield (
15).Reductive dimerization of the tertiary benzylic bro-(+)-1
disulfide
formation
Fig.2.Retrosynthetic analysis of (+)-11,11'-dideoxyverticillin A (1)bad on a biosynthetic hypothesis.
11,R =H 12,R =Me
c.MeI 77%
PhSO 2N
O NHBoc
HN Me CO 2Me
(–)-9
2 d.CoCl(PPh 3)3
46%
2(+)-13
a.TFA;84%
b.Br 2 e.Py AgMnO 63%2g-scale
>10g-scale
(+)-18
NH
H
N
N
S S O
O Me Me S
HN H
N
N S S O O Me
Me
S
h.K 2CS 3TFA 56%
HN
O 2g.Na(Hg)
87%
(+)-11,11'-dideoxyverticillin A (1)
KI 362%
20
2f.TBSCl
55%
Fig.3.Conci enantiolective total synthesis of (+)-11,11'-dideoxyverticillin A (1).Isolated yields are given for each step.Reaction conditions are as follows:(a)trifluoro-acetic acid (TFA),dichloromethane (CH 2Cl 2),23°C,4hours;tert -butanol (t BuOH),morpholine,23°C,48hours.(b)Br 2,acetonitrile (MeCN),0°C,5min.(c)methyl iodide (MeI),K 2CO 3,acetone,23°C,5days.(d)tris(triphenylphosphine)cobalt(I)chloride [CoCl(PPh 3)3],acetone,23°C,30min.(e)bis(pyridine)silver(I)per-manganate (Py 2AgMnO 4),CH 2Cl 2,23°C,2hours.(f)tert -butyl(chloro)dimethylsilane (TBSCl),PPY 5mole %,triethylamine (Et 3N),N ,N -dimethyl formamide (DMF),23°C,30min.(g)5%Na(Hg),NaH 2PO 4,methanol (MeOH),23°C.(h)K 2CS 3,TFA,CH 2Cl 2,23°C,28min.(i)ethanolamine,acetone,23°C;KI 3,pyridine,CH 2Cl 2,23°C.The thermal ellipsoid reprentation of synthetic (+)-1from x-ray crystallographic analysis is shown with most hydrogens omitted for clarity.
mide(+)-12with tris(triphenylphosphine)cobalt(I)
chloride in acetone provided the key dimeric
octacyclic intermediate(+)-13in46%yield(16).
Preference for cis-fusion on5,5-ring systems made
this an effective strategy for simultaneously -
curing the two vicinal C3and C3′quaternary
stereocenters(12).This chemistry is amenable to
multigram scale synthesis of(+)-,43%
yield on8g scale).
Guided by our biosynthetic hypothesis for
late-stage functionalization of the diketopipera-
,7→5,Fig.2),we sought methods for
C a-oxidation of the dimeric octacycle(+)-13.
Initially,we focud on the oxidation of the read-
ily accessible enol tautomers or corresponding
enolates of(+)-13(SOM text).Unfortunately,
the strategies were plagued by formation of
partially oxidized and diastereomeric products
in addition to substantial competing decom-
position.Likewi,a variety of soft-enolization韩国与朝鲜
and electrophilic amide activation strategies failed
to provide the necessary C a-methine oxidation.
Although we ultimately developed conditions
for dihydroxylation(or didehydrogenation)of
a model monomeric tetracyclic diketopiper-
azine21(Fig.4A)along with its conversion to
the corresponding monomeric epidithiodike-
topiperazine23(SOM text),none of the meth-
odologies proved effective when applied to the
more-challenging dimeric octacyclic bisdiketo-
piperazine(+)-13,likely becau of additional
modes of C3–C3′bond fragmentation and/or
unfavorable interactions between the tetracyclic
subunits.
Careful analysis of the bond dissociation ener-
gies(17)involved in our successful radical-bad
abstraction of C a-methines in the model tetracycle 21(SOM text)suggested weak C a–H bonds re-sulting from stabilization of the ensuing C a-
radicals in diketopiperazines.Thus,the u of
mild oxidants typically rerved for hydrogen atom abstraction from formyl groups became a
focus of our efforts in pursuit of an effective strat-
egy for single-step tetrahydroxylation of dimeric
octacycle(+)-13.After extensive experimentation,
we found that the treatment of the diketopiperazine
21with tetra-n-butylammonium permanganate
(3.0equiv)(18)in pyridine at23°C for2hours
provided the desired tetracyclic diol22in78%
yield primarily as one diastereomer.Application
of the conditions to the oxidation of the more-
challenging dimeric octacycle(+)-13resulted in
40%yield of the desired tetraol as a complex mix-
ture of hemiaminal diastereomers.Becau this
tetrahydroxylation was fraught with competing
epimerization of C a-methines and incomplete oxi-
dation leading to complex product mixtures(SOM
text),we sought to refine this reaction.
Further studies revealed that bis(pyridine)-
silver(I)permanganate(Py2AgMnO4)(19)oxi-
dized dimeric octacycle(+)-13lectively and
efficiently.Under optimal conditions,treatment
of dimer(+)-13with Py2AgMnO4(4.8equiv)in
dichloromethane at23°C for2hours afforded
the desired dimeric octacyclic tetraol(+)-14in
63%yield as a single diastereomer(Fig.3).The
high level of diastereolection(SOM text)is
consistent with a fast abstraction-rebound mech-
anism(20,21),as suggested by hydroxylation of
the radical-clock hydantoin24(74%)(Fig.4A)
and x-ray diffraction analysis of tetraol(+)-14.
Oxidation of the corresponding cyclo-D-Trp-L-Ala
derivatives under the conditions resulted only
in oxidation at the alanine C a(L-Ala)-methines,
leaving the C a(D-Trp)-methines unchanged(SOM
text).This obrvation,which has important con-
quences for the choice of natural or unnatural
amino acid precursors,is attributed to a nonoptimal
conformation of the C–H bond for abstraction
and/or the sterically disfavored approach of the
oxidant from the concave face of the5,5-ring
system.
The dimeric octacyclic tetraol(+)-14proved
highly acid-and ba-nsitive.Its treatment with
Brønsted acids led to formation of tetraene26
(Fig.4B)(22),whereas its exposure to ba re-
sulted in either decomposition or conversion to
hemiaminal diastereomers(SOM text).The high
nsitivity of tetraol(+)-14to ba may be at-
tributed to reversible ring opening at the C15-
aminal,allowing deleterious side reactions of the
alpha-keto amide derivative27(Fig.4B).Unex-
pectedly,even dissolution of(+)-14in methanol at
ambient temperature led to slow decomposition.
With multigram access to dimeric octacyclic
tetraol(+)-14,we focud on its conversion to
眉毛长痘痘alkaloid(+)-1.Removal of the benzenesulfonyl
groups with sodium amalgam in methanol buf-
fered with dibasic sodium phosphate unveiled an
unstable diaminotetrahemiaminal28(Fig.4C).
Immediate exposure of this labile compound to
condend hydrogen sulfide at–78°C with a Lewis
acid(6),followed by warming,resulted in forma-
tion of the corresponding tetrathiol29as a mixture
of hemithioaminal diastereomers.Oxidation of
the crude mixture of tetrathiols with potassium
triiodide resulted in(+)-11,11'-dideoxyverticillin
A(1),albeit in low overall yields(2to15%,three
steps)from tetraol(+)-14.
The fragility of tetraol(+)-14and derivatives
28and29,the poor mass balance of this capricious
three-step quence,and our preference to avoid
the u of pressurized toxic hydrogen sulfide led
us to ek a superior strategy for the synthesis of
the epidithiodiketopiperazine substructure of this
family of alkaloids.After substantial experimen-
tation,we realized that a simple tactical conver-
sion of the tetraol(+)-14to the diol(+)-15(Fig.3)
imparted considerable stability to this structure,
consistent with prevention of an undesired diketo-
piperazine ring opening.The u of Fu’s(R)-(+)-4-
pyrrolidinopyridinyl(pentamethylcyclopentadienyl)-
iron(PPY)catalyst(5mole%)(23)was optimal
c.KI
(+)-1 (+)-14
2
H2
Me
14
acidic
conditions
凯仕乐decomposition or
2
MeN
NPh
O
O
R
21,R=H
22,R=OH
23,R,R=S–S
oxidation
thiolation
24,R=H
25,R=OH
太上老君师傅是谁A B
C
b.H S
Hf(OTf)4
Fig.4.Key obrvations enabling our first-generation synthesis of(+)-11,11'-
dideoxyverticillin A(1).(A)Functionalization of exploratory models.(B)
Sensitivity of dimeric octacyclic tetraol(+)-14to both acidic and basic
conditions.(C)Thermal ellipsoid reprentation of(+)-14.Synthesis of
alkaloid(+)-1from dimeric tetraol(+)-14.Conditions:(a)5%Na(Hg),
Na2HPO4,MeOH,23°C.(b)H2S,CH2Cl2,hafnium(IV)trifluoromethane-
sulfonate[Hf(OTf)4],–78→23°C,14hours.(c)KI3,pyridine,CH2Cl2,23°C,
2to15%for three steps.
for the lective derivatization of both alanine-derived hemiaminals of(+)-14(SOM text).Treat-ment of a methanolic solution of diol(+)-15 containing monobasic sodium phosphate with sodium amalgam cleanly unveiled the stable dia-minodiol(+)-16in87%yield as a surrogate for our hypothetical biosynthetic intermediate6(Fig.2).
At this juncture,we envisioned that coor-dinating the introduction of the two sulfur atoms on each diketopiperazine ring would provide greater stereochemical control and structural stability.In-spired by the W oodward-Prévost cis-dihydroxylation of alkenes with carboxylate ions(24)and cog-nizant of the obrvation from Kishi’s minal synthesis of gliotoxin that epidithiodiketopiper-azines are acutely nsitive toward basic,re-ductive,oxidative,and strongly acidic conditions (5),we reasoned that the u of a trithiocarbonate (25)would deliver a sulfurated product poid for mild unveiling of the targeted tetrathiol at an advanced stage.In the event,treatment of diaminodiol(+)-16with potassium trithiocar-bonate and trifluoroacetic acid in dichlorometh-ane resulted in rapid formation and isolation of the desired dimeric bisdithiepanethione(+)-18in 56%yield(26)(SOM text),likely via kinetic trapping of iminium ion17followed by intramo-lecular dithiepanethione formation.In this single operation,four carbon-oxygen bonds are ex-changed for four carbon-sulfur bonds,the stereo-chemistry at all four tertiary thiols is cured,and the targeted cis-dithiodiketopiperazine substruc-ture of5is attained.
Addition of ethanolamine to a solution of bisdithiepanethione(+)-18at23°C rapidly af-forded the propod biosynthetic precursor di-aminotetrathiol5(27),which is subject to mild oxidation to(+)-1upon exposure to air(SOM text). Under optimized conditions,after the formation of diaminotetrathiol5,partitioning of the reaction mixture between aqueous hydrochloric acid and dichloromethane and immediate addition of potassium triiodide to the organic layer provided
(+)-11,11'-dideoxyverticillin A{½a 21
D ¼þ590
(c0.30,CHCl3);for lit.½a 21
D ¼þ624:1(c0.3,
CHCl3);where a is the specific rotation and c is concentration in g/100ml}in62%yield as a colorless solid.All spectroscopic data for(+)-1 matched tho reported in the literature(1). Furthermore,we unambiguously cured the structure of synthetic(+)-1by crystallographic analysis.
This conci strategy for the synthesis of (+)-1required a carefully choreographed -quence of events.In this quence,the inherent chemistry of intermediates was maximally ud in generation of
chemical complexity and stereo-chemical control.For example,unveiling of the aniline nitrogen(N1)of(+)-13followed by at-tempted tetrahydroxylation led to complete de-composition under a variety of conditions.The challenges associated with the high nsitivity of(+)-13toward epimerization at the L-amino acid–derived C a-stereocenters was compounded by the requirement for oxidation before epi-merization(vide supra).Furthermore,thiola-
tion of the oxidized diketopiperazines at an
earlier stage led to substantial reductive cleav-
age or elimination of the nsitive carbon-sulfur
bonds during subquent transformations.The
key insights guided our described strategy,
whereby the conversion of diaminodiol(+)-16
to dimeric dithiepanethione(+)-18enabled tetra-
thiolation with concomitant inversion of all four
C a-stereocenters,allowing rapid epidithiodiketo-
piperazine formation.
Collectively,our obrvations on the in-
herent reactivity of the structures hint at a
plausible biosynthetic quence for alkaloid
(+)-1(Fig.2).Whereas the viability of the pro-
pod biosynthetic intermediates is supported
through chemical synthesis,the successful im-
居家抗疫plementation of our synthetic strategy offers a
potential roadmap to the function of enzymes
involved in the biosynthesis of epidithiodike-
topiperazine alkaloids.For instance,Howlett’s
studies of the epidithiodiketopiperazine bio-
synthetic gene clusters(28,29)have identified
genes encoding proteins with unassigned func-
tion that have quence homology to cytochrome
P450mono-oxygenas.The mechanistic m-
blance of our permanganate diketopiperazine
hydroxylation to the well-studied C–H abstraction-
hydroxylation of substrates by P450oxygenas
(30,31)prompts consideration of the involve-
ment of the genes in the C a-oxidation of the
diketopiperazine core.
Alkaloid(+)-1potently inhibits the tyrosine
kina activity of the epidermal growth factor
receptor(median inhibitory concentration=
0.14nM),exhibits antiangiogenic activity,and
has efficacy against veral cancer cell lines
(32–34).The strategy and methodologies de-
scribed here are expected to yield ready access
to related compounds and provide an inroad to
further biological studies.In this report,we have
attempted to capture the power of biosynthetic
considerations as a guiding principle for synthetic
planning and as an inspiration for the develop-
ment of new reactions.
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Beckman Young Investigator.J.K.and J.A.A.acknowledge
predoctoral(National Defen Science and Engineering
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recherche sur la nature et les technologies(FQRNT)]
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assistance with x-ray structures of(+)-1and(+)-14.
We acknowledge generous support from Amgen,
AstraZeneca,Boehringer Ingelheim,GlaxoSmithKline,
Merck,and Lilly.Structural parameters for(+)-1and
(+)-14are freely available from the Cambridge
Crystallographic Data Centre under CCDC-719219and
CCDC-719218,respectively.
Supporting Online Material
www.sciencemag/cgi/content/full/324/5924/238/DC1
Materials and Methods
SOM Text
Figs.S1to S5
Tables S1to S14
References
12January2009;accepted23February2009
10.1126/science.1170777
