Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (〈)-FR900482

Article abstract of DOI:10.1021/jo2000308

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves

Full text of DOI:10.1021/jo2000308

ARTICLE
pubs.acs.org/joc
Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a
Tandem Ynamide Benzannulation/Ring-Closing Metathesis Strategy.
Application in a Formal Total Synthesis of (þ)-FR900482
Xiao Yin Mak, Aimee L. Crombie, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
ABSTRACT: A two-stage “tandem strategy” for the synthesis of
benzofused nitrogen heterocycles is described that is particularly
useful for the construction of systems with a high level of substitution
on the benzenoid ring. The first stage in the strategy involves a
benzannulation based on the reaction of cyclobutenones with yna-
mides. This cascade process proceeds via a sequence of four pericyclic
reactions and furnishes a multiply substituted aniline derivative which
can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-
closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted
dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in
a concise formal total synthesis of the anticancer agents (þ)-FR900482 and (þ)-FR66979 is described.
’ INTRODUCTION
In its original version, the vinylketene-based benzannulation
strategy developed in our laboratory proceeds via a “cascade”
process involving four successive pericyclic reactions. Scheme 2
outlines the mechanism of the benzannulation, illustrated here
with an ynamine derivative serving as the 2-π annulation partner.
Thermolysis (typically at 80-150 °C) or irradiation of a
cyclobutenone serves as the triggering step for the cascade,
effecting reversible electrocyclic ring-opening to generate the
transient vinylketene intermediate 4. Vinylketene 4 is immedi-
ately intercepted by the alkyne annulation partner in a regiose-
lective [2 þ 2] cycloaddition to afford a new cyclobutenone 5,
which under the reaction conditions undergoes reversible elec-
trocyclic cleavage (vide infra) to generate dienylketene 6. Rapid
6-π electrocyclic closure and then tautomerization furnishes the
desired aromatic product 3.
Benzofused nitrogen heterocycles are important synthetic
targets, incorporated in the structures of numerous natural
products and pharmaceutical compounds. A variety of hetero-
cyclization methods are available for the formation of benzofused
nitrogen heterocycles from ortho-substituted anilines, but the
regiocontrolled synthesis of aniline substrates with a high level of
substitution on the aromatic ring remains a challenging problem
in organic synthesis.
Classically, syntheses of highly substituted benzenoid compounds
have most often been achieved by employing linear substitu-
tion strategies involving sequential electrophilic substitution
and metalation-alkylation reactions. A more effective approach,
however, involves the application of benzannulation methods: con-
vergent strategies in which the aromatic ring system is assembled
from two or more precursors in a single step, with all (or most)
substituents in place.1 Two complementary benzannulation strate-
gies based on the reactions of alkynes and vinylketenes have been
developed in our laboratory,2-4 and these methods have been
successfully applied in total syntheses of a number of bioactive
natural products.5,6 In this paper, we report the extension of this
benzannulation strategy to include ynamine derivatives as the alkyne
annulation partner. As outlined in Scheme 1, we envisioned that this
variant of the benzannulation would provide exceptionally efficient
access to diverse highly substituted aniline derivatives strategically
designed for immediate participation in a subsequent “heterocycli-
zation” reaction.7 If feasible, this combination of ring-forming
processes would constitute a powerful two-stage “tandem strategy”
for the synthesis of several classes of benzofused nitrogen hetero-
cyclic compounds including systems with multiple substituents on
the aromatic ring.
’ RESULTS AND DISCUSSION
Ynamine-Based Benzannulations. Alkynyl ethers have
served as the ketenophilic annulation partners in most prior
applications of this benzannulation strategy, although alkynyl
thioethers and aryl acetylenes can also participate in the reaction.
At the outset of this investigation, the feasibility of employing
ynamine derivatives in efficient benzannulations of this type was
far from certain. In early studies employing ynamines,2a we
isolated allenes such as 10 as minor byproducts in benzannula-
tions with cyclobutenones. On the basis of the work of Ghosez,8
the formation of this allene byproduct is believed to result from
Received: January 5, 2011
Published: February 15, 2011
r
2011 American Chemical Society
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Scheme 1. Tandem Strategy for Synthesis of Benzo-Fused
Nitrogen Heterocycles
Scheme 3. Allene Byproduct Formation in a Cyclobute-
none-Ynamine Benzannulation
Scheme 2. Pericyclic Cascade Mechanism of the Vinylke-
tene-Based Benzannulation
Scheme 4. Alternative Regioisomeric Products in Benzan-
nulations of Vinylketenes and Ynamines
initial addition of the ynamine across the ketene carbonyl group
via a concerted9 or stepwise pathway to form an alkylideneoxete
13. Electrocyclic ring-opening then transforms this strained
intermediate to the allenyl carboxamide (Scheme 3). The aro-
matic product 9 could result from either direct cyclization of the
zwitterionic intermediate 12 or via the usual pericyclic cascade
pathway (Scheme 2).
Although zwitterions of type 14 are capable of cyclizing to
form benzenoid products, in the case of certain substituted vinylk-
etenes the “zwitterionic cyclization” pathway would lead to an
aromatic product of type 15 which is regioisomeric with respect to
the phenol 3 produced via the pericyclic cascade mechanism
(Scheme 4). A second potential complication associated with the
ynamine-based variant of the benzannulation emerges from con-
sideration of an unusual rearrangement observed by Ficini in a study
of the reactions of cyclobutenones with ynamines.10 Should the
Ficini rearrangement be operative, then the reaction of vinylketenes
with ynamines could lead to a third regioisomeric benzannulation
product of type 16. Needless to say, the potential formation of
mixtures of regioisomeric products was alarming as the separation of
closely related annulation productssuchasthesewasexpectedtobea
daunting task.
In order to suppress these alternative pathways leading to
regioisomeric benzannulation products, oxetes, and allenes, we have
focused our attention on reactions of ynamides in which the nucleo-
philicity of the amino alkyne is attenuated by an electron-with-
drawing substituent on the nitrogen atom.11 Ynamides are consider-
ably less nucleophilic than ynamines, and it was our expectation that
they would react with vinylketenes analogously to alkynyl ethers, i.e.,
via the desired concerted [2 þ 2] cycloaddition rather than via
alternative stepwise pathways. This prediction was confirmed in a
preliminary study in which ynamides were found to react smoothly
with simple nonconjugated ketenes to afford the desired 3-amino-
cyclobutenones in excellent yield without detectable formation of
allenyl carboxamide byproducts.12
Synthesis of Ynamides. A number of alternative cyclization
protocols can be envisioned for the formation of the heterocyclic
ring in the second step of the proposed tandem strategy
(Scheme 1). For this initial study we focused our attention on
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Table 1. Synthesis of Ynamides via N-Alkynylation of Carbamates
a Isolated yield of products purified by column chromatography on silica gel. b Reference 12.
the application of ring-closing metathesis (RCM), which is now
well established as a powerful method for the construction of
nitrogen heterocycles.13 It was our expectation that the vinylketene-
based benzannulation reaction could provide an exceptionally
expeditious method for the assembly of RCM substrates bearing a
high level of substitution on the aniline ring. Ynamides bearing
unsaturated substituents on both the nitrogen atom and at C-2 of
the alkyne would be required as benzannulation partners in order to
generate the desired intermediates for ring closing metathesis. The
success of these reactions would of course require that the vinylk-
etene [2 þ 2] cycloaddition proceed with high chemoselectivity at
the triple bond of the ynamide in the presence of the other
unsaturated moieties.
Recent advances in copper-promoted amide coupling reac-
tions have provided the basis for the efficient and convenient
synthesis of a variety of ynamides. Most of the ynamides
employed in the present study were prepared using the N-
alkynylation method recently developed in our laboratory.14
Although this protocol requires the use of 1 equiv of CuI,
coupling proceeds smoothly at room temperature, and this
method thus accommodates the synthesis of a wide range of
alkyne derivatives including thermally unstable systems. For
many of these ynamides, similar results can be obtained by using
the method of Hsung which employs catalytic CuCN or CuSO4
in conjunction with diamine ligands with coupling taking place at
elevated temperatures.15 We have found both methods to be
reliable and reproducible for reactions on both small and large
(i.e., multigram) scale.16
For the preparation of alkynyl carbamates, we have found that
the protocol developed in our laboratory generally affords the best
results (Table 1). The carbamates and alkynyl halides required for
the coupling reactions presented in Table 1 are all commercially
available or can be prepared in one step as detailed in the Experi-
mental Section. In the case of alkynyl sulfonamides, the Hsung
procedure using catalytic CuSO4 was found to be most convenient.
Several ynamides were best prepared by alkylation of terminal yna-
mides obtained by desilylation of C-silyl derivatives (Schemes 5
and 6). For the synthesis of the “skipped” diynamide 34, the
procedure of Caruso and Spinella17 was found to be most effective
for the propargylation of ynamide 33.
Feasibility and Scope of the Benzannulation. The feasi-
bility of applying ynamides as alkyne partners in the benzannula-
tion was initially examined using 3-butylcyclobutenone (35)18
and ynamides 24 and 32 as test substrates. As summarized in
Scheme 7, we found that successful benzannulation could be
achieved by employing either thermal or photochemical activa-
tion and by microwave irradiation. Benzannulation was most
conveniently accomplished in both cases by heating the ynamide
and a slight excess of cyclobutenone in toluene at reflux for 1 h. In
the case of sulfonamide 32, the yield of phenol could be
improved by treating the crude product with KOH in methanol.
This treatment serves to hydrolyze the small amount of phenolic
esters formed by trapping of the benzannulation product
with excess vinylketene during the reaction. Identification of
the benzannulation product as 36, the “pericyclic cascade
product” of type 3 (Scheme 4) rather than the regioisomeric
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Scheme 5. Synthesis of Alkynyl Sulfonamide 32
Scheme 7. Feasibility of the Benzannulation
Scheme 6. Synthesis of Ynamide 34
Scheme 8. Conversion of 4-Vinylcyclobutenone 38 to Phe-
nol 36
“Ficini rearrangement product” of type 16, was confirmed by an
NOE study (see the Experimental Section). Note that in this
benzannulation there would be no difference between the
product formed via the pericyclic cascade mechanism and that
produced by the zwitterionic cyclization pathway.
Optimal conditions for the benzannulation vary from case to
case. Cyclobutenones without substituents at the C-2 position
generate monosubstituted ketene (“aldoketene”) intermediates upon
electrocyclic opening, and these substrates react smoothly at 80-
110 °C. In the case of N-allyl ynamides (e.g., 25, 26, and 34), it was
found important to perform the reaction at the lowest possible
temperature in order to minimize [3,3] sigmatropic rearrangement of
the ynamides which begins to occur at temperatures above 125 °C.
Reactions with these ynamides are best carried out at 80 °C until all
of the starting materials are consumed. In some reactions (entries 1
and 7), this leads to mixtures of the desired phenol and intermediate
4-vinylcyclobutenone, in which case further heating at 110 °C com-
pletes conversion to the aromatic product.
Benzannulations that involve disubstituted ketene (“ketoketene”)
intermediates (e.g., entries 3 and 4) require higher temperatures due
to the slower rate of [2 þ 2] cycloaddition in the case of these
vinylketenes. Increased reaction rates were observed when these
benzannulations were performed in chloroform in place of toluene.
Annulation employing the 4,4-dichlorocyclobutenone 41 affords
the 2-chlorophenol 47, presumably via an intermediate 6,6-dichlor-
ocyclohexadienone intermediate that undergoes radical-mediated
dechlorination at the elevated reaction temperature. Disappoint-
ingly, attempted benzannulation with 2,3,4-trisubstituted cyclobu-
tenones furnished the desired aromatic products in low yield. In
most cases, optimal yields were obtained under thermal benzannu-
lation conditions rather than via photochemical activation. For
example, in the case of the reaction depicted in entry 1, photo-
chemical benzannulation afforded 43 in only 39% yield, presumably
because of further reaction of the product by photoinduced cycliza-
tion to form a dihydrobenzofuran.21
Interestingly, reaction of the cyclobutenone and ynamide 24 at
a lower temperature (80 °C) for 90 min led to the isolation of a
mixture of phenol 36 and a 4-vinylcyclobutenone (38) correspond-
ing to intermediate 5 (Scheme 2) in the pericyclic cascade. Upon
further heating in toluene, this vinylcyclobutenone was converted to
phenol 36 in 97% yield (Scheme 8). The near-quantitative yield
observed for this transformation suggests that either electrocyclic
ring-opening of 38 affords exclusively a (Z)- rather than (E)-dienyl-
ketene intermediate or that formation of the dienylketene (interme-
diate 6 in Scheme 2) is reversible under the reaction conditions. We
favor the latter explanation since computational studies by Houk and
co-workers on the torquoselectivity of the electrocyclic opening of
cyclobutenones suggest that ring-opening to the E isomer should be
favored.19
Benzannulations involving ynamides that incorporate unsatu-
rated substituents can generate products that are potential
substrates for ring-closing metathesis reactions, and systems of
this type were the main focus of this study. As demonstrated with
the examples in Table 2, ynamides of this type participate in the
benzannulation with a variety of cyclobutenones20 to produce
the desired highly substituted aniline derivatives in good to
excellent yield. In no case were we able to detect the formation
of byproducts resulting from competitive addition of the
vinylketene intermediates to alkene double bonds. This im-
portant observation supports our expectation that ynamides
should exhibit greater ketenophilicity as compared to alkenes,
including conjugated double bonds such as those present in
ynamides 26 and 28.
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Table 2. Benzannulations with Ynamides and Cyclobutenones
a Isolated yield of products purified by column chromatography on silica gel. Yields based on ynamide (using 1.2-2.0 equiv of cyclobutenone) unless
otherwise indicated. b Crude product was heated with 5 M KOH in MeOH (65 °C, 2-3.5 h). c Reaction performed in the presence of 2.0 equiv of BHT
using 1.0 equiv of cyclobutenone and 1.5 equiv of ynamide.
Careful examination of the crude products of these benzan-
nulations indicated that in each case a single phenolic product is
generated. As discussed previously, benzannulations involving
disubstituted vinylketenes have the potential to produce regioi-
someric products should the alternative zwitterionic cyclization
or Ficini rearrangement pathways be operative (see Scheme 4).
Confirmation that the benzannulation was proceeding via the
desired pericyclic cascade pathway was obtained by the following
experiments performed on the product of the benzannulation in
entry 3. First, deoxygenation of the phenol22 was accomplished
via the sequence outlined in Scheme 9.23 The strong coupling
(J = 8.5 Hz) observed for the two aromatic protons in the
resulting product 52 indicates that the methyl and allyl groups
(corresponding to R1 and R4 in Scheme 4) cannot both be ortho
to the hydroxyl group in the benzannulation product, ruling out
the zwitterionic cyclization product of type 15. Confirmation
that the allyl substituent (R4 in Scheme 4) must be ortho to the
hydroxyl was then obtained by treatment of the benzannulation
product with N-iodosuccinimide, which promoted iodoetherifi-
cation to form an iodo dihydrobenzofuran that was converted to
53 by elimination of HI with base. This result rules out the
alternative regioisomer of type 16, and confirms the identity of
the benzannulation product as 45, the regioisomer of type 3
predicted by the pericyclic cascade mechanism.
Ring-Closing Metathesis of Benzannulation Products. As
shown in Table 3, exposure of benzannulation products 43-48
to the action of 5 mol % of the “second generation” Grubbs
catalyst 6024 in dichloromethane at reflux furnished the desired
benzofused nitrogen heterocycles in excellent yield. Limiting the
reaction time to under 1 h avoids the formation of byproducts
resulting from double-bond isomerization.25 For example, ex-
tended reaction (12 h) in the case of entry 3 led to the formation
of a 60:40 mixture of 56 and the isomer in which the benzazocine
double bond has moved into conjugation with the aromatic ring.
No isomerization was observed when the reaction was carried
out for 40 min. Disappointingly, attempts to effect enyne ring-
closing metathesis26 with phenol 49 or various derivatives27 with
any of several metathesis catalysts have proved unsuccessful.
Formal Total Synthesis of (þ)-FR900482 and (þ)-FR66979.
We next turned our attention to the application of the tandem
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Scheme 9. Confirmation of Benzannulation Regiochemistry
Table 3. Synthesis of Benzofused Nitrogen Heterocycles via
RCM of Benzannulation Products
Scheme 10. Approaches to the Total Synthesis of (þ)-
FR900482
benzannulation-RCM strategy in a formal total synthesis of the
potent antitumor agents (þ)-FR900482 and (þ)-FR66979.
This exercise was expected to provide an excellent test for our
methodology by examining it in the demanding context of a
densely functionalized and highly substituted system.
a Conditions: 5 mol % of Grubbs-II (60), CH2Cl2 (0.03-0.07 M in
diene substrate), reflux, 40 min (2.5 h for entry 6). b Isolated yields of
products purified by column chromatography.
(þ)-FR900482 (61) and (þ)-FR66979 (62) were isolated in
1987 and 1989 from the fermentation broth of Streptomyces
sandaensis by researchers at the Fujisawa Pharmaceutical Co.28
These highly potent antitumor agents cross-link DNA following
reductive activation and are believed to possess a mode of action
closely related to that of mitomycin C.29 Among the seven total
syntheses30-34 and formal total syntheses35-37 of these anti-
tumor antibiotics reported to date, two proceed via related
benzazocine intermediates (Scheme 10, 63 and 64), with 63
being prepared by an elegant RCM strategy in 16 steps beginning
with 5-nitrovanillin.35 As detailed below, we anticipated that our
tandem ynamide benzannulation/ring closing metathesis strat-
egy would provide an expeditious enantioselective route to
benzazocines of this type requiring as few as nine steps in the
longest linear sequence.
of bromoalkyne 69, which could be derived from an aldehyde of
type 70 by means of any of several homologation methods. For
the enantioselective synthesis of 70, we decided to focus our
attention on a chiral auxiliary-directed syn aldol condensation
involving a suitable enolate derivative and acrolein.
The strategy outlined above in principle can accommodate the
preparation of a variety of benzazocines of type 65 in which the
four hydroxyl groups are differentially protected, thus enabling
maximum flexibility in the later stages of the synthesis. Initially,
Scheme 11 outlines our approach. Union of cyclobutenone 67
and ynamide 68 via benzannulation was expected to provide 66,
the substrate for ring-closing metathesis to generate benzazocine
65. The requisite ynamide would be prepared via N-alkynylation
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Scheme 11. Formal Total Synthesis of (þ)-FR900482: Retrosynthetic Analysis
Scheme 12. Enantioselective Synthesis of Bromoalkyne In-
termediate 76
Scheme 14. Synthesis of the Benzazocine Core of (þ)-
FR900482
Scheme 13. Synthesis of Cyclobutenone Benzannulation
Components
has previously been prepared by Nagao.39b Acylation of (S)-4-
isopropyl-1,3-thiazolidine-2-thione41 with 3-benzyloxypropionyl
chloride42 furnished convenient access to 72, which was treated with
N-ethylpiperidine and freshly prepared tin(II) triflate at -78 °C.
Reaction of the resulting tin enolate with acrolein at -78 °C then
afforded the expected aldol product with greater than 95% selectivity
for the desired isomer.43 Attempts to employ titanium(IV) enolate
derivatives of N-acylthiazolidinethiones according to the method of
Crimmins44 for this transformation led to significant decomposition
of the substrate, and reactions using the corresponding oxazolidi-
nones were not successful under a range of conditions.
Silylation of the secondary alcohol in 73 and reduction of the
N-acylthiazolidinethione with DIBAL-H next furnished aldehyde
74 in excellent yield. The chiral auxiliary, (S)-4-isopropyl-1,3-
thiazolidine-2-thione, was recovered in 75% yield simply by
trituration of the crude product with hexanes prior to purification
of the aldehyde by column chromatography. Conversion of 74 to
the bromo alkyne 76 was effected in a convenient one-pot
operation by the general method of Michel and Rassat.45 Thus,
reaction of the aldehyde with ylide 7546 afforded the expected
we targeted a system with orthogonal blocking groups; specifi-
cally, R1 = TBDMS, R2 = benzyl, and R3 = CH2OMe (MOM
ether). For the syn aldol condensation, an issue of some concern
was the potential for enolate derivatives of type 71 to undergo
β-elimination under the conditions of the reaction. For this reason,
we concentrated our attention on Mukaiyama-type aldol chemistry
involving tin enolates since these reactions are known to tolerate the
use of enolate derivatives with β-alkoxy substituents.38 Best results
were obtained by employing the method of Nagao39,40 and the tin
enolate derivative of thiazolidinethione 72, the enantiomer of which
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Scheme 15. Completion of the Formal Total Synthesis
prepared in racemic form in the course of his synthesis of
FR66979.36 Williams has previously reported conversion of
FR66979 to FR900482 via Swern oxidation.33
For the synthesis of 64, we elected to employ allyl carbamate
86 in which the amino group is protected as a Teoc (2-(trime-
thylsilyl)ethoxycarbonyl) derivative rather than as a BOC deri-
vative. This modification would enable simultaneous deprotec-
tion of the amine and allylic hydroxyl groups in the last step in the
sequence. As shown in Scheme 15, the benzannulation in this
case again proceeded smoothly, and after benzylation of the
phenol, ring-closing metathesis furnished benzazocine 90 in
excellent yield. Exposure of the RCM product to the action of
TBAF in THF then provided 64, with spectroscopic character-
istics identical to those reported by Ducray and Ciufolini.36
’ CONCLUSION
The combination of the ynamide-based benzannulation with
ring-closing metathesis provides an expeditious strategy for the
assembly of benzofused nitrogen heterocycles in which the
aromatic ring can bear a high level of substitution. The synthetic
utility of this tandem strategy is illustrated in its application in an
exceptionally concise enantioselective route to the benzazocine
core of the antitumor agents (þ)-FR900482 and (þ)-FR66979.
Further elaboration of the benzannulation products via transi-
tion-metal-mediated coupling reactions of derivatives of the
phenolic hydroxyl group and via oxidation to benzoquinones
should also be possible on the basis of our previous studies.2,5
Tandem strategies based on the combination of the ynamide-
based benzannulation with other heterocyclization methods are
under investigation in our laboratory and will be reported in due
course.
1,1-dibromoalkene, which without isolation was treated in the
same flask with excess KO-t-Bu to effect elimination producing
bromoalkyne 76 in excellent yield (Scheme 12).
Scheme 13 outlines the preparation of the two cyclobutenones
examined as vinylketene precursors for the key benzannulation step.
Each of these compounds was prepared from 3-ethoxycyclobute-
none47 by addition of an alkoxylithium reagent generated by trans-
metalation from the appropriate organostannane.48 In situ hydrolysis
of the resulting vinylogous hemiacetal employing the protocol
introduced by Liebeskind49 furnished the desired cyclobutenones,
in each case in 65% yield.
The next step in the synthesis, N-alkynylation of allyl carbamate
82 with bromo acetylene 76, proved unexpectedly challenging.
Application of our usual protocol14 afforded 83 in at best 42% yield
accompanied by considerable diyne resulting from homocoupling of
the alkynyl bromide. Improved results were obtained by employing
the Hsung “second generation” protocol15 as outlined in Scheme 13.
In this reaction, homodimerization was minimized by using 3 equiv
of the carbamate and by adding 0.4 equiv of copper sulfate and 0.8
equiv of 1,10-phenanthroline (total) in two equal portions over 46 h
with reaction at 80-85 °C. The desired ynamide 83 was isolated in
68% yield, and none of the homodimer byproduct was detected
under these conditions.
With both ynamide 83 and the requisite cyclobutenones in hand,
we were ready to examine the key tandem benzannulation/RCM
stage of the synthetic plan. As shown in Scheme 14, benzannulation
employing cyclobutenone 81 proceeded smoothly under our
standard conditions to afford 84, and subsequent exposure of the
product to the action of the Grubbs “second generation” metathesis
catalyst provided the desired benzazocine 85 in excellent yield.
Overall, this strategy provides access to the benzazocine core of
(þ)-FR900482 in only nine steps in the longest linear sequence.
Completion of a formal total synthesis of (þ)-FR900482 and
(þ)-FR66979 required that we link our route to an intermediate
previously transformed to the natural products. As outlined in
Scheme 15, we targeted Ciufolini’s intermediate 64, which was
’ EXPERIMENTAL SECTION
General Procedures. All reactions were performed in flame-dried
or oven-dried glassware under a positive pressure of argon. Reaction
mixtures were stirred magnetically unless otherwise indicated. Air- and
moisture-sensitive liquids and solutions were transferred by syringe or
cannula and introduced into reaction vessels through rubber septa.
Reaction product solutions and chromatography fractions were con-
centrated by rotary evaporation at ca. 20 mmHg and then at ca. 0.1
mmHg (vacuum pump) unless otherwise indicated. Thin-layer chro-
matography was performed on precoated glass-backed silica gel 60
F-254 0.25 mm plates. Column chromatography was performed on silica
gel 60 (230-400 mesh).
Materials. Commercial grade reagents and solvents were used
without further purification except as indicated below. Dichloro-
methane, diethyl ether, and tetrahydrofuran were purified by pressure
filtration through activated alumina. Toluene was purified by pressure
filtration through activated alumina and Cu(II) oxide. Chloroform,
pivaloyl chloride, oxalyl chloride, and trifluoroacetic anhydride were
distilled at atmospheric pressure under argon. Triethylamine, pyridine,
N-ethylpiperidine, 2,6-lutidine, and benzene were distilled under argon
from calcium hydride prior to use. Acrolein was distilled under vacuum
at 150 mmHg immediately prior to use. Copper(I) iodide was extracted
with THF for 24 h in a Soxhlet extractor and then dried under vacuum
(0.1 mmHg). N-Bromosuccinimide was recrystallized from boiling
water. Triflic anhydride was distilled under argon from P2O5. n-
Butyllithium was titrated according to the Watson-Eastham method
using BHT in THF with 1,10-phenanthroline as an indicator.50 Potas-
sium tert-butoxide was titrated using p-toluenesulfonic acid in MeOH
with phenolphthalein as an indicator.
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Instrumentation. Melting points are uncorrected. 1H NMR che-
mical shifts are expressed in parts per million (δ) downfield from
tetramethylsilane (with the CHCl3 peak at 7.27 ppm used as a standard).
13C NMR chemical shifts are expressed in parts per million (δ) down-
field from tetramethylsilane (with the central peak of CHCl3 at 77.23
ppm used as a standard).
was cooled at 0 °C while a solution of KHMDS (11.0 mL, 9.98 mmol,
0.91 M in THF, 1.0 equiv) was added dropwise via syringe over 8
min, and the resulting yellow slurry was stirred at 0 °C for 15 min.
Pyridine (20.0 mL, 250 mmol, 25 equiv) was then added in one
portion via syringe, followed by CuI (1.90 g, 9.98 mmol, 1.0 equiv),
also in a single portion. The resulting green reaction mixture was allowed to
warm to rt over 2 h. A solution of bromoalkyne 2214a (2.17 g, 15.0 mmol,
1.5 equiv) in 15 mL of THF was added dropwise over 30 min via cannula,
and the reaction mixture was stirred at rt for 20 h. The reaction mixture
was diluted with 160 mL of Et2O and washed with three 100-mL portions
of a 2:1 mixture of brine and concd aq NH4OH solution. The combined
aqueous phases were extracted with two 60-mL portions of Et2O, and the
combined organic phases were dried over MgSO4, filtered, and concentrated
to give ca. 9.5 g of dark brown oil. Purification by column chromatography on
53 g of silica gel (gradient elution with 0-5% EtOAc-hexanes) afforded
0.880 g (49%) of ynamide 26 as an orange oil: IR (thin film) 3456, 2958,
Experimental Procedures for the Preparation of Yna-
mides and Cyclobutenones.
Pent-4-en-1-ynyl Bromide (21). A 500-mL, one-necked, round-
bottomed flask equipped with a rubber septum and argon inlet needle was
charged with 1-penten-4-yne (4.03 g, 60.5 mmol, 1.0 equiv), N-bromosucci-
nimide (11.8 g, 66.6 mmol, 1,1 equiv), AgNO3 (1.00 g, 6.05 mmol, 0.1
equiv), and 300 mL of acetone, and the resulting mixture was stirred in the
dark at rt for 12.5 h. The cloudy yellow reaction mixture was then diluted with
300 mL of pentane and washed with three 125-mL portions of ice-cold water.
The combined aqueous layers were extracted with 100 mL of pentane, and
the combined organic layers were washed with three 80-mL portions of
saturated aq Na2S2O3 solution and two 80-mL portions of brine, dried over
MgSO4, filtered, and concentrated at atmospheric pressure through a 9-cm
Vigreux column to give 10.27 g of a pale yellow liquid. Bulb-to-bulb
distillation (100 mmHg, 80 °C oven temperature) afforded 6.55 g (75%,
ca. 95% pure) of pent-4-en-1-ynyl bromide 21 as a colorless liquid: IR (thin
film) 2254, 1077, 1006, 895 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.74-
5.86 (m, 1H), 5.53 (app dq, J = 1.7 Hz, 17.0 Hz, 1H), 5.15 (app dq, J = 1.6,
10.0 Hz, 1H), 3.00 (app dt, J = 1.8, 5.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 131.8, 116.8, 77.1, 40.6, 24.2; HRMS-ESI (m/z) calcd for C5H4Br
142.9491, found 142.9493.
1
2257, 1732, 1445, 1368, 1303, 1245, 1150 cm-1; H NMR (300 MHz,
CDCl3) δ 5.82-5.95 (m, 1H), 5.12-5.34 (m, 4H), 4.10 (td, J = 1.3, 6.1 Hz,
2H), 3.83 (s, 3H), 1.91 (dd, J = 1.0, 1.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 155.5, 131.7, 126.5, 119.6, 118.9, 82.2, 72.3, 54.3, 52.9, 23.9;
HRMS-ESI (m/z) [M þ Na] calcd for C10H13NO2 202.0838, found
202.0844.
N-(Methoxycarbonyl)-N-(5-hexen-1-ynyl)-2-propenylamine
(27). Reaction of a solution of carbamate 1952 (0.765 g, 5.92 mmol,
1.0 equiv) in 24 mL of THF with KHMDS (6.50 mL, 5.92 mmol, 0.91 M in
THF, 1.0 equiv), pyridine (12.0 mL, 148 mmol, 25 equiv), CuI (1.20 g, 6.30
mmol, 1.05 equiv), and alkynyl bromide 21 (15.0 mL, 8.88 mmol, 1.5 equiv,
0.6 M in benzene) according to the general procedure gave 3.5 g of brown
oil. Column chromatography on 80 g of silica gel (gradient elution with 5-
10% EtOAc-hexanes) afforded 0.539 g (52%) of ynamide 27 as a yellow
oil: IR (thin film) 3394, 2956, 1726, 1642, 1446, 1391, 1291, 1249, 1154,
915 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.77-5.89 (m, 2H), 5.35 (qd,
J = 1.8, 16.8 Hz, 1H), 5.06-5.16 (m, 2H), 3.80 (s, 3H), 3.54 (t, J = 7.0 Hz,
2H), 3.11 (td, J = 1.8, 5.2 Hz, 2H), 2.43 (q, J = 7.1 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 156.2, 134.3, 132.9, 117.3, 115.8, 76.7, 74.4, 53.9, 49.2,
32.0, 22.8; HRMS-ESI (m/z) [M þ H] calcd for C11H15NO2 194.1176,
found 194.1170.
N-(Methoxycarbonyl)-N-(4-penten-1-ynyl)-2-propenylamine
(25). Reaction of a solution of carbamate 18 (1.06 g, 9.20 mmol, 1.0 equiv)
in 35 mL of THF with KHMDS (10.1 mL, 9.20 mmol, 0.91 M in THF, 1.0
equiv), pyridine (18.0 mL, 230 mmol, 25 equiv), CuI (1.75 g, 9.20 mmol, 1.0
equiv), and alkynyl bromide 21 (2.0 g, 13.8 mmol, 1.5 equiv) in 14 mL of
THF according to the general procedure gave 3.83 g of brown oil. Column
chromatography on 60 g of silica gel (gradient elution with 0-5% EtOAc-
hexanes) afforded 0.951 g of an orange oil which was further purified on 20 g
of silica gel (gradient elution with 0-5% EtOAc-hexanes) to afford 0.722 g
(44%) of ynamide 25 as a yellow oil: IR (thin film) 3395, 2957, 2239, 1729,
1446, 1388, 1280, 1235, and 1152 cm-1; 1H NMR (300 MHz, CDCl3) δ
5.79-5.95 (m, 2H), 5.22-5.38 (m, 3H), 5.09-5.15 (m, 1H), 4.07 (d, J=5.8
Hz, 2H), 3.82 (s, 3H), and 3.09 (td, J = 1.9, 5.2 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 156.1, 133.0, 131.9, 118.5, 116.0, 76.1, 66.7, 54.1, 52.7, and
22.9; HRMS-ESI (m/z) [M þ H] calcd for C10H13NO2 180.1019, found
180.1019.
N-(Methoxycarbonyl)-N-(2-propenyl)-2-(trimethylsilyl)-
ethynylamine (29). Reaction of a solution of carbamate 18 (0.283
g, 2.45 mmol, 1.0 equiv) in 10 mL of pyridine with KHMDS
(2.70 mL, 2.45 mmol, 0.91 M in THF, 1.0 equiv), CuI (0.520 g,
2.71 mmol, 1.0 equiv), and iodoalkyne 23 (6.1 mL, 0.6 M in benzene,
3.67 mmol, 1.5 equiv) in 4 mL of pyridine according to the general
procedure gave 0.754 g of black oil, which was purified by column
chromatography on 20 g of silica gel (gradient elution with 0-10%
EtOAc-hexanes) to afford 0.300 g (58%) of ynamide 29 as a dark
orange oil: IR (thin film) 2958, 2179, 1737, 1444, 1274, 866 cm-1
;
General Procedure for the Synthesis of Ynamides 25-28.
N-(Methoxycarbonyl)-N-(3-methyl-3-buten-1-ynyl)-2-propeny-
lamine (26). A 200-mL, round-bottomed flask fitted with a rubber septum
and argon inlet needle was charged with a solution of allyl carbamate
1851 (1.15 g, 9.98 mmol, 1.0 equiv) in 40 mL of THF. The solution
1H NMR (400 MHz, CDCl3) δ 5.89 (ddt, J = 17.0, 10.3, 6.2 Hz, 1H),
5.25-5.32 (app t, J = 11.2, 17.0 Hz, 2H), 4.07 (d, J = 6.1 Hz, 2H),
3.83, (s, 3H), and 0.21 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
155.6, 131.4, 118.9, 95.5, 72.6, 54.2, 52.7, 0.4 (peaks corresponding
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to minor rotamer: 130.9, 119.5, 87.5, 54.6); HRMS-ESI (m/z) [M þ
argon inlet adapter was charged with N-(methyl)-N-(p-toluenesulfo-
nyl)ethynylamine (0.466 g, 2.23 mmol, 1.0 equiv) and 20 mL of THF.
The solution was cooled to -78 °C, and KHMDS (3.2 mL, 2.89 mmol,
0.91 M solution in THF, 1.3 equiv) was added dropwise via syringe over
3 min. The reaction mixture was stirred at -78 °C for 1.5 h. MeI (0.25
mL, 0.569 g, 4.01 mmol, 1.8 equiv) was then added to the cloudy yellow
reaction mixture in one portion by syringe. The resulting mixture was
allowed to warm to rt over 1.5 h and then diluted with 15 mL of satd
NH4Cl solution and 15 mL of Et2O. The aqueous layer was extracted
with two 10-mL portions of Et2O, and the combined organic layers were
washed with 20-mL of brine, dried over MgSO4, filtered, and concen-
trated to afford 0.520 g of orange-yellow solid. Recrystallization from ca.
5 mL of hot hexanes (with cooling to -18 °C) provided 0.446 g of
ynamide 32 (90%) as pale yellow flakes: mp 93-95 °C; IR (thin film)
2931, 2262, 1595, 1451, 1357, 1169, 1038 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 3.00 (s, 3H),
2.45 (s, 3H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.7, 133.2,
129.8, 127.9, 73.8, 64.2, 39.4, 21.8, 3.3. Anal. Calcd for C11H13NO2S: C,
59.17; H, 5.87; N, 6.27. Found, C, 58.97; H, 5.75; N, 6.27.
Na] calcd for C10H17NO2Si; 234.0921, found 234.0925.
N-(Methyl)-N-(p-toluenesulfonyl)-2-(triisopropylsilyl)ethy-
nylamine (31). A 7-mL capacity resealable tube fitted with a rubber
septum was charged with N-methyltoluenesulfonamide 30 (0.250 g, 1.35
mmol, 1.0 equiv), 1,10-phenanthroline (0.049 g, 0.27 mmol, 0.2 equiv),
K2CO3 (0.373 g, 2.70 mmol, 2.0 equiv), CuSO4 5H2O (0.034 g, 0.135
3
mmol, 0.1 equiv), 1-bromo-2-(triisopropylsilyl)acetylene (0.423 g, 1.62
mmol, 1.2 equiv), and 1.1 mL of toluene. The reaction mixture was heated
at 65 °C for 24 h. The resulting yellow-green reaction mixture was cooled to
rt and filtered, and the filtrate was concentrated to afford 1.1 g of yellow oil
which was purified by column chromatography on 15 g of silica gel (gradient
elution with 0-10% EtOAc-hexanes) to afford 0.326 g (66%) of ynamide
31 as a white solid: mp 50-51 °C; IR (thin film) 2943, 2865, 2166, 1598,
1463, 1371, 1173, 987, 883 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (d,
J= 8.0 Hz, 2H), 7.33 (d, J= 7.9 Hz, 2H), 3.06 (s, 3H), 2.44 (s, 3H), 1.04 (app
br s, 21H); 13C NMR (100 MHz, CDCl3) δ 144.9, 133.3, 129.8, 127.9, 98.2,
67.5, 39.4, 21.7, 18.7, 11.4. Anal. Calcd for C19H31NO2SSi: C, 62.42; H, 8.55;
N, 3.83. Found: C, 62.13; H, 8.67; N, 3.82.
N-(Methoxycarbonyl)-N-(2-propenyl)ethynylamine (33).
A 100-mL recovery flask fitted with a rubber septum and argon inlet needle
was charged with ynamide 29 (1.11 g, 5.25 mmol, 1.0 equiv) and 52 mL of
THF. The yellow solution was cooled to -78 °C, and TBAF (5.80 mL, 1.0
M in THF, 5.78 mmol, 1.1 equiv) was added dropwise via syringe over 8
min. The resulting dark green solution was stirred at -78 °C for 20 min and
then allowed to warm to rt over 20 min. The reaction mixture was quenched
by addition of 40 mL of satd NH4Cl solution, and the aqueous layer was
separated and extracted with three 30-mL portions of Et2O. The combined
organic layers were washed with 50 mL of brine, dried over MgSO4, filtered,
and concentrated to give 1.0 g of dark brown oil. Column chromatography
on 30 g of silica gel (elution with 10% EtOAc-hexanes) provided 0.617 g
(84%) of ynamide 33 as a yellow oil: IR (thin film) 3298, 2958, 2241
(weak), 2146, 1734, 1445, 1362, 1277 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.88 (ddt, J = 6.0, 10.5, 16.9 Hz, 1H), 5.26-5.32 (app t, J = 10.3, 17.2 Hz,
2H), 4.08 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.83 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 155.8, 131.4, 119.0, 77.5, 59.0, 54.4, 52.5; HRMS-ESI (m/
z) [M þ Na] calcd for C7H9NO2 162.0525, found 162.0531.
N-(Methyl)-N-(p-toluenesulfonyl)ethynylamine
(S1). A
two-necked, 50-mL pear flask fitted with a rubber septum and an argon
inlet adapter was charged with ynamide 31 (1.22 g, 3.34 mmol, 1.0 equiv)
and 20 mL of THF. The solution was cooled to -40 °C, and tetrabuty-
lammonium fluoride (3.60 mL, 3.67 mmol, 1.0 M solution in THF, 1.1
equiv) was added dropwise over 2 min via syringe. The resulting cloudy
yellow mixture was allowed to warm to rt over 1 h. The resulting reaction
mixture was diluted with 25 mL of satd NH4Cl solution and 20 mL of Et2O,
and the aqueous phase was extracted with three 10-mL portions of Et2O.
The combined organic phases were washed with 30 mL of brine, dried over
MgSO4, filtered, and concentrated to give 1.41 g of pale yellow solid. This
material was recrystallized from ca. 3 mL of hot hexanes to afford 0.601 g
(86%) of ynamide S1 as white crystals: mp 74-76 °C; IR (thin film) 3280,
2936, 2137, 1597, 1450, 1361, 1174, and 960 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 3.04 (s, 3H),
2.69 (s, 1H), and 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.1,
133.1, 130.0, 127.9, 77.6, 57.6, 39.0, and 21.8. Anal. Calcd for C10H11NO2S:
C, 57.39; H, 5.30; N, 6.69. Found: C, 57.31; H, 5.28; N, 6.56.
N-(Methoxycarbonyl)-N-(2-propenyl)-5-(trimethylsilyl)-
penta-1, 4-diynylamine (34). A 25-mL, pear flask fitted with a rubber
septum and argon inlet needle was charged with ynamide 33 (0.127 g, 0.913
mmol, 1.0 equiv) and 2 mL of DMF. Sodium iodide (0.137 g, 0.913 mmol,
1.0 equiv), Cs2CO3 (0.297 g, 0.913 mmol, 1.0 equiv), and CuI (0.174 g,
0.913 mmol, 1.0 equiv) were added, and the resulting bright yellow
N-(Methyl)-N-(p-toluenesulfonyl)-2-methylethynylamine
(32). A 50-mL, two-necked, pear flask fitted with a rubber septum and
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heterogeneous mixture was stirred at rt for 25 min. 3-Trimethylsilylpro-
pargyl bromide (0.155 mL, 0.209 g, 1.10 mmol, 1.2 equiv) was then added
dropwise over 4 min by syringe, and the reaction mixture was stirred at rt for
16 h. The resulting dark red-brown mixture was diluted with 20 mL of Et2O
and 10 mL of satd NH4Cl solution. The organic layer was washed with two
10-mL portions of H2O, and the combined aqueous layers were extracted
with two 15-mL portions of Et2O. The combined organic layers were
washed with 20 mL of brine, dried over MgSO4, filtered, and concentrated
to give 0.282 g of dark brown oil. Column chromatography on 20 g of silica
gel (elution with 5% EtOAc-hexanes) afforded 0.142 g (62%) of
diynamide 34 as a dark yellow oil: IR (thin film) 2959, 2269, 2182, 1732,
1446, 1251, 845 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.87 (ddt, J = 6.0,
10.1, 15.8 Hz, 1H), 5.23-5.31 (app t, J = 11.1, 19.4 Hz, 2H), 4.06 (d, J = 5.8
Hz, 2H), 3.81 (s, 3H), 3.34 (s, 2H), 0.17 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 156.1, 131.9, 118.9, 100.7, 85.2, 74.3, 64.4, 54.5, 54.3, 52.8, 11.1,
0.2; HRMS-ESI (m/z) [M þ Na] calcd for C13H19NO2Si 272.1077, found
272.1080.
2929, 2858, 1679, 1618, 1583, 1459, 1378, 1198, 1163 cm-1; 1H NMR
(500 MHz, CDCl3) δ 6.60 (s, 1H), 6.55 (s, minor rotamer), 6.53
(s, 1H), 6.50 (s, minor rotamer), 5.47 (br s, minor rotamer), 5.22 (br s,
1H), 3.80 (s, minor rotamer), 3.64 (s, 3H), 3.20 (s, 3H), 2.44-2.53 (m,
4H), 1.47-1.60 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 157.0, 154.7,
142.4, 142.3, 124.4, 120.0, 115.0, 53.1, 38.7, 35.2, 33.4, 32.0, 30.0, 29.3,
25.7, 22.8, 22.6, 14.2; HRMS-ESI (m/z) [M þ Na] calcd for
C19H31NO3 344.2196, found 344.2186. The regiochemistry of the
benzannulation product was confirmed by an NOE study. Irradiation
of the benzylic protons on the butyl substituent resulted in enhancement
of both aromatic ring protons, ruling out the “Ficini rearrangement”-
type product (Scheme 4, 16) in which one of these protons would be
para rather than ortho to the butyl substituent.
Photochemical Benzannulation. A 5-mL Vycor tube equipped
with a rubber septum was charged with cyclobutenone 35 (0.025 g, 0.20
mmol, 1.0 equiv), ynamide 24 (0.059 g, 0.30 mmol, 1.5 equiv), and 0.4
mL of toluene. The solution was then degassed by three freeze-pump-
thaw cycles (-196 °C, 0.02 mmHg). The reaction mixture was
irradiated at 254 nm at rt in a Rayonet photochemical reactor. The
reaction mixture was then concentrated to give 0.148 g of a yellow oil.
Purification by column chromatography on 5 g of silica gel (elution with
10% EtOAc-hexanes) provided 0.042 g (66%) of aniline 36 as a white
solid.
Microwave-Promoted Benzannulation. A 5-mL microwava-
ble glass tube equipped with a rubber septum was charged with
cyclobutenone 35 (0.037 g, 0.29 mmol, 1.0 equiv), ynamide 24 (0.057
g, 0.29 mmol, 1.0 equiv), and 0.3 mL of benzene. The tube was sealed,
and the reaction mixture was heated in a CEM “Discover” microwave
apparatus at 130 °C for 30 min (70-90W, 40 psi). The reaction mixture
was cooled to rt and concentrated to give 0.107 g of a yellow oil. Column
chromatography on 5 g of silica gel (elution of 10% EtOAc-hexanes)
provided 0.069 g (74%) of aniline 36 as a white solid.
3-Methoxy-2-methylcyclobutenone (39). Ketene was gener-
ated by pyrolysis of acetone over an electrically heated metal filament
using the apparatus described by Williams and Hurd.53 A 250-mL, three-
necked flask fitted with a rubber septum, argon inlet adapter, and glass
stopper was charged with methoxypropyne54 (7.60 g, 108 mmol, 1.0
equiv) in 75 mL of CH3CN and cooled to 0 °C. The argon inlet adapter
was replaced with an adapter fitted with a glass pipet connected via
Tygon tubing to the ketene generator. The septum was fitted with an
outlet needle connected via tubing to a column of CaSO4 leading to a
trap of H2O. Ketene was bubbled into the reaction mixture at 0 °C for 8 h
and then concentrated to 15.6 g of red oil. This oil was concentrated at 5
mmHg for 1.5 h to remove excess diketene and then distilled through a
10-cm Vigreux column at 0.4 mmHg (bp 54-55 °C) to give 5.90 g
(49%) of cyclobutenone 39 as a colorless oil: IR (thin film) 2925, 1757,
1627, 1461, 1385, 1343, 1125, 970 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.07 (s, 3H), 3.13 (q, J = 2.5 Hz, 2H), 1.63 (t, J = 2.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 186.0, 177.0, 117.4, 59.9, 46.8, 6.8; HRMS-
ESI (m/z) [M þ H] calcd for C6H8O2 113.0597, found 113.0600.
Experimental Procedures for Benzannulations.
N-(Methyl)-N-(p-toluenesulfonyl)-5-butyl-3-hydroxy-2-
methylamine (37). A 25-mL, round-bottomed flask equipped with a
rubber septum and argon inlet needle was charged with ynamide 32 (0.100
g, 0.448 mmol, 1.0 equiv), cyclobutenone 35 (0.069 g, 0.556 mmol, 1.2
equiv), and 0.8 mL of toluene. The septum and needle were replaced
with a coldfinger condenser with an argon inlet, and the pale yellow
reaction mixture was heated at reflux for 1 h. The reaction mixture
was cooled to rt and concentrated to afford 0.179 g of light brown oil.
This material was diluted with 2 mL of MeOH and ca. 1.5 mL of 5 M
KOH solution and heated at 60-70 °C for 3 h. The resulting mixture
was cooled to rt and then diluted with 2 mL of 10% HCl solution and
8 mL of Et2O. The aqueous layer was separated and extracted with
two 2-mL portions of Et2O, and the combined organic layers were
washed with 5 mL of satd NaHCO3 solution and 5 mL of brine, dried
over MgSO4, filtered, and concentrated to 0.197 g of orange oil.
Purification by column chromatography on 15 g of silica gel (elution
with 15% EtOAc-hexanes) afforded 0.127 g of aniline 37 (81%) as
an off-white solid: mp 96-98 °C; IR (thin film) 3447, 2929, 1618,
N-(Methoxycarbonyl)-N-methyl-5-butyl-2-hexyl-3-hydro-
xyphenylamine (36) Thermal Benzannulation. A 8-mL reseal-
able tube fitted with a rubber septum and argon inlet needle was charged
with ynamide 2412 (0.089 g, 0.50 mmol, 1.0 equiv), cyclobutenone 3518
(0.067 g, 0.54 mmol, 1.2 equiv), and 0.5 mL of toluene. The reaction
mixture was heated at reflux for 1 h, cooled to rt, and concentrated to
0.254 g yellow oil. Purification by column chromatography on 10 g of
silica gel (elution with 10% EtOAc-hexanes) afforded 0.129 g (80%) of
aniline 36 as a white solid: mp 66-68 °C; IR (thin film) 3342, 2956,
1586, 1428, 1342, 1160, 1035, 917 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.59 (s,
1H), 5.97 (s, 1H), 5.27 (br s, 1H), 3.11 (s, 3H), 2.46 (s, 3H), 2.35 (t,
J = 7.6 Hz, 2H), 2.24 (s, 3H), 1.40 (tt, J = 7.2, 7.6 Hz, 2H), 1.26 (m,
2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.0,
143.6, 141.4, 141.1, 135.0, 129.6, 128.3, 122.4, 119.0, 115.4, 39.2,
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35.1, 33.4, 22.4, 21.8, 14.2, 11.2. Anal. Calcd for C19H25NO3S: C,
65.38; H, 7.25; N, 4.03. Found: C, 65.38; H, 7.13; N, 3.92.
(ca. 5 mL capacity) fitted with a rubber septum and argon inlet needle
was charged with ynamide 27 (0.180 g, 0.931 mmol, 1.0 equiv),
cyclobutenone 39 (0.208 g, 1.85 mmol, 2.0 equiv), and 1 mL of CHCl3.
The resulting yellow solution was degassed via three cycles of freeze-
pump-thaw (-196 °C, 0.05 mmHg) and sealed under argon with a
threaded Teflon screw cap. The tube was submerged in an oil bath and
heated at 150 °C for 16.5 h. After being cooled to rt, the reaction mixture
was transferred to a 25-mL, round-bottomed flask and concentrated to
ca. 0.45 g of dark brown oil, which was diluted with 3 mL of MeOH and
2 mL of 5 M KOH solution. The flask was fitted with a reflux condenser,
and the reaction mixture was heated at 65 °C for 2 h, cooled to rt, and
diluted with 2 mL of 10% HCl solution and 10 mL of Et2O. The aqueous
layer was extracted with three 4-mL portions of Et2O, and the combined
organic layers were washed with 8 mL of brine, dried over MgSO4,
filtered, and concentrated to afford 0.355 g of red-brown oil. Column
chromatography on 23 g of silica gel (gradient elution with 20-25%
EtOAc-hexanes) afforded 0.176 g (62%) of aniline 45 as a yellow tinted
solid: mp 167-170 °C; IR (thin film) 3331, 2954, 1677, 1605, 1461,
N-(Methoxycarbonyl)-N-allyl-2-allyl-5-butyl-3-hydroxy-
phenylamine (43). A 15-mL resealable tube fitted with a rubber septum
and argon inlet needle was charged with ynamide 25 (0.093 g, 0.519 mmol,
1.0 equiv), cyclobutenone 35 (0.077 g, 0.623 mmol, 1.2 equiv), and 0.5 mL
of toluene. The reaction mixture was stirred at 80-85 °C for 1.5 h and then
at 110 °C for 1.5 h. The reaction mixture was cooled to rt and concentrated
to afford 0.213 g of orange-red oil. Column chromatography on 11 g of silica
gel (gradient elution with 10-15% EtOAc-hexanes) afforded 0.132 g (84%)
of aniline 43 as a pale yellow solid: mp 39-40 °C; IR (thin film) 3338, 2957,
2930, 1677, 1584, 1459, 1389, 1273, 1197, 1151, 991 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.67 s, 1H), 6.55 (s, 1H), 5.86-5.94 (m, 2H), 5.50-5.54
(m, 2H), 5.41 (br s, 1H), 5.08-5.18 (m, 4H), 4.35 (dd, J = 6.1, 14.7 Hz,
1H), 3.88-3.93 (m, 1H), 3.80 (s, minor rotamer), 3.62 (s, 3H), 3.30 (m,
2H), 2.43 (t, J = 7.6 Hz, 2H), 1.57 (quintet, J = 7.6 Hz, 2H), 1.34 (q, J = 7.4
Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.5,
155.5, 143.1, 140.8, 135.8, 135.4, 121.4, 120.7, 116.9, 116.7, 115.8, 53.1, 50.1,
35.3, 33.3, 30.4, 22.5, 14.1; HRMS-ESI (m/z) [M þ Na] calcd for
C18H25NO3 326.1727, found 326.1741. Anal. Calcd for C18H25NO3: C,
71.26; H, 8.31; N, 4.62. Found: C, 71.05; H, 8.55; N, 4.34.
1
1393, 1327, 1309, 1196, 1172, 1124, 1020, 917 cm-1; H NMR (500
MHz, CDCl3, 50 °C) δ 6.46 (s, 1H), 6.32 (s, minor rotamer), 5.88-5.96
(m, 1H), 5.68-5.76 (m, 1H), 5.48 (s, 1H), 5.12-5.17 (m, 2H), 4.99-
5.11 (m, 2H), 3.81 (s, minor rotamer), 3.80 (s, 3H), 3.74 (s, minor
rotamer), 3.61 (s, 3H), 3.53-3.57 (m, 2H), 3.48-3.51 (m, minor
rotamer), 3.26-3.33 (m, 2H), 2.33 (m, 2H), 2.01 (s, minor rotamer),
2.00 (s, 3H); 13C NMR (125 MHz, CDCl3, 50 °C) δ 157.7, 156.7, 154.1,
140.5, 136.4, 135.3, 117.5, 116.8, 116.4, 115.1, 99.5, 55.7, 53.0, 50.6, 32.3,
30.8, 11.3 (peaks corresponding to minor rotamer: 137.1, 116.1, 99.7,
33.0, 31.0); HRMS-ESI (m/z) [M þ H] calcd for C17H23NO4
306.1700, found 306.1704. Anal. Calcd for C17H23NO4: C, 66.86; H,
7.59; N, 4.59. Found: C, 66.59; H, 7.55; N, 4.54.
N-(Methoxycarbonyl)-N-allyl-5-butyl-3-hydroxy-2-isopro-
penylphenylamine (44). A 10-mL pear flask equipped with a
rubber septum and argon inlet needle was charged with ynamide 26
(0.058 g, 0.324 mmol, 1.0 equiv), cyclobutenone 35 (0.080 g, 0.647
mmol, 2.0 equiv), and 0.4 mL of benzene. The septum was replaced with
a coldfinger reflux condenser, and the yellow reaction mixture was heated
at reflux for 3 h. The resulting dark orange mixture was cooled to rt and
concentrated to afford 0.163 g of orange oil. Columnchromatography on
14 g of silica gel (elution with 15% EtOAc-hexanes) provided 0.066 g
(67%) of aniline 44 as a yellow tinted solid: mp 74-76 °C; IR (thin
film), 3340, 2957, 1679, 1614, 1575, 1457, 1389, 1315, 1269, 1195, 1152
cm-1; 1H NMR (400 MHz, CDCl3) δ 6.75 s, 1H), 6.52 (s, 1H), 5.87-
5.95 (m, 1H), 5.50-5.54 (m, 2H), 5.06-5.14 (m, 3H), 4.54-4.58 (m,
1H), 3.80 (br s, minor rotamer), 3.63 (s, 3H), 2.54 (t, J = 7.4 Hz, 2H),
1.97 (s, 3H), 1.55-1.61 (m, 2H), 1.26-1.40 (m, 2H), 0.93 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 156.3, 152.6, 143.6, 140.1, 139.3,
133.7, 125.1, 121.5, 119.0, 117.9, 114.6, 53.6, 52.9, 35.4, 33.3, 23.4, 22.5,
14.1; HRMS-ESI (m/z) [M þ Na] calcd for C18H25NO3 326.1727,
found 326.1734. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62.
Found: C, 71.17; H, 8.55; N, 4.34.
N-(Methoxycarbonyl)-N-(but-3-enyl)-2-allyl-3-hydroxy-5-
(methoxymethoxymethyl)-5-methylphenylamine (46). A
5-mL threaded Pyrex tube fitted with a rubber septum and argon inlet
needle was charged with ynamide 27 (0.098 g, 0.507 mmol, 1.0 equiv),
cyclobutenone 40 (0.158 g, 1.01 mmol, 2.0 equiv), and 0.7 mL of CHCl3.
The pale yellow solution was degassed via three freeze-pump-thaw cycles
(-196 °C, 0.05 mmHg), sealed under argon with a Teflon screw cap, and
then heated at 150 °C for 16.5 h. The resulting mixture was cooled to rt,
transferred to a 25-mL round-bottomed flask, and concentrated to give 0.410
g of dark brown oil. The flask was equipped with a reflux condenser fitted
with an argon inlet adapter, 3 mL of MeOH and 2 mL of 5 M KOH solution
were added, and the resulting mixture was heated at 60-70 °C for 2.5 h. The
reaction mixture was cooled to rt and diluted with 2 mL of 10% HCl solution
and 4 mL of Et2O. The aqueous layer was extracted with three 2-mL portions
of Et2O, and the combined organic layers were washed with 4 mL of satd
NaHCO3 solution and 4 mL of brine, dried over MgSO4, filtered, and
concentrated to yield 0.222 g of a dark orange oil. Column chromatography
on 20 g of silica gel (elution with 30% EtOAc-hexanes) afforded 0.106 g
(60%) of aniline 46 as an off-white solid: mp 81-83 °C; IR (thin film) 3336,
2952, 1706, 1676, 1453, 1390, 1326, 1150, 1042 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.93 (s, 1H), 6.83 (s, minor rotamer), 6.24 (s, minor rotamer),
6.21 (s, 1H), 5.85-5.97 (m, 1H), 5.64-5.75 (m, 1H), 4.98-5.09 (m, 4H),
4.74 (s, 2H), 4.70 (s, minor rotamer), 4.50-4.57 (m, 2H), 3.81 (s, minor
rotamer), 3.59 (s, 3H), 3.47-3.58 (m, 2H), 3.43 (s, 3H), 3.41 (s, minor
rotamer), 3.25-3.39 (m, 2H), 2.28-238 (br dt, 2H), 2.08 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 156.7, 153.4, 140.2, 136.1, 136.0, 135.1, 126.3,
123.2, 116.9, 116.0, 115.8, 96.1, 67.7, 55.6, 53.1, 32.3, 31.3, 13.6 (peaks
N-(Methoxycarbonyl)-N-(but-3-enyl)-2-allyl-3-hydroxy-5-
methoxy-5-methylphenylamine (45). A threaded Pyrex tube
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corresponding to minor rotamer: 156.4, 153.6, 140.5, 136.2, 126.4, 123.5,
95.9, 53.3, 32.9, 31.2). Anal. Calcd for C19H27NO5: C, 65.31; H, 7.79; N,
4.01. Found: C, 65.07; H 7.65; N, 3.98.
3.72 (s, 3H), 3.28 (s, 3H), 3.17 (s, minor rotamer), 3.03-3.08 (m, 1H),
2.77 (d, minor rotamer), 2.44 (s, minor rotamer), 2.29-2.4 (m, 2H),
1.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 159.4, 156.1, 153.4,
142.8, 139.4, 135.3, 125.7, 118.9, 117.0, 111.6, 109.8, 53.2, 49.7, 37.6,
36.9 (minor rotamer), 32.6, 23.0, 19.0. Anal. Calcd for C18H24N2O5: C,
62.05; H, 6.94; N, 8.04. Found: C, 61.97; H, 6.73; N, 7.83.
N-(Methoxycarbonyl)-N-(but-3-enyl)-2-allyl-5-butyl-4-
chloro-3-hydroxyphenylamine (47). A 5-mL threaded Pyrex tube
fitted with a rubber septum and argon inlet needle was charged with
cyclobutenone 41 (0.100 g, 0.518 mmol, 1.0 equiv), ynamide 27 (0.150 g,
0.777 mmol, 1.5 equiv), BHT (0.342 g, 1.55 mmol, 3.0 equiv), and 0.7 mL of
toluene. The orange-yellow solution was degassed via three freeze-pump-
thaw cycles (-196 °C, 0.05 mmHg), and the tube was sealed under argon
with a threaded Teflon screwcap. The tube was heated in an oil bath at 135 °C
for 4 h. The resulting solution was cooled to rt, diluted with 10 mL of Et2O,
and washed with two 8-mL portions of H2O and 8 mL of satd NaHCO3
solution. The combined aqueous layers were extracted with two 8-mL
portions of Et2O, and the combined organic layers were washed with 10
mL of brine, dried over MgSO4, filtered, and concentrated to give ca. 0.5 g of
dark red-orange oil. Purification by column chromatography on 24 g of silica
gel (eluted with 10% EtOAc-hexanes) and then on 15 g of silica gel (elution
with 7% EtOAc-hexanes) provided 0.082 g (45%) of aniline 47 as a viscous
orange oil: IR (thin film) 3367, 3078, 2956, 2862, 1694, 1455, 1305, 1152,
915 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.62, (s, 1H), 5.73-5.93 (m,
2H),5.82(s,1H), 5.02-5.10(m,4H),2.90-3.95 (m, 1H), 3.77 (br s, minor
rotamer), 3.59, (s, 3H), 3.21-3.32 (m, 3H), 2.64-2.73 (m, 2H), 2.30-2.35
(m, 2H), 1.56-1.64 (app quintet, J= 7.5 Hz, 2H), 1.35-1.45(appsextet, J=
7.5 Hz,2H), 0.96 (t, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 156.3,
150.5, 139.2, 139.0, 135.3, 135.2, 123.1, 122.3, 119.7, 117.0, 115.7, 53.0, 50.1,
33.4, 31.7, 30.9, 22.6, 14.1; HRMS-ESI (m/z) [M þ Na] calcd for
C19H26ClNO3 374.1493, found 374.1506.
N-(Methoxycarbonyl)-N-allyl-5-butyl-2-(3-trimethylsilyl-
prop-2-ynyl)-3-hydroxyphenylamine (49). A 50-mL pear flask
fitted with a rubber septum and argon inlet needle was charged with the
diynamide 34 (0.543 g, 2.18 mmol, 1.0 equiv), cyclobutenone 35
(0.351 g, 2.61 mmol, 1.2 equiv), and 2.1 mL of toluene. The septum
and needle were replaced with a coldfinger condenser with an argon
inlet and the reaction mixture was heated at 80-85 °C for 1.5 h and
then at reflux for 1 h. The resulting dark red reaction mixture was
cooled to rt and concentrated to afford ca. 1.5 g of red liquid. Column
chromatography on 45 g of silica gel (elution with 15% EtOAc-
hexanes) provided 0.644 g (79%) of 49 as a yellow solid: mp 106-
108 °C, IR (CH2Cl2) 3328, 2957, 2174, 1678, 1588, 1458, 1389, 1249,
842 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.72 (s, 1H), 6.56 (s, 1H),
6.11 (s, 1H), 5.92 (ddt, J = 6.4, 10.4, 17.1 Hz, 1H), 5.10-5.14 (m, 2H),
4.52 (app dd, J = 5.8, 6.7, and 14.6, 15.6 Hz, 1H), 4.07-4.10 (m, 1H),
3.65 (s, 3H), 3.45 (s, 2H), 2.53 (t, J = 7.6 Hz, 2H), 1.57 (app quintet, J =
7.6 Hz, 2H), 1.35 (app sextet, J = 7.5 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H),
0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.6, 155.7, 143.7,
140.2, 133.4, 121.0, 118.9, 118.4, 116.6, 103.1, 87.6, 54.1, 53.5, 35.3,
33.5, 22.7, 17.2, 14.3, 0.3; HRMS-ESI (m/z) [M þ Na]þ calcd for
C21H31NO3Si 396.1965, found 396.1955.
N-(Methoxycarbonyl)-N-(but-3-enyl)-3-hydroxy-2-isopro-
penyl-5-(N-methoxycarbonyl-N-methylamino)phenylamine
(48). A 10-mL, pear flask equipped with a rubber septum and argon inlet
needle was charged with ynamide 28 (0.118 g, 0.611 mmol, 1.0 equiv),
cyclobutenone 428 (0.168 g, 1.08 mmol, 1.8 equiv), and 0.8 mL of toluene.
The septum was replaced with a coldfinger reflux condenser, and the mixture
was stirred at 110 °C for 10 h. The reaction mixture was cooled to rt and
concentrated to furnish ca. 0.450 g of a red-brown oil. Unreacted ynamide 28
was removed from this material via column chromatography on 13 g of silica
gel (elution with 50% EtOAc-hexanes) to provide 0.222 g of a viscous
yellow oil which was transferred into a 25-mL, round-bottomed flask and
diluted with 3 mL of MeOH and 2 mL of 5 M KOH. The flask was fitted
with a reflux condenser, and the mixture was stirred at 65 °C for 3.5 h. After
being cooled to rt, the reaction was quenched with 2 mL of 10% HCl
solution and diluted with 10 mL of Et2O. The aqueous layer was
separated and the organic layer was washed with 5 mL of H2O and 5
mL of brine, dried over MgSO4, filtered, and concentrated to 0.169 g
yellow oil. Columnchromatography on 13 g of silica gel (gradient elution
with 40-50% EtOAc-hexanes) afforded 0.112 g (53%) of aniline 48 as
a pale yellow waxy solid: IR (thin film) 3311, 2956, 1709, 1680, 1609,
1452, 1359, 1264, 1157 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.83 (s,
1H), 5.51 (s, 1H), 5.68-5.78 (m, 1H), 5.61 (s, minor rotamer), 5.44 (s,
1H), 5.00-5.06 (m, 3H), 3.90-4.04 (m, 1H), 3.74 (s, minor rotamer),
N-(Methoxycarbonyl)-N-butyl-4-methoxy-5-methyl-2-pro-
pylphenylamine (52). A 25-mL round-bottomed flask fitted with a
rubber septum and argon inlet needle was charged with aniline 45 (0.088
g, 0.288 mmol, 1.0 equiv), 12 mL of EtOH, and 5% Pd/C (0.061 g, 0.029
mmol, 0.1 equiv). The rubber septum and needle were replaced with a
Claisen adapter equipped with an argon stopcock adapter and an adapter
fitted with a glass pipet. Argon was bubbled through the reaction mixture
for 5 min, and then a balloon of H2 was fitted over the pipet. H2 was
bubbled into the solution at a steady rate at rt for 4 h (the balloon was
refilled with H2 at ca. 30-45 min intervals) after which time the reaction
mixture was purged with argon for 5 min. The resulting mixture was then
carefully filtered through a pad of Celite (rinsed with four 10-mL portions
of EtOH), and the filtrate was concentrated to provide 0.077 g (82%) of
N-(methoxycarbonyl)-N-butyl-3-hydroxy-4-methoxy-5-methyl-2-propyl-
phenylamine (50) as a pale yellow oil which was used in the next step
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ARTICLE
without further purification: IR (thin film) 3343, 2959, 1675, 1604, 1464,
45 (0.048 g, 0.157 mmol, 1.0 equiv) and 1.6 mL of CH2Cl2.
N-Iodosuccinimide (0.042 g, 0.189 mmol, 1.2 equiv) was added in
one portion, and the resulting red-orange mixture was stirred at rt for 2 h.
The reaction mixture was diluted with 10 mL of CH2Cl2 and washed
with two 5-mL portions of satd NaS2O3 solution and 5 mL of brine, dried
over MgSO4, filtered, and concentrated to afford 0.092 g of pale yellow oil.
This material was diluted with 3 mL of MeOH, NaOH (ca. 0.050 g, 1.25
mmol) was added, and the resulting mixture was heated at 65 °C for2 h. The
reaction mixture was cooled to rt and diluted with 2 mL of 1 M HCl solution
and 3 mL of CH2Cl2. The aqueous layer was extracted with three 2-mL
portions of CH2Cl2, and the combined organic layers were washed with
5 mL of satd NaHCO3 solution and 5 mL of brine, dried over MgSO4,
filtered, and concentrated to provide 0.062 g of dark yellow oil. Purification
by column chromatography on 5 g of silica (gradient elution with 5-15%
EtOAc-hexanes) afforded 0.027 g (56%) of benzofuran 53 as a white solid:
mp 79-81 °C; IR (thin film) 2952, 1709, 1592, 1452, 1317, 1120 cm-1; 1H
NMR (500 MHz, CDCl3) δ 6.93 (s, 1H), 6.18 (s, 1H), 5.73 (ddt, J = 6.7,
10.4, 17.2 Hz, 1H), 5.04 (d, J = 17.3 Hz, 1H), 5.00 (d, J = 10.4 Hz, 1H), 3.87
(s, 3H), 3.83 (s, minor rotamer), 3.75-3.81 (m, 2H), 3.62 (s, 3H), 3.57-
3.61 (m, minor rotamer), 2.42 (s, 3H), 2.28-2.34 (m, 2H), 2.13 (s, minor
rotamer), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.6, 155.7, 154.4,
153.8, 135.3, 131.6, 120.5, 120.1, 116.9, 100.6, 93.5, 56.1, 53.2, 49.7, 32.8,
14.3, 11.3. Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.24; H, 6.95, N, 4.59.
1
1309, and 1125 cm-1; H NMR (500 MHz, CDCl3) δ 6.39 (s, 1H),
6.21 (s, minor rotamer), 5.43 (s, minor rotamer), 4.91 (s, 1H), 3.82 (s,
minor rotamer), 3.79 (s, 3H), 3.72 (s, minor rotamer), 3.62 (s, 3H),
3.57-3.61 (m, 1H), 3.32 (app ddd, J = 5.5, 11.3, 13.1 Hz), 2.37-2.48 (m,
2H), 1.99 (s, minor rotamer), 1.97 (s, 3H), 1.46-1.64 (m, 4H), 1.22-
1.31 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H).
A 25-mL recovery flask fitted with a rubber septum and argon inlet
needle was charged with phenol 50 (0.074 g, 0.239 mmol, 1.0 equiv),
DMAP (0.066 g, 0.540 mmol, 2.3 equiv), and 1.2 mL of CH2Cl2. The
resulting mixture was cooled to -20 °C, and triflic anhydride (0.100 mL,
0.162 g, 0.574 mmol, 2.4 equiv) was added dropwise via syringe over ca.
1 min, resulting in a white precipitate. The cooling bath was removed, and the
reaction mixture was allowed to warm to rt over 6 h. The resulting mixture
was diluted with 6 mL of CH2Cl2 andwashedwith3mLof H2Oand3mLof
1 M HCl solution. The combined aqueous layers were extracted with three
3-mL portions of CH2Cl2, and the combined organic layers were washed with
6 mL of brine, dried over MgSO4, filtered, and concentrated to afford 0.150 g
of light brown oil. Purification by column chromatography on 6 g of silica gel
(elution with 10% EtOAc-hexanes) provided 0.077 g (73%) of N-(me-
thoxycarbonyl)-N-butyl-4-methoxy-5-methyl-2-propyl-3-(trifluoromethane-
sulfonyl)phenylamine (51) as a pale yellow oil: IR (thin film) 2963, 1777,
1715, 1611, 1445, 1422, 1214, 1143 cm-1; 1H NMR (400 MHz, CDCl3) δ
6.74 (s, 1H), 3.84 (s, 3H), 3.83 (s, minor rotamer), 3.82 (s, minor rotamer),
3.65 (s, 3H), 3.58-3.66 (m, 1H), 3.28-3.33 (app ddd, J = 3.0, 10.9,
13.6 Hz), 2.41-2.59 (m, 2H), 2.07 (s, minor rotamer), 2.04 (s, 3H),
1.43-1.59 (m, 4H), 1.22-1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H), 0.90 (t,
J = 7.3 Hz, 3H).
Experimental Procedures for Ring-Closing Metathesis
Reactions.
A 10-mL pear flask fitted with a rubber septum and argon inlet needle
was charged sequentially with the aryl triflate 51 (0.072 g, 0.163 mmol,
1.0 equiv), 0.4 mL of DMF, Et3N (0.070 mL, 0.489 mmol, 3.0 equiv),
formic acid (0.012 mL, 0.326 mmol, 2.0 equiv), Pd(OAc)2 (0.002 g,
0.0098 mmol, 0.06 equiv), and dppf (0.005 g, 0.0098 mmol, 0.06 equiv).
The rubber septum was replaced with a coldfinger condenser, and the
reaction mixture was heated at 85-90 °C for 12.5 h. The resulting
mixture was cooled to rt, diluted with 6 mL of Et2O, and washed with
two 3-mL portions of 1 M HCl and then 3 mL of H2O. The combined
aqueous layers were extracted with three 3-mL portions of Et2O, and the
combined organic layers were washed with 6 mL of brine, dried over
MgSO4, filtered, and concentrated to provide 0.050 g of dark brown oil.
Column chromatography on 10 g of silica gel (elution with 10%
EtOAc-hexanes) afforded 0.033 g (69%) of aniline 52 as a colorless
oil: IR (thin film) 2958, 1708, 1600, 1486, 1450, 1304, 1261 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.5 Hz), 6.80 (d, J = 8.5 Hz),
3.84 (s, 3H), 3.82 (s, minor rotamer), 3.79 (s, minor rotamer), 3.61 (s,
3H), 3.54-3.60 (m, 1H), 3.38 (app ddd, J = 5.7, 8.8, 10.7 Hz, 1H),
2.35-2.43 (m, 2H), 2.09 (s, minor rotamer), 2.06 (s, 3H), 1.48-1.65
(m, 4H), 1.24-1.33 (app sextet, J = 7.3 Hz), 0.95 (t, J = 7.3 Hz, 3H),
0.90 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 156.3,
140.0, 132.0, 126.8, 125.1, 109.4, 55.7, 52.9, 51.1, 33.0, 30.2, 23.7, 20.6,
14.6, 14.0, 11.7; HRMS-ESI (m/z) [M þ Na] calcd for C17H27NO3
316.1883, found 316.1893.
General Procedure for Ring-Closing Metathesis. 7-Butyl-
5-hydroxy-4-methyl-2H-quinoline-1-carboxylic Acid Methyl
Ester (55). A 100-mL, round-bottomed flask equipped with a rubber
septum and argon inlet needle was charged with a solution of the Grubbs
catalyst 60 (0.015 g, 0.018 mmol, 0.05 equiv) in 28 mL of CH2Cl2. The
aniline 44 (0.109 g, 0.359 mmol, 1.0 equiv) in 5 mL of CH2Cl2 was
added to the reaction flask via cannula in one portion. The rubber
septum was replaced with a reflux condenser fitted with an argon inlet
adapter. The pale pink-colored reaction mixture was heated at reflux for
40 min, allowed to cool to rt, and then concentrated to afford ca. 0.131 g
of green-brown foam. Column chromatography on 10 g of silica gel
(elution with 15% EtOAc-hexanes) provided 0.097 g (98%) of
dihydroquinoline 55 as a tan waxy solid: IR (thin film) 3360, 2957,
2923, 1680, 1616, 1502, 1440, 1351, 1297, 1248, 1220, 1146 cm-1; 1H
NMR (500 MHz, CDCl3) δ 6.97 (br s, 1H), 6.39 (d, J = 1.5 Hz, 1H),
5.72, (dt, J = 1.5, 4.7 Hz, 1H), 5.64 (br s, 1H), 4.14-4.15 (m, 2H), 3.78
(s, 3H), 2.51 (q, J = 7.6 Hz, 2H), 2.24 (q, J = 1.5 Hz, 3H), 1.54-1.60 (m,
2H), 1.36 (app dt, J = 7.5, 15.0 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 154.9, 152.8, 142.8, 138.5, 132.6, 121.6,
117.0, 116.0, 113.2, 53.9, 53.3, 42.9, 35.5, 33.4, 22.5, 21.9, 14.1; HRMS-
ESI (m/z) [M þ Na] calcd for C16H21NO3 298.1414, found 298.1417.
4-[N-(3-Butenyl)-N-(carbomethoxy)amino]-2,5-dimethyl-
6-methoxybenzo[b]furan (53). A 25-mL pear flask fitted with a
rubber septum and argon inlet needle was charged with phenol
8-Butyl-6-hydroxy-2,5-dihydrobenzo[b]azepine-1-carboxy-
lic Acid Methyl Ester (54). Reaction of a solution of aniline 43
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ARTICLE
(0.132 g, 0.435 mmol, 1.0 equiv) in 43 mL of CH2Cl2 with Grubbs catalyst
60 (0.018 g, 0.0217 mmol, 0.05 equiv) at reflux for 40 min according to the
general procedure afforded ca. 0.195 g of brown foam. Column chroma-
tography on 10 g of silica gel (gradient elution with 15-20% EtOAc-
hexanes) provided 0.114 g (95%) of dihydrobenzoazepine 54 as a tan wax:
IR (thin film) 3348, 2956, 2930, 1682, 1620, 1587, 1443, 1364, 1267, 1231,
1020 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 1H), 6.40 (s, 1H),
6.26 (br s, minor rotamer), 5.76-5.83 (m, 2H), 5.49 (d, J = 11.0, 1H), 4.94
(br s, 3H), 4.23 (br s, 1H), 3.83 (s, minor rotamer), 3.68 (s, 3H), 3.38 (br s,
2H), 2.54-2.55 (m, 2H), 1.51-1.62 (m, 2H), 1.25-1.42 (m, 2H), 0.93 (t,
J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.5, 152.6, 142.4,
142.4, 142.3, 127.0, 125.3, 123.6, 120.0, 115.1, 53.4, 47.9, 35.3, 33.4, 22.6,
22.5, 14.1; HRMS-ESI (m/z) [M þ Na] calcd for C16H21NO3 298.1414,
found 298.1424.
1H), 4.37-4.51 (m, 1H), 3.85 (s, minor rotamer), 3.66 (s, 3H), 3.43 (s,
3H), 3.42 (s, minor rotamer), 3.37 (app dd, J = 7.2, 13.3 Hz, 1H), 3.13 (app
dd, J = 8.9, 13.4 Hz, 1H), 2.61-2.76 (m, 1H), 2.54 (app dd, J = 10.0, 13.7
Hz), 2.19 (app quintet, J = 7.3 Hz, 1H), 2.06 (s, minor rotamer), 2.03 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 156.5, 151.6, 140.7, 134.6, 132.1,
128.5, 128.2, 116.3, 115.5, 95.9, 67.8, 55.6, 53.3, 49.0, 27.0, 25.4, 12.6 (peaks
corresponding to minor rotamer: δ 156.6, 151.8, 140.3, 132.8, 127.7, 116.3,
53.4, 27.6). Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found:
C, 63.23; H, 7.11; N, 4.25.
9-Butyl-8-chloro-7-hydroxy-3,6-dihydro-2H-benzo[b]azo-
cine-1-carboxylic Acid Methyl Ester (58). Reaction of a solution
of aniline 47 (0.134 g, 0.381 mmol, 1.0 equiv) in 40 mL of CH2Cl2 with
Grubbs catalyst 60 (0.016 g, 0.019 mmol, 0.05 equiv) at reflux for 30 min
according to the general procedure gave 0.203 g of dark brown foam.
Column chromatography on 11 g of silica gel (elution with 10% EtOAc-
hexanes) yielded 0.107 g (87%) of benzoazocine 58 as a light brown
solid: mp 112-114 °C; IR (thin film) 3367, 2956, 1693, 1571, 1456,
7-Hydroxy-9-methoxy-10-methyl-3,6-dihydro-2H-benzo-
[b]azocine-1-carboxylic Acid Methyl Ester (56). Reaction of a
solution of aniline 45 (0.103 g, 0.337 mmol, 1.0 equiv) in 33 mL of
CH2Cl2 with Grubbs catalyst 60 (0.014 g, 0.0169 mmol, 0.05 equiv) at
reflux for 40 min gave ca. 0.120 g of gray foam. Column chromatography
on 9 g of silica gel (elution with 20% EtOAc-hexane) yielded 0.083 g
(86%) of benzoazocine 56 as a gray-white solid: mp 165-168 °C; IR
(thin film) 3325, 2936, 1704, 1674, 1606, 1464, 1390, 1322, 1192, 1165,
1129, 1105 cm-1; 1H NMR (500 MHz, CDCl3, 55 °C) δ 6.34 (s, 1H),
6.05 (s, minor rotamer), 5.92 (app q, J = 8.7 Hz, 1H), 5.66 (app q, J = 8.4
Hz, 1H), 5.59 (app q, minor rotamer), 4.86 (s, 1H), 4.38 (dd, J = 6.9,
13.0 Hz, 1 H), 4.21 (dd, minor rotamer), 3.88 (s, minor rotamer), 3.79
(s, 3H), 3.69 (s, minor rotamer), 3.67 (s, 3H) 3.26-3.34 (m, 1 H),
3.09-3.14 (m, 1H), 2.57-2.70 (m, 2H), 2.13-2.19 (m, 1H), 1.97 (s,
minor rotamer), 1.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.2,
156.5, 156.4, 155.9, 152.3, 151.5, 140.8, 139.6, 133.5, 132.2, 128.3, 127.1,
120.7, 120.1, 116.9, 115.0, 98.9, 98.8, 55.7, 55.0, 53.6, 53.3, 49.4, 49.2,
27.5, 26.9, 25.1, 25.0, 10.2, 10.0 (peaks corresponding to minor rotamer:
δ 156.4, 151.5, 140.8, 132.2, 128.3, 120.1, 116.9, 98.8, 55.7, 53.3, 49.2,
26.9, 25.0, 10.2). Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05.
Found: C, 64.88; H, 6.83; N, 4.91.
1323, 1181 cm-1 1H NMR (400 MHz, CDCl3) δ 6.67 (s, minor
;
rotamer), 6.60 (s, 1H), 5.93-6.00 (m, 1H), 5.84 (s, 1H), 5.65-5.70 (m,
1H), 4.36-4.40 (m, 1H), 3.82 (s, minor rotamer), 3.66 (s, 3H), 3.42-
3.47 (app dd, J = 13.6, 7.1 Hz, 1H), 3.09-3.15 (m, 1H), 2.60-2.68
(m, 4H), 2.16-2.20 (m, 1H), 1.54-1.62 (tt, J = 7.1, 7.5 Hz, 2H),
1.34-1.43 (app sextet, J = 7.4 Hz, 2H), 0.95 (t, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 156.2, 149.2, 140.4 (minor rotamer), 140.0,
139.1 (minor rotamer), 138.8, 131.7 (minor rotamer), 131.3, 128.9,
128.4 (minor rotamer), 126.9, 121.7, 119.5, 53.1, 49.9, 33.4, 31.7,
27.8 (minor rotamer), 27.1, 25.7, 22.5, 14.0; HRMS-EI (m/z) [M þ ]
calcd for C17H22ClNO3 323.1283, found 323.1286. Anal. Calcd for
C17H22ClNO3: C, 63.06; H, 6.85; N, 4.33. Found: C, 62.88; H, 6.80;
N, 4.35.
8-(N-Methoxycarbonyl-N-methylamino)-5-methyl-2,3-
dihydrobenzo[b]azepine-1-carboxylic Acid Methyl Ester
(59). Reaction of a solution of aniline 48 (0.113 g, 0.324 mmol, 1.0 equiv)
in 26 mL of CH2Cl2 with Grubbs catalyst 60 (0.013 g, 0.0153 mmol, 0.05
equiv) at reflux for 2 h according to the general procedure gave ca. 0.143 g of
brown foam. Column chromatography on 15 g of silica gel (elution with 50%
EtOAc-hexanes) provided 0.079 g (76%) of dihydrobenzoazepine 59 as an
off-white solid: mp 200-202 °C; IR (thin film) 3297, 2954, 1706, 1676,
1609, 1580, 1450, 1365 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.94 (br s,
1H), 6.82 (s, 1H), 6.72 (br s, minor rotamer), 6.61 (s, 1H), 5.90 (m, 1H),
4.35-4.42 (m, 1H), 4.19 (br s, minor rotamer), 3.78 (s, 3H), 3.75 (s, minor
rotamer), 3.60 (s, 3H), 3.48-3.51 (m, 1H), 3.25 (s, 3H), 3.23 (s, minor
rotamer), 2.00 (s, 3H), 1.98-2.01 (m, 2H), 1.85 (br s, minor rotamer); 13C
NMR (100 MHz, CDCl3) δ 157.0, 156.6, 154.6, 142.4, 139.7, 135.9, 126.3,
124.8, 54.9, 53.4, 53.1, 37.7, 22.2, 21.3. Anal. Calcd for C16H20N2O5: C,
59.95; H, 6.29; N, 8.74. Found: C, 59.85; H, 6.15; N, 8.64.
7-Hydroxy-9-(methoxymethoxymethyl)-10-methyl-3,6-
dihydro-2H-benzo[b]azocine-1-carboxylic Acid Methyl Ester
(57). Reaction of a solution of aniline 46 (0.111 g, 0.309 mmol, 1.0 equiv)
in 30 mL of CH2Cl2 with Grubbs catalyst 60 (0.013 g, 0.015 mmol, 0.05
equiv) at reflux for 40 min according to the general procedure afforded ca.
0.125 g of brown foam. Column chromatography on 10 g of silica gel
(elution with 40% EtOAc-hexane) yielded 0.093 g (94%) of benzoazocine
57 as a gray-white solid: mp 110-112 °C; IR (thin film) 3338, 2939, 1704,
1676, 1607, 1454, 1389, 1322, 1037, 919; 1H NMR (500 MHz, CDCl3) δ
6.82 (s, 1H), 6.74 (br s, minor rotamer), 5.95 (app q, J= 8.5 Hz), 5.62-5.70
(m, 1H), 4.73 (s, 3H), 4.70 (s, minor rotamer), 4.52 (AB, J = 12.2 Hz, each
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Experimental Procedures for the Formal Total Synthesis
of (þ)-FR900482.
with 10% EtOAc-hexanes) provided 0.252 g (74%) of the N-acylthia-
zolidinethione 72.
(4S)-3-[(2R,3S-3-Hydroxy-2-[(benzyloxy)methyl]pent-4-
en-oyl]-4-isopropyl-1,3-thiazolidine-2-thione (73). A 200-mL re-
covery flask fitted with a rubber septum and argon inlet needle was charged
with freshly purified tin(II) trifluoromethanesulfonate57 (7.77 g, 18.6 mmol,
1.7 equiv) and 54 mL of CH2Cl2 and cooled to -78 °C. Freshly distilled N-
ethylpiperidine (2.70 mL, 20.6 mmol, 1.8 equiv) was then added in one
portion via syringe. The resulting off-white suspension was stirred at -78 °C
for 5 min, and then a solution of the N-acylthiazolidinethione 72 (3.57 g, 11.0
mmol, 1.0 equiv) in 30 mL of CH2Cl2 was added dropwise via cannula over
20 min. The cloudy yellow reaction mixture was stirred at -78 °C for 3 h,
after which freshly distilled acrolein (1.50 mL, 21.9 mmol, 2.0 equiv) was
added rapidly dropwise via syringe. After being stirred at -78 °C for 1.5 h, the
cold reaction mixture was poured into 80 mL of pH 7 phosphate buffer,
resulting in the formation of a thick white precipitate which was filtered
through Celite with the aid of four 50-mL portions of CH2Cl2. The filtrate
was washed with 250 mL of brine, dried over MgSO4, filtered, and concen-
trated to afford 6.79 g of a viscous orange oil. Purification by column chroma-
tography on 120 g of silica gel (gradient elution with 15-20% EtOAc-
hexanes) afforded 1.94 g (73%) of 73 as a viscous bright yellow oil: [R]21
(4S)-3-[3-(Benzyloxy)propanoyl]-4-isopropyl-1,3-thiazoli-
dine-2-thione (72). Procedure A. A 100-mL, round-bottomed flask
fitted with a rubber septum and argon inlet needle was charged with
3-(benzyloxy)propionic acid55 (3.66 g, 20.3 mmol, 1.0 equiv) and 40 mL
of CH2Cl2. Oxalyl chloride (3.2 mL, 36.6 mmol, 1.8 equiv) was added
dropwise over 3 min via syringe, followed by 1-2 drops of DMF,
resulting in rapid effervescence. The reaction mixture was stirred at rt for
1.5 h and then concentrated to afford the 3-(benzyloxy)propionyl
chloride as pale yellow oil which was used immediately in the next step
without further purification.
A 100-mL, two-necked pear flask fitted with a rubber septum and
argon inlet adapter was charged with thiazolidine thione S256 (2.69 g,
16.67 mmol, 1.0 equiv) and 30 mL of THF. The solution was cooled
at -78 °C, while n-BuLi solution (6.5 mL, 2.57 M in hexanes, 1.0 equiv)
was added dropwise via syringe over 3 min. The resulting mixture was
stirred at -78 °C for 30 min. The solution of 3-(benzyloxy)propionyl
chloride (ca. 1.2 equiv) in 20 mL of THF was rapidly added to the
reaction mixture over 5 min via cannula, and the resulting mixture was
stirred at -78 °C for 30 min. The cooling bath was then removed, and
the reaction mixture was allowed to warm to rt over 1.5 h. To the
resulting bright orange mixture was then added 30 mL of H2O, and the
aqueous layer was separated and extracted with three 20-mL portions of
Et2O. The combined organic phases were washed with 80 mL of brine,
dried over MgSO4, filtered, and concentrated to afford 6.16 g of a dark
orange oil. Purification by column chromatography on 70 g of silica gel
(gradient elution with 5-10% EtOAc-hexanes) provided 4.08 g (76%)
þ354.8 (c 0.95, CHCl3); IR (thin film) 3428, 2964, 1694, 1372, 1160 cm-1D
;
1H NMR (400 MHz, CDCl3) δ 7.24-7.34 (m, 5H), 5.90 (ddd, J =5.7, 10.5,
16.2 Hz, 1H), 5.31 (app dt, J = 1.5, 17.2 Hz, 1H), 5.18-5.23 (m, 1H), 5.17
(app dt, J = 1.5, 10.5 Hz), 5.00 (app t, J = 6.7 Hz, 1H), 4.62-4.67 (m, 1H),
4.41, 4.46 (AB, J = 11.8 Hz, each 1H), 3.86 (app t, J = 8.4 Hz, 1H), 3.71 (dd,
J = 4.8, 9.3 Hz, 1H), 3.25 (dd, J = 7.8, 11.4 Hz, 1H), 3.20 (d, J = 3.1 Hz, 1H),
2.91 (dd, J = 0.9, 11.4 Hz, 1H), 2.27-2.39 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H),
0.94(d,J= 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ204.2, 174.8, 138.1,
137.2, 128.5, 127.9, 127.7, 116.6, 73.6, 72.6, 72.3, 69.2, 48.3, 31.1, 30.9, 19.3,
18.1. Anal. Calcd for C19H25NO3S2: C, 60.13; H, 6.64; N, 3.69. Found: C,
59.95; H, 6.53; N, 3.72.
of the N-acylthiazolidine-2-thione 72 as a bright yellow oil: [R]21
D
þ292.0 (c 1.0, CHCl3); IR (thin film) 2963, 1694, 1365, 1260, 1169,
1094 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38 (app s, 2H), 7.35 (app
s, 2H), 7.27-7.32 (m, 1H), 5.15 (app t, J = 7.0 Hz, 1H), 4.59, 4.53 (AB, J
= 11.9 Hz, 1H each), 3.78-3.90 (m, 2H), 3.53-3.60 (m, 2H), 3.49 (dd,
J = 8.0, 11.4 Hz, 1H), 3.02 (app d, J = 11.5 Hz), 2.32-2.44 (m, 1H), 1.05
(d, J = 7.2 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 203.0, 171.8, 138.3, 128.6, 128.0, 127.9, 73.4, 71.8, 65.6, 39.1,
31.0, 30.7, 19.3, 17.9. Anal. Calcd for C16H21NO2S2: C, 59.41; H, 6.54;
N, 4.33. Found: C, 59.33; H, 6.68; N, 4.26.
Procedure B. A two-necked, 25-mL pear flask fitted with an argon
inlet adapter and rubber septum was charged with a solution of
3-(benzyloxy)propionic acid (0.208 g, 1.15 mmol, 1.1 equiv) in 4 mL
of THF. The solution was cooled to -78 °C, and Et3N (0.15 mL, 1.26
mmol, 1.2 equiv) was added in one portion via syringe, followed by
pivaloyl chloride (0.16 mL, 1.32 mmol, 1.2 equiv) rapidly dropwise via
syringe. The resulting thick white slurry was stirred at 0 °C for 1 h and
then recooled to -78 °C. A solution of thiazolidinone thione S2 (0.169
g, 1.05 mmol, 1.0 equiv), Et3N (0.15 mL, 1.24 mmol, 1.0 equiv), and
DMAP (0.012 g, 0.105 mmol, 0.1 equiv) in 3 mL of THF was added
dropwise over 5 min via cannula, and the resulting mixture was allowed
to warm to rt over 20 h. The reaction mixture was then diluted with
25 mL of Et2O and washed with 10 mL of H2O, three 10-mL portions of
1 M NaOH solution, and 10 mL of brine. The combined organic phases
were dried over MgSO4, filtered, and concentrated to give 0.423 g yellow
oil. Purification by column chromatography on 10 g of silica gel (elution
Assignment of the relative stereochemistry of the major and minor
aldol products was carried out by sodium borohydride reduction of each
compound and comparison of NMR data for the resulting 1,3-diols to
that reported for closely related diols by Breit and Zahn.58 Further
confirmation was obtained by conversion of the diols to cyclic acetals
(PhCH(OMe)2, cat. TsOH, DCM, 4A sieves, rt) and analysis of the
coupling constants for the vicinal protons on the ring. The absolute
stereochemistry of the aldol product was determined by cleavage of the
auxiliary to form the methyl ester (MeOH, imidazole, DCM, rt, 17 h)
and application of Kakisawa’s modified Mosher ester analysis59 to the
(R) and (S)-MPTA esters prepared by reaction with the appropriate
MPTA acids in the presence of EDAC and DMAP (rt, 16 h).
(4S)-3-[(2R,3S-3-tert-Butyldimethylsilyloxy-2-[(benzyloxy)-
methyl]pent-4-en-oyl]-4-isopropyl-1,3-thiazolidine-2-thione
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ARTICLE
(S3). A100-mLrecovery flaskfittedwith arubberseptumandargoninlet
needle was charged with alcohol 73 (2.50 g, 6.59 mmol, 1.0 equiv) and 30
mL of CH2Cl2 and cooled to 0 °C. 2,6-Lutidine (1.7 mL, 1.56 g, 14.6
mmol, 2.2 equiv) and then TBSOTf (1.7 mL, 1.92 g, 7.25 mmol, 1.1 equiv)
were added rapidly dropwise via syringe. The yellow reaction mixture was
stirred at 0 °C for 50 min, and then 25 mL of H2O was added. The aqueous
layer was separated and extracted with two 10-mL portions of CH2Cl2, and
the combined organic phases were washed with 35 mL of brine, dried over
MgSO4, filtered, and concentrated to give 4.40 g of a dark yellow oil.
Purification by column chromatography on 50 g of silica gel (gradient elution
with 0-5% EtOAc-hexanes) provided 3.11 g (96%) of S3 as a viscous
equipped with a rubber septum and argon inlet adapter was charged with
phosphonium bromide 7560 (0.110 g, 0.329 mmol, 2.5 equiv) and 1.6
mL of THF. A solution of KO-t-Bu (0.82 mL, 0.790 mmol, 0.96 M in
THF, 2.4 equiv) was added rapidly dropwise via syringe over 2 min.
The resulting dark brown reaction mixture was stirred for 3 min at rt
and then cooled to 0 °C. A solution of the aldehyde 74 (0.110 g, 0.329
mmol, 1.0 equiv) in 1.6 mL of THF was added dropwise over 4 min
via cannula. The reaction mixture was stirred at 0 °C for 10 min and
then cooled to -78 °C. A second portion of KO-t-Bu solution (1.5
mL, 1.45 mmol) was added rapidly via syringe, resulting in a dark
brown reaction mixture which was allowed to stirred at -78 °C for 20
min. The reaction was diluted with 6 mL of brine, and the aqueous
layer was separated and extracted with three 6-mL portions of Et2O.
The combined organic phases were washed with 10 mL of brine, dried
over MgSO4, filtered, and concentrated to afford 0.562 g of a brown
semisolid which was dissolved with 2 mL of CH2Cl2 and concen-
trated onto ca. 0.8 g of silica. The resulting free-flowing powder was
added to the top of a column of 10 g of silica gel and eluted with 2%
EtOAc-hexanes to provide 0.127 g (92%) of bromoalkyne 76 as a
yellow oil: [R]22D -1.54 (c 0.32, CHCl3); IR (thin film) 2928, 1472,
bright yellow oil, which solidified to a yellow solid: mp 74-76 °C; [R]22
D
þ266.3 (c 0.62, CHCl3); IR (thin film) 2929, 1694, 1471, 1363, 1168, 1091,
838 cm-1; 1H NMR (400 MHz, CDCl3) δ7.25-7.35 (m, 5H), 5.99 (ddd, J
= 7.0, 10.3, 17.2 Hz, 1H), 5.18-5.25 (m, 2H), 5.10 (app d, J = 10.4 Hz, 1H),
4.99 (app t, J = 6.9 Hz, 1H), 4.58 (app t, J = 6.9 Hz, 1H), 4.43, 4.49 (AB, J =
11.9 Hz, each 1H), 3.91 (app t, J= 9.1 Hz, 1H), 3.81 (dd, J= 4.5, 9.1 Hz, 1H),
3.20 (dd, J = 7.8, 11.3 Hz, 1H), 2.88 (app d, J = 11.4 Hz, 1H), 2.30-2.38 (m,
1H), 1.03 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.8, 173.7. 139.3,
138.5, 128.4, 127.7, 127.6, 116.3, 73.9, 73.3, 72.6, 70.7, 49.8, 30.9, 30.8, 26.0,
19.4, 18.3, 18.0, -3.9, -4.8. Anal. Calcd for C25H39NO3S2Si: C, 60.81; H,
7.96; N, 2.84. Found: C, 60.69; H, 8.04; N, 2.87.
1
1361, 1252, 1082, 927, 836 cm-1; H NMR (400 MHz, CDCl3) δ
7.36 (app s, 2H), 7.35 (app s, 2H), 7.28-7.34 (m, 1H), 5.92 (ddd, J =
6.6, 10.4, 17.0 Hz, 1H), 5.23 (app d, J = 17.2 Hz, 1H), 5.17 (app d, J =
10.4 Hz, 1H), 4.53, 4.62 (AB, J = 12.2 Hz, each 1H), 4.32 (app t, J =
6.4 Hz, 1H), 3.59 (d, J = 9.3 Hz, 2H), 2.78 (app q, J = 6.0 Hz, 1H),
0.90 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 139.0, 138.3, 128.5, 127.8, 127.7, 116.3, 79.3, 73.3, 73.2, 69.0, 41.5,
41.2, 25.9, 18.3, -4.2, -4.8. Anal. Calcd for C20H29BrO2Si: C, 58.67;
H, 7.14. Found: C, 58.72; H, 7.09.
(2R,3S)-2-(Benzyloxy)methyl-3-(tert-butyldimethylsily-
loxy)pent-4-en-al (74). A 25-mL recovery flask equipped with a rubber
septum and argon inlet needle was charged with S3 (1.01 g, 2.06 mmol, 1.0
equiv) and 10 mL of CH2Cl2 and cooled to -78 °C. DIBAL-H (1.0 M in
hexanes, 3.7 mL, 3.71 mmol, 1.8 equiv) was added dropwise via syringe over
3 min. The bright yellow solution was stirred for ca. 10 min (until the reaction
mixture became colorless), and 5 mL of satd Na/K tartrate solution was
added. The reaction mixture was allowed to warm to rt over 1.5 h, and the
aqueous layer was then extracted with two 5-mL portions of CH2Cl2. The
combined organic layers were washed with 15 mL of brine, dried over
MgSO4, filtered, and concentrated to provide 1.05 g of an off-white semisolid
consisting of the aldehyde and white crystals of (4S)-4-isopropyl-1,3-
thiazolidine-2-thione. This material was treated with ca. 15 mL of hexanes,
and the resulting solution was separated from the chiral auxiliary, concen-
trated, and purified by column chromatography on 6 g of silica gel (elution
with 5% EtOAc-hexanes) to afford 0.586 g (85%) of the aldehyde 74 as a
very pale yellow oil: [R]22D -2.45 (c 1.35, CHCl3); IR (thin film) 2858,
1727, 1472, 1362, 1254, 1092 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.78
(d, J = 1.8 Hz, 1H), 7.27-7.40 (m, 5H), 5.82 (ddd, J = 6.3, 10.4, 16.9 Hz,
1H), 5.25 (app d, J = 17.1 Hz, 1H) 5.15 (app d, J = 10.4 Hz, 1H), 4.65 (app t,
J = 6.1 Hz, 1H), 4.48, 4.55 (AB, J = 11.9 Hz, 1 H each), 3.91 (dd, J = 7.2, 9.6
Hz, 1H), 3.67 (dd, J = 5.9, 9.6 Hz, 1H), 2.72-2.77 (m, 1H), 0.88 (s, 9H),
0.08 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.7, 138.4,
138.1, 128.6, 127.9, 127.8, 116.4, 73.6, 71.9, 66.0, 58.2, 25.9, 18.3, -4.1, -5.0.
Anal. Calcd for C19H30O3Si: C, 68.22; H, 9.04. Found: C, 68.09; H, 9.08.
(3R,4S)-N-(tert-Butoxycarbonyl)-N-(2-propenyl)hex-5-en-
3-(benzyloxymethyl)-4-(tert-butyldimethylsilanyloxy)-1-ynyl-
amine (83). A 15-mL resealable Pyrex tube fitted with a rubber septum
and argon inlet adapter was charged with CuSO4 5H2O (0.032 g, 0.128
3
mmol, 0.2 equiv), 1,10-phenanthroline (0.046 g, 0.257 mmol, 0.4 equiv),
K3PO4 (0.273 g, 1.28 mmol, 2.0 equiv), and a solution of the bromoalkyne
76 (0.263 g, 0.642 mmol, 1.0 equiv) and tert-butylallyl carbamate
8261 (0.303 g, 1.93 mmol, 3.0 equiv) in 2 mL of toluene. The resulting
heterogeneous reaction mixture was heated at 80-85 °C for 24 h, and
then a second portion of CuSO4 5H2O (0.032 g, 0.128 mmol, 0.2
3
equiv) and 1,10-phenanthroline (0.036 g, 0.257 mmol, 0.4 equiv) was
added. The resulting mixture was stirred at 80-85 °C for 22 h, cooled
to rt, and then filtered through a plug of ca. 2 g of silica gel with the aid
of ca. 15 mL of Et2O and concentrated to give 0.532 g of orange oil.
Purification by column chromatography on 30 g of silica gel (gradient
elution with 2-5% EtOAc-hexanes) afforded 0.039 g (15%) of
unreacted bromoalkyne 76 and 0.213 g (68%) of ynamide 83 as a pale
yellow oil: [R]22D -8.4 (c 0.75, CHCl3); IR (thin film) 3087, 2928,
2263, 1717, 1646, 1473, 1392, 1153, 924 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.28-7.35 (m, 5H), 5.96 (ddd, J = 6.6, 10.4, 17.1 Hz, 1H),
5.85 (ddt, J = 6.6, 10.3, 17.0 Hz, 1H), 5.11-5.25 (m, 4H), 4.55 (AB,
J = 12.1 Hz, each 1H), 4.27 (app t, J = 6.3 Hz, 1H), 3.97 (app bd, J =
5.4 Hz, 2H), 3.57 (app bd, J = 5.5 Hz, 2H), 2.87 (app q, J = 6.1 Hz,
1H), 1.48 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 154.4, 139.5, 138.6, 132.4, 128.5, 127.8, 127.6,
118.0, 115.7, 82.1, 73.6, 73.2, 70.1, 68.0, 51.9, 40.4, 28.2, 26.0, 18.3,
(2R,3S)-2-(Benzyloxy)methyl-1-bromo-3-(tert-butyldime-
thylsilyloxy)hex-5-en-1-yne (76). A two-necked, 25-mL pear flask
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ARTICLE
-4.1, -4.7. Anal. Calcd for C28H43NO3Si: C, 69.24; H, 8.92; N, 2.88.
Found: C, 69.31; H, 8.88; N, 2.67.
49.7; HRMS-ESI (m/z) [M þ Na] calcd for C12H12O2 211.0730, found
211.0735.
3-(Methoxymethoxymethyl)cyclobut-1-enone (81). A 25-
mL, two-necked pear flask fitted with a rubber septum and argon inlet
(3R,4S)-N-(2-Trimethylsilylethoxycarbonyl)-N-(2-propenyl)-
hex-5-en-3-benzyloxymethyl-4-(tert-butyldimethylsilanyl-
oxy)-1-ynylamine (87). A 25-mL pear flask fitted with a coldfinger
condenser with argon inlet was charged with the bromoalkyne 76
(0.161 g, 0.393 mmol, 1.0 equiv), carbamate 8662 (0.238 g, 0.1.18
mmol, 3.0 equiv), 1,10-phenanthroline (0.028 g, 0.157 mmol, 0.4
adapter was charged with
a solution of tributyl[(methoxy-
methoxy)methyl]stannane48b (78) (0.739 g, 2.03 mmol, 1.5 equiv) in
5 mL of THF. The solution was cooled to -78 °C, and n-BuLi solution
(0.69 mL, 2.36 M in hexane, 1.2 equiv) was added rapidly dropwise via
syringe. The reaction mixture was allowed to stir at -78 °C for 2 h, and
then a solution of 3-ethoxycyclobutenone47 79 (0.151 g, 1.35 mmol, 1.0
equiv) in 2 mL of THF was added rapidly dropwise via cannula. The
resulting orange reaction mixture was stirred at -78 °C for 2 h, and then
trifluoroacetic anhydride (0.250 mL, 1.76 mmol, 1.3 equiv) was added
via syringe in a single portion. The reaction mixture was stirred at -
78 °C for 75 min, diluted with 3 mL of satd NaHCO3 solution, and
allowed to warmed to rt over 30 min. The resulting mixture was diluted
with 15 mL of CH2Cl2, and the aqueous phase was separated and
extracted with two 5-mL portions of CH2Cl2. The combined organic
phases were washed with 15 mL of brine, dried over MgSO4, filtered, and
concentrated to give 0.901 g of a dark orange, biphasic oil. Purification by
column chromatography on 19 g of silica gel (elution with 25% EtOAc-
hexanes) afforded 0.125 g (65%) of 81 as an orange oil: FT-IR (neat)
2923, 1772, 1599, 1438, 1152, 1048 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.10 (s, 1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.40 (s, 3H), 3.23 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 186.7, 175.2, 135.0, 96.5, 65.6, 55.8, 49.6;
HRMS-ESI (m/z) [M þ Na] calcd for C7H10O3 165.0522, found
165.0526.
equiv), K3PO4 (0.167 g, 0.0.786 mmol, 2.0 equiv), CuSO45 H2O
3
(0.020 g, 0.0786 mmol, 0.2 equiv), and 1 mL of toluene. The
heterogeneous reaction mixture was heated at 85-90 °C for 24 h,
and then a second portion of CuSO4.5H2O (0.020 g, 0.0786 mmol, 0.2
equiv) and 1,10-phenanthroline (0.028 g, 0.157 mmol, 0.4 equiv) was
added. The reaction mixture was heated at 85-95 °C for 24 h, cooled
to rt, and then filtered through a plug of ca. 3 g of Celite with the aid of
ca. 15 mL of Et2O. Concentration gave ca. 0.4 g of a orange-brown oil.
Purification by column chromatography on 24 g of silica gel (gradient
elution with 2-5% EtOAc-hexanes)63 afforded 0.162 g (78%) of the
ynamide 87 as a pale yellow oil: [R]21D -5.1 (c 0.28, CHCl3); IR (thin
1
film) 2955, 2857, 2265, 1724, 1402, 1251, 1075, 925, 837 cm-1; H
NMR (400 MHz, CDCl3) δ 7.27-7.36 (m, 5H), 5.81-5.99 (m, 2H),
5.11-5.27 (m, 4H), 4.56 (AB, J = 12.1 Hz, 1H each), 4.23-4.30 (m,
3H), 4.02 (d, J = 5.7 Hz, 2H), 3.50-3.61 (m, 2H), 2.87 (app q, J = 6.1
Hz, 1H), 1.04 (t, J = 8.5 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s,
9H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.8, 139.4, 138.6,
132.1, 128.5, 127.8, 127.7, 118.3, 115.9, 76.7, 73.6, 73.2, 70.0, 68.5,
65.5, 52.6, 40.4, 26.0, 18.3, 17.8, -1.3, -4.1, -4.7. Anal. Calcd for
C29H47NO4Si2: C, 65.74; H, 8.94; N, 2.64. Found: C, 65.69; H, 8.96;
N, 2.51.
N-Allyl-N-(tert-butoxycarbonyl)-2-[(1R,2S)-1-(benzyloxy)
methyl-2-(tert-butyldimethylsilanyloxy)but-3-enyl]-3-hy-
droxy-5-(methoxymethoxy)methylphenylamine (84). A 25-
mL pear flask fitted with a rubber septum and argon inlet needle was
charged with a solution of ynamide 83 (0.108 g, 0.222 mmol, 1.0 equiv)
and cyclobutenone 81 (0.041 g, 0.289 mmol, 1.3 equiv) in 0.7 mL of
toluene. The septum was replaced with a coldfinger reflux condenser
with an argon inlet, and the reaction mixture was heated at 80 °C for 1.5
h and then at reflux for 1.5 h. After being cooled to rt, the reaction
mixture was concentrated to 0.200 g of viscous orange oil. Purification by
column chromatography on 14 g of silica gel (elution with 15% EtOAc-
hexanes) provided 0.125 g (94%) of 84 as a viscous pale yellow oil:
[R]21D -6.3 (c = 0.125, CHCl3); IR (thin film) 3281, 2927, 1699, 1667,
1624, 1574, 1437, 1254, 1049, 922 cm-1; 1H NMR (500 MHz, 90 °C,
DMSO-d6) δ 9.20 (s, 1H), 9.13 (s, minor rotamer), 7.22-7.30 (m, 3H),
7.15-7.16 (m, 2H), 6.73 (s, minor rotamer), 6.70 (s, 1H), 6.52 (s, minor
rotamer), 6.43 (s, 1H), 5.93-5.97 (m, minor rotamer), 5.79-5.83 (m,
1H), 5.62-5.68 (m, 1H), 5.03-5.13 (m, minor rotamer), 4.97-4.99
(m, 2H), 4.87 (app d, J = 18.1 Hz, 1H), 4.73-4.80 (m, 2H), 4.61 (s, 2H),
4.41 (s, 4H), 4.31-4.37 (m, 1H), 4.14 (t, J = 9.0 Hz, 1H), 3.90-3.97
(m, 2H), 3.80 (dd, J = 6.8, 15.3 Hz, 1H), 3.61-3.64 (m, minor rotamer),
3.30 (s, 3H), 3.12 (bs, 1H), 1.38 (s, 9H), 1.32 (s, minor rotamer), 0.88 (s,
9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, 90 °C, d6-DMSO)
δ 155.9, 153.8, 142.5, 140.1, 138.2, 136.4, 134.0, 127.6, 126.9, 126.8, 126.7,
3-(Methylbenzyloxy)cyclobut-1-enone (80). A 50-mL, two-
necked pear flask fitted with a rubber septum and argon inlet adapter was
charged with a solution of tributyl(benzyloxymethyl)stannane64 (77)
(1.05 g, 2.59 mmol, 1.2 equiv) in 4 mL of THF. The solution was cooled
to -78 °C, and n-BuLi solution (0.92 mL, 2.59 M in hexanes, 1.1 equiv)
was added rapidly dropwise via syringe. The resulting mixture was stirred
at -78 °C for 5 min, and then a solution of 3-ethoxycyclobutenone47
(79) in 3 mL of THF was added rapidly dropwise via cannula. The
resulting orange reaction mixture was stirred at -78 °C for 2.5 h, and
then trifluoroacetic anhydride (0.544 g, 0.36 mL, 2.59 mmol, 1.2 equiv)
was added via syringe in a single portion. The reaction mixture was
stirred at -78 °C for 3 h, diluted with 10 mL of satd NaHCO3 solution,
and allowed to warm to rt over 30 min. The aqueous phase was extracted
with three 10-mL portions of Et2O, and the combined organic phases
were washed with 15 mL of brine, dried over Na2SO4, filtered, and
concentrated to 1.43 g of a biphasic orange oil. Purification by column
chromatography on 30 g of acetone-deactivated silica gel (elution with
20% EtOAc-hexanes) afforded 0.265 g (65%) of cyclobutenone 80 as a
yellow oil: FT-IR (thin film) 2920, 1769, 1597, 1497, 1454, 1225, 1143,
1095 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.29-7.47 (m, 5H), 6.14 (s,
1H), 4.65 (s, 2H), 4.48 (s, 2H), 3.22 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 186.8, 175.4, 137.7, 135.1, 128.8, 128.3, 128.0, 73.5, 68.3,
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123.6, 119.9, 116.0, 113.6, 113.4, 94.9, 78.5, 73.0, 72.2, 70.0, 67.8, 54.4, 52.2,
46.7, 27.7, 25.4, 17.4, -4.4, -4.9 (peaks corresponding to minor rotamer:
δ 134.1, 116.4, 113.5, 95.0, 70.8, -4.5, -5.1). Anal. Calcd for C35H53NO7-
Si: C, 66.95; H, 8.51; N, 2.23. Found: C, 66.91; H, 8.46; N, 2.40.
3.66 (dd, minor rotamer), 3.11 (dt, J = 4.2, 14.6 Hz, 1H), 0.93 (s, minor
rotamer), 0.91 (s, 11H), 0.08 (s, 3H), 0.06 (s, minor rotamer), 0.04 (s, 3H),
0.01 (s, 9H), -0.07 (s, minor rotamer); 13C NMR (100 MHz, 70 °C,
DMSO-d6) δ 156.1, 154.7, 140.1, 138.1, 138.0, 136.9, 133.8, 127.8, 127.7,
127.1, 127.0, 126.9, 126.8, 126.7, 123.6, 119.7, 116.4, 113.7, 113.3, 72.6,
72.2, 71.0, 70.6, 69.8, 62.3, 52.2, 46.8, 25.5, 17.5, 17.0, -1.94, -4.36, -4.95;
peaks corresponding to the minor rotamer: δ 133.9, 116.7, 72.4, 71.8, 71.1,
62.5, 16.9, -2.01, -4.48, -5.07. Anal. Calcd for C41H59NO6Si2: C, 68.58;
H, 8.28; N, 1.95. Found: C, 68.67; H, 8.19; N, 1.94.
(5S,6R)-6-Benzyloxymethyl-5-(tert-butyldimethysilanyloxy)-
7-hydroxy-9-methoxymethoxymethyl-5,6-dihydro-2H-benzo-
[b]azocine-1-carboxylic Acid tert-Butyl Ester (85). A50-mL, reco-
very flask fitted with a rubber septum and argon inlet needle was charged
with a solution of the Grubbs catalyst 60 (0.005 g, 0.00593 mmol, 0.05
equiv) in 9 mL of CH2Cl2. The aniline 84 (0.0745 g, 0.119 mmol, 1.0 equiv)
in 3 mL of CH2Cl2 was added to the reaction flask via cannula in one
portion, and the rubber septum was replaced with a reflux condenser fitted
with an argon inlet adapter. The pale pink-colored reaction mixture was
heated at reflux for 5.5 h, allowed to cool to rt, and then concentrated to
afford ca. 0.134 g of yellow-brown foam. Column chromatography on 11 g
of silica gel (elution with 15% EtOAc-hexanes) yielded 0.057 g (80%) of
N-Allyl-N-(2-trimethylsilanyloxycarbonyl)-2-(1R,2S)-[1-(ben-
zyloxy)methyl-2-(tert-butyldimethylsilanyloxy)but-3-en-
yl]-3-benzyloxy-5-(benzyloxy)methylphenylamine (89). A 25-
mL pear flask fitted with a rubber septum and argon inlet needle was charged
with a solution of the phenol 88 (0.099 g, 0.138 mmol, 1.0 equiv) in 0.7 mL of
DMF. NaH (0.011 g, 0.276 mmol, 2.0 equiv, 60% dispersion in mineral oil)
was added to the solution in a single portion. The reaction mixture was stirred
at rt for 2-3min,andbenzylbromide(0.025mL,0.207mmol,1.5equiv) was
added rapidly dropwise via microsyringe. The reaction mixture was stirred at
rt for 3 h and then diluted with 10 mL of H2O and 10 mL of Et2O. The
aqueous phase was extracted with two 8-mL portions of Et2O, and the
combined organic phases were washed with 15 mL of brine, dried over
MgSO4, filtered, and concentrated to afford 0.152 g of dark yellow oil.
Purification by column chromatography on 8 g of silica gel (elution with 10%
benzoazocine 85 as a viscous pale yellow oil: [R]21 -18.7 (c 0.44,
D
CHCl3); IR (thin film) 3343, 2927, 1694, 1670, 1624, 1573, 1442, 1391,
1258, 1075 cm-1; 1HNMR (500 MHz, 55 °C, DMSO-d6) δ 9.21 (s, 1H),
7.22-7.28 (m, 5H), 6.77 (s, 1H), 6.49 (s, 1H), 5.38-5.41 (m, 1H), 5.19-
5.21 (m, 1H), 5.04 (app t, J = 7.9 Hz, 1H), 4.78 (app d, J = 15.4 Hz, 1H),
4.63 (s, 2H), 4.42 (s, 2H), 4.39-4.46 (m, 2H), 3.76 (br s, 1H), 3.64 (app t, J
= 8.4 Hz, 1H), 3.48-3.56 (m, 2H), 3.30 (s, 3H), 1.37 (br s, 9H), 0.87 (s,
9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, 55 °C, DMSO-d6) δ
156.0, 139.7, 138.6 137.5, 136.2, 127.8, 127.0, 126.8, 122.7, 118.5, 113.3,
95.1, 79.2, 71.6, 70.4, 70.3, 67.8, 54.6, 48.3, 45.0, 27.9, 25.6, 25.5, 17.6,
-4.71, -5.13; (peaks corresponding to minor rotamer: 156.5, 139.3, 138.4,
130.3, 72.4). Anal. Calcd for C33H49NO7Si: C, 66.08; H, 8.23; N, 2.34.
Found: C, 65.96; H, 8.23; N, 2.42.
EtOAc-hexanes) afforded 0.103 g (92%) of 89 as a pale yellow oil: [R]21
-
D
18.4 (c 0.92, CHCl3); IR (neat) 3032, 2953, 2856, 1700, 1613, 1577, 1454,
1436, 1402, 1361, 1312, 1251, 1094, 920, 837 cm-1; 1HNMR (500 MHz,
70 °C, DMSO-d6) δ 7.09-7.40 (m, 15H), 7.03 (s, minor rotamer), 7.00 (s,
1H), 6.71 (s, minor rotamer), 6.64 (s, 1H), 5.89-5.98 (m, minor rotamer),
5.84 (ddd, J = 7.0, 12.3, 17.2 Hz, 1H), 5.58 (ddd, minor rotamer), 5.46-5.52
(m, 1H), 4.97-5.11 (m, 4H), 4.85 (dd, J = 10.4, 16.4 Hz, 2H), 4.70 (d, J =
10.4 Hz, 1H), 4.60 (app t, J = 8.4 Hz, 1H), 4.54 (s, minor rotamer), 4.53 (s,
2H), 4.51 (s, minor rotamer), 4.50 (s, 2H), 4.44 (dd, J = 5.0, 15.5 Hz, 1H),
4.36 (AB, J = 12.3 Hz, 1H each), 4.12-4.19 (m, 1H), 4.05-4.11 (m, minor
rotamer), 3.97 (app t, J = 9.3 Hz, 1H), 3.86 (dd, J = 7.4, 15.4 Hz, 1H), 3.79-
3.83 (m, 1H), 3.58 (dd, minor rotamer), 3.10-3.13 (m, 1H), 0.88 (br s, 2H),
0.80 (s, minor rotamer), 0.78 (s, 9H), -0.03 (s, 9H), -0.12 (s, minor
rotamer), -0.18 (s, 3H), -0.22 (s, minor rotamer), -0.24 (s, 3H); 13C
NMR (125 MHz, 55 °C, DMSO-d6) δ 157.3, 154.7, 139.9, 138.1, 137.3,
136.3, 133.7, 128.1, 127.8, 127.74, 127.68, 127.1, 127.03, 126.98, 126.9, 125.4,
121.4, 116.7, 113.7, 110.1, 72.7, 72.1, 71.1, 70.7, 69.8, 62.4, 52.3, 46.9, 25.4,
25.3, 17.3, 17.0, -1.9, -4.6, -5.3. Anal. Calcd for C48H65NO6Si2: C, 71.33;
H, 8.11; N, 1.73. Found: C, 71.06; H, 8.19; N, 1.89.
N-Allyl-N-(2-trimethylsilanyloxycarbonyl)-2-(1R,2S)-[1-(ben-
zyloxy)methyl-2-(tert-butyldimethylsilanyloxy)but-3-en-
yl]-3-hydroxy-5-(benzyloxy)methylphenylamine (88). A 25-
mL pear flask fitted with a rubber septum and argon inlet needle was
charged with a solution of ynamide 87 (0.077 g, 0.145 mmol, 1.0 equiv) and
cyclobutenone 80 (0.036 g, 0.189 mmol, 1.3 equiv) in 0.4 mL of toluene.
The septum was replaced with a coldfinger reflux condenser with an argon
inlet, and the reaction mixture was heated at 80 °C for 1.5 h and then at
reflux for 1.5 h. After being cooled to rt, the reaction mixture was
concentrated to yield 0.121 g of viscous orange oil. Purification
by column chromatography on 10 g of silica gel (gradient elution with
5-10% EtOAc-hexanes) provided 0.086 g (83%) of 88 as a viscous pale
yellow oil: [R]21D -4.05 (c 0.35, CHCl3); IR (thin film) 3272, 2954, 2857,
1703, 1624, 1573, 1454, 1404, 1251, 1075, 924, 837 cm-1; 1H NMR (400
MHz, 70 °C, DMSO-d6) δ 9.38 (s, 1H), 9.33 (s, minor rotamer), 7.23-
7.41 (m, 9H), 7.17-7.19 (m, 1H), 6.81 (s, minor rotamer), 6.79 (s, 1H),
6.58 (s, minor rotamer), 6.51 (s, 1H), 5.98 (dddd, minor rotamer), 5.86
(dddd, J = 5.2, 7.1, 10.2, 17.3 Hz, 1H), 5.68-5.73 (m, minor rotamer), 5.63
(ddd, J = 6.8, 10.3, 17.2 Hz, 1H), 4.77-5.16 (m, 5H), 4.55 (s, minor
rotamer), 4.54 (s, 2H), 4.46 (s, minor rotamer), 4.45 (s, 4H), 4.43 (m, 1H),
4.09-4.23 (m, 2H), 3.91-4.05 (m, 2H), 3.86 (dd, J = 7.2, 15.4 Hz, 1H),
(5S,6R)-7-Benzyloxy-6,9-benzyloxymethyl-5-(tert-butyl-
dimethylsilanyloxy)-5,6-dihydro-2H-benzo[b]azocine-1-car-
boxylic Acid (2Ttrimethylsilyl)ethyl Ester (90). A 50-mL recov-
ery flask fitted with a rubber septum and argon inlet needle was charged
with a solution of the Grubbs catalyst 60 (0.005 g, 0.0057 mmol,
0.05 equiv) in 9 mL of CH2Cl2. The aniline 89 (0.092 g, 0.114 mmol,
1.0 equiv) in 2.4 mL of CH2Cl2 was added via cannula in one portion,
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1
and the septum was replaced with a reflux condenser fitted with an argon
inlet adapter. The pale pink-colored reaction mixture was heated at reflux
for 4.5 h and then allowed to cool to rt and concentrated to afford ca.
0.110 g of yellow brown oil. Column chromatography on 12 g of silica gel
(elution with 10% EtOAc-hexane) yielded 0.082 g (92%) of benzoa-
zocine 90 as a viscous pale yellow oil: [R]22D -48.6 (c 0.38, CHCl3); IR
(thin film) 3031, 2954, 2856, 1699, 1613, 1577, 1453, 1403, 1311, 1250,
1073 cm-1; 1HNMR (400 MHz, CDCl3) δ 7.32-7.40 (m, 10H), 7.12-
7.25 (m, 5H), 6.94 (s, 1H), 6.66 (s, 1H), 5.54 (ddd, J = 3.0, 7.3, 10.5 Hz,
1H), 5.17-5.26 (m, 1H), 5.04 (app AB, J = 11.9 Hz, 3H), 4.57 (s, 2H),
4.52 (s, 2H), 4.39-4.47 (m, 2H), 4.14-4.24 (m, 1H), 3.86-3.96 (m,
1H), 3.83-3.86 (m, 1H), 3.72-3.79 (m, 2H), 3.60 (dd, J = 5.4, 16.6
Hz, 1H), 0.91 (s, 10 H), 0.09 (s, 3H), 0.06 (s, 3H), -0.08 (s, 9H);
13CNMR (100 MHz, CDCl3) δ 158.1, 138.3, 137.7, 137.3, 128.6,
128.2, 128.0, 127.9, 127.8, 127.5, 127.2, 127.1, 72.3, 72.0, 71.7, 70.9,
70.2, 64.1, 49.1, 45.9, 26.1, 18.4, 18.1, -1.44, -4.26, -4.73. Anal.
Calcd for C46H61NO6Si2: C, 70.82; H, 7.88; N, 1.80. Found: C, 70.71;
H, 7.72; N, 1.62.
Table 4. H NMR (CDCl3) Spectral Data for Compound
64a
Ciufolini
compd 64
(300 MHz)
(400 MHz)
δ
J (Hz)
δ
J (Hz)
H(Ph)
H(4)
7.25-7.41 (m, 15H)
6.78 (s, 1H)
7.25-7.42 (m, 15H)
6.77 (s, 1H)
H(2)
6.67 (s, 1H)
6.66 (s, 1H)
H(10)
H(9)
H(8)
5.83-5.88 (m, 1H)
5.58-5.65 (m, 1H)
5.23-5.30 (m, 1H)
5.06 (AB, 2H)
5.85 (app t, 1H)
5.60 (ddd, 1H)
5.24-5.29 (m, 1H)
5.05 (AB, 2H)
4.55 (s, 2H)
7.4
2.8, 6.7, 9.6
H(17)
H(13, 14, 15) 4.56 (s, 2H)
4.53 (s, 2H)
4.52 (s, 2H)
4.48 (s, 2H)
4.47 (s, 2H)
H(11,16)
3.69-3.96 (cplx, 4H)
3.91-3.94 (m, 1H)
3.85 (app dt, 1H)
3.69-3.76 (m, 2H)
3.8, 13.5
5.6, 16.2
H(7)
3.54 (dd, 1H)
5.6, 16.2 3.53 (dd, 1H)
a Chemical shifts are expressed in ppm relative to tetramethylsilane.
Table 5. 13C NMR (CDCl3) Spectral Data for 64
Ciufolini (75 MHz) δ
compd 64 (100 MHz) δ
156.6
147.9
138.4
138.1
137.8
137.0
135.0
128.4
128.3
127.76
127.74
127.6
127.5
127.4
127.1
126.0
124.8
118.9
107.7
74.2
156.8
148.2
138.6
138.3
138.0
137.2
135.2
128.7
128.58
128.57
127.99,127.97
127.9
127.8
127.7
127.3
126.3
125.0
119.2
107.9
74.5
(5S,6R)-7-Benzyloxy-6,9-benzyloxymethyl-5-hydroxyl-
5,6-dihydro-2H-benzo[b]azocine (64). A 10-mL pear flask fitted
with a rubber septum and argon inlet needle was charged with a solution
of benzoazocine 90 (0.051 g, 0.0654 mmol, 1.0 equiv) and 0.9 mL of
THF. TBAF (0.24 mL, 0.235 mmol, 3.6 equiv) was added rapidly
dropwise via syringe, and the reaction mixture was sealed with a glass
stopper under argon and stirred at rt for 39 h. The resulting mixture was
then diluted with 5 mL of Et2O and 5 mL of H2O, and the aqueous layer
was extracted with two 5-mL portions of Et2O. The combined organic
phases were washed with 10 mL of brine, dried over MgSO4, filtered, and
concentrated to afford 0.040 g of orange oil. Purification by column
chromatography on 4 g silica gel (elution with 30% EtOAc-hexanes)
provided 0.025 g (74%) of benzazocine 64 as a viscous pale yellow oil:
[R]21D -111.5 (c 0.41, CHCl3); IR (thin film) 3390, 3029, 2860, 1608,
1580, 1496, 1453, 1360, 1311, 1205, 1112, 1074, 1027, 839, 736, 697
1
cm-1; HNMR (400 MHz, CDCl3) δ 7.25-7.42 (m, 15H), 6.77 (s,
1H), 6.66 (s, 1H), 5.85 (app t, J = 7.4 Hz, 1H), 5.60 (ddd, J = 2.8, 6.7, 9.6
Hz, 1H), 5.24-5.29 (m, 1H), 5.05 (AB, J = 7.3 Hz, 1H each), 4.55 (s,
2H), 4.52 (s, 2H), 4.47 (s, 2H), 3.91-3.94 (m, 1H), 3.85 (dt, J = 3.8,
13.5 Hz, 1H), 3.69-3.76 (m, 2H), 3.53 (dd, J = 5.6, 16.2 Hz, 1H);
13CNMR (100 MHz, CDCl3) δ 156.8, 148.2, 138.6, 138.3, 138.0, 137.2,
135.2, 128.7, 128.58, 128.57, 127.99, 127.97, 127.9, 127.8, 127.7, 127.3,
126.3, 125.0, 119.2, 107.9, 74.6, 73.5, 73.3, 72.5, 72.0, 70.4, 51.2, 46.2.
Anal. Calcd for C34H35NO4: C, 78.28; H, 6.76; N, 2.69. Found: C, 78.18;
H, 6.87; N, 2.77.
73.18
73.13
72.2
73.5
73.3
72.5
71.7
72.0
50.9
51.2
Comparison of NMR Data for 64 with Data Reported by
Ducray and Ciufolini (Tables 4 and 5)36.
46.0
46.2
a Chemical shifts are expressed in ppm relative to tetramethylsilane.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
See: Ficini, J.; Falou, S.; d’Angelo, J. Tetrahedron Lett. 1977, 18,
1931–1934.
(11) For recent reviews on the chemistry of ynamides, see: (a)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.;
Hsung, R. P. Chem. Rev. 2010, 110, 5064–5106. (b) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840–2859.
Corresponding Author
*E-mail: danheisr@mit.edu.
’ ACKNOWLEDGMENT
(12) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser,
R. L. Tetrahedron 2006, 62, 3815–3822.
We thank the National Institutes of Health (GM 28273),
Merck Research Laboratories, and Boehringer Ingelheim Phar-
maceuticals for generous financial support.
(13) For recent reviews on the application of RCM to the synthesis
of heterocyclic compounds, see: (a) Phillips, A. J.; Abell, A. D. Aldrichim.
Acta 1999, 32, 75–89. (b) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem.
2003, 3693–3712. (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199–2238. (d) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem.,
Int. Ed. 2006, 45, 2664–2670. (e) Compain, P. Adv. Catal. Synth. 2007,
349, 1829–1846. (f) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev.
2007, 36, 55–66.
(14) (a) Dunetz, J.R.;Danheiser, R.L.Org. Lett. 2003,5,4011–4014. (b)
Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88–101.
(15) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas J. Am. Chem. Soc. 2003, 125,
2368–2369. (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151–1154. (c) Zhang, X.; Zhang, Y.;
Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen,
M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71,
4170–4177. (d) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org.
Synth. 2007, 84, 359–367.
(16) For other useful coupling routes to ynamides, see: (a) Hamada,
T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835. (b) Coste,
A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48,
4381–4385.
(17) Caruso, T.; Spinella, A. Tetrahedron 2003, 59, 7787–7790.
(18) Danheiser, R. L.;Savariar, S.;Cha, D. D.Org. Synth. 1990,68, 32–40.
(19) (a) Niwayama, S.; Kallel, E. A.; Sheu, C.; Houk, K. N. J. Org.
Chem. 1996, 61, 2517–2522. (b) Niwayama, S.; Kallel, E. A.; Spellmeyer,
D. C.; Sheu, C.; Houk, K. N. J. Org. Chem. 1996, 61, 2813–2825.
(20) Cyclobutenones were prepared via ketene-alkyne cycloaddi-
tions: 35, ref 18; 39, via addition of ketene to methoxypropyne (see the
Experimental Section); 40, ref 5a; 41, ref 18; 42, ref 12.
(21) For examples of the photocyclization of 2-allylphenols, see:
Jimꢀenez, M. C.; Mꢀarquez, F.; Miranda, M. A.; Tormos, R. J. Org. Chem.
1994, 59, 197–202 and references cited therein..
(22) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541–5544. (b) Cabri, W.; De Bernardinis, S.; Francalanci,
F.; Penco, S.; Santi, R. J. Org. Chem. 1990, 55, 350–353.
(23) Hydrogenation of the alkene double bonds was necessary to
avoid the formation of byproducts in the triflate reduction step.
(24) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(25) For a discussion of alkene isomerization in RCM reactions, see:
Schmidt, B. Eur. J. Org. Chem. 2004, 1865–1880.
’ REFERENCES
(1) Reviews: (a) Kotha, S.; Misra, S.; Halder, S. Tetrahedron 2008, 64,
10775–10790. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901–2915.
(2) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672–
1674. (b) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F.
J. Am. Chem. Soc. 1990, 112, 3093–3100.
(3) For reviews of the chemistry of vinylketenes, see: (a) Danheiser,
R. L.; Dudley, G. B.; Austin, W. F. Alkenylketenes. In Science of Synthesis;
Danheiser, R. L., Ed.; Thieme: Stuttgart, 2006; Vol. 23; pp 493-568.
(b) Tidwell, T. T. Ketenes, 2nd ed.; John Wiley & Sons: Hoboken, NJ,
2006; pp 206-214.
(4) A related, complementary strategy has been reported by Lie-
beskind and Moore. See ref 3a and (a) Liebeskind, L. S.; Iyer, S.; Jewell,
C. F. J. Org. Chem. 1986, 51, 3065–3067. (b) Perri, S. T.; Foland, L. D.;
Decker, O. H. H.; Moore, H. W. J. Org. Chem. 1986, 51, 3067–3068.
(5) Examples: (a) Danheiser, R. L.; Gee, S. K.; Perez, J. J. J. Am.
Chem. Soc. 1986, 108, 806–810. (b) Danheiser, R. L.; Cha, D. D.
Tetrahedron Lett. 1990, 31, 1527–1530. (c) Danheiser, R. L.; Casebier,
D. S.; Loebach, J. L. Tetrahedron Lett. 1992, 33, 1149–1152. (d)
Danheiser, R. L.; Casebier, D. S.; Huboux, A. H. J. Org. Chem. 1994,
59, 4844–4848. (e) Danheiser, R. L.; Helgason, A. L J. Am. Chem. Soc.
1994, 116, 9471–9479. (f) Danheiser, R. L.; Trova, M. P. Synlett 1995,
573–574. (g) Danheiser, R. L.; Casebier, D. S.; Firooznia, F. J. Org. Chem.
1995, 60, 8341–8350. (h) Dudley, G. B.; Takaki, K. S.; Cha, D. D.;
Danheiser, R. L. Org. Lett. 2000, 2, 3407–3410.
(6) For additional examples of the application of this benzannulation
strategy in natural product synthesis, see: (a) Kowalski, C. J.; Lal, G. S. J. Am.
Chem. Soc. 1988, 110, 3693–3695. (b) Smith, A. B., III; Adams, C. M.;
Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925–5937.
(7) For notable recent examples of “aminobenzannulation” ap-
proaches to the synthesis of anilines, see: (a) Merlic, C. A.; Burns,
E. E. Tetrahedron Lett. 1993, 34, 5401–5404. (b) Padwa, A.; Dimitroff,
M.; Waterson, A. G.; Wu, T. J. Org. Chem. 1997, 62, 4088–4096. (c)
Saito, S.; Uchiyama, N.; Gevorgyan, V.; Yamamoto, Y. J. Org. Chem.
2000, 65, 4338–4341. (d) Barluenga, J.; Lꢀopez, L. A.; Martínez, S.;
Tomꢀas, M. Tetrahedron 2000, 56, 4967–4975. (e) Neumann, H.; von
Wangelin, A. J.; Klaus, S.; Str€ubing, D.; G€ordes, D.; Beller, M. Angew.
Chem., Int. Ed. 2003, 42, 4503–4507. (f) Tiano, M.; Belmont, P. J. Org.
Chem. 2008, 73, 4101–4109. (g) Kiren, S.; Padwa, A. J. Org. Chem. 2009,
74, 7781–7789.
(8) (a) Delaunois, M.; Ghosez, L. Angew. Chem., Int. Ed. 1969, 8, 72–
73. See also:(b) Ficini, J.; Pouliquen, J. Tetrahedron Lett. 1972, 1135–
1138. (c) Himbert, G. Liebigs Ann. Chem. 1979, 829–841. (d) Henn, L.;
Himbert, G. Chem. Ber 1981, 114, 1015–1026. (e) D€otz, K. H.;
M€uhlemeier, J.; Trenkle, B. J. Organomet. Chem. 1985, 289, 257–262.
(f) Henn, L.; Himbert, G.; Diehl, K.; Kaftory, M. Chem. Ber 1986, 119,
1953–1963. (g) Barbaro, G.; Battaglia, A.; Giorgianni, P. J. Org. Chem.
1987, 52, 3289–3296. (h) Schulte, N.; M€oller, M. H.; Rodewald, U.;
W€urthwein, E.-U. Chem. Ber 1994, 127, 1287–1293.
(9) Koch, R.; Wentrup, C. Org. Biomol. Chem. 2004, 2, 195–199.
(10) Ficini observed that the reaction of certain ynamines and
cyclobutenones forms strained bicyclo[2.2.0]hexenones that under-
go π2s þ σ2s þ σ2s rearrangement to generate a vinylcyclobute-
none. This vinylcyclobutenone is isomeric with respect to general
structure 5 and would yield a phenol of type 16 upon 4-electron
electrocyclic opening followed by 6-electron electrocyclic closure.
(26) Reviews: Mori, M. Adv. Synth. Catal. 2007, 349, 121–135. (b)
Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382.
(27) Derivatives examined include the corresponding N-tosylsulfo-
namide corresponding to 49 and the (desilylated) terminal alkyne, as
well as its TBDMS phenol ether derivative.
(28) (a) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.; Hashimoto,
M.; Tada, T.; Koda, S.; Morimoto, Y. J. Am. Chem. Soc. 1987, 109, 4108–
4109. (b) Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. J. Antibiot.
1989, 42, 145–148.
(29) Rajski, W. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723–2796.
(30) (a) Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114,
383–385. (b) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T.
Angew. Chem., Int. Ed. 2002, 41, 4686–4688. (c) Suzuki, M.; Kambe, M.;
Tokuyama, H.; Fukuyama, T. J. Org. Chem. 2004, 69, 2831–2843.
(31) Schkeryantz, J. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 4722–4723.
(32) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
1997, 53, 10229–10238. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.;
1872
dx.doi.org/10.1021/jo2000308 |J. Org. Chem. 2011, 76, 1852–1873

The Journal of Organic Chemistry
ARTICLE
Katoh, T.; Terashima, S. Tetrahedron 1997, 53, 10239–10252. (c) Katoh,
T.; Nagata, Y.; Yoshino, T.; Nakatani, S.; Terashima, S. Tetrahedron 1997,
53, 10253–10270.
(33) (a) Judd, T. C.; Williams, R. M. Angew. Chem., Int. Ed. 2002, 41,
4683–4685. (b) Judd, T. C.; Williams, R. M. J. Org. Chem. 2004, 69,
2825–2830. (c) Ducept, P.; Gubler, D. A.; Williams, R. M. Heterocycles
2006, 67, 597–619.
(34) For a recent very efficient route to 7-epi-(þ)-FR900482, see:
Trost, B. M.; O’Boyle, B. M. Org. Lett. 2008, 10, 1369–1372.
(35) Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J. Am. Chem. Soc.
2000, 122, 10781–10787.
(36) Ducray, R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41,
4688–4691.
1986, 108, 6757. What was estimated to be the desired amount of
Sn(OTf)2 was transferred to the tared 200-mL recovery flask as a
suspension in 50 mL of anhydrous Et2O via cannula. Et2O was removed
from the flask via cannula by applying a positive pressure of argon, and
the Sn(OTf)2 was washed with three 40-mL portions of Et2O while
under argon. Following the addition of each portion of Et2O, the
resulting suspension was stirred vigorously for 1-2 min and then
allowed to stand for 1-2 min before removal of the Et2O via cannula.
After the final wash, the Sn(OTf)2 was dried overnight at 0.3-0.5
mmHg at 100 °C for ca. 16 h.
(58) Breit, B.; Zahn, S. K. J. Org. Chem. 2001, 66, 4870–4877.
(59) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(37) Paleo, M. R.; Aurrecoechea, N.; Jung, K. Y.; Rapoport, H. J. Org.
Chem. 2003, 68, 130–138.
(60) The phosphonium bromide 75 was prepared according to the
procedure reported in ref 46.
(38) Iwasawa, N.; Huang, H.; Mukaiyama, T. Chem. Lett. 1985,
1045–1048.
(61) Prepared via the reaction of allylamine with di-tert-butyl
dicarbonate as reported in: Kirkland, T. A.; Lynn, D. M.; Grubbs,
R. H. J. Org. Chem. 1998, 63, 9904–9909.
(39) (a) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391–2393. (b) Nagao,
Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.; Shimada, O.;
Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243–4249.
(40) For a review on the use of oxazolidinonethione and thiazolidi-
nethione chiral auxiliaries, see: Velꢀazquez, F.; Olivo, H. F. Curr. Org.
Chem. 2002, 6, 303–340.
(62) (a) Shu, L.; Sch€afer, A.; Schl€uter, A. D. Macromolecules 2000,
33, 4321–4328.(b) Carbamate 86 used in this reaction was prepared in
near quantitative yield from the reaction of 2-trimethylsilylethanol with
1.2 equiv of allyl isocyanate in the presence of 2.0 equiv of i-Pr2NEt in
toluene at 65 °C for 20 h.
(63) Further elution with 10% EtOAc-hexanes resulted in the
recovery of 2.1 equiv of unreacted carbamate 86.
(64) (a) Still, C. W. J. Am. Chem. Soc. 1978, 100, 1481.(b) Tributyl-
(41) Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60,
6604–6607.
(42) Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J. Org.
Chem. 1997, 62, 7546–7547.
(benzyloxymethyl)stannane was prepared according to ref 48a.
(43) For details on the assignment of the relative and absolute
stereochemistry of 73, see the Experimental Section.
(44) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883–7884. (b) Crimmins, T.; Chaudhary, K. Org. Lett.
2000, 2, 775–777. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894–902. (d) Crimmins, M. T.;
She, J. Synlett 2004, 1371–1374.
(45) Michel, P.; Gennet, D.; Rassat, A. Tetrahedron Lett. 1999, 40,
8575–8578.
(46) Ylide 75 was generated in situ by treatment of dibromomethyl-
(triphenyl)phosphonium bromide with KO-t-Bu (rt, 5 min). For best
results, it is crucial to employ solvent-free phosphonium salt prepared by
the method of: Lerm, M.; Gais, H.-J.; Cheng, K.; Vermeeren, C. J. Am.
Chem. Soc. 2003, 125, 9654–9667.
(47) Prepared by addition of ketene to ethoxyacetylene as described
by: Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. J. Org. Chem. 1973,
38, 1451–1455.
(48) (a) Synthesis of 77: Kaufman, T. S. Synlett. 1997, 1377–1378.
(b) Synthesis of 78: Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee,
S. K.; Johnson, C. R.; Medich, J. R. Org. Synth. 1993, 71, 133–139.
(49) Liebeskind, L. S.; Wirtz, K. R. J. Org. Chem. 1990, 55, 5350–5358.
(50) (a) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
165–168. (b) Ellison, R. A.; Griffin, R.; Kotsonis, F. N. J. Organomet.
Chem. 1972, 36, 209–213.
(51) Prepared from the reaction of allylamine and methyl chlor-
oformate according to the procedure of: Kozmin, S. A.; Iwama, T.;
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628–4641.
(52) Carbamate 19 was prepared following the general method of:
Capson, T. L.; Poulter, D. C. Tetrahedron Lett. 1984, 25, 3515–3518.
(53) Williams, J. W.; Hurd, C. D. J. Org. Chem. 1940, 5, 122. See also:
Hanford, W. E.; Sauer, J. C. Preparation of Ketenes and Ketene Dimers.
Org. React. 1958, 3, 108–140.
(54) Methoxypropyne was prepared according to: Hine, J.; Mahone,
L. G.; Liotta, C. L. J. Org. Chem. 1967, 32, 2600–2609.
(55) Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J. Org.
Chem. 1997, 62, 7546–7547.
(56) Prepared from (S)-valinol as reported in: Delaunay, D.; Toupet,
L.; Le Corre, M. J. Org. Chem. 1995, 60, 6604–6607.
(57) Tin(II) trifluoromethanesulfonate was prepared according to
the procedure reported in: Evans, D. A.; Weber, A. E. J. Am. Chem. Soc.
1873
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