Will R Gutekunst1, Phil S Baran. 1. Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Abstract
The application of C-H functionalization logic to target-oriented synthesis provides an exciting new venue for the development of new and useful strategies in organic chemistry. In this article, C-H functionalization reactions are explored as an alternative approach to access pseudodimeric cyclobutane natural products, such as the dictazole and the piperarborenine families. The use of these strategies in a variety of complex settings highlights the subtle geometric, steric, and electronic effects at play in the auxiliary guided C-H functionalization of cyclobutanes.
The application of C-H functionalization logic to target-oriented synthesis provides an exciting new venue for the development of new and useful strategies in organicchemistry. In this article, C-H functionalization reactions are explored as an alternative approach to access pseudodimericcyclobutane natural products, such as the dictazole and the piperarborenine families. The use of these strategies in a variety of complex settings highlights the subtle geometric, steric, and electronic effects at play in the auxiliary guided C-H functionalization of cyclobutanes.
C–H functionalization
logic is rapidly permeating the way
organicchemists approach synthesis and deconstruct target molecules.
With methodological advances developing at an increasing pace, new
disconnections and strategies once thought impossible are now available
for consideration during synthesis planning. While these methods have
sporadically been utilized to great effect for decades, only recently
have these strategies been formalized and articulated as an efficient
and effective means to construct molecules of interest. In comparison
to traditional prefunctionalization approaches, there are inherent
benefits to using C–H bonds as latent functional groups in
terms of redox, atom, and step economy. Furthermore, many issues of
chemoselectivity are frequently mitigated by simply removing the functional
groups from the equation altogether. C–H functionalization
methods are particularly compelling from a strategic standpoint because
they can challenge preconceived notions in order to provide solutions
to longstanding problems in organicchemistry.[1]Stereocontrolled synthesis of complex cyclobutanes is one
such
problem that was identified while surveying the wide diversity of
cyclobutane-containing natural products that have been reported in
the literature. Figure 1 shows a handful of
these natural products. Common among all of these cyclobutanes, with
the exception of tripartilactam[2] (4), is that they are pseudodimeric; they are composed of two
similar, but distinct, olefin precursors. For instance, the piperarborenines
(1 and 2) have differing degrees of oxidation
on the aryl rings, with one ring containing two methoxy substituents
and the other possessing three.[3] The dictazoles
(5 and 6), anthocertotonic acid (3), and pipercyclobutanamide A (8), on the other hand,
are fully unsymmetrical with four different substituents on the cyclobutane
ring.[4] Additionally, a wide variety of
cyclobutane stereochemistries are observed, furthering the difficulty
of general strategies for their construction.
Figure 1
Complex cyclobutane natural
products.
Complex cyclobutane natural
products.With increasing interest apparent
in the fields of medicinal chemistry,
polymer, and material science, a dearth of methods for the construction
of cyclobutanes has been revealed, particularly in comparison to its
smaller and larger homologues.[5] The most
commonly considered and direct approach to cyclobutane synthesis is
through a [2 + 2] photocycloaddition.[6] While
this strategy has proven useful in many intramolecular contexts and
homodimerizations, the successful heterodimerization
of two olefins is highly dependent upon the proper steric and electronic
properties of the monomers. Additionally, the resulting stereochemistry
is largely at the mercy of the substrates chosen. For the heterodimerization
of two similar monomers, a photochemical approach could be highly
inefficient, as illustrated in Figure 2. This
first issue, presuming a photocycloaddition reaction is viable, is
one of statistics. Since the two monomers are effectively identical
in terms of steric and electronic parameters, there is likely no preference
for heterodimerization over homodimerization. The orientation of the
olefin monomers during the dimerization is another point of consideration,
since both head-to-head and head-to-tail modes of cyclization are
possible. When these factors are combined with facile E/Z isomerism of the starting materials under photochemical
conditions, a potentially very complex mixture of dimeric products
could arise that presumably would be very challenging to purify. Further
supporting this line of reasoning, the homodimerization of methyl cinnamate in the presence of BF3·Et2O leads to 8 of the 11 possible isomericcyclobutane products.[7]
Figure 2
Potential products of a hypothetical photochemical [2
+ 2] heterodimerzation
reaction.
Potential products of a hypothetical photochemical [2
+ 2] heterodimerzation
reaction.Partial solutions to this problem
have emerged from solid-state
photochemistry, template-directed photochemistry, and photoredox catalysis.
As shown in Figure 3A, seminal studies on topochemistry
by Schmidt demonstrated that direct irradiation of different crystal
polymorphs of cinnamic acid (9) in the solid state leads
to different cyclobutane dimers.[8] The α
polymorph leads to α-truxillic acid (10), while
the β form gives exclusively β-truxinic acid (11). This chemistry was the basis for the syntheses of the symmetrical
cyclobutane dimers dipiperamide A and incarvillateine.[9] Notably, the γ polymorph of cinnamic acid is photoinert
due to improper olefin spacing and alignment in the solid state. This
strategy is not well suited for heterodimerizations, however, since
a 1:1 cocrystallization and precise packing of the two different olefins
in the crystal lattice would be required, a challenging crystal engineering
problem that has only been observed in highly biased systems.[10] Template-directed photochemistry has also seen
success in controlling the stereo- and regiochemistry of [2 + 2] reactions
by placing two olefins in close proximity through molecular imprinting,[11a] supramolecular encapsulation,[11b] or other noncovalent interactions (e.g., hydrogen bonding).[11c,11d] While this approach has allowed the controlled dimerization of several
cinnamic derivatives that are otherwise unreactive, the scope is still
quite limited. Recently, impressive progress has been made using visible
light photoredox catalysis for highly efficient and stereoselective
dimerization of olefins, including reports of controlled heterodimerization
by Yoon and co-workers (Figure 3B).[12] Currently, these methods are limited to aryl
enone (e.g., 12) or an electron-rich styrene (e.g., 15) substrate for productive cyclization and only generate
head-to-head adducts. Nonphotochemical methods are also available
for the preparation of cyclobutanes. Direct ring-closing strategies
are entropically disfavored and are frequently low yielding, even
for simple substrates.[13] Ketenecycloaddition
is one of the most useful methods for cyclobutane synthesis, due to
the high levels of regio- and stereoselectivity frequently observed
and a variety of methods for ketene formation, though the product
always results in a cyclobutanone.[14]
Figure 3
Examples of
(A) solid-state photochemistry and (B) photoredox-catalyzed
[2 + 2] cycloadditions.
Examples of
(A) solid-state photochemistry and (B) photoredox-catalyzed
[2 + 2] cycloadditions.Cyclobutane natural products also have proven to be challenging
to properly elucidate using standard spectroscopic methods, particularly
NMR.[15] Numerous stereochemical and constitutional
errors have been made in the literature when attempting to determine
the structure of cyclobutane-containing natural products.[16] These misinterpretations likely derive from
the fluxional nature of the cyclobutane ring system that rapidly undergoes
ring flipping, resulting in unpredictable NMR chemical shifts that
have been described as “rather erratic”.[17] Proton–proton coupling constants, which
are routinely used as a diagnostic stereochemical tool in other cyclic
systems, are widely varied for cyclobutanes, with cis and trans vicinal coupling ranging 4.6–11.5
and 2.0–10.7 Hz, respectively.[17] In combination with the frequently observed long-range 4JH,H coupling across the ring, compounds
of mistaken identity are frequently proposed. From the viewpoint of
structural confirmation, a direct dimerization strategy would be at
a disadvantage, since the true structure would likely not be challenged
if the spectral and physical data matched those which were reported.
Reassignments are generally reliant upon X-ray crystallography,[9a,18] chemical synthesis,[19] and, more recently,
computational methods.[20] Since the majority
of cyclobutane-containing natural products have not been evaluated
by one of these means, it stands to reason that many of the structures
suggested in the literature are in fact incorrect.While many
terpene-derived cyclobutanes are produced through cationicpolyolefincyclization, the role of enzymes in the production of many
cyclobutane dimers is unclear.[21] The marine
natural products dictazole A (5), dictazole B (6), and sceptrin (19) are isolated from deep-sea
sponges where very little sunlight penetrates, making a purely photochemical
[2 + 2] pathway improbable. Furthermore, sceptrin (19) is isolated as an enantiopure molecule, almost certainly implying
enzymatic intervention.[22] A recent report
by Molinski demonstrated the production of benzosceptrin C from its
monomer, oroidin, using a “metabiosynthetic” approach
with cell-free enzyme extracts.[23] This
oxidative dimerization, proposed to occur through a series of single-electron-transfer
events, suggests that a similar enzymatic pathway is operative for
the conversion of hymenidin (18) to sceptrin (19) (Figure 4). Additional support for this
arises from the reluctance of hymenidin (18) and aplysinopsin
(21) to undergo photochemical [2 + 2] reactions.[22,24] The piperine cyclobutane natural products (23–25), on the other hand, are isolated from pepper plants and
are necessarily exposed to light. These molecules are isolated as
racemic mixtures and could be produced by unselective photochemical
[2 + 2] photocycloaddition reactions, as a variety of dimeric products
with differing stereochemical patterns have been isolated.[25] Curiously, the intermolecular [2 + 2] photocycloaddition
of these monomers is highly inefficient; therefore, additional templating
or intervention within the plant cell has been proposed.[26]
Figure 4
Biosynthetic relationships between various dimeric natural
products.
Biosynthetic relationships between various dimeric natural
products.[4 + 2] adducts, such as ageliferin
(20), dictazoline
C (22), and chabamide (25), are also isolated
alongside the cyclobutane dimers. Hymenidin (18) and
aplysinopsin (21) also do not engage in Diels–Alder
reactions when heated.[4a] Piperine (23) can undergo thermal dimerization to chabamide (25), but forcing conditions are required (>130 °C) and the
reaction
is unselective.[27] An alternate biosynthetic
hypothesis for formation of these [4 + 2] dimers has been proposed
by our group, in which a vinyl cyclobutane rearrangement (VCB) gives
the six-membered-ring natural products from the respective cyclobutane
dimers. Experimental support for this pathway has been provided by
the direct conversion of sceptrin (19) into ageliferin
(20) and the epimericnagelamide E in 50% and 28% yields,
respectively, after microwave irradiation in water at 200 °C.[28] Williams also suggested this as a possible pathway
for the biogenesis of dictazoline C (22) on the basis
of preliminary experiments with naturally isolated dictazole A (5).[4a]
Results and Discussion
C–H
Functionalization Approach to Cyclobutane Synthesis
Taking
into account the limitations of regio- and stereocontrol
of a direct dimerization strategy, an unconventional retrosynthesis
of unsymmetrical cyclobutane dimers was considered using C–H
functionalization logic as an alternative to intermolecular photocycloaddition.
Common among many of the cyclobutane natural products shown in Figure 1 is a carbonyl group attached directly to the cyclobutane
ring. This led us to consider a general cyclobutane strategy in which
the carbonyl is viewed as a latent directing group for C–H
functionalization. This would permit the direct installation of the
desired functionality in a facially controlled manner, guided by the
preexisting stereocenter. If two C–H functionalization reactions
could be employed sequentially, the syntheticchallenge of pseudosymmetry
and stereochemistry would be greatly simplified. While C–H
functionalization of cyclopropanes had received some attention at
the time,[29] examples of direct cyclobutane
functionalization were limited to a harsh magnesiation procedure described
by Eaton and co-workers.[30] Other examples
of cross-coupling to sp3 C–H bonds in the literature
were generally limited, but a seminal report by Daugulis and co-workers
in 2005 appeared promising (Figure 5A).[31] Employing an aminoquinoline directing group,
a wide variety of methylene C–H bonds could be arylated under
palladium (II/IV) catalysis. Furthermore, the only cyclic substrate
examined, cyclohexane 26, delivered the bis-arylated
product 27 in 61% yield as the all-syn isomer. To test the competence of four-membered rings in this methodology,
cyclobutane 28 was prepared and subjected to the reaction
conditions with iodobenzene. Encouragingly, this substrate outperformed
any of the examples described in the original report, giving the bis-phenylated
cyclobutane 29 in 97% isolated yield and as a single
diastereomer. Additionally, the palladium loading could be lowered
to 1 mol %, making this one of the most efficient sp3 C–H
functionalization reaction reported to date using a Pd (II/IV) manifold.
Figure 5
(A) Daugulis’ methylene C–H arylation. (B) Statistical
arylation of 28 with 1 equiv of iodobenzene.
Following this initial proof of concept, studies were directed
toward two potential problems: sequential cross-coupling reactions
and the scope of coupling partners. In order to access the unsymmetrical
cyclobutane targets in Figure 1, the C–H
functionalization reactions would need to be performed sequentially
in a controlled manner. To test the viability of a monofunctionalization,
the phenylation reaction was repeated with 1 equiv of iodobenzene
(Figure 5B). A statistical mixture (1:1.5:1)
of starting material 28, monoarylated cyclobutane 30, and bis-arylated cyclobutane 29 resulted,
implying that the rate of the second arylation is nearly identical
with that of the first arylation. While this was initially discouraging,
we were hopeful that the issue could be overcome through alteration
of the reaction conditions or substrate control on a more functionalized
system.(A) Daugulis’ methylene C–H arylation. (B) Statistical
arylation of 28 with 1 equiv of iodobenzene.To test the generality of the C–H cross-coupling
reaction,
other coupling partners were explored and the scope was found to be
broad (Scheme 1). Electron-rich arenes, such
as those found in the piperarborenine natural products (1 and 2), performed excellently to give 31 and 32 in 98% and 96% yield, respectively. Two N-tosylated indoles were introduced onto the cyclobutane
ring in 92% yield, encouraging potential access to the dictazole natural
products (5 and 6). Additionally, the C–H
olefination reaction needed for pipercyclobutanamide A (8) was successful in the Daugulischemistry, with iodostyrene giving 34 in 77% yield. Even the bis-dienoate 35 could
be prepared using this strategy, introducing a substructure found
in tripartilactam (4). Finally, alkynylation proved facile
according to Chatani’s protocol to give 36 in
83% yield,[32] which could serve as an alternate
entry to the dictazole natural products through a Larock indole synthesis.
With these preliminary results, efforts were directed toward the total
synthesis of the dictazole and piperarborenine families of natural
products.
Scheme 1
Coupling Partner Scope for Cyclobutane C–H
Functionalization
Reagents and conditions: (a)
5 mol % of Pd(OAc)2, 80 °C, 5 h.
Reagents and conditions: 10 mol %
of Pd(OAc)2, 80 °C, 12 h.
Reagents and conditions: 5 mol % of Pd(OAc)2, LiCl (3 equiv), 100 °C, 12 h.
Coupling Partner Scope for Cyclobutane C–H
Functionalization
Reagents and conditions: (a)
5 mol % of Pd(OAc)2, 80 °C, 5 h.Reagents and conditions: 10 mol %
of Pd(OAc)2, 80 °C, 12 h.Reagents and conditions: 5 mol % of Pd(OAc)2, LiCl (3 equiv), 100 °C, 12 h.
Studies
toward Dictazole A
The structure of dictazole
A (5) offers a number of difficulties for synthesis;
the most notable is the four contiguous stereocenters around the congested
cyclobutane core, two of which are quaternary spiroiminoimidazolidinone
rings.[4a] Furthermore, each of the substituents
is unique, as only one of the indoles is brominated and a single spiro
ring bears methyl groups. To add to this challenge, the spiro stereocenter
at C-3 could not be determined by standard spectroscopic means and
its relative configuration is unknown. Applying the cyclobutane C–H
functionalization strategy, a retrosynthesis of dictazole A (5) was devised (Figure 6). The spiroiminoimidazolidinone
rings were first deconstructed; one could arise through Strecker type
chemistry (further disconnected to a protected alcohol) and another
from an aminoquinoline amide, leading back to intermediate 37. Two sequential C–H arylation reactions with appropriate
3-iodoindoles would remove two of the stereocenters and lead back
to symmetrical cyclobutane 38. Notably, the bromide present
on one of the indoles in dictazole A (5) should be tolerated
in the arylation chemistry, since it proceeds through a palladium
(II/IV) catalyticcycle.[33] Finally, the
quaternary amino-amide stereocenter at C-1 could arise from an Ugi
four-component coupling of cyclobutanone 40, 8-isocyanoquinoline 39, methylamine, and a suitable carboxylic acid.[34]
Figure 6
Retrosynthesis of dictazole A (5) employing
C–H
arylation and an Ugi reaction.
Retrosynthesis of dictazole A (5) employing
C–H
arylation and an Ugi reaction.To test the viability of this approach, (benzyloxy)cyclobutanone 42 was prepared by thermal [2 + 2] cycloaddition of benzyl
vinyl ether (41) and in situ formed dichloroketene following
Poisson’s one-pot procedure[35] in
50% yield (Scheme 2). Unfortunately, it was
wholly ineffective in the Ugi reaction under a variety of reaction
conditions explored, despite ample precedent for the use of cyclobutanones
in Ugi reactions.[36] Interestingly, the
side reactions were determined to be direct addition reactions of
isonitrile 39 with the carboxylic acid or an alcoholic
solvent to give dearomatized benzimidazoles (45). While
the pivalic acid adduct 45ccould be observed by crude 1HNMR, it was not isolable and hydrolyzed to 45a, which was characterized by X-ray crystallography. These bizarre
addition reactions can be rationalized by considering the cyclized
zwitterionic isomer 44, wherein a deprotonation/addition
mechanism would generate the observed products.
Scheme 2
Attempted Ugi Reaction
and Abnormal Reactivity of Isonitrile 39
During the exploration of an Ugi strategy, a model study
was also
under investigation to examine the effect of quaternary α-amino
substituents in the DaugulisC–H arylation reaction.[37] A series of substrates were synthesized from
commercially available ethyl 1-amino-1-cyclobutanecarboxylate (see
the Experimental Section for preparations).
Surprisingly, these proved to have highly deleterious effects on the
C–H arylation chemistry. Azide 46a and Cbz-protected
amine 46b gave no detectable arylated products on reaction
with iodoindole 47, simply decomposing or remaining unreactive
after prolonged heating, respectively (Table 1). Phthalimide-derived 46c required heating to 130 °C
to initiate the reaction and was accompanied by nonspecific decomposition,
yielding only 14% of bis-indolated 48c with full consumption
of the starting material. This lowered reactivity was attributed to
the coordinating nature of the nitrogen substituents, generating an
unreactive chelate with the directing group and preventing cyclometalation.[38] Ester-derived cyclobutane 46d was
examined next, since it is less coordinating and could be converted
to the requisite amine through a Curtius rearrangement. While this
substrate was also significantly less reactive than the parent cyclobutane 28, it performed the arylation chemistry at much lower temperature
(90 °C) than phthalimide46c and the mass balance
was largely unreacted starting material. Therefore, a 1,1-cyclobutanedicarboxylate
derivative was targeted for the second-generation approach to dictazole
A (5).
Table 1
Surprising Effects
of α Substituents
on C–H Arylation Chemistry
entry
R
temp (°C)
% yield (%)
1
N3 (46a)
130
decomp
2
NHCbz (46b)
140
NR
3
NPhth (46c)
130
14 (48c)a
4
CO2Me (46d)
90
21 (48d)b
Starting material
fully consumed.
62% starting
material recovered.
Starting material
fully consumed.62% starting
material recovered.A diastereoselective
synthesis of the C–H activation precursor
began following a report from Merck for the preparation of cyclobutanehydroxy acids that is scalable and employs inexpensive starting materials.[39] In this reaction, the dianion of 4-methoxyphenylacetic
acid (49) was treated with epichlorohydrin in a double-alkylation
reaction to deliver hydroxy acid 50 as a single diastereomer
(Scheme 3). The observed relative stereochemistry
can be rationalized by invoking a magnesiumchelate that templates
the final ring-closing alkylation. Fischer esterification and alcohol
protection with TBSCl generated cyclobutane 51 in 55%
yield over the three steps. The electron-rich methoxyarene was selected
in anticipation of the ruthenium tetroxidecatalyzed arene degradation,
which gave acid 52 in 70% yield. Notably, performing
the reaction in the absence of acetonitrile and at dilute concentrations
were necessary to avoid overoxidation of the TBS alcohol to the corresponding
cyclobutanone.
Scheme 3
Diastereoselective Synthesis of 52
With the key cyclobutane substrate 52 prepared, studies
on the C–H functionalization chemistry commenced. Two directing
groups developed by Daugulis and co-workers, 8-aminoquinoline (53a) and o-thioanisidine (53b), were tested in the arylation reaction and were coupled to the
carboxylic acid with EDC to give 54a and 54b in 75% and 84% yields, respectively (Scheme 4).[33] Similar to the case for 46d, aminoquinoline 54a was found to be poorly suited for
the direct arylation chemistry, delivering bis-indolated cyclobutane 55a in 21% yield (unoptimized) with primarily starting material
remaining. The thioanisidine 54b, on the other hand,
performed better. Under the same reaction conditions, the starting
material was fully consumed to give 55b in 51% yield.
This was especially peculiar, because the thioanisidine-derived directing
group was reported to generally be less reactive toward methylene
C–H bonds in comparison to the aminoquinoline directing group.[33] This observation, combined with the significant
effect of α substitution, highlights the subtle geometric factors
at play in the C–H functionalization chemistry.
Scheme 4
Successful
C–H Arylation Reaction, but Unsuccessful Directing
Group Deprotection
Temporarily bypassing the problem of sequential arylation
of the
two different indoles, attention was directed at removal of the directing
groups for the construction of the guanidine-containing spirocycle.
Removal of the directing group proved to be very challenging, since
the inherently strong amide bond is quite sterically hindered after
introduction of the indoles. Many conditions explored for amide deprotection
met with failure,[40] and even hydrolysis
of the ester in 55a for a Curtius rearrangement resulted
in primarily decarboxylation of the generated acid. The difficulty
in removal of the amide-based directing groups is consistent with
previous studies by Chen and co-workers, in which considerable functional
group manipulation was required to cleave the aminoquinoline auxiliary.[38]Recognizing the need for a new directing
group that could be more
easily deprotected, we considered an imide-based strategy. Since picolinamide
was reported to be a competent directing group by Daugulis in his
2005 communication, a picolinimide-based directing
group seemed logical.[31] Imides in general
are much more susceptible to hydrolysis than amides, and this would
give a second, less hindered carbonyl group for reaction and removal.
To test this hypothesis, picolinimide 57 was prepared
via the pentafluorophenyl ester according to the Andrus protocol in
79% yield over two steps (Scheme 5).[41] Gratifyingly, this directing group was found
to be competent in the C–H arylation chemistry, giving the
bis-indolated imide 58 along with the corresponding palladiumcomplex Pd(58)2 (confirmed by X-ray crystallography).
As anticipated, the imide motif was found to be much more easily cleaved
than then traditional amide-based systems. Treating the mixture of 58 and Pd(58)2 with a DCM/2-propanol
solution saturated with ammonia in the presence of catalytic scandium
triflate generated the primary amide 59 in 53% yield
from 57. While it was possible to separate 58 from its palladiumcomplex, it was more convenient to subject both
to the ammonolysis, as they converge to the same product. The acetate
derivative of 60 was prepared in an analogous fashion
(see the Experimental Section for details)
but strangely proved unsuccessful in the C–H arylation chemistry
under the same reaction conditions. It is possible that the inductive
effect of the acetate influences the efficiency of the reaction or
the larger TBS ether locks the ring into a more favorable geometry
for C–H insertion and cross-coupling.
Scheme 5
Successful Deprotection
of the Picolinimide Directing Group
With the successful deprotection of the picolinimide directing
group, the synthesis of the C-1 spirocycle using a Curtius strategy
was investigated. Since this ring required regioselective methylation,
attempts were made to prepare substrates that would allow for selective
alkylation, through either a hydantoin or an appropriately protected
spiroguanidine. Hydantoin 63 was the expected product
from a Curtius rearrangement of 59, since the primary
amidecould intramolecularly collapse onto the intermediate isocyanate
(Scheme 6). Unexpectedly, hydantoin 63 was isolated as the minor product (23% yield) and aminonitrile 62 was isolated as the major product (69% yield) when the
carboxylic acid was treated with excess diphenylphosphoryl azide (DPPA).
This suggests that the hindered primary amide dehydrates competitively
with the rearrangement of the intermediate acyl azide under the reaction
conditions. Interested in moving forward, we alkylated hydantoin 63 with methyl iodide to give 64 in 80% yield,
but conversion of the carbonyl to the imino group of 65 through activation with Meerwein’s salt or Lawesson’s
reagent met with failure.
Scheme 6
Unexpected Curtius Rearrangement Product
Reconsidering the strategy,
we turned our attention to the major
product of the Curtius reaction, aminonitrile 62, as
an intermediate to carry forward. An aza variant of the Bucherer–Bergs
hydantoin synthesis was envisioned in which an isocyanate would replace
carbon dioxide to directly generate the desired heterocycle. In this
reaction, 62 was treated with tosyl isocyanate and heated
in ethanol to produce the undesired spirocycle 66. The
true identity of the product was initially uncertain because of the
ambiguous spectroscopic and mass spectrometry (MS) data (Scheme 7). Spirocycle 66 could be dimethylated
with methyl iodide to give 67, which also appeared to
be in agreement with the desired ring system (e.g., 65). During this time, however, crystals were obtained of 66, and the aza-Bucherer–Bergs reaction was demonstrated to
be unsuccessful through X-ray crystallographic analysis. Instead of
the desired oxygenclosure, the nitrogen of urea 72 cyclized
onto the nitrile to give intermediate 73, which underwent
additional sulfonyl migration to produce the observed product 66.
Scheme 7
Failure of Aza-Bucherer–Bergs Reaction and
Unexpected Dehydration
of 71
Still interested in utilizing aminonitrile 62, we
were successful in hydrating amide 69 using Parkin’s
platinumcatalyst (68), tolerating the free primary amine
(Scheme 7).[42] Unfortunately,
this amine was reluctant to react with a number of electrophiles for
spirocycle synthesis (isothioureas, cyanogen bromide, bis(methylthio)methylenesulfonamides,
etc.) even when combined with a range of bases and salt additives
(Ag+, Hg2+, etc.). Recalling the facile reaction
of 62 with tosyl isocyanate, amide 69 was
also found to react to give urea 71. Dehydration of this
urea was expected to generate a carbodiimide that would cyclize to
the desired product (70), but treatment with Burgess
reagent gave 66 as the exclusive product in 67% yield
for the two steps. Again, the hindered primary amide was surprisingly
susceptible to dehydration, leading to intermediate 72.Given the unforeseen difficulty in constructing the requisite
spirocycles,
efforts at this time were directed to a separate set of pseudodimericcyclobutane natural products, the piperarborenines, whose synthesis
was being explored concurrently. Despite the initial challenges in
the synthesis of dictazole A (5), further efforts are
aimed at construction of the spirocycles at an earlier stage in the
synthesis and application of knowledge gained during the piperarborenine
projects for sequential introduction of the differentiated indole
substituents.
Synthesis and Revision of the Piperarborenines
and Pipercyclobutanamide
A
Contemporaneous with the dictazole studies, efforts were
also being directed toward the synthesis of stereoisomericpiperarborenines
B (1) and D (2). The central challenge associated
with the piperarborenine natural products is the controlled, sequential
installation of the two different aryl rings on the cyclobutane core.
Piperarborenine B (1) has a cis,trans,cis relative configuration with the
two aryl substituents on opposite sides of the cyclobutane ring, whereas
the arenes are on the same face of the cyclobutane in the trans,trans,trans piperarborenine D (2) (Figure 7).[3] Continuing with our
general C–H functionalization strategy, we viewed the dihydropyridone
motif as a latent directing group for C–H arylation and devised
a divergent strategy from the all-cis cyclobutane 74. From this intermediate, piperarborenine B (1)could be prepared by an epimerization at C-1, directed C–H
arylation, and further functional group manipulations to install the
imide side chains. Alternatively, piperarborenine D (2)could be accessed by performing a C–H arylation directly
on 74, followed by epimerization of both C-1 and C-3
stereocenters. The divergent intermediate 74 was envisioned
arising from a desymmetrizing monoarylation reaction of a cyclobutanedicarboxylate
derived from 75. While the 1,3-cyclobutanedicarboxylate 75 appears to be quite simple, the shortest synthesis reported
in the literature was eight steps in 20% overall yield starting from
pentaerythritol (76).[43] Viewing
this route unsuitable for our needs, we envisioned a new synthesis
of 1,3-cyclobutanedicarboxylates starting from methyl coumalate (78).
Figure 7
Retrosynthesis of the piperarborenines from methyl coumalate
(78).
Retrosynthesis of the piperarborenines from methyl coumalate
(78).Inspired by Corey’s
seminal work on pyrone photochemistry
and more recent studies by Maulide and co-workers, we selected methyl
coumalate (78) as a potential starting material to solve
the 1,3-cyclobutanedicarboxylate problem.[44] Upon irradiation with ultraviolet light, methyl coumalate (78) was reported to undergo a successful photochemical 4π
electrocyclization reaction to generate photopyrone 77.[45] This intermediate was attractive,
since only two reductions would be needed to arrive at the desired
cyclobutane monocarboxylic acid 75. In practice, it was
found that the intermediate photopyrone 77 is quite reactive,
rapidly decomposing when treated with acid/base and thermally reverting
back to the parent coumalate along with nonspecific decomposition.
Consistent with earlier reports by Corey, hydrogenation of photopyrone 77 with palladium on carbon resulted in varying mixtures of
β-lactone 79 and the desired acid 75 (Scheme 8).[44a] Resubjection of β-lactone 79 to the reaction
conditions did not result in further reduction, implying that the
C–O bond must be reduced first to produce 75.
Gratifyingly, switching the heterogeneous catalyst to platinum on
carbonconsistently gave the monoacid 75 as the sole
product and diastereomer observed by 1HNMR. Furthermore,
both the 4π electrocyclization and the hydrogenation reactions
could be performed with DCM as the solvent, allowing the sequence
to be further telescoped to an EDCcoupling with o-thioanisidine (53b), giving 80 in 61%
yield in a single operation from methyl coumalate (78).
Scheme 8
New Synthesis of 1,3-Cyclobutanedicarboxylates
With the cyclobutanedicarboxylate problem resolved,
studies commenced
toward the development of a desymmetrizing C–H monoarylation
reaction of cyclobutane 80 with 3,4,5-trimethoxyiodobenzene
(81). Preliminary results were promising, with the conditions
originally reported by Daugulis and co-workers (6 equiv of ArI, no
solvent, 110 °C) giving the desired monoarylated cyclobutane 82 in 30% isolated yield (Table 2,
entry 1). Since the carboxylate ligands on the palladium are proposed
to be directly involved in the C–H cleavage event, it was reasoned
that a bulkier carboxylatecould hinder the second cyclometalation
event and the production of doubly arylated 83. Indeed,
pivalic acid in combination with tert-butyl alcohol
as a solvent proved to be effective (entry 2), though the overall
conversion of the reaction was also lowered.[46] Further screening of solvents revealed that trifluoroethanol (TFE)
improved the reaction, permitting the temperature and catalyst loading
to be lowered slightly, but more of the overarylation byproduct 83 was produced (entry 3). Switching the solvent to hexafluoro-2-propanol
(HFIP) maintained the accelerating effects of TFE but almost fully
suppressed the second arylation, possibly due to the increased steric
bulk. With these optimized conditions, monoarylated cyclobutane 82 was obtained in 65% isolated yield, though the conversion
dropped slightly when the reaction was scaled up, leading to a 52%
yield on a gram scale. Additionally, the beneficial effects of fluorinated
alcoholic solvents on C–H activation reactions has been reported
in other palladium-catalyzed systems since the disclosure of this
work.[47]
In order to access piperarborenine B (1), a selective
inversion of the directing group stereocenter at C-1 was needed, followed
by a second C–H arylation reaction. While the epimerization
of the amide is energetically favorable to create a trans relationship to the aryl ring, the issue is complicated by the presence
of the also epimerizable ester moiety at C-3. Since inversion of both
of the stereocenters is the most thermodynamically favorable result,
initial experiments were stopped at incomplete conversion of the starting
material to observe the selectivity of the initial epimerization.
Upon screening various bases, C-3 epimer 85 and double
epimer 86 were observed, along with an unexpected transannular
cyclization to form imide 87 (Table 3). Sodium methoxide in MeOH/THF showed very little selectivity,
resulting in roughly equal quantities of 84 and 85 (entry 1). The hindered amine base DBU showed some selectivity
for C-1 epimerization (3/1), though more forceful reaction conditions
were required. Interestingly, a counterion effect was observed with
hindered alkoxide bases (entries 3 and 4). Potassium tert-butoxide slightly favored ester epimer 85, while lithium tert-butoxide favored C-1 epimer 84. Extending
the reaction time of entry 3 to 24 h resulted in nearly full conversion
to 86, as anticipated. Encouraged by the lithium tert-butoxide result, the solvent was changed to toluene
(entry 5). This slowed the reaction rate (15% conversion in 24 h)
but only the desired 84 was detectable in the crude 1HNMR, in addition to starting material. Further optimization
of temperature, concentration, and reaction time resulted in entry
6, which minimized undesired side reactions while maintaining high
conversion of starting material to give 84 in 79% yield.
The origins of selectivity in this system are uncertain and are currently
under investigation.
Table 3
Selective C-1 Epimerization
of 82
entry
conditions
conversion (%)
84:85:86:87
1
1 equiv NaOMe, MeOH/THF, room temp, 16 h
55
1:1:0:0
2
3 equiv DBU, THF, 80 °C, 24 h
66
5.4:1:0.7:0
3
1 equiv t-BuOK,
THF, room temp, 3 h
72
2:3:0.1:0.1
4
1 equiv t-BuOLi, THF, room temp, 3 h
47
3.3:1:0:0.5
5
1 equiv t-BuOLi, PhMe, room temp, 24 h
15
1:0:0:0
6
1 equiv t-BuOLi,
PhMe (0.3 M), 50 °C, 36 h
95
20:1:1:2
Completion of the piperarborenine B (1) synthesis
is shown in Scheme 9A. A second, directed C–H
arylation reaction with 3,4-dimethoxyiodobenzene (88)
provided 89 in 46% yield. The reaction conditions developed
for C–H monoarylation of 80 proved ineffective
for this reaction, but performing the reaction in tert-butyl alcohol at high reaction concentrations (1 M) gave acceptable
results. Attempts to further conversion of the reaction by raising
the temperature to 110 °C resulted in the production of tris-
and tetraarylated cyclobutanes (tentatively assigned by 1HNMR and LC-MS) in small quantities, along with significant decomposition.
With the second C–H arylation secured, all that remained to
complete piperarborenine B (1) was the conversion of
the directing group and ester moieties to dihydropyridoneimides.
This could also prove problematic, since methods for direct amide
bond cleavage are generally very harsh, requiring strong acid or base
and heat. This is further complicated by the stereochemical lability
of the ester and amide functionalities. While 1,2-trans relationships in cyclobutanes are energetically favored over cis relationships, the 1,3-cis and trans orientations are nearly thermoneutral
(0.1 kcal/mol difference for dimethyl 1,3-cyclobutanedicarboxylate).[43a] Kibayashi and co-workers observed this problem
during the synthesis of the natural product dipiperamide A, wherein
hydrolysis of 93 with barium hydroxide resulted in equal
amounts of the two inseparable epimers 94 and 95 (Scheme 9B).[9a] Fortunately, the two-step deprotection strategy developed by Grieco
and Evans allowed for retention of the carefully constructed stereotetrad.[40,48] In this reaction, DMAP-catalyzed carbamoylation with Boc anhydride
generated 90 in 90% yield, with X-ray crystallographic
analysis confirming the presumed stereochemistry. Warming 90 in the presence of lithium hydroperoxide resulted in the hydrolysis
of both the amide directing group and the methyl ester in 83% yield.
Bis-acid 91 was converted to the corresponding bis-acidchloride and heated with dihydropyridone 92 to give piperarborenine
B (1) in 77% isolated yield, which matched the spectral
and experimental data reported in the isolation paper. The use of
4 Å molecular sieves as an acid scavenger was uniquely effective
for this reaction, with traditional bases resulting in low yields
and significant formation of byproducts (possibly resulting from epimerization
and ketene generation).[49]
Scheme 9
Completion
of Piperarborenine B (1)
Initial attempts to synthesize piperarborenine D (2) focused on the resubjection of 82 to the C–H
arylation reaction conditions (Scheme 10A).
Unfortunately, this consistently resulted in low yields (<20%)
and significant decomposition. The presence of the methyl ester substituent
on the same face as the directing group and aryl ring, which was critical
for monoarylation, presumably hindered the second reaction. Taking
this into consideration, we hypothesized that epimerization of the
ester stereocenter (C-3) would alleviate this issue. Previous epimerization
studies (vide supra) suggested that thermodynamically controlled conditions
would not deliver epimer 85 selectively; therefore, an
alternative approach was devised. Treating 82 with 2.2
equiv of KHMDS and quenching the resulting dianion with ammonium chloride,
delivered C-3 epimer 85 in 65–80% yield as the
only observable product. The rationalization of this selectivity is
shown in Scheme 10B. Initial amideN–H
deprotonation allows for exclusive formation of ester enolate 98 as a result of charge separation. When this dianion was
quenched with ammonium chloride, the C-3 epimer was produced as a
single diastereomer. The somewhat low and ranging yield of this transformation
results from the rapid decomposition of intermediate dianion 98, along with a sluggish second deprotonation at reduced
temperatures. In agreement with the proposed blocking role of the
methyl ester, C-3 epimer 85 readily underwent the desired
C–H arylation reaction. Notably, the combination of HFIP and
pivalic acid again proved superior to all other reaction conditions
examined and delivered the bis-arylated 99 in 81% yield
(Scheme 11). Refluxing 99 in an
ethanolic solution of sodium hydroxide effected epimerization at C-1,
hydrolysis of the amide directing group, and hydrolysis of the methyl
ester to produce the bis-acid in 86% yield. Conversion to the bis-acidchloride and heating according to the piperarborenine B protocol gave
piperarborenine D (2), which did not match the spectroscopic data from the original isolation report.[3b] Examination of the isolation data revealed a
number of inconsistencies—particularly the number of unique
peaks in the 13CNMR for a compound containing a σv plane of symmetry. Further analysis led to the consideration
of a head-to-head type dimer (100) for piperarborenine
D that was more consistent with the data provided, and this structure
was confirmed through synthesis using an intramolecular photocycloaddition
strategy.[50]
Scheme 10
Controlled C-3 Epimerization
of 82
Scheme 11
Structural Revision of Piperarborenine D (100)
Synthesis of the Proposed
Structure of Pipercyclobutanamide
A
After the successful synthesis of the piperarborenine natural
products, we were interested in extending our general C–H functionalization
strategy to more complex members of the family, and pipercyclobutanamide
A (8) was selected to further explore the cyclobutaneC–H olefination chemistry.[4c] Additionally,
if this C–H functionalization strategy could be coupled to
a vinylcyclobutane rearrangement, access to unsymmetrical [4 + 2]
adducts in the natural product family could also be possible.[27] The general synthetic strategy is analogous
to the approach used for the piperarborenines, involving controlled,
sequential C–H functionalizations and epimerizations.The appropriate C–H functionalization precursor (101) was prepared using the methodology developed in the piperarborenine
syntheses.[50] Methyl coumalate (78) was reacted in a telescoped sequence involving photochemical electrocyclization,
hydrogenation, and EDCcoupling to 8-aminoquinoline (53a)[5] to give 101 in 54% yield
(Scheme 12). A mono-olefination reaction was
initially examined with iodostyrene 102 as the coupling
partner, but the reaction surprisingly gave the tetrasubstituted all-cis cyclobutane 103 in 50% yield. X-ray crystallographic
analysis confirmed that no epimerizations took place during the course
of the reaction and the highly strained cyclobutane was successfully
obtained. This is in direct contrast to the arylation chemistry, in
which only small quantities of 96 could be produced.
Taking this result into consideration, we reversed the order of synthetic
operations with a C–H monoarylation reaction performed first,
followed by the olefination. While the HFIP solvent that was critical
in the monoarylation of 80 was ineffective due to the
intolerance of methylenedioxy aryl iodide 104, the pivalic
acid additive still proved beneficial and delivered 105 in 54% yield. Recalling the facile formation of all-cis-cyclobutane 103, we directly olefinated monoarylated 105 with iodostyrene 106 to give the tetrasubstituted
cyclobutane 107 in 59% yield, without needing to epimerize
the C-3 ester stereocenter.
Scheme 12
Sequential Cyclobutane C–H
Arylation and Olefination
From cyclobutane 107, two epimerization events
were
needed to obtain the relative stereochemistry found in pipercyclobutanamide
A (8). This transformation was expected to occur easily,
due to the thermodynamically favorable release of strain leading to
the all-trans isomer, as well as previous experience
during the synthesis of the proposed structure of piperarborenine
D (2) (vide supra). Addition of sodium methoxide to a
THF solution of 107 at room temperature rapidly epimerized
the C-1 stereocenter, and warming the reaction mixture to 45 °C
inverted the C-3 methyl ester stereocenter (Scheme 13). An aqueous solution of sodium hydroxide was added at the
end of the reaction to give acid 108. Treatment of the
crude carboxylic acid with excess DIBAL transformed the aminoquinoline
directing group into an aldehyde, providing the proper oxidation state
required for pipercyclobutanamide A (8). The free carboxylic
acid was intentionally used in the reaction to preserve this oxidation
state, with the initially generated aluminum carboxylate protecting
the functional group from further reduction. Reductions of secondary
amides to aldehydes with DIBAL have scarcely been reported, and the
success of this case is due to the chelating aminoquinoline amide
and the pendant carboxylate.[51] This is
supported by the complete failure of the reaction when more coordinating
solvents, such as THF, were employed. The structure of pipercyclobutanamide
A (8) was completed by peptide coupling of aldehyde 109 with piperidine (40–45% overall yield from 107) and olefination following Ando’s protocol for cis-selective unsaturated amide synthesis in 80% isolated
yield.[52] Unfortunately, the 1H and 13CNMR data of 8 did not match the
data reported for the natural product.[4c,53] Contemporaneous
with our work, the Tang group also synthesized the proposed structure
of pipercyclobutanamide A (8) and discovered that the
data reported by the isolation chemists were identical with those
of the [4 + 2] adduct chabamide (25), thereby revising
its structure (Scheme 13).[19c]
Scheme 13
Synthesis of the Proposed Structure of Pipercyclobutanamide
A (8)
While the proposed structure of pipercyclobutanamide A
(8) proved to be incorrect, we were still interested
in the possibility
of vinylcyclobutane rearrangements to test the biogenetic hypothesis
and give stereocontrolled access to the unsymmetrical cyclohexene
derived natural products. To test this possibility, the symmetrical
bis-olefinated cyclobutane 34 was suspended in water
and heated to 200 °C for 5 min in a microwave reactor, the conditions
developed for the conversion of sceptrin (19) to ageliferin
(20) (Scheme 14). While the starting
material cleanly transformed into a new compound, it was identified
as epimer 112. This result was further confirmed by treatment
of 34 with potassium tert-butoxide to
give the same compound. Curious if the electron-rich styrenes present
in the piperine family would be more amenable to vinylcyclobutane
rearrangement, we also subjected the proposed structure of pipercyclobutanamide
A (8) to the microwave conditions. In this case, only
starting material was recovered and even the cis-olefin
stereochemistry remained intact. Both of these compounds also failed
to give any of the desired cyclohexene isomers when reacted with the
radical cation salttris(p-bromophenyl)aminium hexachloroantimonate.[54]
Scheme 14
Attempted Vinylcyclobutane Rearrangements
Conclusion
In
conclusion, the use of C–H functionalization logic to
tackle unaddressed problems in organicchemistry has provided an expedient
and broadly applicable solution to the construction of stereochemically
complex cyclobutanes.[55] In addition to
the successful synthesis and structural revision of the piperarborenine
natural products (1, 2, 8),
a number of general discoveries were also made en route. During the
investigations toward the dictazoles (5, 6), a scalable, diastereocontrolled synthesis of 1,1-cyclobutanedicarboxylates
was devised, the surprising reactivity of 8-isocyanoquinoines was
unveiled, and a new, easily removable picolinimide directing group
for the C–H functionalization chemistry was invented. The piperarborenines
(1, 2, 8) led to the development
of a new, one-step route to cis-1,3-cyclobutanedicarboxylates,
divergent access to multiple cyclobutane stereoisomers through controlled
epimerization reactions, and a reductive conversion of the 8-aminoquinolineamide directing group to an aldehyde under mild conditions. With this
case study as additional support for the utility of C–H disconnections
in synthesis, innumerable possibilities exist for creative scientists
to imagine how the historically inert C–H bonds can be used
as latent functional groups in synthesis planning, inevitably leading
to the generation of new, useful methodologies and discoveries.
Experimental Section
General Methods
All reactions were carried out under
an argon atmosphere with dry solvents using anhydrous conditions unless
otherwise stated. Dry diethyl ether (Et2O), dichloromethane
(CH2Cl2), acetonitrile (CH3CN), toluene
(PhMe), N,N-dimethylformamide (DMF),
tetrahydrofuran (THF), methanol (MeOH), and triethylamine (Et3N) were obtained by passing these previously degassed solvents
through activated aluminacolumns. Reagents were purchased at the
highest commercial quality and used without further purification,
unless otherwise stated. Yields refer to chromatographically and spectroscopically
(1HNMR) homogeneous materials. Reactions were monitored
by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck
silica gel plates (60F-254) using UV light as the visualizing agent,
as well as one of the following mixtures as a developing agent followed
by heating of the TLC plate: anisaldehyde, phosphomolybdic acid, ceric
ammonium molybdate, or potassium permanganate. E. Merck silica gel
(60, particle size 0.043–0.063 mm) was used for flash column
chromatography. Preparative thin-layer chromatography (PTLC) separations
were carried out on 0.25 or 0.5 mm E. Merck silica gel plates (60F-254).
NMR spectra were recorded on 600, 500, and 400 MHz instruments and
calibrated using residual undeuterated solvent as an internal reference
(CHCl3 at 7.26 ppm for 1HNMR and 77.16 ppm
for 13CNMR). The following abbreviations (or combinations
thereof) are used to explain the multiplicities: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; b, broad. High-resolution mass
spectra (HRMS) were recorded on an LC/MSD TOF time-of-flight mass
spectrometer by electrospray ionization time-of-flight reflectron
experiments. IR spectra were recorded on a FTIR spectrometer. Melting
points were recorded on a melting point apparatus and are uncorrected.
N-(Quinolin-8-yl)cyclobutanecarboxamide (28)
Cyclobutanecarbonyl chloride (2.47 g, 20.8 mmol,
1 equiv) in DCM (50 mL) was added dropwise to a vigorously stirred
biphasic solution of 8-aminoquinoline (3.00 g, 20.8 mmol) in DCM/saturated
aqueous sodium bicarbonate (50 mL/100 mL) at room temperature. The
reaction mixture was stirred for 3 h, and the layers were separated,
extracted with DCM (2 × 50 mL), washed with brine, and dried
over sodium sulfate. After filtration and concentration, the product
was filtered through a silica plug (3% Et2O in DCM) to
give 28 (4.58 g, 97%) as a colorless oil that slowly
crystallizes upon standing: white crystalline solid (53–54
°C): Rf = 0.45 (silica gel, 3/1 hexanes/EtOAc);
HRMS (m/z) calcd for C14H14N2O ([M + H]+) 227.1184, found
227.1188; IR (film) νmax 3351, 2942, 1680, 1521,
1484, 1323, 790 cm–1; 1HNMR (500 MHz,
CDCl3) δ 9.73 (br s, 1 H), 8.80 (dd, J = 7.6, 1.4 Hz, 1 H), 8.75 (dd, J = 4.2, 1.7 Hz,
1 H), 8.09 (dd, J = 8.3, 1.7 Hz, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.43 (dd, J = 8.3, 1.4
Hz, 1 H), 7.38 (dd, J = 8.2, 4.2 Hz, 1 H), 3.37 (p, J = 8.5 Hz, 1 H), 2.54–2.41 (m, 2 H), 2.35–2.19
(m, 2 H), 2.09–1.99 (m, 1 H), 1.99–1.89 (m, 1 H); 13CNMR (CDCl3, 126 MHz) δ 173.7, 148.1, 138.4,
136.3, 134.6, 127.9, 127.4, 121.5, 121.3, 116.3, 41.4, 25.5, 18.2.
28 (200 mg, 0.884 mmol), Pd(OAc)2 (10.0 mg, 0.045 mmol, 0.05 equiv), silver acetate (443 mg,
2.65 mmol, 3 equiv), lithium chloride (112 mg, 2.64 mmol, 3 equiv),
and TIPS-bromoacetylene[32] (693 mg, 2.65
mmol, 3 equiv) were placed in a sealed tube, and toluene (1.76 mL)
was added under ambient conditions. The tube was flushed with argon,
sealed, and placed in a 100 °Coil bath for 12 h. The reaction
mixture was cooled to room temperature, diluted with DCM (3 mL), filtered
through a pad of Celite, and concentrated. The resulting orange oil
was purified by silica gelchromatography (2.5–7% Et2O in hexanes) to give 36 (430 mg, 83%) as a light yellow
oil that crystallized upon standing: light yellow crystalline solid
(61–63 °C); Rf = 0.7 (silica
gel, 3/1 hexanes/EtOAc); HRMS (m/z) calcd for C36H54N2OSi2 ([M + H]+) 587.3853, found 587.3857; IR (film) νmax br 3355, 2942, 2864, 2159, 1698, 1524, 882, 675 cm–1; 1HNMR (400 MHz, CDCl3) δ
10.01 (s, 1 H), 8.90 (dd, J = 7.5, 1.6 Hz, 1 H),
8.77 (dd, J = 4.2, 1.7 Hz, 1 H), 8.13 (dd, J = 8.3, 1.7 Hz, 1 H), 7.53–7.44 (m, 2 H), 7.41 (dd, J = 8.2, 4.2 Hz, 1 H), 3.68 (td, J = 8.5,
3.5 Hz, 1 H), 3.41 (dt, J = 11.1, 8.4 Hz, 2 H), 3.06
(q, J = 11.0 Hz, 1 H), 2.70 (dtd, J = 10.5, 8.4, 3.0 Hz, 1 H), 0.85–0.75 (m, 42 H); 13CNMR (CDCl3, 101 MHz) δ 167.5, 148.0, 138.8, 136.2,
135.0, 127.8, 127.5, 121.3, 121.1, 117.1, 106.7, 84.0, 52.8, 36.2,
26.6, 18.5, 11.2.
3-(Benzyloxy)cyclobutan-1-one (42)
To
benzyl vinyl ether (2.50 g. 18.6 mmol, 1 equiv) in dry diethyl ether
(300 mL) at room temperature was added Zn–Cu (18.27 g, 279
mmol, 15 equiv), followed by trichloroacetyl chloride (5.30 mL, 46.5
mmol, 2.5 equiv) dropwise over 3 h. A saturated solution of ammonium
chloride in methanol (250 mL) was added, and the mixture was refluxed
for 30 min. The crude product was filtered through Celite and concentrated.
The crude reaction product was partitioned between diethyl ether (200
mL) and water (200 mL), the layers were separated, and the aqueous
layer was extracted with diethyl ether (2 × 75 mL). The combined
organics were washed with brine (150 mL) and dried over Na2SO4. After filtration and concentration, the crude product
was purified by column chromatography (10% Et2O in hexanes)
to give 42 (1.65 g, 50%) as a colorless oil with spectroscopic
data that matched those previously reported.[58]
8-Isocyanoquinoline (39)
Triethylamine
(1.0 mL, 7.17 mmol, 2.5 equiv) was added to a solution of 8-formamidoquinoline
(500 mg, 2.9 mmol) in DCM (4 mL) at room temperature in a two-neck
flask equipped with a reflux condenser. A toluene solution of phosgene
(1.9 M, 1.83 mL, 3.48 mmol, 1.2 equiv) was added dropwise, and the
exothermic reaction was allowed to reflux gently. After the mixture
was cooled to room temperature, ammonia gas was bubbled through the
solution to quench any unreacted phosgene and then the mixture was
purged with nitrogen. The black reaction mixture was diluted with
DCM (4 mL) and filtered through Celite. The black filtrate was concentrated,
and Et2O (4 mL) was added. The soluble portion was filtered
through Celite again, washing with Et2O (3 × 3 mL).
The resulting yellow solution was concentrated, giving an oily yellow
solid. Trituration of this material with hexanes (3 × 2 mL) left
the desired isonitrile 39 (285 mg, 64%) as a light yellow
solid (>75 °C, decomp): Rf = 0.5
(silica gel, 1/1 hexanes/EtOAc) [reactive; spot is from the resulting
formamide]; HRMS (m/z) N/A, unstable;
IR (film) νmax 3047, 2127, 1682, 1596, 1498, 1389,
826, 762 cm–1; 1HNMR (400 MHz, CDCl3) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1 H),
8.20 (dd, J = 8.4, 1.7 Hz, 1 H), 7.87 (dd, J = 8.3, 1.3 Hz, 1 H), 7.79 (dd, J = 7.5,
1.4 Hz, 1 H), 7.57–7.47 (m, 2 H); 13CNMR (CDCl3, 101 MHz) δ 152.0, 142.8, 136.4, 129.5, 128.8, 127.8,
125.9, 122.7, 77.5, 77.2, 76.8.
4-Methoxy-4H-imidazo[4,5,1-ij]quinolone (45b)
Methanol (0.5 mL) was added
to a solution of 39 (40 mg, 0.26 mmol) in DCM (0.5 mL)
at room temperature. After 4 h, the mixture was concentrated and purified
directly by column chromatography (25–50% EtOAc in hexanes)
to give methanol adduct 45b (25.3 mg, 52%) as a light
yellow oil: Rf = 0.2 (silica gel, 1/1
hexanes/EtOAc); HRMS (m/z) calcd
for C11H10N2O ([M + H]+) 187.0871, found 187.0875; IR (film) νmax br 3373,
2931, 1477, 1340, 1192, 1062, 803, 740 cm–1; 1HNMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.74
(d, J = 8.1 Hz, 1H), 7.27 (dd, J = 15.3, 8.0 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H),
7.10 (dd, J = 9.8, 1.1 Hz, 1H), 6.66 (dd, J = 3.6, 1.1 Hz, 1H), 5.91 (dd, J = 9.8,
3.6 Hz, 1H), 3.01 (s, 3H); 13CNMR (CDCl3, 126
MHz) δ 141.6, 140.2, 130.9, 128.1, 123.1, 122.0, 121.0, 120.2,
117.5, 80.4, 50.3.
Ethyl 1-Azidocyclobutane-1-carboxylate (S3)
Potassium carbonate (960 mg, 6.96 mmol, 2.5 equiv),
copper sulfate
(7 mg, 0.028 mmol, 0.01 equiv), and the diazo transfer agent S2 (700 mg, 3.34 mmol, 1.2 equiv) were successively added
to a solution of commercially available ethyl 1-amino-1-cyclobutanecarboxylate
monohydrochloride (S1; 500 mg, 2.78 mmol) in methanol
(14 mL) at room temperature. After 24 h, the mixture was concentrated,
dissolved in EtOAc (20 mL), washed with 1 N aqueous HCl (10 mL) and
brine, and dried over sodium sulfate. After concentration, the crude
product was purified by column chromatography (25% Et2O
in hexanes) to give S3 (324 mg, 78%) as a colorless oil
with spectral data which matched those reported[59] (contained 20% of inconsequential methyl ester from concomitant
transesterification during the reaction).
Lithium hydroxide hydrate (131 mg, 3.12
mmol, 2 equiv) was added to a solution of azido ester S3 (265 mg, 1.57 mmol) in THF/H2O (10 mL, 3/1 v/v). The
reaction mixture was stirred vigorously for 24 h and quenched with
3 N aqueous HCl (2 mL). The mixture was separated and extracted with
EtOAc (3 × 5 mL), and the extract was washed with brine (10 mL)
and dried over sodium sulfate. After concentration, azido acid S4 (230 mg, 99%) was isolated as a colorless oil: Rf = 0.15 (silica gel, 3/1 hexanes/EtOAc); HRMS
(m/z) calcd for C5H7N3O2 ([M – H]−) 140.0465, found 140.0464; IR (film) νmax br 3001,
2100, 1706, 1416, 1248 cm–1; 1HNMR (400
MHz, CDCl3) δ 2.73–2.61 (m, 1H), 2.41–2.26
(m, 1H), 2.16–1.96 (m, 1H). 13CNMR (CDCl3, 101 MHz) δ 178.6, 64.8, 31.2, 14.7.
Triphenylphosphine
(367 mg, 1.4 mmol, 1.2 equiv) was added to a solution of 46a (312 mg, 1.17 mmol) in dioxane/H2O (11 mL, 10/1 v/v)
at room temperature. A reflux condenser was attached to the flask,
and the reaction mixture was placed in an oil bath preheated to 110
°C for 36 h. After it was cooled to room temperature, the reaction
mixture was acidified with 1 N aqueous HCl (5 mL) and extracted with
EtOAc (3 × 15 mL). The aqueous layer was basified with 3 N aqueous
NaOH (5 mL), saturated with NaCl, extracted with EtOAc (3 × 25
mL), and dried over sodium sulfate. After filtration and concentration,
the crude yellow oil was purified by silica gelchromatography (50–100%
EtOAc in hexanes) to give S5 (257 mg, 91%) as a colorless
oil: Rf = 0.4 (silica gel, 1/1 hexanes/EtOAc);
HRMS (m/z) calcd for C14H15N3O ([M + H]+) 242.1293, found
242.1294; IR (film) νmax br 3291, 2935, 1671, 1513,
1482, 1324, 790 cm–1; 1HNMR (400 MHz,
CDCl3) δ 8.84 (dd, J = 7.6, 1.5
Hz, 1 H), 8.80 (dd, J = 4.2, 1.7 Hz, 1 H), 8.06 (dd, J = 8.3, 1.7 Hz, 1 H), 7.48 (t, J = 7.9
Hz, 1 H), 7.42 (dd, J = 8.2, 1.4 Hz, 1 H), 7.36 (dd, J = 8.3, 4.2 Hz, 1 H), 2.99–2.70 (m, 2 H), 2.20–1.84
(m, 6 H); 13CNMR (CDCl3, 101 MHz) δ 175.0,
148.5, 139.1, 136.2, 134.7, 128.0, 127.3, 121.5, 121.4, 116.1, 60.0,
35.3, 14.3.
Dimethyl cyclobutanedicarboxylate
(3.50 g, 20.33 mmol)
was dissolved in MeOH (150 mL) and cooled to 0 °C. An aqueous
solution of NaOH (813 mg in 150 mL H2O) was then added
dropwise over 30 min. The reaction mixture was slowly warmed to room
temperature and stirred for 12 h. The MeOH was removed in vacuo, and
the resulting aqueous solution was washed with Et2O (100
mL). The resulting aqueous phase was acidified with 3 N aqueous HCl
(10 mL) and extracted with EtOAc (100 mL, 2 × 50 mL). The combined
organics were washed with brine (100 mL), dried over sodium sulfate,
and concentrated to give S6 (3.00 g, 93%) as a colorless
oil: Rf = 0.1 (silica gel, 3/1 hexanes/EtOAc);
HRMS (m/z) calcd for C7H10NaO4 ([M + H]+) 181.0477, found
181.0478; IR (film) νmax br 3504, 2956, 1705, 1281,
1202, 1138, 688 cm–1; 1HNMR (400 MHz,
CDCl3) δ 3.77 (s, 1H), 2.59 (t, J = 8.1 Hz, 1H), 2.08–1.95 (m, 1H); 13CNMR (CDCl3, 101 MHz) δ 177.9, 172.2, 100.1, 52.9, 52.6, 29.0,
16.3.
4-Methoxyphenylacetic acid (49; 2.00 g, 12.0 mmol)
was dissolved in dry THF (3 mL) and added dropwise to a solution of
isopropylmagnesium chloride in THF (2 M, 13.2 mL, 26.4 mmol, 2.2 equiv)
dropwise, keeping the internal temperature below 50 °C. The reaction
mixture turned heterogeneous during the addition and was stirred for
30 min at room temperature. Epichlorohydrin (1.7 mL, 21.6 mmol, 1.8
equiv) was added dropwise, keeping the internal temperature below
35 °C, and the mixture was stirred at room temperature for 45
min. During the addition the solution homogenizes. A solution of isopropylmagnesiumchloride (2 M in THF, 12 mL, 24 mmol, 2 equiv) was added to the reaction
mixture, which was then warmed to 60 °C overnight (14 h). The
reaction mixture was carefully quenched with 3 N aqueous HCl (20 mL),
keeping the internal temperature below 35 °C. The resulting biphasic
solution was separated and extracted with EtOAc (2 × 50 mL).
The combined organics were washed with 1 N aqueous NaOH (2 ×
25 mL), and the combined aqueous layer was acidified with 3 N aqueous
HCl and extracted with EtOAc (3 × 25 mL). The combined organic
layers were washed with brine (25 mL), dried over Na2SO4, and concentrated to give the crude hydroxy acid 50 (2.16 g) as a white solid that was used directly in the next reaction.
To a solution of the crude hydroxy acid in MeOH (20 mL) was added
concentrated sulfuric acid (54 μL, 1 mmol), and the mixture
was warmed to 60 °C for 12 h. The reaction mixture was cooled
to room temperature and neutralized with saturated sodium bicarbonate
solution (2 mL), and the MeOH was removed in vacuo. The resulting
mixture was diluted with EtOAc (50 mL), washed with brine (25 mL),
dried over Na2SO4, and concentrated to give
the crude methyl ester (2.16 g), which was used directly in the next
step. This material could be further purified using silica gelchromatography
(30–60% Et2O in hexanes) for characterization to
give the methyl ester S7 as colorless crystals (mp 64–65
°C): Rf = 0.4 (silica gel, 1/1 hexanes/EtOAc);
HRMS (m/z) calcd for C13H16O4 ([M + H]+) 237.1127, found
237.1131; IR (film) νmax br 3419, 2950, 1727, 1511,
1250, 1130, 1031, 832 cm–1; 1HNMR (400
MHz, CDCl3) δ 7.32–7.21 (m, 2 H), 6.90–6.83
(m, 2 H), 4.16 (apparent p, J = 6.9 Hz, 1 H), 3.79
(s, 3 H), 3.62 (s, 3 H), 2.97–2.82 (m, 2 H), 2.72–2.61
(m, 2 H), 2.56 (br s, 1 H); 13CNMR (CDCl3,
101 MHz) δ 176.4, 158.5, 133.3, 128.1, 113.9, 62.7, 55.4, 52.6,
44.0, 42.8.
Sodium periodate (31.5 g, 147.3 mmol,
15 equiv) was added to a vigorously stirred biphasic solution of 51 (3.44 g, 9.82 mmol) in EtOAc/H2O (390 mL/1.15
L) at 4 °C. Ruthenium oxide hydrate (148 mg, 0.98 mmol, 0.1 equiv)
was added in a single portion, and the light yellow mixture was slowly
warmed to room temperature and stirred for 14 h. The resulting black
mixture was separated and extracted with EtOAc (2 × 200 mL).
The combined organics were washed with a brine/saturated sodium sulfite
solution (200 mL, 10/1 v/v), dried over Na2SO4 and concentrated. The crude product was filtered through a plug
of silica gel (with EtOAc as eluent) to give 52 (1.97
g, 70%) as a semicrystalline waxy solid. (The yield of this reaction
at different scales has varied between 62 and 70%; larger scales were
generally higher yielding.): Rf = 0.5
(silica gel, EtOAc); HRMS (m/z)
calcd for C13H24O5Si ([M –
H]−) 287.1320, found 287.1328; IR (film) νmax br 3418, 2955, 1712, 1251, 1135, 1048, 835 cm–1; 1HNMR (400 MHz, CDCl3) δ 4.40 (apparent
p, J = 7.3 Hz, 1 H), 3.78 (s, 3 H), 2.85 (ddd, J = 9.9, 7.1, 2.8 Hz, 2 H), 2.53 (ddd, J = 10.1, 7.5, 2.8 Hz, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13CNMR (CDCl3, 101 MHz) δ 177.9, 171.4, 62.0, 53.0,
45.8, 41.1, 25.9, 18.0, −4.7.
Triethylamine
(450 μL, 3.23 mmol, 1.5 equiv) was added to a solution of S7 (505 mg, 2.14 mmol) in DCM (20 mL) cooled to 0 °C
in an ice bath, followed by acetic anhydride (300 μL, 3.23 mmol,
1.5 equiv) and DMAP (14 mg, 0.11 mmol, 0.05 equiv). The reaction was
mixture was stirred at 0 °C for 2 h and then was quenched with
saturated aqueous sodium bicarbonate (10 mL). The biphasic reaction
mixture was separated, extracted with DCM (2 × 10 mL), washed
with 1 N aqueous HCl (10 mL), washed with brine (20 mL), and dried
over sodium sulfate. After filtration and concentration, the crude
product was purified by silica gelchromatography (25% Et2O in hexanes) to give S7 (552 mg, 93%) as a colorless
oil: Rf = 0.35 (silica gel, 3/1 hexanes/EtOAc);
HRMS (m/z) calcd for C15H18O5 ([M + H]+) 279.1232, found
279.1231; IR (film) νmax 2953, 1727, 1512, 1229,
1030, 832 cm–1; 1HNMR (400 MHz, CDCl3) δ 7.33–7.27 (m, 2 H), 6.92–6.84 (m,
2 H), 4.86 (p, J = 7.2 Hz, 1 H), 3.80 (s, 3 H), 3.63
(s, 3 H), 3.04–2.91 (m, 2 H), 2.88–2.75 (m, 2 H), 2.03
(s, 3 H); 13CNMR (CDCl3, 101 MHz) δ 175.5,
170.6, 158.8, 132.6, 128.1, 114.0, 64.5, 55.4, 52.6, 45.1, 39.7, 21.1.
Sodium
periodate (3.8 g, 17.7 mmol, 10 equiv) was added to a vigorously stirred
biphasic solution of S8 (493 mg, 1.77 mmol) in EtOAc/MeCN/H2O (9 mL/9 mL/30 mL) cooled to 0 °C in an ice bath. Ruthenium
oxide hydrate (13.4 mg, 0.09 mmol, 0.05 equiv) was added in a single
portion, and the light yellow mixture was vigorously stirred for 20
h, while being slowly warmed to room temperature. The resulting black
mixture was separated and extracted with EtOAc (2 × 20 mL). The
combined organics were washed with a brine/saturated sodium sulfite
solution (200 mL, 10/1 v/v), dried over Na2SO4, and concentrated to give a crude acid that was used directly in
the next reaction without further purification (1HNMR
(400 MHz, CDCl3) δ 5.11 (p, J =
7.6 Hz, 1H), 3.79 (s, 3H), 3.22–2.92 (m, 2H), 2.80–2.60
(m, 2H), 2.04 (s, 3H)). Oxalyl chloride (182 μL, 2.12 mmol,
1.2 equiv) was added dropwise to a solution of the acid (ca. 1.77
mmol) in DCM (10 mL) containing 1 drop of DMF. After the reaction
mixture was stirred at room temperature for 4 h, toluene was added
(5 mL) and the solvent concentrated to give the crude acid chloride.
This material was dissolved in toluene, and 2-picolinamide (325 mg,
2.66 mmol, 1.5 equiv) was added, followed by 4 Å molecular sieves
(1.7 g). The heterogeneous reaction mixture was heated to 90 °C
for 16 h, and then the reaction mixture was filtered through Celite,
concentrated, and purified by column chromatography (25–40%
EtOAc in hexanes) to give 60 (251 mg, 44% for two steps)
as colorless crystals (mp 138–139 °C): Rf = 0.25 (silica gel, 1/1 hexanes/EtOAc); HRMS (m/z) calcd for C15H16N2O6 ([M + H]+) 321.1087, found
321.1095; IR (film) νmax br 3319, 1735, 1726, 1698,
1481, 1234, 1044, 747 cm–1; 1HNMR (400
MHz, CDCl3) δ 10.70 (s, 1 H), 8.61 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 H), 8.16 (dt, J = 7.9, 1.1 Hz, 1 H), 7.89 (td, J = 7.7, 1.7 Hz,
1 H), 7.53 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 4.91
(p, J = 7.7 Hz, 1 H), 3.71 (s, 3 H), 3.06 (ddt, J = 9.6, 7.7, 2.4 Hz, 2 H), 2.76 (ddt, J = 10.7, 7.8, 2.6 Hz, 2 H), 2.02 (s, 3 H); 13CNMR (CDCl3, 126 MHz) δ 171.2, 170.4, 170.4, 162.6, 148.6, 147.5,
138.0, 127.9, 123.3, 63.7, 53.0, 49.4, 36.8, 20.9.
1-Amino-3-((tert-butyldimethylsilyl)oxy)-2,4-bis(1-tosyl-1H-indol-3-yl)cyclobutane-1-carbonitrile (62) and 2-((tert-Butyldimethylsilyl)oxy)-1,3-bis(1-tosyl-1H-indol-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione (63)
59 (400 mg, 0.484 mmol) was dissolved
in THF (4.8 mL), and H2O (1.6 mL) was added, followed by
lithium hydroxide hydrate (102 mg, 2.43 mmol, 5 equiv). The biphasic
reaction mixture was stirred vigorously for 12 h and quenched with
1 N aqueous HCl (3 mL). The layers were separated and extracted with
EtOAc (4 × 5 mL), and the extract was washed with brine (10 mL),
dried over sodium sulfate, filtered, and concentrated to give the
carboxylic acid (388 mg, 99%) as a white foam ,which was dissolved
in dry DCM (4.8 mL) and cooled to 0 °C. Triethylamine (0.27 mL,
1.94 mmol, 4 equiv) was added, followed by diphenylphosphoryl azide
(0.42 mL, 1.94 mmol, 4 equiv). The reaction mixture was slowly warmed
to room temperature and stirred for 24 h. The reaction mixture was
then heated to 50 °C for 6 h and quenched with saturated aqueous
sodium bicarbonate (5 mL). The layers were separated and extracted
with DCM (2 × 3 mL). The combined organics were washed with brine
(5 mL) and dried over sodium sulfate. After filtration and concentration,
the crude product was purified by column chromatography (25–50%
EtOAc in hexanes) to give aminonitrile 62 (257 mg, 69%)
as a white foam and hydantoin 63 (91 mg, 23%) as a white
solid.62: white foam; Rf = 0.25 (silica gel, 3/1 hexanes/EtOAc); HRMS (m/z) calcd for C41H44N4O5S2SiNa ([M + Na]+) 787.2420,
found 787.2421; IR (film) νmax 2928, 1597, 1447,
1368, 1174, 1129, 746 cm–1; 1HNMR (400
MHz, CDCl3): 8.02 (dt, J = 8.3, 0.9 Hz,
2 H), 7.85 (d, J = 8.4 Hz, 4 H), 7.80–7.79
(m, 2 H), 7.63 (ddd, J = 7.9, 1.3, 0.7 Hz, 2 H),
7.39–7.33 (m, 2 H), 7.31–7.25 (m, 2 H), 7.25–7.20
(m, 4 H), 4.57 (t, J = 8.3 Hz, 1 H), 3.66 (dd, J = 8.4, 0.9 Hz, 2 H), 2.33 (s, 6 H), 0.76 (s, 9 H), −0.12
(s, 6 H); 13CNMR (CDCl3, 101 MHz) δ 145.1,
135.1, 135.1, 130.6, 130.0, 127.2, 125.4, 124.2, 123.6, 119.6, 119.4,
118.0, 114.0, 77.5, 77.2, 76.8, 69.6, 58.2, 52.2, 25.7, 21.7, 17.8,
−4.4.63: white solid (>180 °C,
decomp); Rf = 0.4 (silica gel, 1/1 hexanes/EtOAc);
HRMS (m/z) calcd for C42H44N4O7S2SiNa ([M + Na]+) 831.2318, found 831.2332; IR (film) νmax br 3358,
2928, 1727, 1367, 1173, 1127, 745 cm–1; 1HNMR (400 MHz, 1/1 MeOD/CDCl3) δ 7.91 (d, J = 8.3 Hz, 2 H), 7.74 (d, J = 8.4 Hz,
4 H), 7.65 (d, J = 0.9 Hz, 2 H), 7.54 (ddd, J = 7.9, 1.2, 0.7 Hz, 2 H), 7.28 (ddd, J = 8.4, 7.3, 1.3 Hz, 2 H), 7.25–7.16 (m, 6 H), 5.02 (t, J = 8.1 Hz, 1 H), 3.88 (dd, J = 8.1, 1.0
Hz, 2 H), 2.30 (s, 6 H), 0.73 (s, 9 H), −0.11 (s, 6 H); 13CNMR (1/1 MeOD/CDCl3, 101 MHz) δ 173.5,
157.8, 145.8, 135.4, 135.3, 131.2, 130.4, 127.3, 125.5, 125.3, 124.0,
119.7, 117.7, 114.1, 68.9, 67.3, 50.3, 25.8, 21.6, 18.1, −4.2.
69 (90 mg, 0.115 mmol) was
dissolved in THF (2.3 mL), and tosyl isocyanate (21 μL, 0.138
mmol, 1.2 equiv) was added at room temperature. After the reaction
mixture was stirred for 30 min, the reaction mixture was quenched
with aqueous ammonium hydroxide (2 mL). The layers were separated
and extracted with EtOAc (3 × 2 mL), and the extract was washed
with brine (2 mL) and dried over sodium sulfate. After filtration
and concentration, the crude 71 (91.1 mg) was obtained
as a pale yellow foam and was used directly in the following reaction.
Burgess reagent (7 mg, 0.03 mmol) was added to a heterogeneous solution
of crude 71 (10 mg, 0.010 mmol) in DCM (200 μL).
The reaction mixture was warmed to 50 °C for 2 h (mixture turns
homogeneous after 15 min). After concentration, the crude product
was purified directly by column chromatography (2% acetone in DCM)
to give 66 (8.2 mg, 67%, two steps) as a white solid
that is very sparingly soluble when purified, preventing NMR analysis.
This compound was methylated to facilitate characterization. Colorless
crystals serendipitously formed from slow evaporation of a dilute
TLC sample in wet DCM to further confirm the structure: colorless
crystals (>200 °C, decomp); Rf =
0.5 (silica gel, 1/1 hexanes/EtOAc); HRMS (m/z) calcd for C49H51N5O8S3Si ([M + H]+) 962.2747, found 962.2734;
IR (film) νmax br 3532, br 3395, 2928, 1771, 1636,
1358, 1172, 670 cm–1;
Potassium carbonate (6.9 mg, 0.05 mmol,
6 equiv) was added to a solution of 66 (8.0 mg, 8.3 μmol)
in DMF (100 μL), followed by methyl iodide (2.0 μL, 3.2
μmol, 4 equiv). The heterogeneous reaction mixture was stirred
at room temperature for 30 min. The reaction mixture was quenched
with saturated aqueous ammonium chloride (200 μL) and stirred
for 30 min. The reaction mixture was concentrated and taken up in
EtOAc (1 mL)/brine (1 mL). The mixture was separated and extracted
with EtOAc (2 × 1 mL) and dried over sodium sulfate. After filtration
and concentration, the crude product was purified by column chromatography
(20% EtOAc in hexanes) to give 67 (7.8 mg, 95%) as a
white foam. Alternate procedure: tosyl isocyanate (12 μL, 0.08
mmol, 1.25 equiv) was added to a solution of 62 (50 mg,
0.065 mmol) in THF (1.3 mL) at room temperature. The reaction mixture
was concentrated after 15 min and dissolved in absolute ethanol (1.3
mL). This reaction mixture was heated to 70 °C for 14 h, and
then the solvent was evaporated to give crude 66. Potassium
carbonate (54 mg, 0.39 mmol, 6 equiv) was added to a solution of crude 66 in DMF (650 μL), followed by methyl iodide (16.3
μL, 0.26 mmol, 4 equiv). The heterogeneous reaction mixture
was warmed to 50 °C. After 2 h, the reaction mixture was quenched
with saturated aqueous ammonium chloride (500 μL) and stirred
for 30 min. The reaction mixture was concentrated and taken up in
EtOAc (2 mL)/brine (2 mL). The mixture was separated and extracted
with EtOAc (2 × 2 mL) and dried over sodium sulfate. After filtration
and concentration, the crude product was purified by column chromatography
(20% EtOAc in hexanes) to give 67 (47.2 mg, 73% over
2 steps) as a white foam: Rf = 0.6 (silica
gel, 1/1 hexanes/EtOAc); HRMS (m/z) calcd for C51H55N5O8S3Si ([M + H]+) 990.3060, found 990.3071; IR
(film) νmax 2927, 1764, 1627, 1447, 1370, 1173, 776,
669 cm–1; 1HNMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.3 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4 Hz,
4 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.49 (s, 2 H), 7.32
(ddd, J = 8.4, 5.5, 2.9 Hz, 2 H), 7.25–7.17
(m, 8 H), 4.74 (t, J = 8.1 Hz, 1 H), 3.92 (dd, J = 8.2, 1.0 Hz, 2 H), 3.41 (s, 3 H), 3.30 (s, 3 H), 2.52
(s, 3 H), 2.33 (s, 6 H), 0.67 (s, 9 H), −0.36 (s, 6 H); 13CNMR (CDCl3, 126 MHz) δ 158.9, 154.9, 145.2,
143.5, 139.8, 135.2, 134.7, 130.5, 130.1, 130.1, 127.4, 126.9, 125.2,
125.1, 123.6, 118.4, 115.4, 114.1, 69.5, 68.1, 48.2, 30.8, 26.1, 25.7,
21.7, 21.7, 17.8, −4.9.
Authors: Renhe Liu; Min Zhang; Thomas P Wyche; Gabrielle N Winston-McPherson; Tim S Bugni; Weiping Tang Journal: Angew Chem Int Ed Engl Date: 2012-06-19 Impact factor: 15.336
Authors: Li-Jun Xiao; Kai Hong; Fan Luo; Liang Hu; William R Ewing; Kap-Sun Yeung; Jin-Quan Yu Journal: Angew Chem Int Ed Engl Date: 2020-04-01 Impact factor: 15.336
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Scheme 1
Figure 6
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Figure 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14