Diversity-oriented synthesis leads to an effective class ...Diversity-oriented synthesis leads to an...
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Diversity-oriented synthesis leads to an effectiveclass of bifunctional linchpins uniting anionrelay chemistry (ARC) with benzyne reactivityAmos B. Smith III1 and Won-Suk Kim
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia,PA 19104
Edited by Stuart L. Schreiber, Broad Institute, Cambridge, MA, and approved December 16, 2010 (received for review October 27, 2010)
In conjunction with the construction of a diversity-oriented syn-thesis library of 10-membered ring “natural product-like” macro-lides, the design, synthesis, and validation of a unique class ofbifunctional linchpins, uniting benzyne reactivity initiated by typeII anion relay chemistry (ARC) has been achieved, permitting accessto diverse [2+2], [3+2], and [4+2] cycloadducts.
benzyne cycloaddition | natural product-like macrolides
The discovery of chemical reactivity, coupled with innovativesynthetic strategies, comprises the hallmark of complex mol-
ecule synthesis. Toward this end, we recently embarked on a re-search program to demonstrate the potential utility of anion relaychemistry (ARC) (1), a strategic reaction paradigm recently in-troduced by our laboratory for the iterative construction of ar-chitecturally complex natural and unnatural products (Scheme 1).The driving force for this program was based on the recognition
that although numerous elegant strategies, complete with exqui-site stereochemical control, have been devised and implementedover the past several decades to access complex natural and un-natural products, the individual steps required for the multistepsequences often produce only minimal augmentation in structuralcomplexity (2–5). In addition, the requisite purifications add timeand costs, not to mention material loss and/or production ofa significant waste stream. ARC, a multicomponent union tactic(6–8), holds the potential to alleviate, at least in part, theseshortcomings. Particularly important is the potential to improvestep efficiency, a critical aspect of complex molecule construction.As defined, ARC entails orchestration of negative charge
migration either through the bonding network of a molecule, asin the well recognized Michael or conjugate addition reaction, oralternatively transfer of charge “across space” by using a relayagent. An early example of the latter is the classic [1,2]-Brookrearrangement of α-trialkylsilyl alcohols (9, 10) initiated bystrong base. Further analysis of the across space tactic revealstwo subtypes (I and II), differentiated by the final locus of thereactive center after rearrangement. In Type I ARC (Scheme1A), the negative charge is returned to the original carbon,permitting the reactive anion to serve as an effective tricompo-nent linchpin, a tactic (Scheme 2) that has served us well bothduring our 1-g synthesis of (+)-spongistatin 1 (17) (11) and theconstruction of alkaloid (–)-205B (22) (12).For the Type II protocol (Scheme 1B), the negative charge is
transferred to a distal site, available for reaction either with simpleterminating electrophiles, or for iterative reactions with a series ofbifunctional linchpins, a process not dissimilar to “living poly-merization” (13). It is the iterative reaction sequence, with diversebifunctional linchpins that holds the greatest potential both forefficient construction of complex natural and unnatural products,as well as for diversity-oriented synthesis (DOS) (14). Of con-siderable significance, members of the DOS-derived librariesgenerated by this strategy would have a high ratio of sp3 to sp2
hybridized carbon atoms, an important structural feature missingin many existing screening collections (15, 16).
Early on, the synthetic potential of theType IIARCprotocol waslimited by the lack of bifunctional linchpins. Fully convinced of thesynthetic potential of the ARC concept, especially the iterativeprotocol, we set out to design, synthesize and validate effective newlinchpins and then to demonstrate the potential of this tactic inDOS. Initial studies led to a series of bifunctional linchpins(Scheme 3A), comprising vinyl silanes, bearing β- or γ-electrophilicsites (aldehyde or epoxide). Application of carefully defined Brookrearrangement conditions [temperature, solvent polarity, andcounter ion such as Li, K, and Cu(I)] to trigger the requisite [1,4]-C(sp2)→O silyl group migration permitted the development ofmulticomponent alkylation and cross-coupling reaction sequences(17). Equally effective, a series of three and four carbon benzyl andphenylthiomethyl silane bifunctional linchpins (Scheme 3B), bear-ing electrophilic sites either β or γ to a trialkylsilyl group, proved tobe competent linchpins in multicomponent reactions (18).To demonstrate the potential of the iterative Type II ARC
tactic for DOS, we selected our original epoxy silyl dithianelinchpin (–)-28 and the newly reported ortho-trimethylsilyl (TMS)benzaldehyde (29) to validate a proof of concept reaction se-quence (19). The targets were syn and anti natural product-likemacrolides 31a and 31b (Scheme 4). In the event, the reactionsequence proceeded in six steps, with an overall yield of 25% (i.e.,13 and 12%, respectively), which corresponds to an average yieldof 80% per transformation.Having achieved the reaction sequence proof of concept, we
turned to the construction of a focused library of 10-membered ringmacrolides based on 31 (Scheme 5), using several different acids(33) as coupling partners for Steglich esterification (DMAP/DCC)(20).We set as a goal a prospective tenet forDOS that we hope willbecomewidely adopted by theDOS community: construction of allpossible diastereomers and enantiomers of a chosen scaffold (21).Such a goal would, at least for some congeners, demand the de-velopment of innovative chemistry, as occurs in the field of naturalproduct total synthesis. Pleasingly, we record here the successfulcompletion of a library consisting of the 24 possible congeners of31, including both saturated and unsaturated 10-membered ringmacrolides, which has been submitted to the National Institutesof Health Molecular Libraries Small-Molecule Repository(MLSMR) for high-throughput screening (SI Appendix).
Design, Synthesis, and Validation of an Effective Class ofBifunctional Linchpins Capable of Benzyne ReactivityDuring the construction of the macrolide library (Scheme 5), werecognized the opportunity to develop a class of Type II ARC
Author contributions: A.B.S. designed research; W.-S.K. performed research; W.-S.K.analyzed data; and A.B.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.1To whom correspondence should be addressed. E-mail: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1015265108/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1015265108 PNAS | April 26, 2011 | vol. 108 | no. 17 | 6787–6792
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bifunctional linchpins based on the ortho-TMS benzaldehydeskeleton (29; Scheme 4) that held the promise of uniting ARCwith the rich reactivity of benzyne. Specifically, by placing an ef-fective leaving group ortho to the TMS group in either 29 or the
corresponding ketone to furnish linchpins 34 and 35 (22), applica-tion of the now-validated conditions to trigger a [1,4]-Brook rear-rangement with linchpin 29 [CuI and/or hexamethylphosphoramide(HMPA)] could be envisioned to furnish a benzyne intermediate
SiR3
ASG
O
R
ASG R
SiR3 O Brook
ASG R
OSiR3 E
ASG R
OSiR3E
1
2
3 45
O
R
SiR3
ASG
Nu
ASG
O SiR3 Brook
ASG
E
Nu R Nu R
OSiR3
ASG
R
OSiR3E
6
7
8 9 10
n m
n n n
Num m mn = 0 (Aldehyde)
n = 1 (Epoxide) m = 0,1
ASG = Anion Stabilizing Group
ype I Anion Relay ChemistryA T
B Type II Anion Relay Chemistry
1) 72) E
R
OSiR3ASG
11
n
Nu
m
OSiR3
R
E
ASGn m
Scheme 1. Type I and II ARC.
Et2O, –78 to –25 °C
b)
1. a) t-BuLi, Et2O, –78 to –45 °C
THF/HMPA, –45 to –25 °C
c)R = TES, (58%)
Performed on a 10 g scale !
The AB Spiroketal Fragmentof Spongistatin 1
S S
TES
O
O
O
O
O
O
O
O
HO
OMe
OH
H
HO
OH
OH
H
H
H
H
H
H
OH
AcO
OH
O
OAc
Cl
E
F D
C
17
A
B
(+)-Spongistatin 1
S S
TBS
18
O
OBPS
1. a) t-BuLi, Et2O, –78 to –45 ºC b)
Et2O, –78 to –20 ºC
c)
O O
NTs
THF/DME, –78 to 0 ºC
19
20
O O
SS
TBSO
BPSO
NHTs
21
N
H
HH
(–)-Alkaloid 205B22
12
15
16
NapO13
O
14
OLi
OPMB
OTESO
NapO
O OR SS OH OH
OPMB
TES
OO
TIPSO
O
AcO
H
A
BO
OTES
H
Scheme 2. Demonstration of ARC in total synthesis.
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capable of undergoing a wide variety of inter- or intramolecular[2+2], [3+2], and [4+2] cycloaddition reactions (Scheme 6).Critical for success in the multicomponent manifold would be theprecise timing of the [1,4]-Brook rearrangement, required to ac-cess the benzyne intermediate, in conjunction with sufficientlydilute conditions to avoid possible intermolecular reactions(vide infra).
Linchpin Synthesis and Initial Validation of BenzyneReactivityBifunctional linchpins 34 and 35 (Scheme 7) required to explorethis scenario were readily prepared from 2-bromo-3-hydroxy-benzaldehyde 36 (23), beginning by acetalization with (EtO)3CHin ethanol (1:2 vol/vol), by using 2,4,4,6-tetrabromo-2,5-cyclo-hexadienone (24) as catalyst. A five-stage sequence, involvingmetalation, followed by silylation, removal of the diethyl acetal,and triflation converted acetal 37 to 34, the requisite aldehydelinchpin. The corresponding ketone linchpin 35 was prepared byaddition of MeMgBr to 34 followed by pyridinium chlorochromate(PCC) oxidation (25).To demonstrate the feasibility of benzyne reactivity induced via
the proposed [1,4]-Brook rearrangement, we initially used alcohol38 (Scheme 8). For the arynophile, we selected benzyl azide 39.Surprisingly, unlike the conditions required to trigger silyl groupmigration ([1,4]-C(sp2)→O) with ortho-TMS benzaldehyde 29(19), namely CuI in a polar solvent such as HMPA, the Brookrearrangement proceeded both rapidly and efficiently at lowtemperature in either Et2O or THF by using potassium hexame-thyldisilazane (KHMDS) without addition of CuI. Removal of theTMS group (1 M HCl) furnished 40 and 41 as a mixture ofregioisomers in 83–85% yield. Presumably silyl group migration,an equilibrium process (9, 10), is driven in this case by formationof the benzyne functionality, whereas for the parent linchpin 29,Cu(I) is required to facilitate the Brook rearrangement.Encouraged by these results, we turned to explore the feasi-
bility of intermolecular tricomponent [2+2], [3+2], and [4+2]cycloadditions to be achieved in a “single-flask” by using linch-pins 34 and 35. For the Type II ARC process, MeLi was selectedas the initiating nucleophile.
As illustrated in Scheme 9, addition of MeLi to 34 and 35 using1,1-diethoxyethylene (42) and benzyl azide (39), respectively, asthe arynophiles for 34 and 2,5-dimethylfuran (44) for 35, fur-nished the [2+2], [3+2], and [4+2] cycloadducts in 78, 67, and78% yields. Solvent polarity, temperature, and reaction time withthe timing of arynophile introduction proved critical. In the caseof the intermolecular [2+2] and [4+2] cycloadditions, a mixtureof linchpin and arynophile was treated with MeLi at −78 °C for 10min in THF, followed, in turn, by warming to 0 °C for 10 minbefore the silyl group was removed. However, with benzylazide,an arynophile known to react with alkyl lithium (26), linchpin 34was first reacted with MeLi in Et2O for 5 min at −78 °C. In turn,benzyl azide was then added in THF at −78 °C and allowed toreact for 2 min exploiting a solvent, temperature, and reactiontime known to initiate and complete the Type II ARC/benzynereaction sequence. Treatment with 1 M HCl to remove the TMS
TMS
O
n
n = 0 (Aldehyde)n = 1 (Epoxide)
*
E
n
OH
Nu ***
ARC with Pd-Mediated Cross Coupling
O
n
*
R1
TMS
R2
*
1) a) Nu b) HMPA
c) Ed) HCl
n
*
R1
E
R2
*
OH
Nu
R1 = H, Me; R2 = Ph, SPh
Uniting
Benzyl and Phenylthiomethyl Silanes
(E ; Alkylation + Cross Coupling)
1) a) Nu b) CuI, HMPA:THF = (1:1)
c) Ed) HCl23 24
25 26
n = 0 (Aldehyde)n = 1 (Epoxide)
A
B
Scheme 3. Recently introduced bifunctional linchpins for Type II ARC.
S SSS OTBS
OTMS27
SS
63% (syn:anti = 1.25:1)
1. a) t-BuLi, KOt-Bu, THF, –78 ºC, 30 min b) (–)-28, THF, – 78 ºC, 20 min c) 29, THF, – 78 ºC, 30 min
30
91% average yield per ARC step
OSS
TBS TMS
O
(–)-28 29
LinchpinsO OOH
OO
31a-31b
Longest linear sequence: 6 stepsOverall yield: (syn : 13%) (anti : 12%)
d) CuI (1.2 equiv), HMPA/THF = (1/1) 0 ºC to rt, 30 mine) allyl bromide, THF, rt, 1 h
5 steps
Scheme 4. Synthesis of macrocyclic natural product-like molecules.
OH
OO
O O OH
OO
O O
OH
OO
O O OH
OO
O O
HO
O
R
1. Esterification2. RCM3. Dithiane Removal4. Silyl Deprotection
OH
OO
O O R
31 (R = H, Methyl)
SS OTBS
OH
SS
32
24 Possible Diastereomers and Enantiomers (31a-31x)
14
33
4 7
22 = 4 compounds
22 = 4 compounds
23 = 8 compounds
23 = 8 compounds
44 7 14
4
4
4
7
7 7
14
14
Unsaturated Lactones
(C4C7)(RR)(RS)(SR)(SS)
Saturated Lactones
(C4C7)(RR)(RS)(SR)(SS)
Unsaturated Lactones(C4C7C14)
(RRR) (RRS)(RSR) (RSS)(SRS) (SRR)(SSR) (SSS)
Saturated Lactones(C4C7C14)
(RRR) (RRS)(RSR) (RSS)(SRS) (SRR)(SSR) (SSS)
ZZ
7
Scheme 5. Natural product-like library synthesis using the ARC tactic.
O R
TMS
OTf
NuNu
OTMSR
1. a) Nucleophile
b) Arynophile
34 (R = H)35 (R = CH3)
34a (R = H)35a (R = CH3)
Nucleophile Arynophile
TMS
OTf
NuOR
OTf
NuOTMSR
NuOTMSR
Brook
rearrangement
Elimination
Scheme 6. Potential benzyne reactivity initiated via the Type II ARC tactic.
Smith and Kim PNAS | April 26, 2011 | vol. 108 | no. 17 | 6789
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group then furnished adducts 40 and 41 in 67%, again as a 3.3:1mixture of regioisomers. Of note, the conversion of ketone 35 to45 represents an example of a multicomponent Type II ARCprocess using a ketone-based linchpin.
To expand further the utility of the ketone-based linchpin (35),we explored the possibility of using the oxygen anion of the de-rived enolate to trigger [1,4]-C(sp2)→O silyl group migration (forthe first example demonstrating a ketone enolate in a BrookRearrangement, see ref. 27) (Scheme 10). Elimination of thetriflate group would then permit in situ benzyne formation to befollowed by a [4+2] intermolecular cycloaddition with an appro-priate arynophile.As predicted, treatment of 35 with KHMDS at −78 °C in the
presence of 2,5-dimethylfuran furnished the [4+2] cycloadduct(46) in 52% yield, after removal of the TMS group using tetra-butylammonium fluoride (TBAF). Here again [1,4]-C(sp2)→Osilyl group migration proceeded without the need of Cu(I), fur-ther supporting the suggestion that formation of the resultingbenzyne intermediate drives the silyl group migration to the ox-ygen of the ketone enolate. This observation is the opposite of theFallis’ observation (28), demonstrating that aryl anions generatedvia metal-halogen exchange of o-bromoacetophenone trime-thylsilyl enol ether at −78 °C in THF undergo rapid [1,4]-O→C(sp2) retro-Brook rearrangement.Turning next to the feasibility of the intramolecular cycload-
dition manifold, we note that such cycloadditions have beenachieved by using fixed cisoid dienes, such as furan and othercyclic dienes in natural product total synthesis (29–31). However,intramolecular [2+2], [3+2], or [4+2] benzyne cycloadditionswith simple alkenes, azides, or acyclic dienes are rare. Indeed, tothe best of our knowledge, only two examples have been reported,the first by Buszek (32), who demonstrated that treatment of arylbromides possessing appropriate tethered dienes upon treatmentwith strong base afforded [4+2] cycloadducts, albeit in modestyield (20–28%). Later, Danheiser and coworkers (33) reportedthat treatment of o-(trimethylsilyl)aryl triflates with tetrabuty-lammonium triphenyldifluorosilicate (TBAT) undergo effectiveintramolecular [4+2] cycloadditions with conjugated enynes,arenynes, and dienes to generate highly condensed polycylic ar-
omatic compounds. With these caveats in mind, we expanded ourprogram to explore the feasibility of intramolecular [2+2], [3+2],and [4+2] cycloadditions exploiting benzyne intermediates gen-erated via a [1,4]-C(sp2)→O Brook rearrangement.For the prospective intramolecular [2+2] and [3+2] cyclo-
additions, the substrate alcohols (47b, 47c, and 49a) were con-structed as outlined in Scheme 11. Specifically, addition of therequisite Grignard reagents to 34 afforded 47b and 47c for theproposed intramolecular [2+2] cycloadditions. Azide 49a, sub-strate for a potential [3+2] intramolecular cycloaddition, waselaborated via a five-step sequence beginning with alcohol 47a.Protection of the hydroxyl as the t-butyldimethylsilyl (TBS) ether,followed by ozonolysis/reduction (NaBH4), mesylation, azidedisplacement, and TBS group removal led to 49a. Overall yieldswere good to excellent.Turning to intramolecular [2+2] cycloadditions induced via
[1,4]-C(sp2)→O Brook rearrangement, we quickly realized thatthe terminal olefins in 47b and 47c were simply too unreactive toserve as a viable arynophile. Success, however, was achieved withthe intramolecular [3+2] cycloaddition by using alcohol 49a(Scheme 11) when the reaction was carried out in a dilute THFsolution (0.005 M) to avoid intermolecular reaction withKHMDS (1.1 equiv) to trigger the Brook rearrangement; theyield of 50a was 76%. To the best of our knowledge, this is the
O
Br
OH
TABCO
(EtO)3CH, EtOH, 40 ºC, 30 min
EtO
Br
OH
OEt
92%36 37
1. a) NaH, THF, 0 ºC, 1 h b) n-BuLi, 0 ºC, 40 min
TMS
OTf
O
34
71% over 2 steps
MeMgBr, Et2O, 0 ºC
89%
TMS
OTf
HO
38
PCC, CH2Cl2, rt
6 h
TMS
OTf
O
3586%
5 min
c) TMSCl, 0 ºC to rt, 2 h d) 5% HCl in H2O, rt, 12 h2. Tf2O,CH2Cl2, pyridine, rt, 20 min
Scheme 7. Synthesis of aldehyde and ketone linchpins 34 and 35.
TMS
OTf
HO
38
1. a) KHMDS, – 78 ºC, 10 min
b) 1N HCl, rt, 10 min
N3
THF : 85%Et2O: 83%
HO
N
N
N
Ph
HO
N
N
N
Ph
regioisomeric ratio 3.3:1
+
40 41
39
Scheme 8. Demonstration of benzyne reactivity.
TMS
OTf
O
34
1. a) MeLi, THF, – 78 ºC, 10 min
HO
43
EtO OEt
then 0 ºC, 10 min
42
b) 1N HCl, rt, 1 hsingle regioisomer
78%
TMS
OTf
O
34
1. a) MeLi, Et2O, – 78 ºC, 5 min
c) 1N HCl, rt, 10 min
N3b)
THF, – 78 ºC, 2 min
67%
HO
N
N
N
Ph
HO
N
N
N
Ph
regioisomeric ratio 3.3:1
+
40 41
39
TMS
OTf
O
35
1. a) MeLi, THF, – 78 ºC, 10 min
O
44
b) TBAF, rt, 30 min
HO
45
O
78%
O
Scheme 9. Intermolecular [2+2], [3+2], and [4+2] benzyne cycloadditions.
O
TMS
OTf
35
TMS
OTf
O
OTf
OTMS OTMS
O
46
1. a) KHMDS, – 78 ºC, THF, 10 min
O
44
b) TBAF, 5 min
52%a) KHMDS
O
O
Elimination
rearrangement
Brook
b) F
Scheme 10. Enolate initiation of the Type II ARC tactic leading to benzynereactivity.
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first example of an intramolecular [3+2] cycloaddition usinga benzyne intermediate.Substrate alcohols 51 and 54 for prospective intramolecular
[4+2] cycloadditions were also readily prepared via addition ofthe corresponding Grignard reagents to aldehyde 34 (Scheme 12).Validation of the intramolecular [4+2] cycloaddition process
was first achieved upon treatment of alcohol 51 with KHMDSat –78 °C in a dilute THF solution (0.005 M), followed by PCCoxidation to furnish 52, a process that entailed oxidative aro-matization after the initial [4+2] cycloaddition (Scheme 12A).The yield was 71%. Intramolecular cycloaddition using MnO2 asthe terminal oxidant proceeded in similar fashion to provide phe-nalenone 53 in 58% over two steps (congeners of phenalenone53 are of interest do to their bioactivity as the probes to analyzethe role of DNA polymerase, see ref. 34). A third exampleentailed the intramolecular [4+2] cycloaddition of 54, carryinga pendent furan moiety; subsequent PCC oxidation furnished 55in 82% yield for the two steps (Scheme 12B).We turned next to the possibility of a two-component reaction by
using the Type II ARC protocol to trigger an intramolecular [4+2]aryne cycloaddition. High dilution conditions would be required,given the anticipated competitive intermolecular reactivity of thebenzyne intermediate. To overcome this issue, we first explored theuse of concentration, solvent polarity (Et2O→THF) and counterion exchange (Li+→K+) to trigger the [1,4]-C(sp2)→O Brook
rearrangement leading to the benzyne intermediate, based on ourearlier work demonstrating that such reaction conditions comprisecompetent Brook rearrangement triggers (35). Pleasingly, uponrevisiting the conversion of 51 to 52 (Scheme 12A), decreasing theconcentration with Et2O after addition of MeLi followed by ad-dition of KOt-Bu in THF to trigger the Brook rearrangement wasalso effective. Oxidation with PCC furnished cycloadduct 52 in75% yield for the two steps (Scheme 13).
Encouraged by these results, we turned to validation of a “one-pot” two-component protocol, using linchpin 34 and the alkyllithium derived from iodide 56 carrying a furan (Scheme 14),taking advantage of the conditions used above (Scheme 13). In theevent, addition of the alkyl lithium derived from 56 in Et2O(0.1 M), followed in turn by dilution with Et2O to a substrate con-centration of 0.005 M, transmetallation using KOt-Bu in THF,and PCC oxidation of the derived adduct pleasingly furnishedcycloadduct 55, albeit in a modest 33% yield for the two steps.
SummaryDuring the development and application of an iterative Type IIARC strategy for DOS, that permitted construction of the 24possible congeners of a focused library of 10-membered ring nat-ural product-like macrolides, we designed, synthesized, and vali-dated a unique class of bifunctional linchpins that led to the unionof ARC with benzyne reactivity. This union greatly enhances thefuture potential of the ARC tactic by permitting access to diversescaffolds that arise via inter- and intramolecular [2+2], [3+2], and[4+2] cycloaddition reactions. Particularly significant was the de-velopment of reaction conditions (temperature, solvent polarity,and counter ion) that permit the precise timing of the [1,4]-C(sp2)→O Brook rearrangement required to generate the benzyneintermediates for cycloaddition reactions.
Materials and MethodsGeneral. Unless otherwise indicated, all reactions were carried out under anargon atmosphere in flame- or oven-dried glassware, and solvents werefreshly distilled or obtained from a solvent deoxygenation system.
TMS
OTf
34
O
TMS
OTf
47a-47c
HO1.
Et2O, 0 ºC, 5 min1. TBSOTf, 2,6-lutidine, CH2Cl2, rt, 20 min
2. a) O3, CH2Cl2:MeOH (5:1), –78 ºC, 10 min b) NaBH4, rt, 1 h
70% over 2 steps
TMS
OTf
48a
TBSO
1. MsCl, Et3N, 0 ºC, 30 min2. NaN3, DMF, 15-crown-5, 70 ºC, 12 h
3. 3% HCl in MeOH, rt, 12 h
57% over 3 steps
TMS
OTf
49a
HO
N3
N
HO
N
N
50a
1. a) KHMDS (0.005M), THF – 78ºC to rt, 2 h
b) 1N HCl, rt, 10 min
76%
n = 1, 2, 4
n = 1; 47a (92%)n = 2; 47b (80%)n = 4; 47c (78%)
n = 1, 2, 4BrMg
OH
Scheme 11. Intramolecular [3+2] benzyne cycloaddition.
TMS
OTf
51
HO1. a) MeLi, Et2O (0.1 M), –78 ºC, 5 min b) Et2O (0.005 M) c) KOt-Bu in THF, –78 ºC to rt, 2 h
75% over 2 steps
2O
52
d) TBAF, 30 min, THF2. PCC, CH2Cl2, rt, 1 h
Scheme 13. Intramolecular [4+2] benzyne cycloaddition.
TMS
OTf
O c) Et2O (0.005 M), d) KOt-Bu in THF, –78 ºC to rt, 2 he) TBAF, 30 min, THF
55
O
O
2. PCC, CH2Cl2, rt, 1 h
33% over 2 steps
OI
34
1. a)
t-BuLi, Et2O, –78 ºC,30 min, rt, 5 min
TMS
OTf
LiO2
O d) KOt-Bu in THFTMSO
O
Cycloaddition,Desilylationthen Oxidation
b) Et2O (0.1 M)c) Et2O (0.005 M)
56
2
2
57 58
b) –78 ºC, 10 min, Et2O (0.1M)
Scheme 14. One-pot intramolecular [4+2] benzyne cycloaddition.TMS
OTf
34
O
TMS
OTf
51
HO
Et2O, 0 ºC, 5 min
O
52
76%
71% over 2 steps
TMS
OTf
O
TMS
OTf
54
HO
Et2O, 0 ºC, 5 min
82%
1. a) KHMDS, THF (0.005 M), –78 ºC to rt, 2 h
55
O
O b) TBAF, THF, rt, 30 min 2. PCC, CH2Cl2, rt, 1 h
82% over 2 steps
OOBrMg
34
O
53
1. a) KHMDS, THF (0.005 M), –78ºC to rt, 2 h b) TBAF, THF, rt, 30 min2. PCC, CH2Cl2, rt, 1 h
58% over 2 steps
Intramolecular [4+2] Benzyne Cycloaddition with Acyclic Diene
BrMg
1. a) KHMDS, THF (0.005 M), –78 ºC to rt, 2 h b) TBAF, THF, rt, 30 min2. MnO2, Et2O, rt, 12 h
Intramolecular [4+2] benzyne cycloaddition with furan moiety
22
2
A
B
Scheme 12. Intramolecular [4+2] benzyne cycloaddition.
Smith and Kim PNAS | April 26, 2011 | vol. 108 | no. 17 | 6791
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Chemical Synthesis. Details for the synthesis of linchpins, intermediates, andcycloadducts, as well as spectroscopic/analytical data for all new compounds,are available at SI Appendix.
Representative Procedure for ARC Tactic. To a precooled (–78 °C) solution of2-methyl-1,3-dithiane 27 (1.24 g, 9.2 mmol, 1.2 equiv) in THF (15 mL) wasadded KOt-Bu (1.0 M in THF, 9.7 mL, 9.7 mmol, 1.26 equiv) and t-BuLi(1.7 M in pentane, 5.7 mL, 9.7 mmol, 1.26 equiv). The resulting solution wasstirred at –78 °C for 30 min, and a solution of epoxy silyl dithiane linchpin(–)-28 (2.24 g, 7.7 mmol, 1.0 equiv) in THF (15 mL) was added. The mixturewas stirred for 20 min at –78 °C and then a solution of aldehyde 29 (1.64 g,9.2 mmol, 1.2 equiv) in THF (15 mL) was added via cannula. After stirring for30 min at –78 °C, the resulting solution was transferred via cannula toa mixture of CuI (1.75 g, 9.2 mmol, 1.2 equiv) and HMPA/THF (10 mL/10 mL)
at 0 °C and then warmed to ambient temperature and stirred for 30 min.Allyl bromide (2.0 mL, 23.1 mmol, 3.0 equiv) was next added at ambienttemperature and after 1 h, the reaction was quenched with saturated
aqueous NH4Cl solution (100 mL). The resulting mixture was then extracted
with Et2O (100 mL × 3) and the organic layers were combined, washed with
brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (Et2O/hexane; 1/50) provided a 1.25:1 di-
astereomeric mixture of 30 (3.13 g, 4.87 mmol, 63%) as pale yellow oil. Rf =
0.8 (hexane/Et2O = 10/1).
ACKNOWLEDGMENTS. Support for this research program was provided bythe National Institutes of Health (Institute of General Medical Sciences)through Grants GM-081253 and 29028.
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6792 | www.pnas.org/cgi/doi/10.1073/pnas.1015265108 Smith and Kim
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