Carbon-carbon bond-forming reactions of α-thioaryl carbonyl compounds for the synthesis of complex heterocyclic molecules

Article abstract of DOI:10.1021/jo201541e

Strategies for the formation of carbon-carbon bonds from the α-thioaryl carbonyl products of substituted lactams are described. Although direct functionalization is possible, a two step process of oxidation and magnesium-sulfoxide exchange has proven optimal. The oxidation step results in the formation of two diastereomers that exhibit markedly different levels of stability toward elimination, which is rationalized on the basis of quantum mechanical calculations and X-ray crystallography. Treatment of the sulfoxide with i-PrMgCl results in the formation of a magnesium enolate that will undergo an intramolecular Michael addition reaction to form two new stereogenic centers. The relationship between the substitution patterns of the sulfoxide substrate and the efficiency of the magnesium exchange reaction are also described.

Full text of DOI:10.1021/jo201541e

Article
pubs.acs.org/joc
Carbon−Carbon Bond-Forming Reactions of α-Thioaryl Carbonyl
Compounds for the Synthesis of Complex Heterocyclic Molecules
James E. Biggs-Houck, Rebecca L. Davis, Jingqiang Wei, Brandon Q. Mercado, Marilyn M. Olmstead,
Dean J. Tantillo, and Jared T. Shaw*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: Strategies for the formation of carbon−carbon
bonds from the α-thioaryl carbonyl products of substituted
lactams are described. Although direct functionalization is
possible, a two step process of oxidation and magnesium-
sulfoxide exchange has proven optimal. The oxidation step
results in the formation of two diastereomers that exhibit
markedly different levels of stability toward elimination, which
is rationalized on the basis of quantum mechanical calculations
and X-ray crystallography. Treatment of the sulfoxide with
i-PrMgCl results in the formation of a magnesium enolate that will undergo an intramolecular Michael addition reaction to form
two new stereogenic centers. The relationship between the substitution patterns of the sulfoxide substrate and the efficiency of
the magnesium exchange reaction are also described.
and selenides undergo intermolecular carbon−carbon bond-
forming reactions readily,7 the reactions of sulfides are often
limited to cyclizations8 and reductions.9 At the outset of our
studies, there were only isolated examples of intermolecular
trapping of radicals derived from sulfides to yield new C−C
bonds.10 These two potential reaction manifolds are comple-
mentary in their chemistry and produce similar substitution
patterns, i.e., quaternary stereogenic centers adjacent to a
carbonyl. The use of sulfides as precursors to carbocations that
are trapped with nucleophilic alkenes is also possible with
substrates that, unlike 6, have electron-donating groups
attached to the reacting carbon.11 The ability of thioethers to
serve as precursors to cations, anions, and radicals places this
class of functional group among the most versatile function-
alities in organic synthesis.
Carbon−Carbon Bond-Formation via Radical Inter-
mediates. Radicals generated from 4CR products were
initially investigated in intermolecular reactions with alkenes.
The propensity of these substrates to form radicals was well-
established by our previous studies that employed tris-
(trimethylsilyl)silane or tributyltin hydride to quench radicals
formed under thermal conditions with AIBN as an initiator.12
We first attempted to intercept the radical with t-butylacrylate
and observed only reduction product 17, suggesting that the
radical intermediate was bypassing the alkene (eq 1). Lactam
17 is formed with high diastereoselectivity in accord with our
previous results, which we attribute to delivery of the hydrogen
atom from the face of the radical opposite to the neighboring
phenyl ring.2 The slow rate of alkene addition can be
INTRODUCTION
■
Multicomponent reactions (MCRs) can form the starting point
for highly efficient stereoselective syntheses.1 We recently
disclosed a new one-pot, four-component reaction (4CR) that
produces highly substituted γ-lactams in high yield and with
high diastereoselectivity for the formation of two or three
stereogenic centers (eq 1).2 We subsequently applied this
reaction to the synthesis of the γ-lactam natural product
heliotropamide, wherein the C−S bond in the 4CR product
was cleaved to a C−H bond under conditions that initiate
radical formation from the α-thioaryl ester.3 In order to further
exploit this functional unit within the 4CR products, we have
investigated radical and anionic conditions for the formation of
C−C bonds to generate quaternary stereogenic centers
(Scheme 1A). Herein, we provide a detailed account of these
studies as they were applied to the preparation of a model
system possessing the connectivity of the core of nakadomarin
A (Scheme 1B). The techniques described could also prove
useful for the preparation of core structures featured in several
related alkaloids4 with quaternary stereogenic centers at the
3-position of a pyrrolidine ring (Scheme 1B).
RESULTS AND DISCUSSION
■
Carbon−sulfur bonds can be cleaved under a variety of
conditions that result in carbon−carbon bond formation. C−S
bond breakage under reducing conditions to produce an anion
is relatively straightforward, depending on the stability of the
anion that is formed. In the case of enolate formation, recent
examples of reducing agents for this process include lithium-di-
tert-butyl biphenyl (LiDBB)5 and SmI2.6 We also set out to
explore the possibility of using the sulfide group of 4CR
products as a radical precursor. Although bromides, iodides,
Received: August 8, 2011
Published: October 24, 2011
© 2011 American Chemical Society
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Scheme 1. (A) Thioaryl-Substituted Gamma Lactams from a 4CR as Substrates for C−C Bond-Forming Reactions and (B)
Targets with Arylpyrrolidine Substructures Accessible by a 4CR-Alkylation Sequence
replaced with a phenyl ring. 2-Iodobenzaldehyde is commer-
cially available and can be prepared on large scale using IBX to
oxidize the much more cost-effective 2-iodobenzyl alcohol. The
4CR followed by esterification proceeds smoothly to produce
lactam 27 in 58% yield. Heck reaction with ethyl acrylate
produced substrate 28 in high yield (Scheme 2B). Use of
several different potential catalysts revealed that Pd(OAc)2
provided the most consistently high conversions.14 Unfortu-
nately, when 28 was treated with AIBN and (TMS)3SiH (or
Bu3SnH, not shown) and heated to reflux, only starting material
was recovered, demonstrating that making the reaction
rationalized by a prohibitively high LUMO−SOMO energy gap
between the electron-withdrawing group substituents on both
the alkene and the radical. A related example with a secondary
radical and t-butyl acrylate produces modest yield of the
intramolecular was not sufficient to favor propagation of the
addition product.10c In that case, the radical is not stabilized by
radical process. This result was surprising, given the similarity
a carbonyl group and is expected to exhibit a more nucleophilic
to a related “radical Michael” reaction reported by Posner,8a
character.
albeit on a less sterically demanding substrate. The increased
We elected to study the possibility of cyclization in the
steric demand of the neighboring ortho-substituted phenyl ring
context of an intramolecular radical-based Michael-type
could be hindering the approach of the propagating reagent,
reaction that would provide an entry into the stereoselective
i.e., the radicals formed from either Bu3SnH or (TMS)3SiH.
synthesis of polycyclic products, e.g., the core of nakadomarin A.
Intermolecular reactions with a nucleophilic alkene were also
This hexacyclic marine alkaloid was first isolated in 19974c and
attempted. Literature examples of secondary and tertiary
has subsequently been the subject of intense synthetic effort,
culminating in several total syntheses.13 Retrosynthetic analysis
reveals that the tetracyclic core could emerge from a Michael
reaction of susbstrate 19, which is available in three steps by
4CR, methylation, and Heck reaction (Scheme 2A). For this
study, we opted for a model system in which the furan ring is
radicals formed from phenyl sulfides suggested that this
strategy could be applied to the 4CR lactams.10 When ester
16 was treated with AIBN and allyltributyltin under thermal
conditions, the starting material was recovered unchanged
(Scheme 3A). We next explored the analogous nitrile 30, which
is easily formed in two steps from acid 15 (Scheme 3B).
Scheme 2. (A) Retrosynthetic Analysis of Nakadomarin A and (B) Synthesis of Radical Michael Reaction Precursor and
Attempted Cyclization
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Scheme 3. (A) Attempted Formation of a Radical from Ester
16 and Trapping with Allyltributyltin and (B) Synthesis,
Radical Formation, and Trapping of Nitrile 30
Table 1. Attempted Reductive Enolate Generation Using
Various Reported Reducing Conditions
entry
reagent(s)
solvent
temp (°C)
result
1
2
3
4
5
SmI2 HMPA, i-PrCHO
LiDBB/MeI
THF
THF
THF
THF
DCM
−78
−78
−78
23
no reaction
decomp
LiDBB/allylBr
LiCl/PPh3
decomp
no reaction
no reaction
Zn(OTf)2/PPh3
23
conditions for which isolated examples have been documented
were not attempted.21
In contrast to sulfides, aryl sulfoxides undergo rapid exchange
reactions at low temperatures with alkyl Grignard reagents to
produce an aryl-alkyl sulfoxide and a new Grignard reagent.
This reaction has been used in both capacities, i.e., for the
unsymmetrical synthesis of sulfoxides22 and for the preparation
of complex Grignard reagents.23,24 In addition, Hoffmann
showed that the exchange reaction could be used for the
synthesis of configurationally defined organomagnesium
halides.25 Among Satoh’s reports of preparing magnesium
carbenoids was one example of using magnesium-sulfoxide
exchange for the preparation of α-halogenated enolates.26
Although this sequence would require two steps for our system,
the ease with which sulfides can be oxidized to sulfoxides in the
presence of a variety of functional groups made this route
attractive.
Conversion of acid 15 to amide 29 resulted in epimerization to
a nearly 50:50 mixture of epimers, which was converted to a
similar mixture of nitrile diastereomers. When nitrile 30 was
treated with AIBN and allyltributylstannane, allylated product
31 was formed as a single diastereomer (>95:5 selectivity). The
relative anti-configuration between the allyl group and the
phenyl ring was established by NOESY correlation. This
reaction demonstrates that steric effects play an important role
in propagation of the radical process, i.e., in the accessibility of
the tributyltin radical to the C−S bond, which is easier in the
case of the nitrile when compared to the more sterically
demanding ester. Although this reaction successfully installed
the quaternary center needed for the core of nakadomarin A,
the steps necessary to form the cyclopentene ring detracted
from the viability of this route. Current studies are exploring
related cyclization reactions to form larger rings.
Initial attempts at oxidation of thioaryl-substituted lactams
proceeded in highly variable yields (Table 2). Initial use of
Table 2. Entries 1−5 Converted 28 to 34, Whereas Entries
5−13 Converted 33 to 35
Reductive Enolate Formation. We initially explored the
ability of reducing agents to cleave the C−S bonds of 4CR
lactam products to form enolates that could react with
electrophiles. The most widely used protocol for the reductive
formation of organolithium reagents from thioethers was
originally reported by Cohen15,16 and Screttas,17 each of
whom has also reported subsequent refinements.18 Following
the examples of Gleason, whose protocol is specifically for
enolate generation,5a we treated lactam 16 with LiDBB and
observed decomposition of the starting material after attempted
trapping with electrophiles or protonation (Table 1). Close
inspection of the proline-derived substrates used by Gleason
revealed that most were devoid of multiple-bonded function-
ality that might be more easily reduced than the desired
C−S bond.5,19 We next attempted SmI2 and observed no
reaction.6 The authors of ref 6 note that related reactions of
γ-lactams were unsuccessful, suggesting that the additional
inductive stabilization in a succinimide enolate intermediate
facilitates the reduction by SmI2 in that case. We also observed
no reaction between 16 and ZnBr2 or p-TsOH in the presence
of PPh3, as was used for the reduction of oxindoles resulting
from the Gassman synthesis.20 In the case of 3-thiomethylox-
indoles, the resultant anion is quasi-aromatic and, thus, more
stable by many orders of magnitude than enolate 32. Other
yield
entry
oxidant
solvent
DCM
temp (°C)
(%)
1
2
3
4
5
6
1 equiv m-CPBA
1 equiv m-CPBA
1 equiv Oxone, Al2O3
1 equiv NaIO4
−42 to 23
−78 to −10
reflux
24
33
DCM
DCM
NR
15
CH3OH
DCM
0 to 23
23
1 equiv IBX, TBAB
1 equiv H2O2
NR
31
PhOH/
H2O
23
7
0.5 equiv m-CPBA
DCM
−78
23
14
NR
NR
NR
8
1 equiv MnO2
CHCI3
9
1 equiv m-CPBA, PhCO2H DCM
−78
23
10
1 equiv MnO2, 3 equiv
HCl
CH3OH
11
10 equiv MnO2, 20 equiv
HCl
CH3OH
23
NR
11
12
1 equiv m-CPBA
1 equiv m-CPBA
THF
ether
0
0
45
43
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Figure 1. (A) Proposed mechanism for the formation of 37 from (R*,R*,R*)-34. (B) Computed structures and relative energies for the elimination
of (R,R,S)-38. (C) Computed structures and relative energies for the elimination of (R,R,R)-38. Energies (kcal/mol) shown for A and B are all
relative to the energy of the lowest energy conformer of (R,R,S)-38 and are Gibbs free energies calculated at 25 °C. Selected bond lengths are shown
in Å. (D) Crystal structure of sulfoxide 39.
m-CPBA (Table 2, entry 12) was encouraging, producing the
desired product in 45% yield. A scan of oxidants known to
produce sulfoxides from sulfides in the presence of alkenes was
evaluated.27 Yields comparable to that of m-CPBA could be
obtained with H2O2/phenol (Table 2, entry 6). Extensive
variation of the oxidant revealed that the yield could never be
increased above 50%. In addition, we noted that 34 or 35 was
formed as a single diastereomer in all cases, despite related
precedent indicating that the diastereoselectivity of this process
was often modest.
the reaction mixture from m-CPBA oxidation, unsaturated
lactam 37 was isolated in 33% yield (Figure 1A). This product
would seem to emerge from elimination of the sulfoxide or
perhaps sulfone arising from overoxidation. We favored the
former explanation from the outset, as it would be adequately
explained by preferential elimination of one diastereomer over
the other, thus explaining both the low yield of sulfoxide and
the high apparent diastereoselectivity of this process.
Furthermore, sulfones are far less prone to elimination when
compared to sulfoxides.28 In fact, alkyl sulfides have often
served as synthetic equivalents for alkenes by virtue of the
efficient oxidation/elimination sequence that can reveal the
double bond.29
The inescapably low yield paired with the inexplicably high
diastereoselectivity prompted us to more carefully scrutinize
the byproduct of this reaction. Upon careful purification of
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Scheme 4. Synthesis of Sulfoxide Substrates to Avoid Elimination
Our hypothesis regarding preferential elimination of one
isomer of sulfoxide is supported by quantum chemical
calculations and X-ray crystallography. Calculation of the
structures of the two possible isomers of sulfoxide (B3LYP/6-
31G+(d,p))30 indicates that they differ in energy by several kcal/
mol (Figure 1). Nonetheless, both could likely be formed under
the reaction conditions. The preferred isomer, (R*,R*,R*)-38,
positions the sulfoxide oxygen distal to the α-proton of the ester,
while isomer (R*,R*,S*)-38 positions the sulfoxide oxygen
directly over the α-proton, preorganizing the molecule for
elimination. Significant differences in the barriers to elimination
are predicted, with elimination preferred for (R*,R*,S*)-38. We
were able to obtain a single crystal of 39, the structure of which
has the same relative configuration of isomer (R*,R*,R*)-38. The
structural similarity of 39 and (R*,R*,R*)-38 is consistent with
the hypothesis that this isomer is less likely to undergo
elimination on the basis of conformational preferences conferred
by the sulfoxide stereogenic center. Although an enantioselective
catalyst for sulfoxide formation might conceivably provide a
solution to this problem, it would not be easy to test on a racemic
mixture of lactams and may be investigated on an enantiomeri-
cally pure substrate when it becomes available. In addition, most
chiral catalysts to date do not function well on hindered
sulfoxides, e.g., those with one tertiary substituent.31
elimination. A mixture of diastereomers of the two sulfoxides
was obtained in 65% combined yield.
Sulfoxides 34, 42, 46, 49a, and 49b were examined in
magnesium exchange reactions. 34 reacted smoothly with
i-PrMgCl to produce tricyclic product 50 in high yield and with
high diastereoselectivity (Scheme 5). The relative configuration
Scheme 5. (A) Cyclization of Lactam Sulfoxide 34 to 50 by
Magnesium-Sulfoxide Exchange/Michael Addition and X-ray
Crystal Structure of Amide Derivative 51 and (B) Attempted
Cyclizations of n-Butyl Sulfoxides 46, 49a, and 49b
Two strategies for avoiding elimination were evaluated. First,
we prepared a substrate with the carbonyl group of the lactam
core removed to reduce the acidity of the proton that is
implicated in the sulfoxide elimination. Lactam 27 reacted
smoothly with BH3·DMS to produce substituted pyrrolidine 40,
which was carried on through the Heck reaction in modest yield
(Scheme 4). Subsequent oxidation proceeded smoothly without
affecting the tertiary amine. Unfortunately, elimination product
43 was still observed along with a single diastereomer of 42,
suggesting the course of the reaction was similar to that of the
lactam. Interestingly, the product of pyrrolidine elimination was
pyrroline 43, in which there was no isomerization of the alkene
into conjugation with the nitrogen. We next hypothesized that
an aliphatic, rather than aromatic, sulfoxide would be less prone
to elimination. Heck product 45 was prepared in analogy to 28
and was shown to give similar results in the oxidation. Finally,
combining these two modifications in the form of n-butyl
substituted pyrrolidines 49a and 49b effectively avoided
of the product was established through X-ray crystallography
after conversion to the bis-p-bromobenzyl amide 51 using the
method of Weinreb.32 The relative stereochemistry for the ring
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junction was cis, as expected; however, the stereogenic center
arising from facial selectivity on the Michael acceptor was syn
to the ring juncture, counter to our expectation and opposite in
configuration to the analogous position on nakadomarin A. The
analogous pyrrolidine sulfoxide 42 did not undergo efficient
cyclization. The origin of this lack of reactivity is unclear,
potentially arising from a result of conformation preferences,
complexation of the basic nitrogen to the Grignard reagent,
reduced enolate stability of the pyrrolidine relative to the
lactam, or some other effect. Although aromatic sulfoxides are
almost universally employed in the exchange reactions that
have been performed to date, we investigated n-butyl sulfoxide-
substituted substrates because of their superior stability when
compared to the aromatic sulfoxides. Neither lactam 46 nor
pyrrolidines 49a and 49b underwent cyclization.
The diastereoselectivity of the intramolecular Michael
addition reaction probably originates from chelate organization
of the magnesium enolate and the unsaturated ester carbonyl.
Although we have no insight as to the geometry of the
presumed enolate intermediate, or even whether or not there is
a preponderance of one isomer, we propose that the syn
diastereoselection could originate from either Z- or E-enolate
(Z-52, E-52, Scheme 6). Previous mechanistic proposals by
Figure 2. Michael reaction/Dieckmann cyclization of 34 to aza-
triquinane 53 and X-ray crystal structure of 53.
variant of the core of 53, similar structures with nitrogen in the
periphery are far less common.35 Furthermore, there is only
one case of a triquinane structure featuring an amide in direct
analogy to 53.36
The changes in sulfoxide structure that conferred stability
suggested that modulation of the carbonyl group might allow
stable arylsulfoxides to be accessed. An amide would be
expected to be less electron-withdrawing than an ester and less
likely to enable elimination. On the other hand, a nitrile would
be comparably electron withdrawing and less sterically
demanding than the ester. Starting with carboxylic acid 26,
the corresponding pyrrolidine amide and nitrile could be
accessed in one or two steps, respectively. The Heck reaction
was executed without incident in each case. Oxidation of the
pyrrolidine amide resulted in exclusive recovery of the
elimination product (Scheme 7), suggesting that the more
easily eliminated diastereomer is formed preferentially or that
both diastereomers undergo facile elimination due to conforma-
tional influences. Conversion of acid 26 into amide 59 and then
into nitrile 60 was achieved under standard conditions.
Unfortunately, oxidation to sulfoxide 61 was accompanied by
a significant amount of elimination. Furthermore, treatment of
the sulfoxide with i-PrMgCl did not result in any cyclization.
Although this result was disappointing, there are few previous
examples of nitrile-stabilized Grignard reagents formed from
sulfoxide exchange, and in one case, the substrate benefits from
additional stabilization from cyclopropyl substitution.37
Scheme 6. Proposed Transition State Model to Explain
Stereochemical Outcome of the Michael Addition from the
Two Possible Enolate Isomers Indicated Z-52 and E-52
CONCLUSION
■
Several approaches to the construction of C−C bonds from
thioethers that result in quaternary stereogenic centers have
been explored. Although radical C−S bond cleavage for
reduction is facile, the analogous process for C−C bond
formation is more limited, requiring a nitrile substituent and
more forcing conditions. The latter reaction exhibits high
diastereoselection with the same sense of induction as was
observed for reduction. Anionic methods were also explored,
and the most productive emerged from magnesium-sulfoxide
exchange. This method proved to be limited to ester-containing
substrates and proceeded in high yield and with high
diastereoselectivity. The lone drawback of this approach is a
poor yield in the sulfoxidation step, which was traced to
differential propensities for elimination of the diastereomeric
sulfoxides that are formed. Future studies will explore the
development of substrates for asymmetric oxidation that
Heathcock33 and recent computational evidence from Evans34
suggest a closed transition state for the Michael addition, in
which the acceptor carbonyl is activated by the enolate metal.
Application of these models to either E- or Z-52 explains the
observed formation of 50.
Tricyclic product 50 is also capable of undergoing a
subsequent Dieckmann cyclization. In one run of the Michael
addition of sulfoxide 34, the reaction was quenched with
methanol and left to stand at room temperature for several
hours. A reduced yield of 50 was obtained along with 33% of a
new product. NMR spectroscopy and mass spectrometry
supported the assignment of keto amide 53, and the structure
was eventually confirmed by X-ray crystallography (Figure 2).
Although a large body of literature surrounds the chemistry of
fused triquinanes and related triquinacenes, i.e., the all-carbon
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Scheme 7. Attempted Preparation of Amide Sulfoxide 54 and Preparation and Attempted Cyclization of Nitrile Sulfoxide 61
14.6; HRMS (FTMS + p ESI) m/z calcd for C31H31NO5S (M + H)+
eschew the elimination problem. We anticipate that the
strategies described herein will pave the way for the assembly
of complex 5-arylpyrrolidine motifs as intermediates in the
synthesis of alkaloid natural products and other biologically
530.1996, found 530.1995; IR (thin film) 1731, 1699 cm−1; TLC (20%
EtOAc/hexanes) Rf = 0.20.
4CR Lactam Amide 29. To a solution of para-thiocresol (30 mL,
30 mmol, 1 M) in toluene were added melaic anhydride (2.9418 g,
30 mmol), benzaldehyde (3.06 mL, 30 mmol), and benzylamine
important organic molecules.
(3.28 mL, 30 mmol). The mixture was stirred for 24 h at reflux under a
EXPERIMENTAL SECTION
Dean−Stark trap and then cooled to 23 °C. Toluene was removed in
vacuo to yield a yellow crude mixture. This was dissolved in benzene
(40 mL) and cooled to 0 °C, at which time SOCl2 (4.36 mL 60 mmol)
was added and the mixture was heated to reflux for 12 h. After cooling
to 23 °C, the solvent was removed in vacuo, and the residue was
dissolved in DCM (40 mL). This was cooled to 0 °C, and NH4OH
(12 mL, 300 mmol) was added slowly via syringe. After the addition
was complete, the reaction was allowed to warm to 23 °C and stirred
for 5 h. Finally, water was added, and the mixture was partitioned
between water (25 mL) and DCM (40 mL). The layers were
separated, and the aqueous layer was extracted with 2 × 50 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 15.3985 g of a brown oil. The oil was
purified by flash chromatography (35:65 EtOAc/hexanes) to yield the
product as a mixture of diastereomers that formed a yellow oil (8.5043 g,
68%). This product epimerizes slowly at room temperature and
spectral data is provided for the major diastereomer: 1H NMR (400 MHz,
CDCl3) δ 7.45 (s, 4H), 7.41−7.27 (m, 9H), 7.25−7.19 (m, 6H),
7.19−7.05 (m, 9H), 6.95 (s, 3H), 6.74 (s, 1H), 6.60 (s, 1H), 5.68 (s,
1H), 5.33 (s, 1H), 5.23 (dd, J = 6.6, 14.8, 3H), 4.68 (s, 1H), 4.24 (s,
1H), 3.68 (d, J = 18.0, 1H), 3.60 (d, J = 14.6, 1H), 3.50−3.38 (m, 3H),
2.74 (d, J = 17.6, 1H), 2.57 (d, J = 18.0, 1H), 2.34 (s, 3H), 2.29 (d, J =
12.1, 3H); 13C NMR (101 MHz, CDCl3) δ 173.8, 173.2, 172.3, 170.6,
140.3, 139.6, 135.5, 135.4, 135.0, 134.5, 134.1, 133.2, 130.5, 130.4,
129.7, 129.6, 129.4, 129.1, 129.0, 128.9, 128.9, 128.8, 128.7, 128.6,
128.0, 127.9, 126.3, 105.0, 69.4, 68.9, 60.8, 59.6, 44.9, 44.8, 40.5, 38.1,
34.9, 21.4, 21.4; HRMS (FTMS + p ESI) m/z calcd for C25H24N2O2S
(M + H)+ 417.1631, found 417.1628; IR (thin film) 1700, 1671, 1650 cm−1.
4CR Lactam Nitrile 30. Amide 29 (0.289 g, 0.694 mmol) was
dissolved in benzene (5 mL) and cooled to 0 °C. To this was added
POCl3 (0.32 mL, 3.470 mmol), and the mixture was heated to reflux
under a reflux condenser for 12 h, turning a dark red color. After being
cooled to 0 °C, the reaction was quenched and neutralized carefully
using water saturated with K2CO3. At pH = 7, the mixture was
partitioned between water and DCM (15 mL). The layers were
separated, and the aqueous layer was extracted with 2 × 20 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.231 g of an inseparable mixture of
diastereomers that was purified by flash chromatography (EtOAc/
■
4CR Ester 27. To a solution of para-thiocresol (3.42 mL, 3.42
mmol, 1 M) in toluene were added melaic anhydride (0.335 g, 3.42
mmol), o-iodobenzaldehyde (0.793 g, 3.42 mmol), and benzylamine
(0.37 mL, 3.42 mmol). The mixture was stirred for 24 h at reflux under
a Dean−Stark trap and then cooled to 23 °C. Toluene was removed in
vacuo to yield a yellow crude mixture. This was dissolved in acetone (5
mL) and K2CO3 (0.945 g, 6.83 mmol), and iodomethane (1.02 mL
13.668 mmol) was added. After stirring at 23 °C for 24 h, the resulting
mixture was partitioned between water (25 mL) and DCM (15 mL).
The layers were separated, and the aqueous layer was extracted with 2
× 20 mL of DCM. The combined organic layers were dried (MgSO4)
and concentrated in vacuo to afford 3 g of a brown oil. The oil was
purified by flash chromatography (15:85 EtOAc/hexanes) to yield the
product as a yellow oil (1.109 g, 58%): 1H NMR (400 MHz, CDCl3) δ
7.95 (d, J = 7.3, 1H), 7.43 (t, J = 7.6, 1H), 7.28 (dd, J = 5.8, 7.7, 3H),
7.12 (dd, J = 4.5, 12.0, 2H), 7.06−7.00 (m, 6H), 5.39 (s, 1H), 5.08 (d,
J = 14.5, 1H), 3.55 (s, 3H), 3.41 (d, J = 14.0, 1H), 3.18 (d, J = 17.0,
1H), 2.82 (dd, J = 1.0, 17.0, 1H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.0, 171.6, 140.7, 140.4, 137.0, 136.5, 135.4, 130.9, 130.0,
129.0, 128.9, 128.8, 128.8, 128.3, 128.2, 128.1, 126.3, 105.0, 102.3,
70.5, 58.8, 53.2, 45.2, 41.0, 21.5; HRMS (FTMS + p ESI) m/z calcd
for C26H24INO3S (M + H)+ 558.0595, found 558.0595; IR (thin film)
1730, 1696 cm−1; TLC (20% EtOAc/hexanes) Rf = 0.15.
Ester 28. To a flame-dried flask were added palladium acetate
(0.045 g, 0.199 mmol) and iodide 27 (1.11 g, 1.99 mmol) as a solution
in DMF (10 mL). Next were added ethyl acrylate (0.84 mL, 7.96 mmol)
and triethylamine (0.55 mL, 3.98 mmol). The mixture was heated to
105 °C under argon and a reflux condenser for 24 h and then cooled
to 23 °C. The resulting mixture was partitioned between DCM (30 mL)
and water (40 mL). The layers were separated, and the water layer was
extracted with 2 × 20 mL DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 1.5 g of a bright
red oil. The oil was purified by flash chromatography (20:80 EtOAc/
1
hexanes) to yield the product as a red oil (0.990 g, 94%): H NMR
(600 MHz, CDCl3) δ 7.99 (d, J = 15.7, 1H), 7.67−7.62 (m, 1H), 7.46
(pd, J = 1.6, 7.3, 2H), 7.27−7.20 (m, 4H), 7.04−6.99 (m, 4H), 6.96−
6.92 (m, 2H), 6.32 (t, J = 12.6, 1H), 5.34 (s, 1H), 5.12 (d, J = 6.6, 1H),
4.28−4.23 (m, 2H), 3.58 (s, 3H), 3.42 (d, J = 14.6, 1H), 3.30 (d, J =
14.6 1H), 2.89 (dd, J = 1.1, 17.1, 1H), 2.29 (s, 3H), 1.35−1.32
(m, 3H); 13C NMR (151 MHz, CDCl3) δ 172.0, 171.6, 166.5, 141.7,
140.4, 136.3, 136.2, 135.4, 133.4, 130.2, 130.0, 129.5, 128.9, 128.4,
128.0, 127.6, 127.3, 126.1, 121.7, 62.6, 60.7, 58.6, 53.2, 45.0, 41.3, 21.5,
1
hexanes) to yield a clear oil (0.1999 g, 72%): H NMR (400 MHz,
CDCl3) δ 7.50−7.44 (m, 4H), 7.44−7.40 (m, 3H), 7.39−7.34 (m,
5H), 7.32−7.27 (m, 4H), 7.26−7.21 (m, 5H), 7.16 (d, J = 7.9, 2H),
7.12−7.04 (m, 6H), 6.81 (s, 1H), 5.33 (d, J = 14.5, 1H), 5.25
166
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Article
(d, J = 14.7, 1H), 4.84 (s, 1H), 4.34 (s, 1H), 3.64 (d, J = 14.7, 1H),
3.47 (d, J = 14.5, 1H), 3.23 (dd, J = 0.9, 17.5, 1H), 3.05 (dd, J = 0.9,
17.2, 1H), 2.92−2.86 (m, 1H), 2.81−2.75 (m, 1H), 2.37 (s, 2H), 2.35
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.2, 169.3, 141.7, 141.4,
137.1, 136.9, 135.2, 134.8, 134.2, 132.1, 130.6, 130.6, 130.3, 129.9,
129.7, 129.4, 129.2, 129.1, 129.1, 128. 6, 128.4, 128.4, 125.2, 125.0,
120.6, 118.1, 68.3, 66.8, 47.8, 47.3, 45.3, 45.0, 43.4, 40.7, 21.6; HRMS
(FTMS + p ESI) m/z calcd for C25H22N2OS (M + H)+ 399.1526,
130.0, 129.9, 129.0, 128.6, 128.2, 128.2, 127.3, 125.4, 122.7, 72.4, 61.3,
60.6, 45.2, 34.7, 21.8, 14.6; HRMS (FTMS + p ESI) m/z calcd for
C31H31NO6S (M + H)+ 546.1945, found 546.1947; IR (thin film)
1728, 1704, 1685 cm−1; TLC (50% EtOAc/hexanes) Rf = 0.21.
4CR Sulfoxide 35. To a cooled (−78 °C) solution of 32 (0.2483 g,
0.555 mmol) in 10 mL of THF was added m-CPBA (0.1243 g,
0.555 mmol, 77%). The mixture was stirred for 3 h and then allowed
to warm to 25 °C, and a saturated solution of Na2S2O3 in water
(10 mL) was added. The resulting mixture was partitioned between
water and 15 mL of DCM. The layers were separated, and the aqueous
layer was extracted with 2 × 15 mL of DCM. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to afford 0.2438 g
of a purple oil. This was purified by flash chromatography (20:80
EtOAc/hexanes) to yield the product as a clear oil (0.1234 g, 48%
yield): 1H NMR (400 MHz, CDCl3) δ 7.52−7.45 (m, 3H), 7.42−7.35
(m, 1H), 7.31−7.30 (m, 1H), 7.29−7.25 (m, 4H), 7.04−6.99 (m, 2H),
6.96−6.91 (m, 2H), 5.28 (s, 1H), 5.11 (d, J = 14.7, 1H), 3.82 (s, 3H),
3.58 (s, 3H), 3.53 (d, J = 14.7, 1H), 2.74 (dd, J = 16.4, 0.8, 1H), 2.68
(d, J = 16.4, 1H); 13C NMR (101 MHz, CDCl3) δ 170.5, 166.9, 163.1,
135.4, 133.0, 130.2, 129.8, 129.4, 128.9, 128.4, 128.1, 127.1, 114.7,
77.6, 77.3, 77.0, 73.0, 65.6, 55.7, 53.4, 45.0, 34.3; HRMS (FTMS + p
ESI) m/z calcd for C26H25NO5S (M + H)+ 464.1526, found 464.1524;
IR (thin film) 1724, 1698, 1592 cm−1; TLC (50% EtOAc/hexanes)
Rf = 0.19.
2-Pyrrolin-5-one Ester 37. Isolated at the same time as 34 to
yield the product as a purple oil (0.1236 g, 55% yield): 1H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 7.5, 1H), 7.41 (t, J = 7.7, 1H), 7.31
(t, J = 7.5, 1H), 7.23 (d, J = 15.9, 1H), 7.10−7.01 (m, 3H), 6.98 (d, J =
7.6, 1H), 6.69 (d, J = 6.0, 2H), 6.14 (d, J = 15.9, 1H), 4.42 (d, J = 15.2,
1H), 4.36 (d, J = 15.2, 1H), 4.17 (q, J = 7.1, 2H), 3.63 (d, J = 24.3,
1H), 3.55 (d, J = 24.4, 1H), 3.47 (s, 3H), 1.27 (t, J = 7.1, 3H); 13C
NMR (101 MHz, CDCl3) δ 175.9, 166.4, 163.3, 153.2, 140.3, 136.5,
133.7, 130.6, 130.3, 129.8, 129.7, 128.5, 128.3, 127.8, 127.8, 126.3,
120.5, 106.9, 77.7, 77.4, 77.1, 60.7, 51.4, 44.5, 37.2, 14.5; HRMS
(FTMS + p ESI) m/z calcd for C24H23NO5 (M + H)+ 406.1649, found
406.1649; IR (thin film) 1701, 1636, 1594 cm−1; TLC (50% EtOAc/
hexanes) Rf = 0.40.
found 399.1521; IR (thin film) 2233, 1701 cm−1
.
Allylated Lactam Nitrile 31. Nitrile 30 was dissolved in dry
toluene (10 mL), to which was added allyl tributyl tin and heated to
80 °C. AIBN was then added, and the reaction was heated to reflux for
3 h. After 3 h, more allyl tributyl tin and AIBN were added, and the
reaction remained at reflux for 3 additional hours. The reaction was
then cooled to 23 °C, quenched with saturated sodium thiosulfate
solution, and partitioned between water and DCM. The layers were
separated, and the aqueous layer was extracted with 2 × 15 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.1134 g as a yellow oil. The oil was
purified by flash chromatography (hexanes to flush out the excess tin,
followed by 20:80 EtOAc/hexanes) to yield the product as a clear oil
(0.0737 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.49−7.40 (m, 3H),
7.36−7.28 (m, 3H), 7.21−7.14 (m, 2H), 7.13−7.05 (m, 2H), 5.82−
5.65 (m, 1H), 5.22 (d, J = 14.4, 1H), 5.17 (d, J = 10.2, 1H), 4.78 (dd,
J = 17.0, 1.2, 1H), 4.26 (s, 1H), 3.47 (d, J = 14.3, 1H), 3.10 (dd, J =
17.0, 0.8, 1H), 2.61 (d, J = 17.0, 1H), 2.40 (dd, J = 13.7, 6.3, 1H), 2.28
(dd, J = 13.8, 8.4, 1H); 13C NMR (101 MHz, CDCl3) δ 170.4, 135.5,
134.9, 130.7, 129.8, 129.6, 129.1, 129.0, 128.4, 122.3, 119.7, 66.1, 45.1,
42.5, 42.4, 40.45, 28.1, 27.1, 17.8, 13.8; HRMS (FTMS + p ESI) m/z
calcd for C21H20N2O (M + H)+ 317.1649, found 317.1650; IR (thin
film) 2245, 1702, 1362 cm−1; TLC (20:80 EtOAc/hexanes) Rf = 0.18.
4CR Ester 33. para-Methoxy-thiophenol (0.31 mL, 3.00 mmol),
melaic anhydride (0.294 g, 3.00 mmol), benzaldehyde (0.31 mL,
3.00 mmol), and benzylamine (0.33 mL, 3.00 mmol) were mixed in
toluene (10 mL). The mixture was stirred for 16 h at reflux under a
Dean−Stark trap and then cooled to 23 °C. Toluene was removed in
vacuo to yield a yellow crude mixture. This was dissolved in acetone
(15 mL) and K2CO3 (0.830 g, 6.00 mmol), and iodomethane (0.89 mL
12.00 mmol) was added. After stirring at 23 °C for 24 h, the resulting
mixture was partitioned between water (25 mL) and DCM (20 mL).
The layers were separated, and the aqueous layer was extracted with
2 × 25 mL of DCM. The combined organic layers were dried
(MgSO4) and concentrated in vacuo to afford 1.254 g as a yellow oil.
The oil was purified by flash chromatography (20:80 EtOAc/hexanes)
to yield the product as a yellow oil (0.342 g, 25%): 1H NMR (400 MHz,
CDCl3) δ 7.48−7.41 (m, 3H), 7.30−7.22 (m, 6H), 7.11−7.06 (m,
2H), 7.03−6.96 (m, 2H), 6.77−6.72 (m, 2H), 5.17 (d, J = 17.4, 1H),
4.92 (s, J = 7.0, 1H), 3.75 (s, 3H), 3.53 (s, 3H), 3.48 (d, J = 17.4, 1H),
3.19 (d, J = 15.7, 1H), 2.85 (s, J = 15.5, 1H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 171.9, 161.2, 138.1, 135.9, 134.2, 129.4, 128.8, 128.3,
127.9, 120.4, 114.7, 67.0, 59.0, 59.0, 55.5, 53.1, 44.8, 40.9; HRMS
(FTMS + p ESI) m/z calcd for C26H25NO4S (M + H)+ 448.1577,
found 448.1576; IR (thin film) 1731, 1698 cm−1; TLC (50% EtOAc/
hexanes) Rf = 0.68.
4CR Ester Sulfoxide 39. To a cooled (−78 °C) solution of 16
(1.3823 g, 3.2 mmol) in 7 mL of THF was added m-CPBA (0.7179 g,
3.2 mmol, 77%). The mixture was stirred for 3 h and then allowed to
warm to 25 °C, and a saturated solution of Na2S2O3 in water (10 mL)
was added. The resulting mixture was partitioned between water and
15 mL of DCM. The layers were separated, and the aqueous layer was
extracted with 2 × 15 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 1.5126 g of a
yellow oil. The oil was purified by flash chromatography (10:90 to
20:80 EtOAc/hexanes) to yield the product as a yellow oil (0.401 g,
29%). This was recrystallized from DCM to yield a crystalline solid:
1
mp 92−95 °C; H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.43−
7.33 (m, 1H), 7.31−7.22 (m, 8H), 7.01 (m, 2H), 5.27 (s, 1H), 5.12 (d,
J = 14.7, 1H), 3.56 (s, 3H), 3.53 (d, J = 14.9, 1H), 2.78 (d, J = 16.4,
1H), 2.70 (d, J = 16.3, 1H), 2.39 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 170.4, 166.8, 143.2, 136.3, 135.4, 133.0, 129.9, 129.9, 129.4,
128.9, 128.4, 128.1, 125.2, 72.8, 65.6, 53.4, 45.0, 34.2, 21.8; HRMS
(FTMS + p ESI) m/z calcd for C26H25NO4S (M + H)+ 448.1572,
found 448.1576; IR (thin film) 1723, 1699, 1686, 698 cm−1; TLC
(50% EtOAc/hexanes) Rf = 0.33.
Sulfoxide 34. To a cooled (−78 °C) solution of 28 (0.990 g,
1.869 mmol) in 10 mL of THF was added m-CPBA (0.419 g, 1.869
mmol, 77%). The mixture was stirred for 3 h and then allowed to
warm to 23 °C, and a saturated solution of Na2S2O3 in water (5 mL)
was added. The resulting mixture was partitioned between water (10 mL)
and DCM (15 mL). The layers were separated, and the aqueous layer
was extracted with 2 × 20 mL of DCM. The combined organic layers
were dried (MgSO4) and concentrated in vacuo to afford 0.1059 g of
clear oil. The oil was purified by flash chromatography (20:80 EtOAc/
hexanes to 30:70 EtOAc/hexanes) to yield the product as white solid
Pyrrolidine Ester 40. Acid 27 (2.1526 g, 3.86 mmol) was
dissolved in THF (25 mL) and cooled to 0 °C. To this was added
BH3·DMS (3.8616 mL, 7.72 mmol) as a 2 M solution in THF. The
solution was immediately heated to reflux and stirred for 2.5 h and
then cooled to 0 °C and quenched with MeOH. The mixture was then
partitioned between water (50 mL) and DCM (50 mL). The layers
were separated, and the aqueous layer was extracted with 2 × 50 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 2.1135 g of a white oil. The oil was
purified by flash chromatography (5:95 EtOAc/hexanes) to yield the
1
(0.4990 g, 49%): H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 15.8,
1H), 7.65−7.58 (m, 1H), 7.51−7.42 (m, 2H), 7.30−7.20 (m, 9H),
6.93 (dd, J = 2.9, 6.5, 2H), 6.28 (d, J = 15.8, 1H), 5.50 (s, 1H), 5.03 (d,
J = 14.4, 1H), 4.32−4.18 (m, 2H), 3.68 (s, 3H), 3.42 (d, J = 14.5, 1H),
2.83 (s, 2H), 2.38 (s, 3H), 1.33 (t, J = 7.1, 3H); 13C NMR (101 MHz,
CDCl3) δ 169.9, 167.1, 166.4, 143.4, 142.3, 137.4, 136.6, 134.9, 132.3,
1
product as a clear oil (1.6973 g, 81%): H NMR (400 MHz, CDCl3)
δ 7.96 (dd, J = 1.7, 7.9, 1H), 7.86 (dd, J = 1.2, 7.9, 1H), 7.44 (m, 1H),
7.24 (m, 5H), 7.15 (m, 2H), 7.02 (m, 3H), 4.57 (s, 1H), 3.71 (m, 4H),
167
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Article
3.28 (d, J = 13.2, 1H), 3.13 (m, 1H), 2.62−2.56 (m, 1H), 2.42 (m,
1H), 2.30−2.24 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 173.4,
140.4, 139.7, 139.3, 139.1, 136.0, 132.6, 130.2, 129.7, 128.9, 128.8,
128.4, 128.3, 127.7, 127.2, 102.8, 77.7, 64.3, 57.9, 53.0, 51.5, 37.2, 21.5;
HRMS (FTMS + p ESI) m/z calcd for C26H26INO2S (M + H)+
544.0802, found 544.0791; IR (thin film) 1705, 698 cm−1; TLC (20%
EtOAc/hexanes) Rf = 0.65.
removed via rotary evaporation, producing a thiol-substituted
anhydride. Concurrently, in a separate flask, o-iodobenzaldehyde
(2.026 g, 8.720 mmol) was dissolved in DCM (20 mL), after which
were added benzyl amine (0.95 mL, 8.720 mmol) and anhydrous
MgSO4 (2.89 g, 24 mmol). This was stirred for 14 h, after which the
MgSO4 was removed by filtration, and the DCM removed by rotary
evaporation, producing an imine. After being dissolved in toluene, the
thiol-substituted anhydride was added to the imine, and the mixture
was heated to reflux for 6 h. Toluene was removed in vacuo to yield a
yellow/brown crude mixture. This was dissolved in acetone (20 mL)
and K2CO3 (2.4131 g, 17.45 mmol), and iodomethane (2.60 mL 34.92
mmol) was added. After stirring at 20 °C for 24 h, the resulting
mixture was partitioned between water (25 mL) and DCM (20 mL).
The layers were separated, and the aqueous layer was extracted with
2 × 20 mL of DCM. The combined organic layers were dried (MgSO4)
and concentrated in vacuo to afford 5.1352 g of a brown oil. This was
purified by flash chromatography (10:90 EtOAc/hexanes) to yield the
Pyrrolidine Ester 41. To a flame-dried flask were added
palladium acetate (0.075 g, 0.333 mmol) and iodide 40 (1.70 g,
3.12 mmol) as a solution in DMF (20 mL). Next were added ethyl
acrylate (1.41 mL, 13.33 mmol) and triethylamine (0.93 mL, 6.66 mmol).
The mixture was heated to 100 °C under argon and a reflux condenser
for 24 h and then cooled to 23 °C. The resulting mixture was
partitioned between DCM (30 mL) and water (40 mL). The layers
were separated, and the water layer was extracted with 2 × 30 mL
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 1.62 g of a bright red oil. The oil was
purified by flash chromatography (10:90 EtOAc/hexanes) to yield the
product as a red oil (0.7572 g, 47%) containing approximately 5% of
1
product as a light yellow oil (2.6781 g, 59% yield): H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 7.9, 1H), 7.28 (t, J = 7.5, 1H), 7.17 (t, J =
7.6, 3H), 7.02 (d, J = 7.8, 1H), 7.00−6.88 (m, 3H), 5.35 (s, 1H), 4.97
(d, J = 14.6, 1H), 3.56 (d, J = 3.8, 3H), 3.42 (d, J = 16.9, 1H), 3.29 (d,
J = 14.6, 1H), 2.76 (d, J = 16.9, 1H), 2.25 (t, J = 7.3, 2H), 1.21−1.06
(m, 4H), 0.68 (t, J = 7.2, 3H); 13C NMR (101 MHz, CDCl3) δ 171.8,
171.6, 140.4, 137.5, 135.5, 130.8, 128.8, 128.7, 128.7, 128.4, 128.0,
101.6, 70.6, 70.5, 55.4, 53.3, 45.2, 41.3, 31.0, 30.7, 22.1, 13.8; HRMS
(FTMS + p ESI) m/z calcd for C23H26INO3S (M + H)+ 524.0751,
found 524.0743; IR (thin film) 1724, 1697 cm−1; TLC (20% EtOAc/
hexanes) Rf = 0.18.
1
the minor diastereomer carried from the 4CR to make the lactam: H
NMR (400 MHz, CDCl3) δ 8.40 (d, J = 15.7, 1H), 8.16 (d, J = 7.8,
1H), 7.60 (d, J = 7.4, 1H), 7.51 (t, J = 7.5, 1H), 7.38 (d, J = 6.8, 1H),
7.29−7.18 (m, 5H), 7.06 (s, 2H), 7.00 (d, J = 8.3, 2H), 6.37 (d, J =
15.7, 1H), 4.58 (s, 1H), 4.30 (q, J = 7.1, 2H), 3.75−3.66 (m, 4H), 3.20
(d, J = 13.0, 1H), 3.08 (d, J = 6.2, 1H), 2.63 (d, J = 8.2, 1H), 2.32−
2.21 (m, 5H), 1.37 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ
173.4, 167.3, 143.2, 139.5, 138.8, 138.1, 136.5, 136.1, 135.6, 131.4,
129.6, 129.4, 128.9, 128.4, 128.4, 128.1, 127.2, 126.5, 120.1, 69.3, 64.6,
60.7, 58.1, 52.8, 51.6, 37.9, 21.4, 14.6; HRMS (FTMS + p ESI) m/z
calcd for C31H33NO4S (M + H)+ 516.2203, found 516.2192; IR (thin
film) 1713, 1637, 1599 cm−1; TLC (10% EtOAc/hexanes) Rf = 0.40.
Pyrrolidine Sulfoxide 42. To a cooled (−78 °C) solution of 41
(0.734 g, 1.42 mmol) in 10 mL of THF was added m-CPBA (0.328 g,
1.42 mmol, 75%). The mixture was stirred for 3 h and then allowed to
warm to 23 °C, and a saturated solution of Na2S2O3 in water (10 mL)
was added. The resulting mixture was partitioned between water and
15 mL of DCM. The layers were separated, and the aqueous layer was
extracted with 2 × 15 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 0.823 g of a yellow
oil. This was purified by flash chromatography (15:85 EtOAc/
hexanes) to yield the product as a clear oil (0.3932 g, 52% yield)
containing approximately 5% of the minor diastereomer carried from
Butyl Ester 45. To a flame-dried flask were added palladium
acetate (0.057 g, 0.252 mmol) and iodide 43 (1.32 g, 2.52 mmol) as a
solution in DMF (10 mL). Next were added ethyl acrylate (1.07 mL,
10.08 mmol) and triethylamine (0.70 mL, 5.04 mmol). The mixture
was heated to 105 °C under argon and a reflux condenser for 24 h and
then cooled to 23 °C. The resulting mixture was partitioned between
DCM (25 mL) and water (25 mL). The layers were separated and the
water layer was extracted with 2 × 25 mL DCM. The combined
organic layers were dried (MgSO4) and concentrated in vacuo to
afford 1.6 g of a red oil. This was purified by flash chromatography
(15:85 EtOAc/hexanes) to yield the product as a red oil (0.751 g, 60%
1
yield): H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 15.7, 1H), 7.57−
7.53 (m, 1H), 7.43−7.34 (m, 2H), 7.25−7.15 (m, 4H), 6.92 (dd, J =
2.8, 6.6, 2H), 6.24 (d, J = 15.7, 1H), 5.32 (s, 1H), 5.10 (d, J = 14.6,
1H), 4.20 (dt, J = 6.7, 13.5, 2H), 3.65 (s, 3H), 3.55 (d, J = 17.0, 1H),
3.35 (d, J = 14.0, 1H), 2.81 (d, J = 17.0, 1H), 2.19 (qd, J = 5.8, 11.4,
2H), 1.28 (t, J = 7.1, 3H), 1.26−1.06 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 171.9, 166.4, 141.5, 135.8, 135.4, 133.7, 130.1, 129.4,
128.9, 128.4, 128.1, 127.5, 121.7, 62.3, 62.3, 60.6, 55.2, 53.4, 45.1, 41.6,
30.9, 30.6, 22.1, 14.6, 13.7; HRMS (FTMS + p ESI) m/z calcd for
C28H33NO5S (M + H)+ 496.2152, found 496.2147; IR (thin film)
1717, 1688, 1628 cm−1; TLC (20:80 EtOAc/hexanes) Rf = 0.19.
Sulfoxide 46. To a cooled (−78 °C) solution of 45 (0.751 g,
1.52 mmol) in 10 mL of THF was added m-CPBA (0.340 g, 1.52 mmol,
77%). The mixture was stirred for 3 h and then allowed to warm to
23 °C, and a saturated solution of Na2S2O3 in water (10 mL) was
added. The resulting mixture was partitioned between water and 15 mL
of DCM. The layers were separated, and the aqueous layer was
extracted with 2 × 15 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 0.823 g of a purple
oil. This was purified by flash chromatography (20:80 EtOAc/hexanes
to 40:60 EtOAc/hexanes) to yield the product as a yellow oil (0.2409 g,
1
the 4CR to make the lactam: H NMR (400 MHz, CDCl3) δ 8.55 (d,
J = 15.8, 1H), 8.19 (d, J = 7.8, 1H), 7.64 (d, J = 7.6, 1H), 7.53 (s, 1H),
7.39 (d, J = 7.4, 1H), 7.35 (d, J = 8.2, 2H), 7.26 (m, 2H), 7.21 (m,
5H), 6.40 (d, J = 15.7, 1H), 4.76 (s, 1H), 4.29 (q, J = 7.1, 2H), 3.86 (s,
3H), 3.73 (d, J = 13.0, 1H), 3.22 (d, J = 13.0, 1H), 3.09−3.02 (m, 1H),
2.36 (s, 3H), 2.30−2.22 (m, 1H), 2.02 (s, 2H), 1.36 (t, J = 7.1, 3H);
13C NMR (101 MHz, CDCl3) δ 168.7, 167.4, 143.7, 142.5, 138.4,
137.7, 136.9, 136.6, 130.6, 129.7, 129.5, 128.9, 128.8, 128.5, 127.3,
127.1, 126.2, 120.4, 77.7, 67.7, 60.6, 57.5, 53.1, 50.9, 31.5, 21.7, 14.7;
HRMS (FTMS + p ESI) m/z calcd for C31H33NO5S (M + H)+
532.2152, found 532.2140; IR (thin film) 1707, 1635, 1596 cm−1
;
TLC (20% EtOAc/hexanes) Rf = 0.34.
Pyrroline Ester 43. Isolated at the same time as 42 as a purple oil
1
(0.2645 g, 47%): H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 15.8,
1H), 7.48 (dd, J = 3.5, 7.6, 2H), 7.34 (d, J = 7.6, 1H), 7.27−7.12
(m, 7H), 6.90 (d, J = 2.1, 1H), 6.26 (d, J = 15.8, 1H), 5.16 (s, 1H),
4.24 (t, J = 7.1, 2H), 4.01−3.91 (m, 1H), 3.58 (d, J = 5.3, 1H), 3.54 (s,
3H), 3.52−3.43 (m, 1H), 1.33 (t, J = 7.1, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.3, 163.7, 143.4, 140.9, 140.3, 139.0, 137.0, 134.9, 130.3,
129.7, 128.6, 128.4, 127.9, 127.2, 127.0, 119.6, 70.3, 60.6, 58.5, 57.1,
51.6, 14.6; HRMS (FTMS + p ESI) m/z calcd for C24H25NO4 (M +
1
31%). Elimination product 37 was also isolated (0.4086 g, 67%): H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 15.8, 1H), 7.60 (d, J = 8.9,
1H), 7.50−7.39 (m, 2H), 7.31−7.23 (m, 3H), 7.15−7.08 (m, 1H),
6.97 (s, 2H), 6.25 (d, J = 15.8, 1H), 5.57 (s, 1H), 5.07 (d, J = 14.4,
1H), 4.28−4.12 (m, 2H), 3.80 (s, 3H), 3.39 (d, J = 14.4, 1H), 3.18 (d,
J = 16.7, 1H), 2.54 (d, J = 17.0, 2H), 2.33 (dd, J = 9.9, 19.4, 1H), 1.62
(s, 1H), 1.53 (s, 1H), 1.30 (m, 5H), 0.85 (t, J = 7.3, 3H); 13C NMR
(101 MHz, CDCl3) δ 169.5, 167.8, 166.3, 142.0, 137.0, 135.0, 132.1,
130.0, 129.9, 129.0, 128.6, 128.2, 128.2, 127.2, 122.5, 69.7, 61.3, 60.5,
54.1, 49.1, 45.2, 34.2, 25.5, 22.2, 14.6, 13.8; HRMS (FTMS + p ESI)
H)+ 392.1857, found 392.1852; IR (thin film) 1704, 1633, 1600 cm−1
;
TLC (20% EtOAc/hexanes) Rf = 0.49.
Butyl Ester 44. Melaic anhydride (1.177 g, 12.00 mmol) was
dissolved in benzene (100 mL), and triethylamine (1 drop) was added.
This was heated to 60 °C, and butane thiol (1.29 mL, 12.00 mmol)
was added dropwise over 5 min. This was stirred for 30 min and
cooled to room temperature, and the benzene and triethylamine were
168
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Article
m/z calcd for C28H33NO6S (M + H)+ 512.2102, found 512.2100;
IR (thin film) 1707, 1634, 1596 cm−1; TLC (20% EtOAc/hexanes)
Rf = 0.20.
MHz, CDCl3) δ 170.4, 167.1, 142.3, 138.2, 135.4, 135.3, 131.8, 130.2,
128.9, 128.8, 128.5, 127.3, 126.9, 120.3, 75.3, 70.7, 60.8, 57.4, 53.1,
51.8, 48.4, 25.3, 24.1, 22.1, 14.6, 13.8; HRMS (FTMS + p ESI) m/z
calcd for C28H35NO5S (M + H)+ 498.2309, found 498.2297; IR (thin
film) 1708, 1632, 1453 cm−1; TLC (50% EtOAc/hexanes) Rf = 0.60.
Sulfoxide 49b. Isolated at the same time as 49a. The data listed
below is for the second compound off the column. This was purified
by flash chromatography (20:80 EtOAc/hexanes) to yield the product
Pyrrolidine Ester 47. Iodide 44 (0.2096 g, 0.400 mmol) was
dissolved in THF (15 mL) and cooled to 0 °C. To this was added
BH3·DMS (0.40 mL, 0.801 mmol) as a 2 M solution in THF. The
solution was immediately heated to reflux and stirred for 2 h and then
cooled to 0 °C and quenched with MeOH (2 mL). The mixture was
then partitioned between water (20 mL) and DCM (10 mL). The
layers were separated, and the aqueous layer was extracted 2 × 30 mL
of DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.2040 g of a yellow oil. This was
purified by flash chromatography (5:95 EtOAc/hexanes) to yield the
product as a light yellow oil (0.196 g, 96% yield): 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 7.9, 1H), 7.82 (d, J = 7.9, 1H), 7.40 (t, J = 7.5,
1H), 7.27−7.20 (m, 5H), 7.00 (t, J = 6.7, 1H), 4.55 (s, 1H), 3.82 (s,
3H), 3.69 (d, J = 13.2, 1H), 3.23 (d, J = 13.2, 1H), 3.08 (d, J = 8.4,
1H), 2.80 (dd, J = 6.2, 12.7, 1H), 2.45−2.37 (m, 1H), 2.32−2.25 (m,
1H), 2.18−2.09 (m, 1H), 1.99 (d, J = 11.5, 1H), 1.29−1.16 (m, 4H),
0.78 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ 173.9, 140.9,
139.4, 139.1, 132.9, 129.9, 128.8, 128.8, 128.4, 127.6, 127.1, 102.5,
77.8, 61.3, 57.8, 51.6, 38.2, 31.1, 30.5, 22.3, 13.8; HRMS (FTMS + p
ESI) m/z calcd for C23H28INO2S (M + H)+ 510.0958, found
510.0952; IR (thin film) 1720 cm−1; TLC (20% EtOAc/hexanes)
Rf = 0.68.
1
as a clear oil (0.0072 g, 20% yield): H NMR (400 MHz, CDCl3) δ
8.43 (d, J = 15.7, 1H), 8.06 (d, J = 7.9, 1H), 7.61 (d, J = 7.6, 1H), 7.48
(t, J = 7.6, 1H), 7.37 (t, J = 7.6, 1H), 7.29 (m, 1H), 7.21 (m, 4H), 6.37
(d, J = 15.7, 1H), 4.75 (s, 1H), 4.27 (q, J = 7.1, 2H), 3.93 (s, 3H), 3.72
(d, J = 13.0, 1H), 3.19 (d, J = 13.0, 1H), 3.11−3.06 (m, 1H), 2.50 (m,
2H), 2.35 (m, 1H), 1.74 (m, 1H), 1.63 (m, 1H), 1.55 (m, 1H), 1.35
(m, 6H), 0.87 (t, J = 7.3, 3H); 13C NMR (101 MHz, CDCl3) δ 169.5,
167.4, 143.5, 138.4, 136.4, 136.3, 130.6, 129.7, 128.8, 128.8, 128.5,
127.4, 127.0, 120.1, 75.1, 67.7, 60.6, 57.4, 53.6, 51.0, 48.3, 31.0, 25.8,
22.3, 14.6, 13.9; HRMS (FTMS + p ESI) m/z calcd for C28H35NO5S
(M + H)+ 498.2309, found 498.2300; IR (thin film) 1707, 1634, 1455
cm−1; TLC (50% EtOAc/hexanes) Rf = 0.45.
Tricyclic Lactam 50. To a flame-dried flask was added 33 (0.154
g, 0.283 mmol) dissolved in dry THF and cooled to −78 °C. To this
was added i-PrMgCl (0.353 mL, 0.565 mmol) as a 1.6 M solution in
Et2O. This was stirred at −78 °C for 2 h and then allowed to warm to
23 °C. After quenching with MeOH, the mixture was quickly
partitioned between water (10 mL) and DCM (10 mL). The layers
were separated, and the aqueous layer was extracted with 2 × 10 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.1001 g of yellow oil. The oil was
purified by flash chromatography (50% Et2O/toluene) to yield the
product as a clear oil (0.0880 g, 77%): 1H NMR (400 MHz, CDCl3) δ
7.37−7.26 (m, 8H), 7.16 (d, J = 7.4, 1H), 5.30 (d, J = 15.1, 1H), 4.92
(s, 1H), 4.27−4.11 (m, 4H), 3.67 (s, 3H), 2.98 (d, J = 16.8, 1H), 2.89
(dd, J = 6.4, 16.3, 1H), 2.59 (dd, J = 8.6, 16.3, 1H), 2.44 (d, J = 16.8,
1H), 1.28 (t, J = 7.2, 3H); 13C NMR (101 MHz, CDCl3) δ 174.3,
172.7, 171.9, 142.9, 138.9, 135.9, 129.5, 129.0, 128.5, 128.4, 128.1,
124.9, 124.3, 68.8, 68.8, 61.2, 57.6, 53.0, 52.9, 46.0, 44.5, 35.8, 35.1,
14.4; HRMS (FTMS + p ESI) m/z calcd for C24H25NO5 (M + H)+
408.1806, found 408.1801; IR (thin film) 1731, 1693 cm−1; TLC
(33:67 MeOH/DCM) Rf = 0.49.
Pyrrolidine Ester 48. To a flame-dried flask were added
palladium acetate (0.042 g, 0.188 mmol) and iodide 47 (0.959 g,
1.88 mmol) as a solution in DMF (15 mL). Next were added ethyl
acrylate (0.80 mL, 7.54 mmol) and triethylamine (0.52 mL, 3.77
mmol). The mixture was heated to 105 °C under argon and a reflux
condenser for 24 h and then cooled to 23 °C. The resulting mixture
was partitioned between DCM (30 mL) and a saturated LiCl solution
in water (40 mL). The layers were separated, and the aqueous layer
was extracted with 2 × 30 mL DCM. The combined organic layers
were dried (MgSO4) and concentrated in vacuo to afford 1.1043 g of a
red oil. This was purified by flash chromatography (5:95 EtOAc/
hexanes) to yield the product as a light yellow oil (0.5372 g, 60%
yield) containing approximately 5% of the minor diastereomer carried
1
from the 4CR to make the lactam: H NMR (400 MHz, CDCl3) δ
8.42 (d, J = 15.7, 1H), 8.10 (d, J = 7.9, 1H), 7.56 (d, J = 7.0, 1H), 7.45
(t, J = 7.6, 1H), 7.33 (d, J = 6.6, 1H), 7.24 (dt, J = 7.0, 15.6, 5H), 6.37
(d, J = 15.7, 1H), 4.53 (s, 1H), 4.28 (t, J = 7.1, 2H), 3.81 (s, 3H), 3.69
(d, J = 13.1, 1H), 3.16−3.09 (m, 1H), 3.10−3.04 (m, 1H), 2.87 (dd,
J = 5.2, 12.6, 1H), 2.28 (s, 1H), 2.13 (dd, J = 7.7, 19.6, 2H), 1.88 (s,
1H), 1.35 (t, J = 7.1, 3H), 1.28−1.09 (m, 4H), 0.75 (t, J = 7.1, 3H);
13C NMR (101 MHz, CDCl3) δ 173.8, 167.3, 143.2, 138.8, 138.0,
135.3, 131.6, 129.4, 128.8, 128.4, 128.3, 127.2, 126.3, 120.0, 69.2, 61.1,
60.6, 57.9, 53.0, 51.6, 38.1, 31.0, 30.3, 22.3, 14.6, 13.8; HRMS (FTMS +
p ESI) m/z calcd for C28H35NO4S (M + H)+ 482.2360, found
482.2353; IR (thin film) 1705, 1635 cm−1; TLC (20% EtOAc/
hexanes) Rf = 0.58.
Bis-p-bromobenzylamide 51. To a flame-dried flask was added
para-bromobenzylamine (0.152 g, 0.822 mmol), which was dissolved
in CDCl3 (5 mL) under argon. This was cooled to 0 °C, and
trimethylaluminum (0.411 mL, 0.8220 mmol, 2.0 M) was added, and
then the mixture stirred and allowed to return to 23 °C. Diester 50
dissolved in dry DCM (5 mL) was added slowly via syringe. This
mixture was allowed to stir at 23 °C for 8 h. After careful quenching
with MeOH, the mixture was partitioned between water (10 mL) and
DCM (10 mL). The layers were separated, and the aqueous layer was
extracted with 2 × 15 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 0.0321 g of clear
oil. The oil was purified by flash chromatography (10:90 EtOAc/
hexanes to 60:40 EtOAc/hexanes) to yield the product as a clear oil
(0.0113 g, 20%) that was approximately 90% pure. Recrystallization
from 50:50 EtOAc/hexanes yielded a small number of crystals that
Sulfoxide 49a. To a cooled (−78 °C) solution of 48 (0.0358 g,
0.074 mmol) in 5 mL of THF was added m-CPBA (0.017 g, 0.074
mmol, 77%). The mixture was stirred for 4 h and then allowed to
warm to 23 °C, and a saturated solution of Na2S2O3 in water (10 mL)
was added. The resulting mixture was partitioned between water and
10 mL of DCM. The layers were separated, and the aqueous layer was
extracted with 2 × 10 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 0.0390 g of a
yellow oil. The data listed below is for the first compound off the
column. Afforded a clear oil. This was purified by flash
chromatography (20:80 EtOAc/hexanes) to yield the product as a
1
were used for crystallography: H NMR (400 MHz, CDCl3) δ 8.15
(t, J = 5.8, 1H), 7.48−7.45 (m, 3H), 7.41 (d, J = 8.3, 2H), 7.36−7.30
(m, 3H), 7.28 (d, J = 9.1, 2H), 7.22 (dd, J = 6.4, 13.5, 4H), 7.15 (d, J =
8.3, 2H), 7.11 (d, J = 8.3, 2H), 6.66 (t, J = 5.7, 1H), 5.46 (s, 1H), 5.02
(d, J = 15.4, 1H), 4.51−4.45 (m, 1H), 4.31 (dd, J = 5.5, 18.6, 3H), 4.17
(d, J = 7.9, 1H), 3.86 (d, J = 15.3, 1H), 2.78 (d, J = 17.6, 2H), 2.62
(d, J = 17.5, 1H); 13C NMR (101 MHz, CDCl3) δ 174.5, 172.5, 171.5,
145.0, 138.4, 137.7, 136.9, 135.7, 132.1, 131.9, 131.8, 129.7, 129.7,
129.5, 129.2, 129.1, 128.0, 128.0, 127.9, 126.2, 125.0, 121.9, 121.3,
105.4, 67.9, 56.0, 47.0, 44.2, 43.6, 43.4, 39.8, 38.5, 21.4; HRMS
(FTMS + p ESI) m/z calcd for C35H31Br2N3O3 (M + H)+ 700.0805,
1
clear oil (0.0167 g, 45% yield): H NMR (400 MHz, CDCl3) δ 8.16
(dd, J = 7.1, 8.4, 2H), 7.63 (dd, J = 1.1, 7.8, 1H), 7.53−7.46 (m, 1H),
7.40−7.34 (m, 1H), 7.30−7.27 (m, 1H), 7.23 (t, J = 7.9, 4H), 6.40 (d,
J = 15.7, 1H), 4.35 (s, 1H), 4.29 (m, 2H), 3.76 (s, 3H), 3.70 (d, J =
13.2, 1H), 3.23 (t, J = 7.7, 1H), 3.04 (d, J = 13.2, 1H), 2.77 (dd, J =
1.7, 7.8, 1H), 2.49−2.37 (m, 2H), 2.28 (ddd, J = 5.0, 9.4, 12.3, 1H),
2.07−1.92 (m, 1H), 1.68−1.53 (m, 1H), 1.46 (d, J = 6.2, 1H), 1.35 (t,
J = 7.1, 3H), 1.30−1.20 (m, 2H), 0.81 (t, J = 7.3, 3H); 13C NMR (101
found 700.0825; IR (thin film) 1638, 1545 cm−1
.
Tetracyclic Ketone 53. Isolated concurrently with 50 after
quenching with MeOH (5 mL) and stirring at room temperature for
3 h (0.043 g, 33%) as a white solid: mp 166 °C; 1H NMR (300 MHz,
169
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CDCl3) δ 7.42−7.29 (m, 9H), 5.26 (d, J = 15.6, 1H), 5.18 (s, 1H),
4.31 (dd, J = 4.8, 10.7, 1H), 4.01 (d, J = 15.6, 1H), 3.87 (s, 1H), 3.75
2H), 7.08 (d, J = 7.0, 3H), 6.72 (d, J = 7.9, 2H), 6.26 (d, J = 15.9, 1H),
4.59 (d, J = 15.3, 1H), 4.35 (d, J = 15.3, 1H), 4.22 (q, J = 7.1, 2H),
3.68 (s, 2H), 3.25 (m, 4H), 1.69 (m, 4H), 1.32 (t, J = 7.1, 3H); 13C
NMR (101 MHz, CDCl3) δ 176.0, 166.4, 163.6, 145.1, 140.8, 136.7,
133.6, 130.9, 130.6, 130.3, 130.1, 128.9, 128.7, 128.5, 127.7, 127.6,
126.6, 120.5, 112.7, 60.8, 44.6, 38.9, 14.5; HRMS (FTMS + p ESI)
m/z calcd for C27H28N2O4 (M + H)+ 445.2122, found 445.2121; IR
(thin film) 1706, 1630, 1622 cm−1.
(s, 3H), 3.15 (dd, J = 10.7, 18.1, 1H), 2.63 (dd, J = 4.8, 18.1, 1H); 13
C
NMR (75 MHz, CDCl3) δ 207.2, 173.4, 165.3, 144.9, 138.8, 135.1,
130.5, 129.3, 128.3, 128.1, 125.8, 125.7, 67.6, 60.0, 59.7, 53.5, 47.6,
46.2, 45.1; HRMS (FTMS + p ESI) m/z calcd for C22H19NO4 (M +
H)+ 362.1387, found 362.1389; IR (thin film) 1733, 1677, 1603 cm−1
.
Pyrrolidine Amide 54. To a solution of para-thiocresol (3.89 mL,
3.89 mmol, 1 M) in toluene were added melaic anhydride (0.381 g,
3.89 mmol), o-iodobenzaldehyde (0.902 g, 3.89 mmol), and
benzylamine (0.42 mL, 3.89 mmol). The mixture was stirred for 14
h at reflux under a Dean−Stark trap and then cooled to 23 °C. The
toluene was removed by rotary evaporation to yield a crude oil. This
crude oil was split, and 0.704 g (1.296 mmol) was dissolved in DMF.
Next were added HATU (0.542 g, 1.425 mmol) and pyrrolidine (0.32
mL, 3.887 mmol), and this was heated to 50 °C under a reflux
condenser for 14 h and cooled to 23 °C. The resulting mixture was
partitioned between water (25 mL) and DCM (15 mL). The layers
were separated, and the aqueous layer was extracted with 2 × 20 mL of
DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.6821 g of a brown oil. The oil was
purified by flash chromatography (20:80 to 50:50 EtOAc/hexanes)
4CR Lactam Amide 58. To a solution of para-thiocresol (4.66 mL,
4.66 mmol, 1 M) in toluene were added melaic anhydride (0.457 g,
4.66 mmol), o-iodobenzaldehyde (1.082 g, 4.66 mmol), and benzylamine
(0.51 mL, 4.66 mmol). The mixture was stirred for 14 h at reflux under
a Dean−Stark trap and then cooled to 23 °C. The toluene was
removed in vacuo to yield a crude oil. This crude oil was redissolved
in benzene and cooled to 0 °C. Next was added SOCl2, (0.68 mL
9.32 mmol) and this was heated to 80 °C under a reflux condenser for
14 h and cooled to 23 °C. The benzene and excess SOCl2 were
removed in vacuo, and this crude mixture was redissolved in DCM
(10 mL) and cooled to 0 °C. Ammonium hydroxide (0.85 mL, 21.33
mmol) was added very slowly and then allowed to warm to 23 °C over
5 h. The resulting mixture was partitioned between water (25 mL) and
DCM (15 mL). The layers were separated, and the aqueous layer was
extracted with 2 × 20 mL of DCM. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to afford 2.8 g of a brown oil.
The oil was purified by flash chromatography (20:80 to 40:60 EtOAc/
1
to yield the product as a pale yellow oil (0.422 g, 57%): H NMR
(400 MHz, CDCl3) δ 7.76 (d, J = 7.9, 1H), 7.32 (t, J = 7.5, 1H), 7.26
(d, J = 6.3, 1H), 7.19−7.13 (m, 3H), 7.04−6.96 (m, 3H), 6.92 (d, J =
8.0, 2H), 6.79 (d, J = 8.1, 2H), 5.71 (s, 1H), 4.89 (d, J = 14.9, 1H),
3.65−3.36 (m, 6H), 2.91 (d, J = 17.2, 1H), 2.21 (s, 3H), 1.72 (d, J =
43.8, 5H); 13C NMR (101 MHz, CDCl3) δ 172.1, 167.2, 140.3, 139.1,
138.0, 135.6, 133.9, 130.8, 130.7, 130.0, 128.7, 128.7, 128.4, 127.7,
127.3, 102.9, 71.8, 58.7, 45.5, 42.3, 21.4; HRMS (FTMS + p ESI) m/z
calcd for C29H29IN2O2S (M + H)+ 597.1067, found 597.1064; IR (thin
film) 1701 cm−1.
1
hexanes) to yield the product as a pale yellow oil (1.675 g, 66%): H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 6.9, 1H), 7.47 (t, J = 7.1, 1H),
7.31−7.22 (m, 4H), 7.20−7.11 (m, 3H), 7.08−6.96 (m, 5H), 5.93 (s,
1H), 5.13 (d, J = 14.6, 1H), 5.08 (s, 1H), 3.43 (d, J = 14.7, 1H), 3.37 (d,
J = 16.8, 1H), 2.83 (d, J = 16.8, 1H), 2.29 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 173.8, 172.8, 140.4, 139.8, 136.8, 135.1, 134.4, 131.2, 130.3,
129.2, 129.0, 129.0, 128.8, 128.0, 126.6, 101.7, 71.7, 58.8, 45.1, 41.3,
21.4; HRMS (FTMS + p ESI) m/z calcd for C25H23IN2O2S (M + H)+
543.0598, found 543.0596; IR (thin film) 1710, 1678, 1587 cm−1; TLC
(50% EtOAc/hexanes) Rf = 0.46.
Pyrrolidine Amide 55. To a flame-dried flask were added
palladium acetate (0.0060 g, 0.027 mmol) and iodide 54 (0.157 g,
0.266 mmol) as a solution in DMF (8 mL). Next were added ethyl
acrylate (0.11 mL, 1.06 mmol) and triethylamine (0.074 mL, 0.532
mmol). The mixture was heated to 100 °C under argon and a reflux
condenser for 24 h and then cooled to 23 °C. The resulting mixture
was partitioned between DCM (20 mL) and water (30 mL). The
layers were separated, and the water layer was extracted with 2 × 20
mL DCM. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to afford 0.1723 g of a red oil. This was purified
by flash chromatography (20:80 EtOAc/hexanes to 50:50 EtOAc/
4CR Lactam Amide 59. To a flame-dried flask were added
palladium acetate (0.010 g, 0.045 mmol) and iodide 58 (0.241 g, 0.445
mmol) as a solution in DMF (8 mL). Next were added ethyl acrylate
(0.19 mL, 1.78 mmol) and triethylamine (0.12 mL, 0.889 mmol). The
mixture was heated to 105 °C under argon and a reflux condenser for
24 h and then cooled to 23 °C. The resulting mixture was partitioned
between DCM (15 mL) and water (20 mL). The layers were
separated, and the water layer was extracted with 2 × 20 mL DCM.
The combined organic layers were dried (MgSO4) and concentrated in
vacuo to afford 0.4123 g of a red/brown oil. The oil was purified by
flash chromatography (33:67 EtOAc/hexanes) to yield the product as
1
hexanes) to yield the product as a red oil (0.0567 g, 37% yield): H
NMR (600 MHz, CDCl3) δ 7.54 (d, J = 15.7, 1H), 7.48 (d, J = 7.7,
1H), 7.45 (d, J = 7.5, 1H), 7.43−7.39 (m, 1H), 7.36 (d, J = 7.7, 1H),
7.29−7.24 (m, 3H), 7.00 (dd, J = 10.3, 13.9, 2H), 6.92 (t, J = 11.0,
2H), 6.84−6.77 (m, 2H), 6.17 (d, J = 15.7, 1H), 5.29 (s, 1H), 5.12 (d,
J = 14.7, 1H), 4.24−4.16 (q, J = 7.1, 2H), 3.58 (d, J = 16.6, 1H), 3.50−
3.22 (m, 5H), 2.92 (d, J = 16.6, 1H), 2.24 (s, 3H), 1.72 (s, 4H), 1.31
(t, J = 7.1, 3H); 13C NMR (151 MHz, CDCl3) δ 172.5, 167.1, 166.2,
142.1, 139.3, 136.3, 135.8, 134.3, 130.0, 129.8, 129.4, 129.0, 128.8,
128.6, 128.0, 127.9, 122.1, 61.7, 60.7, 59.2, 48.9, 45.1, 42.9, 31.8, 22.8,
21.3, 14.5, 14.3; HRMS (FTMS + p ESI) m/z calcd for C34H36N2O4S
1
a red-orange solid (0.1503 g, 66%): H NMR (400 MHz, CDCl3) δ
7.59−7.50 (m, 3H), 7.46 (t, J = 7.5, 1H), 7.40 (d, J = 7.7, 1H), 7.24
(dd, J = 1.9, 5.0, 3H), 7.13 (d, J = 8.2, 2H), 7.05 (d, J = 8.1, 2H),
6.98−6.93 (m, 2H), 6.77 (s, 1H), 6.24 (d, J = 15.6, 1H), 5.48 (s, 1H),
5.20 (d, J = 14.7, 1H), 5.12 (s, 1H), 4.22 (q, J = 7.1, 2H), 3.50 (d, J =
14.6, 1H), 3.37 (d, J = 17.0, 1H), 2.82 (d, J = 17.0, 1H), 2.29 (s, 3H),
1.31 (t, J = 7.1, 3H); 13C NMR (75 MHz, CDCl3) δ 174.2, 172.8,
166.4, 140.7, 139.6, 135.5, 135.0, 134.1, 133.1, 130.3, 130.1, 129.6,
128.9, 128.7, 128.5, 128.0, 127.6, 126.7, 122.3, 63.8, 60.9, 58.9, 45.2,
41.5, 21.3, 14.5; HRMS (FTMS + p ESI) m/z calcd for C30H30N2O4S
(M + H)+ 515.1999, found 515.1996; IR (thin film) 1705, 1677, 1655,
1598 cm−1; TLC (50% EtOAc/hexanes) Rf = 0.23.
4CR Nitrile 60. Amide 59 (0.150 g, 0.292 mmol) was dissolved in
benzene and cooled to 0 °C. POCl3 (0.14 mL, 1.46 mmol) was added
slowly via syringe, and the mixture was heated to reflux for 14 h and
then cooled to 23 °C. The resulting mixture was partitioned between
water (20 mL) and DCM (20 mL). The layers were separated, and the
aqueous layer was extracted with 2 × 20 mL of DCM. The combined
organic layers were dried (MgSO4) and concentrated in vacuo to
afford 0.1523 g of a brown oil. The oil was purified by flash
chromatography (20:80 EtOAc/hexanes) to yield the product as a
white solid (0.1281 g, 88%): 1H NMR (400 MHz, CDCl3) δ 7.57 (dd,
J = 9.0, 11.6, 2H), 7.51 (td, J = 1.9, 4.3, 2H), 7.39−7.24 (m, 7H), 7.14
(d, J = 8.3, 2H), 6.99 (d, J = 2.7, 2H), 6.21 (d, J = 15.6, 1H), 5.21
(M + H)+ 569.2469, found 569.2470; IR (thin film) 1697, 1624 cm−1
;
TLC (50:50 EtOAc/hexanes) Rf = 0.31.
Pyrroline 56. To a cooled (−78 °C) solution of 53 (0.670 g, 1.18
mmol) in 10 mL of THF was added m-CPBA (0.0.2642 g, 1.18 mmol,
77%). The mixture was stirred for 3 h and then allowed to warm to 23 °C,
and a saturated solution of Na2S2O3 in water (5 mL) was added.
The resulting mixture was partitioned between water and 15 mL of
DCM. The layers were separated, and the aqueous layer was extracted
with 2 × 15 mL of DCM. The combined organic layers were dried
(MgSO4) and concentrated in vacuo to afford 0.8538 g of a purple oil.
This was purified by flash chromatography (10:90 EtOAc/hexanes to
50:50 EtOAc/hexanes) to yield the product as a purple oil (0.1888 g,
36% yield). Multiple rotomers complicated NMR characterization at
room temperature. For high temperature experiments, please see the
1
Supporting Information: H NMR (400 MHz, CDCl3) δ 7.60 (d, J =
7.3, 1H), 7.44 (d, J = 15.8, 1H), 7.39 (s, 1H), 7.32−7.27 (m, J = 8.6,
170
dx.doi.org/10.1021/jo201541e|J. Org. Chem. 2012, 77, 160−172

The Journal of Organic Chemistry
Article
(d, J = 14.5, 2H), 4.24 (q, J = 7.1, 2H), 3.58 (d, J = 14.5, 1H), 3.08 (d, J =
17.4, 1H), 2.94 (d, J = 17.4, 1H), 2.34 (s, 3H), 1.32 (t, J = 7.1, 3H);
13C NMR (101 MHz, CDCl3) δ 170.1, 165.9, 141.6, 140.1, 136.8,
136.2, 134.2, 130.8, 130.6, 130.3, 129.9, 129.3, 128.7, 128.6, 128.4,
128.3, 124.7, 123.8, 120.3, 63.4, 60.9, 46.5, 45.6, 43.9, 21.5, 14.5;
HRMS (FTMS + p ESI) m/z calcd for C30H28N2O3S (M + H)+
(5) (a) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123,
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497.1893, found 497.1892; IR (thin film) 2235, 1702, 1635 cm−1
;
TLC (20% EtOAc/hexanes) Rf = 0.09.
Nitrile Sulfoxide 61. To a cooled (−78 °C) solution of 60 (0.120 g,
0.242 mmol) in 5 mL of THF was added m-CPBA (0.0542 g, 0.242
mmol, 77%). The mixture was stirred for 3 h and then allowed to
warm to 23 °C, and a saturated solution of Na2S2O3 in water (5 mL)
was added. The resulting mixture was partitioned between water
(10 mL) and DCM (10 mL). The layers were separated, and the
aqueous layer was extracted with 2 × 15 mL of DCM. The combined
organic layers were dried (MgSO4) and concentrated in vacuo to
afford 0.1059 g of a purple oil. The oil was purified by flash
chromatography (20:80 EtOAc/hexanes to 30:70 EtOAc/hexanes) to
yield the product as a purple oil (0.0356 g, 30%): 1H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 15.7, 1H), 7.59 (t, J = 6.9, 3H), 7.51 (dt, J = 3.7,
4.4, 2H), 7.35 (d, J = 8.3, 2H), 7.33−7.27 (m, 3H), 7.21−7.15 (m,
1H), 7.01 (dd, J = 2.8, 6.5, 2H), 6.21 (d, J = 15.7, 1H), 5.23 (s, 1H),
5.11 (t, J = 9.1, 1H), 4.28−4.18 (m, 2H), 3.54 (d, J = 14.5, 1H), 2.91
(d, J = 17.1, 1H), 2.43 (s, 3H), 2.37−2.31 (m, 1H), 1.32 (t, J = 7.1,
3H); 13C NMR (101 MHz, CDCl3) δ 168.1, 165.9, 144.8, 140.7,
137.5, 135.6, 133.8, 130.8, 130.4, 130.2, 130.0, 129.3, 129.0, 128.7,
127.2, 125.9, 124.2, 116.1, 106.1, 64.1, 62.7, 60.8, 45.8, 36.5, 21.8, 14.5;
HRMS (FTMS + p ESI) m/z calcd for C30H28N2O4S (M + H)+
513.1843, found 513.1846; IR (thin film) 2235, 1703, 1635 cm−1; TLC
(10% EtOAc/hexanes) Rf = 0.39.
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ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental methods, 1H and 13C NMR spectra for all
new compounds, experimental details for computational studies
of 38, and X-ray crystallographic information for 39, 51, and
53. This material is available free of charge via the Internet at
http://pubs.acs.org/.
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Bari, S. S. Tetrahedron 2006, 62, 5054−5063. (b) Bhalla, A.; Rathee, S.;
Madan, S.; Venugopalan, P.; Bari, S. S. Tetrahedron Lett. 2006, 47,
5255−5259.
(12) Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999.
(13) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc.
2003, 125, 7484−7485. (b) Ono, K.; Nakagawa, M.; Nishida, A.
Angew. Chem., Int. Ed. 2004, 43, 2020−2023. (c) Young, I. S.; Kerr, M.
A. J. Am. Chem. Soc. 2007, 129, 1465−1469. (d) Jakubec, P.; Cockfield,
D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632−16633.
(e) Martin, D. B.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2010, 49,
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4915.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jtshaw@ucdavis.edu.
■
ACKNOWLEDGMENTS
■
This work was supported by startup funds from the University
of California, Davis and by the National Science Foundation
(CAREER award to J.T.S.). The authors thank the National
Science Foundation (Award CHE-0840444) for the purchase of
the Bruker SMART DUO diffractometer and the National
Institutes of Health (Grant RR1973) for the purchase of the
Bruker Avance III 600 MHz NMR. Jerry Dallas (UC Davis
NMR Facility) is acknowledged for assistance in performing
NOESY and variable temperature NMR experiments.
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