Diversity-oriented synthesis leads to an effective class of bifunctional linchpins uniting anion relay chemistry (ARC) with benzyne reactivity

Article abstract of DOI:10.1073/pnas.1015265108

In conjunction with the construction of a diversity-oriented synthesis library of 10-membered ring "natural product-like" macrolides, the design, synthesis, and validation of a unique class of bifunctional linchpins, uniting benzyne reactivity initiated by type II anion relay chemistry (ARC) has been achieved, permitting access to diverse [2+2], [3+2], and [4+2] cycloadducts.

Full text of DOI:10.1073/pnas.1015265108

Diversity-oriented synthesis leads to an effective
class of bifunctional linchpins uniting anion
relay chemistry (ARC) with benzyne reactivity
Amos 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 of
bifunctional linchpins, uniting benzyne reactivity initiated by type
II anion relay chemistry (ARC) has been achieved, permitting access
to diverse [2+2], [3+2], and [4+2] cycloadducts.
Early on, the synthetic potential of the Type II ARC protocol was
limited by the lack of bifunctional linchpins. Fully convinced of the
synthetic potential of the ARC concept, especially the iterative
protocol, we set out to design, synthesize and validate effective new
linchpins and then to demonstrate the potential of this tactic in
DOS. Initial studies led to a series of bifunctional linchpins
(Scheme 3A), comprising vinyl silanes, bearing β- or γ-electrophilic
sites (aldehyde or epoxide). Application of carefully defined Brook
rearrangement conditions [temperature, solvent polarity, and
counter ion such as Li, K, and Cu(I)] to trigger the requisite [1,4]-C
(sp2)→O silyl group migration permitted the development of
multicomponent alkylation and cross-coupling reaction sequences
(17). Equally effective, a series of three and four carbon benzyl and
phenylthiomethyl silane bifunctional linchpins (Scheme 3B), bear-
ing electrophilic sites either β or γ to a trialkylsilyl group, proved to
be 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 dithiane
linchpin (–)-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-like
macrolides 31a and 31b (Scheme 4). In the event, the reaction
sequence proceeded in six steps, with an overall yield of 25% (i.e.,
13 and 12%, respectively), which corresponds to an average yield
of 80% per transformation.
Having achieved the reaction sequence proof of concept, we
turned to theconstruction of a focusedlibrary of 10-memberedring
macrolides 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 for DOS that we hope will
become widely adopted by the DOS community: construction of all
possible 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 natural
product total synthesis. Pleasingly, we record here the successful
completion of a library consisting of the 24 possible congeners of
31, including both saturated and unsaturated 10-membered ring
macrolides, which has been submitted to the National Institutes
of Health Molecular Libraries Small-Molecule Repository
(MLSMR) for high-throughput screening (SI Appendix).
benzyne cycloaddition natural product-like macrolides
|
he discovery of chemical reactivity, coupled with innovative
T
synthetic 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 relay
chemistry (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 implemented
over the past several decades to access complex natural and un-
natural products, the individual steps required for the multistep
sequences often produce only minimal augmentation in structural
complexity (2–5). In addition, the requisite purifications add time
and costs, not to mention material loss and/or production of
a significant waste stream. ARC, a multicomponent union tactic
(6–8), holds the potential to alleviate, at least in part, these
shortcomings. Particularly important is the potential to improve
step 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, as
in the well recognized Michael or conjugate addition reaction, or
alternatively transfer of charge “across space” by using a relay
agent. An early example of the latter is the classic [1,2]-Brook
rearrangement of α-trialkylsilyl alcohols (9, 10) initiated by
strong base. Further analysis of the across space tactic reveals
two subtypes (I and II), differentiated by the final locus of the
reactive center after rearrangement. In Type I ARC (Scheme
1A), 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 both
during our 1-g synthesis of (+)-spongistatin 1 (17) (11) and the
construction of alkaloid (–)-205B (22) (12).
Design, Synthesis, and Validation of an Effective Class of
Bifunctional Linchpins Capable of Benzyne Reactivity
During the construction of the macrolide library (Scheme 5), we
recognized the opportunity to develop a class of Type II ARC
For the Type II protocol (Scheme 1B), the negative charge is
transferred to a distal site, available for reaction either with simple
terminating electrophiles, or for iterative reactions with a series of
bifunctional linchpins, a process not dissimilar to “living poly-
merization” (13). It is the iterative reaction sequence, with diverse
bifunctional linchpins that holds the greatest potential both for
efficient 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 libraries
generated by this strategy would have a high ratio of sp3 to sp2
hybridized carbon atoms, an important structural feature missing
in many existing screening collections (15, 16).
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: smithab@sas.upenn.edu.
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

A Type I Anion Relay Chemistry
O
R
SiR3
E
OSiR3
R
OSiR3
R
SiR3
3
O
2
Brook
E
ASG
ASG
ASG
ASG
R
1
4
5
B Type II Anion Relay Chemistry
SiR3
O
ASG
n
m
7
R
OSiR3
OSiR3E
O
SiR3
Brook
ASG
m
E
Nu
6
ASG
m
ASG
m
n
n
n = 0 (Aldehyde)
n = 1 (Epoxide)
m = 0,1
n
Nu
R
9
Nu
R
Nu
R
8
10
ASG = Anion Stabilizing Group
1) 7
2) E
OSiR3ASG OSiR3E
ASG
m
n
n
m
Nu
R
R
11
Scheme 1. Type I and II ARC.
bifunctional linchpins based on the ortho-TMS benzaldehyde
skeleton (29; Scheme 4) that held the promise of uniting ARC
with 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
1. a) t-BuLi, Et2O, –78 to –45 °C
OTES
O
O
TES
OR
OH OH
S
S
b)
NapO
13
NapO
Et2O, –78 to –25 °C
S
S
15 R = TES, (58%)
c)
OLi
O
TES
12
OPMB
OPMB
Performed on a 10 g scale !
14
OH
THF/HMPA, –45 to –25 °C
E
O
HO
O
H
O
OH
H
A
H
O
TIPSO
AcO
H
D
H
OMe
O
F
O
H
A
O
C
O
HO
H
O
H
OH
B
O
O
H
O
OH
OTES
O
Cl
16
B
AcO
OAc
The AB Spiroketal Fragment
of Spongistatin 1
OH
17
(+)-Spongistatin 1
1. a) t-BuLi, Et2O, –78 to –45 ºC
b)
O
TBSO
H
S
19
OBPS
BPSO
S
Et2O, –78 to –20 ºC
N
S
S
H
H
c)
NHTs
TBS
18
NTs
O
O
22
(–)-Alkaloid 205B
O
O
20
THF/DME, –78 to 0 ºC
21
Scheme 2. Demonstration of ARC in total synthesis.
6788
|
www.pnas.org/cgi/doi/10.1073/pnas.1015265108
Smith and Kim

Linchpin Synthesis and Initial Validation of Benzyne
Reactivity
Uniting ARC with Pd-Mediated Cross Coupling
O
A
B
OH
*
1) a) Nu
*
Nu
*
*
Bifunctional linchpins 34 and 35 (Scheme 7) required to explore
this scenario were readily prepared from 2-bromo-3-hydroxy-
benzaldehyde 36 (23), beginning by acetalization with (EtO)3CH
in ethanol (1:2 vol/vol), by using 2,4,4,6-tetrabromo-2,5-cyclo-
hexadienone (24) as catalyst. A five-stage sequence, involving
metalation, followed by silylation, removal of the diethyl acetal,
and triflation converted acetal 37 to 34, the requisite aldehyde
linchpin. The corresponding ketone linchpin 35 was prepared by
addition of MeMgBr to 34 followed by pyridinium chlorochromate
(PCC) oxidation (25).
b) CuI, HMPA:THF = (1:1)
n
n
E
TMS
23
c) E
d) HCl
24
n = 0 (Aldehyde)
n = 1 (Epoxide)
(E ; Alkylation + Cross Coupling)
Benzyl and Phenylthiomethyl Silanes
1) a) Nu
OH
E
TMS
*
b) HMPA
O
*
*
Nu
*
R2
R2
n
n
c) E
d) HCl
R1
26
R1
25
To demonstrate the feasibility of benzyne reactivity induced via
the proposed [1,4]-Brook rearrangement, we initially used alcohol
38 (Scheme 8). For the arynophile, we selected benzyl azide 39.
Surprisingly, unlike the conditions required to trigger silyl group
migration ([1,4]-C(sp2)→O) with ortho-TMS benzaldehyde 29
(19), namely CuI in a polar solvent such as HMPA, the Brook
rearrangement proceeded both rapidly and efficiently at low
temperature in either Et2O or THF by using potassium hexame-
thyldisilazane (KHMDS) without addition of CuI. Removal of the
TMS group (1 M HCl) furnished 40 and 41 as a mixture of
regioisomers in 83–85% yield. Presumably silyl group migration,
an equilibrium process (9, 10), is driven in this case by formation
of 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 selected
as the initiating nucleophile.
n = 0 (Aldehyde)
n = 1 (Epoxide)
R1 = H, Me; R2 = Ph, SPh
Scheme 3. Recently introduced bifunctional linchpins for Type II ARC.
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
OTBSS
30
S
S
S
S
S
d) CuI (1.2 equiv), HMPA/THF = (1/1)
0 ºC to rt, 30 min
e) allyl bromide, THF, rt, 1 h
OTMS
27
63%
(syn:anti = 1.25:1)
91% average yield per ARC step
5 steps
Linchpins
O
OH
O
O
O
O
S
S
O
TBS
TMS
31a-31b
(–)-28
29
Longest linear sequence: 6 steps
Overall yield: (syn : 13%)
(anti : 12%)
Nu
Scheme 4. Synthesis of macrocyclic natural product-like molecules.
R
Nu
O
R
OTMS
1. a) Nucleophile
b) Arynophile
TMS
OTf
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 the
precise timing of the [1,4]-Brook rearrangement, required to ac-
cess the benzyne intermediate, in conjunction with sufficiently
dilute conditions to avoid possible intermolecular reactions
(vide infra).
34 (R = H)
35 (R = CH3
34a (R = H)
)
35a (R = CH3)
Nucleophile
Nu
Arynophile
Nu
Nu
R
O
R
OTMS
OTf
R
OTMS
TMS
OTf
Brook
Elimination
O
rearrangement
14
O
R
O
OH
4
HO
O
OTBSS
4
S
S
S
O
33
R
14
7
Scheme 6. Potential benzyne reactivity initiated via the Type II ARC tactic.
7
1. Esterification
2. RCM
3. Dithiane Removal
4. Silyl Deprotection
OH
32
31 (R = H, Methyl)
As illustrated in Scheme 9, addition of MeLi to 34 and 35 using
1,1-diethoxyethylene (42) and benzyl azide (39), respectively, as
the arynophiles for 34 and 2,5-dimethylfuran (44) for 35, fur-
nished the [2+2], [3+2], and [4+2] cycloadducts in 78, 67, and
78% yields. Solvent polarity, temperature, and reaction time with
the timing of arynophile introduction proved critical. In the case
of the intermolecular [2+2] and [4+2] cycloadditions, a mixture
of linchpin and arynophile was treated with MeLi at −78 °C for 10
min in THF, followed, in turn, by warming to 0 °C for 10 min
before the silyl group was removed. However, with benzylazide,
an arynophile known to react with alkyl lithium (26), linchpin 34
was 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 to
react for 2 min exploiting a solvent, temperature, and reaction
time known to initiate and complete the Type II ARC/benzyne
reaction sequence. Treatment with 1 M HCl to remove the TMS
O
O
Unsaturated
O
OH
4
O
OH
Unsaturated
Lactones
O
O
Lactones
(C4C7)
(RR)
(RS)
(SR)
O
O
14
4
(C4C7C14
)
7
7
(RRR) (RRS)
(RSR) (RSS)
(SRS) (SRR)
(SSR) (SSS)
Z
Z
(SS)
23 = 8 compounds
22 = 4 compounds
O
O
O
OH
O
OH
Saturated
Lactones
(C4C7)
(RR)
(RS)
(SR)
Saturated
Lactones
O
O
O
O
14
4
4
(C4C7C14
)
7
7
(RRR) (RRS)
(RSR) (RSS)
(SRS) (SRR)
(SSR) (SSS)
(SS)
2 = 4 compounds
2
3 = 8 compounds
2
24 Possible Diastereomers and Enantiomers (31a-31x)
Scheme 5. Natural product-like library synthesis using the ARC tactic.
Smith and Kim
PNAS
|
April 26, 2011
|
vol. 108
|
no. 17
|
6789

EtO
OEt
Br
O
O
HO
1. a) NaH, THF, 0 ºC, 1 h
O
TABCO
b) n-BuLi, 0 ºC, 40 min
1. a) MeLi, THF, – 78 ºC, 10 min
EtO OEt
TMS
OTf
Br
TMS
OTf
(EtO)3CH, EtOH,
40 ºC, 30 min
c) TMSCl, 0 ºC to rt, 2 h
d) 5% HCl in H2O, rt, 12 h
2. Tf2O,CH2Cl2, pyridine, rt,
20 min
OH
OH
O
92%
37
34
36
34
43
42
then 0 ºC, 10 min
b) 1N HCl, rt, 1 h
71% over 2 steps
single regioisomer
O
HO
78%
PCC, CH2Cl2, rt
MeMgBr, Et2O, 0 ºC
TMS
OTf
TMS
1. a) MeLi, Et2O, – 78 ºC, 5 min
5 min
89%
6 h
HO
HO
O
Ph
b)
OTf
N3
86%
TMS
OTf
35
38
39
N
N
N
N
+
N
N
Scheme 7. Synthesis of aldehyde and ketone linchpins 34 and 35.
THF, – 78 ºC, 2 min
c) 1N HCl, rt, 10 min
Ph
34
40
regioisomeric ratio 3.3:1
HO
41
67%
group then furnished adducts 40 and 41 in 67%, again as a 3.3:1
mixture of regioisomers. Of note, the conversion of ketone 35 to
45 represents an example of a multicomponent Type II ARC
process using a ketone-based linchpin.
O
1. a) MeLi, THF, – 78 ºC, 10 min
TMS
OTf
O
O
44
b) TBAF, rt, 30 min
78%
35
45
N3
HO
HO
HO
Ph
39
Scheme 9. Intermolecular [2+2], [3+2], and [4+2] benzyne cycloadditions.
TMS
OTf
N
N
1. a) KHMDS, – 78 ºC, 10 min
N
N
+
N
N
b) 1N HCl, rt, 10 min
omatic compounds. With these caveats in mind, we expanded our
program 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.
Ph
40
41
38
THF : 85%
Et2O: 83%
regioisomeric ratio 3.3:1
Scheme 8. Demonstration of benzyne reactivity.
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 the
requisite Grignard reagents to 34 afforded 47b and 47c for the
proposed intramolecular [2+2] cycloadditions. Azide 49a, sub-
strate for a potential [3+2] intramolecular cycloaddition, was
elaborated 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, azide
displacement, and TBS group removal led to 49a. Overall yields
were good to excellent.
Turning to intramolecular [2+2] cycloadditions induced via
[1,4]-C(sp2)→O Brook rearrangement, we quickly realized that
the terminal olefins in 47b and 47c were simply too unreactive to
serve as a viable arynophile. Success, however, was achieved with
the intramolecular [3+2] cycloaddition by using alcohol 49a
(Scheme 11) when the reaction was carried out in a dilute THF
solution (0.005 M) to avoid intermolecular reaction with
KHMDS (1.1 equiv) to trigger the Brook rearrangement; the
yield of 50a was 76%. To the best of our knowledge, this is the
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 (for
the first example demonstrating a ketone enolate in a Brook
Rearrangement, see ref. 27) (Scheme 10). Elimination of the
triflate group would then permit in situ benzyne formation to be
followed 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)→O
silyl group migration proceeded without the need of Cu(I), fur-
ther supporting the suggestion that formation of the resulting
benzyne intermediate drives the silyl group migration to the ox-
ygen of the ketone enolate. This observation is the opposite of the
Fallis’ observation (28), demonstrating that aryl anions generated
via 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.
O
O
Turning next to the feasibility of the intramolecular cycload-
dition manifold, we note that such cycloadditions have been
achieved by using fixed cisoid dienes, such as furan and other
cyclic dienes in natural product total synthesis (29–31). However,
intramolecular [2+2], [3+2], or [4+2] benzyne cycloadditions
with simple alkenes, azides, or acyclic dienes are rare. Indeed, to
the best of our knowledge, only two examples have been reported,
the first by Buszek (32), who demonstrated that treatment of aryl
bromides possessing appropriate tethered dienes upon treatment
with strong base afforded [4+2] cycloadducts, albeit in modest
yield (20–28%). Later, Danheiser and coworkers (33) reported
that treatment of o-(trimethylsilyl)aryl triflates with tetrabuty-
lammonium triphenyldifluorosilicate (TBAT) undergo effective
intramolecular [4+2] cycloadditions with conjugated enynes,
arenynes, and dienes to generate highly condensed polycylic ar-
1. a) KHMDS, – 78 ºC, THF, 10 min
TMS
O
O
OTf
44
46
35
b) TBAF, 5 min
52%
O
a) KHMDS
b) F
O
OTMS
OTMS
Brook
rearrangement
Elimination
TMS
OTf
OTf
Scheme 10. Enolate initiation of the Type II ARC tactic leading to benzyne
reactivity.
6790
|
www.pnas.org/cgi/doi/10.1073/pnas.1015265108
Smith and Kim

OH
rearrangement leading to the benzyne intermediate, based on our
earlier work demonstrating that such reaction conditions comprise
competent Brook rearrangement triggers (35). Pleasingly, upon
revisiting the conversion of 51 to 52 (Scheme 12A), decreasing the
concentration with Et2O after addition of MeLi followed by ad-
dition of KOt-Bu in THF to trigger the Brook rearrangement was
also effective. Oxidation with PCC furnished cycloadduct 52 in
75% yield for the two steps (Scheme 13).
HO
TBSO
n = 1, 2, 4
TMS
O
1. BrMg
n = 1, 2, 4
1. TBSOTf, 2,6-lutidine,
CH2Cl2, rt, 20 min
TMS
OTf
TMS
OTf
Et2O, 0 ºC, 5 min
2. a) O3, CH2Cl2:MeOH
n = 1; 47a (92%)
n = 2; 47b (80%)
n = 4; 47c (78%)
OTf
(5:1), –78 ºC, 10 min
b) NaBH4, rt, 1 h
47a-47c
48a
34
70% over 2 steps
N3
1. MsCl, Et3N, 0 ºC, 30 min
2. NaN3, DMF, 15-crown-5,
70 ºC, 12 h
HO
HO
1. a) KHMDS (0.005M), THF
– 78ºC to rt, 2 h
N
N
N
TMS
OTf
1. 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
3. 3% HCl in MeOH, rt, 12 h
57% over 3 steps
b) 1N HCl, rt, 10 min
76%
HO
O
2
TMS
OTf
49a
50a
d) TBAF, 30 min, THF
2. PCC, CH2Cl2, rt, 1 h
Scheme 11. Intramolecular [3+2] benzyne cycloaddition.
51
52
75% over 2 steps
first example of an intramolecular [3+2] cycloaddition using
a benzyne intermediate.
Scheme 13. Intramolecular [4+2] benzyne cycloaddition.
Substrate alcohols 51 and 54 for prospective intramolecular
[4+2] cycloadditions were also readily prepared via addition of
the 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 KHMDS
at –78 °C in a dilute THF solution (0.005 M), followed by PCC
oxidation 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 as
the terminal oxidant proceeded in similar fashion to provide phe-
nalenone 53 in 58% over two steps (congeners of phenalenone
53 are of interest do to their bioactivity as the probes to analyze
the role of DNA polymerase, see ref. 34). A third example
entailed the intramolecular [4+2] cycloaddition of 54, carrying
a pendent furan moiety; subsequent PCC oxidation furnished 55
in 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 the
benzyne intermediate. To overcome this issue, we first explored the
use of concentration, solvent polarity (Et2O→THF) and counter
ion exchange (Li+→K+) to trigger the [1,4]-C(sp2)→O Brook
Encouraged by these results, we turned to validation of a “one-
pot” two-component protocol, using linchpin 34 and the alkyl
lithium derived from iodide 56 carrying a furan (Scheme 14),
taking advantage of the conditions used above (Scheme 13). In the
event, 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 furnished
cycloadduct 55, albeit in a modest 33% yield for the two steps.
O
1. a)
I
2
56
O
O
c) Et2O (0.005 M),
t-BuLi, Et2O, –78 ºC,
30 min, rt, 5 min
d) KOt-Bu in THF, –78 ºC to rt, 2 h
e) TBAF, 30 min, THF
TMS
OTf
O
b) –78 ºC, 10 min,
Et2O (0.1M)
2. PCC, CH2Cl2, rt, 1 h
33% over 2 steps
34
55
b) Et2O (0.1 M)
c) Et2O (0.005 M)
Cycloaddition,
Desilylation
then Oxidation
TMSO
2
LiO
O
O
2
d) KOt-Bu in THF
TMS
OTf
Intramolecular [4+2] Benzyne Cycloaddition with Acyclic Diene
58
A
57
HO
O
2
Scheme 14. One-pot intramolecular [4+2] benzyne cycloaddition.
BrMg
TMS
OTf
TMS
OTf
Et2O, 0 ºC, 5 min
76%
Summary
34
51
During the development and application of an iterative Type II
ARC strategy for DOS, that permitted construction of the 24
possible 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 union
of ARC with benzyne reactivity. This union greatly enhances the
future potential of the ARC tactic by permitting access to diverse
scaffolds 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 benzyne
intermediates for cycloaddition reactions.
1. a) KHMDS, THF (0.005 M),
–78 ºC to rt, 2 h
b) TBAF, THF, rt, 30 min
2. MnO2, Et2O, rt, 12 h
1. a) KHMDS, THF (0.005 M),
–78ºC to rt, 2 h
b) TBAF, THF, rt, 30 min
2. PCC, CH2Cl2, rt, 1 h
58% over 2 steps
71% over 2 steps
O
O
53
52
B
Intramolecular [4+2] benzyne cycloaddition with furan moiety
O
HO
O
O
O
1. a) KHMDS, THF (0.005 M),
BrMg
2
2
TMS
OTf
TMS
–78 ºC to rt, 2 h
O
b) TBAF, THF, rt, 30 min
2. PCC, CH2Cl2, rt, 1 h
Et2O, 0 ºC, 5 min
82%
Materials and Methods
General. Unless otherwise indicated, all reactions were carried out under an
argon atmosphere in flame- or oven-dried glassware, and solvents were
freshly distilled or obtained from a solvent deoxygenation system.
OTf
34
82% over 2 steps
54
55
Scheme 12. Intramolecular [4+2] benzyne cycloaddition.
Smith and Kim
PNAS
|
April 26, 2011
|
vol. 108
|
no. 17
|
6791

Chemical Synthesis. Details for the synthesis of linchpins, intermediates, and
cycloadducts, as well as spectroscopic/analytical data for all new compounds,
are available at SI Appendix.
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 ambient
temperature 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).
Representative Procedure for ARC Tactic. To a precooled (–78 °C) solution of
2-methyl-1,3-dithiane 27 (1.24 g, 9.2 mmol, 1.2 equiv) in THF (15 mL) was
added 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 was
stirred 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 mixture
was 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 for
30 min at –78 °C, the resulting solution was transferred via cannula to
a mixture of CuI (1.75 g, 9.2 mmol, 1.2 equiv) and HMPA/THF (10 mL/10 mL)
ACKNOWLEDGMENTS. Support for this research program was provided by
the National Institutes of Health (Institute of General Medical Sciences)
through Grants GM-081253 and 29028.
1. Smith A-B, III, Wuest W-M (2008) Evolution of multi-component anion relay chemistry
(ARC): Construction of architecturally complex natural and unnatural products. Chem
Commun (Camb) 5883–5895.
21. Marcaurelle L-A, et al. (2010) An aldol-based build/couple/pair strategy for the
synthesis of medium- and large-sized rings: Discovery of macrocyclic histone
deacetylase inhibitors. J Am Chem Soc 132:16962–16976.
2. Wender P-A, Verma V-A, Paxton T-J, Pillow T-H (2008) Function-oriented synthesis,
step economy, and drug design. Acc Chem Res 41:40–49.
3. Wender P-A, Croatt M-P, Witulski B (2006) New reactions and step economy: The total
22. Himeshima Y, Sonoda T, Kobayashi H (1983) Fluoride-induced 1,2-elimination of o-
trimethylsilylphenyl triflate to benzyne under mild conditions. Chem Lett 12:1211–1214.
23. Stavrakov G, Keller M, Breit B (2007) From central to axial to central chirality:
Eanantioselective construction of the trans-4,5,9,10-tetrahydorxy-9,10-dihydro-
phenanthrene system. Eur J Org Chem 2007:5726–5733.
24. Firouzabadi H, Iranpoor N, Shaterian H-R (2002) 2,4,4,6-Tetrabromo-2,5-
cyclohexadienone (TABCO) as a versatile, efficient, and chemoselective catalyst for
the acetalization and transacetalization of carbonyl compounds, the preparation of
acetonides from epoxides and acylals (1,1-diacetates) from aldehydes. Bull Chem Soc
Jpn 75:2195–2205.
synthesis of
( )-salsolene oxide based on the type II transition metal-catalyzed
intramolecular [4+4] cycloaddition. Tetrahedron 62:7505–7511.
4. Bertz S-H (1981) The first general index of molecular complexity. J Am Chem Soc 103:
3599–3601.
5. Bertz S-H, Sommer T-J (1997) Rigorous mathematical approaches to strategic bonds
and synthetic analysis based on conceptually simple new complexity indices. Chem
Commun (Camb) 2409–2410.
6. Dömling A, Ugi I I (2000) Multicomponent reactions with isocyanides. Angew Chem
Int Ed Engl 39:3168–3210.
7. Tietze L-F (1996) Domino reactions in organic synthesis. Chem Rev 96:115–136.
8. Dömling A (2005) Multicomponent Reactions, eds Zhu J, Bienaymé H (Wiley-VCH,
Weinheim, Germany), pp 76–94.
9. Brook A-G (1958) Isomerism of some α-hydorxysilanes to silyl ethers. J Am Chem Soc
80:1886–1889.
10. Brook A-G (1974) Molecular rearrangements of organosilicon compounds. Acc Chem
Res 7:77–84.
11. Smith A-B, III, et al. (2009) Spongipyran synthetic studies. Evolution of a scalable total
synthesis of (+)-spongistatin 1. Tetrahedron 65:6489–6509.
12. Smith A-B, III, Kim DS (2005) Total synthesis of the neotropical poison-frog alkaloid
(-)-205B. Org Lett 7:3247–3250.
13. Webster OW (1991) Living polymerization methods. Science 251:887–893.
14. Schreiber S-L (2000) Target-oriented and diversity-oriented organic synthesis in drug
discovery. Science 287:1964–1969.
15. Clemons P-A, et al. (2010) Small molecules of different origins have distinct
distributions of structural complexity that correlate with protein-binding profiles.
Proc Natl Acad Sci USA 107:18787–18792.
16. Dandapani S, Marcaurelle LA (2010) Grand challenge commentary: Accessing new
chemical space for ‘undruggable’ targets. Nat Chem Biol 6:861–863.
17. Smith A-B, III, Kim WS, Tong R (2010) Uniting anion relay chemistry with Pd-mediated
cross coupling: Design, synthesis and evaluation of bifunctional aryl and vinyl silane
linchpins. Org Lett 12:588–591.
18. Smith A-B, III, Tong R (2010) Benzyl and phenylthiomethyl silanes: A new class of
bifunctional linchpins for type II anion relay chemistry (ARC). Org Lett 12:1260–1263.
19. Smith A-B, III, Kim WS, Wuest W-M (2008) Ortho-TMS benzaldehyde: An effective
linchpin for type II anion relay chemistry (ARC). Angew Chem Int Ed Engl 47:7082–7086.
20. Steglich W, Neises B (1978) Simple method for the esterification of carboxylic acids.
Angew Chem Int Ed Engl 17:522–524.
25. Corey E-J, Suggs
W (1975) Pyridinium chlorochromate. An efficient reagent for
oxidation of primary and secondary alcohols to carbonyl compounds. Tetrahedron
Lett 16:2647–2650.
26. Sieh D-H, Wilbur D-J, Michejda C-J (1980) Preparation of trialkyltriazenes.
A
comparison of the N-N bond rotation in trialkyltriazenes and aryldialkyltriazenes by
variable temperature 13C NMR. J Am Chem Soc 102:3883–3887.
27. Tsubouchi A, Matsuda H, Kira T, Takeda T (2009) Silyl migration in conjunction with
substitution on silicon in copper(I) t-butoxide-promoted coupling between o-
silylphenyl ketones and organic halides. Chem Lett 38:1180–1181.
28. Comanita B-M, Woo S, Fallis A-G (1999)
A versatile tandem retro-[1,4]-Brook
rearrangement-condensation reaction of o-bromoacetopheone silyl enol ethers.
Tetrahedron Lett 40:5283–5286.
29. Best W-M, Wege
D (1981) Intramolecular Diels-Alder reactions of benzynes
application to the total synthesis of mansonone E. Tetrahedron Lett 22:4877–4880.
30. Buszek K-R, Bixby D-L (1995) Total synthesis of pseudopterosin A and E aglycon.
Tetrahedron Lett 36:9129–9132.
31. Chen CL, Sparks S-M, Martin S-F (2006) C-Aryl glycosides via tandem intramolecular
benzyne-furan cycloadditions. Total synthesis of vineomycinone B2 methyl ester. J Am
Chem Soc 128:13696–13697.
32. Buszek K-R (1995) First intramolecular benzyne diels-alder reaction with an acyclic
diene. Unusual effect of diene geometry on the course of the reaction. Tetrahedron
Lett 36:9125–9128.
33. Hayes M-E, Shinokubo H, Danheiser R-L (2005) Intramolecular [4 + 2] cycloadditions of
benzynes with conjugated enynes, arenynes, and dienes. Org Lett 7:3917–3920.
34. Perpelescu M, et al. (2002) Novel phenalenone derivatives from a marine-derived
fungus exhibit distinct inhibition spectra against eukaryotic DNA polymerases.
Biochemistry 41:7610–7616.
35. Smith A-B, III, Xian M, Kim WS, Kim DS (2006) The [1,5]-Brook rearrangement: An
initial application in anion relay chemistry. J Am Chem Soc 128:12368–12369.
6792
|
www.pnas.org/cgi/doi/10.1073/pnas.1015265108
Smith and Kim