Synthesis of Alstoscholarisines A-E, Monoterpene Indole Alkaloids with Modulating Effects on Neural Stem Cells

Article abstract of DOI:10.1021/acs.joc.8b00889

A divergent synthetic strategy has been developed for stereoselective total syntheses of alstoscholarisines A-E, monoterpenoid indole alkaloids which are modulators of adult neuronal stem cells. A pivotal step includes an intermolecular Michael addition of an indole-2-acetic acid methyl ester enolate to an α,β-unsaturated N-sulfonyllactam to form the C15, C16 bond of the alkaloids. Other features of the strategy involve a selective partial reduction of an intermediate N-sulfonyllactam followed by cyclization to a bridged aminal system that serves as a key precursor for all five of the alkaloids as well as the use of an allyl group as a masked aldehyde equivalent.

Full text of DOI:10.1021/acs.joc.8b00889

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Featured Article
Synthesis of Alstoscholarisines A-E, Monoterpene Indole
Alkaloids with Modulating Effects on Neural Stem Cells
Jeremy D Mason, and Steven M. Weinreb
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00889 • Publication Date (Web): 07 May 2018
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REVISED MANUSCRIPT
Synthesis of Alstoscholarisines A-E, Monoterpene Indole Alkaloids with
Modulating Effects on Neural Stem Cells
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Jeremy D. Mason and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University
University Park, Pennsylvania 16802, United States
ABSTRACT: A divergent synthetic strategy has been developed for stereoselective total
syntheses of alstoscholarisines A-E, monoterpenoid indole alkaloids which are modulators of adult
neuronal stem cells. A pivotal step includes an intermolecular Michael addition of an indole-2-
acetic acid methyl ester enolate to an α,β-unsaturated-N-sulfonyllactam to form the C15, C16 bond
of the alkaloids. Other features of the strategy involve a selective partial reduction of an
intermediate N-sulfonyllactam, followed by cyclization to a bridged aminal system which serves
as a key precursor for all five of the alkaloids, as well as the use of an allyl group as a masked
aldehyde equivalent.
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INTRODUCTION AND BACKGROUND
The development of therapies for treatment of neurodegenerative ailments has been a
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notoriously difficult and daunting challenge. However, neural stem cells have shown promise for
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the invention of new CNS therapies. For example, several phase I/II clinical trials using stem cell
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strategies are currently underway for Alzheimer’s disease. In addition, many natural products are
known to modulate stem cell fate and population, and such compounds may have a key role to
play in the development of treatments for neurogenic disorders.3
In an ongoing search for biologically active natural products, the Luo group found in 2014
that the crude leaf extract of the Asian tree Alstonia scholaris, a plant with a long history of use in
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traditional medicine in China, India and Southeast Asia, increases the proliferation of adult mouse
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hippocampal neural stem cells in vitro. Upon chromatographic purification of the mixture, five
novel, structurally related monoterpenoid indole alkaloids, (-)-alstoscholarisines A-E (1-5), were
isolated (Figure 1). The structures of these metabolites were assigned by extensive NMR studies,
as well as by X-ray crystallographic analysis of 1 and 3. Each purified compound showed enhanced
promotion of stem cell growth compared to the total alkaloid mixture, and alstoscholarisine A (1)
was found to increase the propensity of neural stem cells to differentiate into neurons.
The structures of 1-5 are unusual among monoterpenoid indole alkaloids in that they lack
one of the two sidechain carbons originating from tryptamine, one of the biogenetic building
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blocks. Furthermore, the alkaloids all contain a unique pentacyclic ring system that includes five
contiguous stereogenic centers incorporated into an interesting bridged aminal scaffold fused to a
tetrahydropyran moiety. Alstoscholarisines A (1) and B (2) contain an equatorial methyl group at
C19 of the tetrahydropyran ring, but differ in the nature of the substituent at C16 (i.e. H or CO
Alkaloids 3-5 include an axial methyl group at C19 of the tetrahydropyran and again differ in the
C16 substituent (CO Me, CO H, or H).
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Me).
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Alstoscholarisine A (1), the most biologically potent member of the class, has recently
attracted interest from the synthetic community. Bihelovic and Ferjancic completed a total
synthesis of racemic alkaloid 1 in 2016 by a twelve-step route which featured an intramolecular
enamine Michael reaction/aminal formation domino sequence to construct the bridged core of the
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metabolite. In the same year, Yang and coworkers completed an enantioselective synthesis of (−)-
alstoscholarisine A through a twelve-step sequence that utilized a strategy based on an iridium-
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catalyzed intramolecular asymmetric Friedel-Crafts alkylation of an indole. However, no
synthetic work had been reported on the other four members of the class. We became interested in
developing a divergent approach to the alstoscholarisines which would allow an efficient entry to
all five alkaloids, and the details of this work are reported here.9
RESULTS AND DISCUSSION
Synthesis Plan. Our initial retrosynthetic analysis for construction of the alstoscholarisines
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-5 is depicted in Scheme 1. Thus, the general plan was to construct a bridged tetracyclic system
6, which would act as a common intermediate to access all five of the alkaloids. Our intention was
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to utilize the C16 and C20 substituents in intermediate 6 as handles for subsequent formation of
the requisite tetrahydropyran moieties of the metabolites. We surmised that such a compound
could be produced from 7 by a selective partial reduction of the N-sulfonyllactam carbonyl group,
followed by a ring closure involving the indole nitrogen to form the bridged aminal. It was
expected that the configuration at C16 should be adjustable by epimerization of the ester to the
more stable stereoisomer shown in 6. In turn, we planned to produce tricycle 7 via a convergent,
early-stage Michael coupling of an indole acetic ester enolate 8 and an α,β-unsaturated-N-
sulfonyllactam 9 to form the C15,16 bond. These two fragments contain most of the carbons of
the natural products.
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Michael Reactions. The components needed for the projected Michael reaction are readily
available. Therefore, known α,β-unsaturated-N-sulfonyllactams 14 and 15 were prepared by a
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modification of the procedure described in the literature starting from N-tosylvalerolactam (10)
Scheme 2). Deprotonation of 10 with 2.2 equivalents of LiHMDS, followed by sequential
(
treatment with methyl chloroformate or benzyl chloroformate and then phenylselenyl bromide in
a one-pot protocol led to the methyl and benzyl esters 11 and 12, respectively. In addition, the
same procedure was used to synthesize the analogous, previously unknown allyl ester 13. Upon
oxidation with m-chloroperbenzoic acid, the selenides 11-13 formed the corresponding
selenoxides, which underwent spontaneous in situ elimination to produce the desired unsaturated
lactams 14-16. However, these compounds proved unstable to column chromatography and
therefore were used in crude form for the Michael step.
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For the coupling reaction, known, easily prepared 3-methylindole-2-acetic acid methyl
ester (17) was first protected as the N-Boc derivative 18 (Scheme 3). This ester was deprotonated
with LiHMDS at -78 °C, and to the resulting enolate 19 were added the crude α,β-unsaturated-N-
sulfonyllactams 14-16, leading to the Michael adducts 20-22, respectively, in good yields (based
on selenides 11-13), each as a mixture of stereoisomers.
Studies on Formation of a Bridged Aminal System. With the Michael adducts in hand,
studies were initiated to construct a bridged aminal intermediate like 6, and our first experiments
were conducted with the methyl ester 20. We were pleased to find that the N-sulfonyllactam
functionality of 20 could be selectively reduced with diisobutylaluminum hydride at low
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temperature to afford N,O-hemiacetal 23 without affecting either of the ester groups (Scheme 4).12
However, when exposed to trifluoroacetic acid, intermediate 23 was not converted to the desired
bridged aminal 26, but rather produced the vinylogous carbamate 25 in good yield. This
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transformation probably occurs via the N-sulfonyliminium intermediate 24, which, rather than
closing to aminal 26, tautomerizes to the conjugated system 25. Compound 25 was found to be
quite stable and resisted cyclization to the bridged aminal 26 under a variety of acidic conditions.
Under basic conditions, only cyclization occurred to form a single diastereomeric lactam 27
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(configuration not determined).
Since having a carbonyl group at C20 did not provide a viable pathway for construction of
a bridged aminal, another type of functionalized one-carbon substituent was explored. Therefore,
benzyl ester-containing Michael adduct 21 was first treated with aqueous formaldehyde in an aldol
reaction promoted by trimethylamine, leading to hydroxymethyl compound 28 (mixture of
stereoisomers) (Scheme 5). Subsequent catalytic hydrogenolysis of the benzyl ester resulted in
decarboxylation to yield a mixture of hydroxymethyl lactam 29 along with the elimination product
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0. Partial reduction of the N-sulfonyllactam 29 with Dibal-H gave the corresponding N,O-
hemiacetal 31 (41% unoptimized yield). However, subsequent treatment of this compound with
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TFA to our surprise cleanly produced the tetracyclic indole 33 in good yield. It seems reasonable
that TFA promotes Boc removal and concurrent dehydration of the hydroxymethyl N,O-
hemiacetal 31 to generate the α,β-unsaturated-N-tosyliminium ion 32. Rather than cyclize onto the
indole nitrogen to form the bridged aminal 34, this intermediate undergoes a conjugate addition of
the unsaturated N-sulfonyliminium moiety with C3 of the indole to yield the observed product 33.
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Faced with the problems described above, we considered other possible substitutents that
(1) could be conveniently installed at C20, (2) would not interfere with formation of the bridged
aminal and (3) could easily be transformed into an aldehyde group. We believed that an allyl group
might meet these requirements and act as a suitable aldehyde equivalent. Towards this end, in
order to effect a direct O- to C-allyl transfer, Michael adduct 22 was treated with a catalytic amount
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of Pd(PPh
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) , leading to the desired C20 allyl compound 36 in 52% yield along with some of the
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decarboxylated starting lactam (Scheme 6). Since the yield here was only moderate, a more
efficient procedure for synthesis of 36 was investigated. Thus, an alternative one-pot protocol was
developed whereby lactam ester 22 could first be C-allylated using allyl iodide/K
acetonitrile to form 35, which was not isolated, followed by in situ-addition of
Pd(PPh /morpholine to promote decarboxylation of the allyl ester, leading to the desired C-
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CO
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in
)
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allylated lactam 36 in 74% overall yield for the two steps. Interestingly, in both approaches to 36,
this product was exclusively the more stable C15, C20 trans isomer shown, but as mixtures of
stereoisomers at the C16 ester-bearing center.15
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To continue the synthesis, N-sulfonyllactam 36 was partially reduced to the isolable N,O-
hemiacetal 37 using DibalH (Scheme 7). Exposure of this material to trifluoroacetic acid at room
temperature resulted in removal of the Boc group on the indole nitrogen and subsequent closure
via an N-sulfonyliminium ion to afford the desired bridged aminal 38 in good yield as a mixture
of C16 ester stereoisomers. We were pleased to find that this mixture could be epimerized under
mild conditions with sodium methoxide/methanol to yield exclusively the more stable ester isomer
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9, allowing this compound to be fully characterized, including an X-ray analysis, as well as
establishing the requisite functionality and stereochemistry at C16 for eventual conversion to
alstoscholarisines A and E (vide infra).
Syntheses of (±) Alstoscholarisines B, C and D. We initially focused on completing total
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syntheses of the three alstoscholarisines bearing a C16 carboxyl group. Thus, a mixture of ester
epimers 38 was converted to the corresponding enolate with potassium hexamethyldisilazide at -
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8 °C, followed by an aldol reaction with anhydrous monomeric formaldehyde that occurred
from the least hindered face, leading to hydroxymethyl compound 40 as a single stereoisomer in
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excellent yield (Scheme 8). The alcohol 40 could then be protected as the TBS ether 41.
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Our initial plan had been to isomerize the allyl group of 40/41 to the corresponding
propenyl systems using transition-metal catalysis, followed by oxidative double bond cleavage to
the aldehyde. As discussed below, preliminary experiments aimed at effecting this transformation
were rather discouraging. Therefore, a strategy was explored for isomerizing the allylic double
bond by an ene reaction of intermediates 40/41. Indeed, heating silyl-protected substrate 41 with
DEAD in toluene at reflux overnight led to the desired ene product 42, formed exclusively as the
(E)-geometric isomer, in good yield (Scheme 9).18
Interestingly, if the unprotected alcohol 40 was used in this reaction, the major product
formed was ene product-carbonate 43, along with allyl compound 44, which had not undergone
an ene reaction (Scheme 9). Since attempted removal of the carbonate group of the ene product 43
by basic hydrolysis led to partial retro-aldol loss of formaldehyde, the latter sequence was not
optimized, and the TBS-protected series was used for subsequent work.
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It was found that cleavage of the double bond in the allylic hydrazine derivative 42 could
be effected by a two-step procedure involving an initial dihydroxylation with osmium
tetraoxide/NMO, followed by exposure of the diol to lead tetraacetate to afford the axial aldehyde
45 (Scheme 10). The TBS group of 45 could then be removed under acidic conditions using HCl
to produce alcohol 46. Utilizing a strategy similar to one used in the Bihelovic/Ferjancic synthesis
7
of alstoscholarisine A, aldehyde 46 was treated with DBU in chloroform at room temperature,
resulting in epimerization to the equatorial hydroxyl aldehyde 47, which subsequently cyclizes to
the isolable lactol 48. This lactol could be O-acylated with acetic anhydride to produce acetate 49,
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and, in addition, could be oxidized with iodobenzene diacetate/TEMPO to yield the δ-lactone
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As mentioned above, we had initially aimed at degrading the allyl group of an intermediate
such as 39 to an aldehyde by first effecting a transition-metal catalyzed isomerization to a propenyl
system like 51 (Scheme 11). However, some early preliminary experiments towards this end were
not promising. Initially discouraged by these results, we moved on to investigate the alternative
ene strategy shown in Scheme 9 for degradation of the allyl group. However, at this stage we
decided to return to the double bond isomerization to see if we could develop a shorter route to
aldehyde 46 which would not require protection of the hydroxymethyl group. Thus, exposing allyl
compound 39 to the Grubbs II ruthenium catalyst in methanol at 60 °C (10 mol % of catalyst, 12
hours)20 indeed led to the desired propenyl derivative 51 in 90% isolated yield (~2.8:1 E/Z
mixture).
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Similarly, the allyl group in the unprotected hydroxymethyl compound 40 could be
isomerized to the requisite propenyl intermediate 52 in 89% yield as a ~3.6:1 mixture of E/Z
isomers (Scheme 11). Oxidative cleavage of alkene 52 by the usual two-step protocol then led to
the corresponding aldehyde, which without purification was epimerized with DBU and the
resulting lactol was acetylated to produce acetate 49 (72% overall yield from 52). In addition,
lactone 50 could be obtained from alkene 52 in a four-step sequence via TEMPO/PhI(OAc)
2
19
oxidation of the crude intermediate lactol (72% overall yield).
For the synthesis of alstoscholarisine C (3), lactol acetate 49 was first treated with a mixture
of trimethylsilyl triflate and trimethylaluminum21,22 to afford α-methyl tetrahydropyran 54 as a
single stereoisomer having the configuration shown (Scheme 12). This transformation probably
involves initial formation of an intermediate oxocarbenium ion 53, followed by methyl group
transfer from the aluminum reagent onto the least encumbered face. It should be noted that a
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similar methylation was also attempted with lactol 48, but in this case the major product formed
was the corresponding O-silylated lactol along with only small amounts of tetrahydropyran 54
(~10%).
To complete synthesis of the alkaloid, the N-Ts group of intermediate 54 was removed
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reductively with magnesium metal in methanol, providing amine 55, followed by N-methylation
2
4
with formalin and sodium cyanoborohydride, to give (±) alstoscholarisine C (3) having proton
-
and carbon NMR spectra identical with those reported for the natural metabolite (see Supporting
Information).5a
A basic hydrolysis of the methyl ester with sodium hydroxide in aqueous ethanol at 70 °C
served to convert alstoscolarisine C (3) to alstoscholarisine D (4) in good yield. Purification of this
amino acid by silica gel chromatography proved rather troublesome, but pure material could be
obtained by reverse phase preparative TLC. Synthetic (±)-alstoscholarisine D (4) had proton and
carbon NMR spectra that matched those described for the natural alkaloid.5a
The synthesis of alstoscholarisine B (2) made use of the δ-lactone 50 (Scheme 13). Thus,
methyllithium could be added selectively to the lactone carbonyl group of 50 at -78 °C to afford
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hemiketal 56 as a single stereoisomer (configuration not determined). Treatment of this compound
with TMS-triflate and triethylsilane7,25 at -78 °C presumably generates oxocarbenium species 57,
which is then reduced from the less hindered face to afford the equatorial α-methyl
tetrahydropyran 58 as a single stereoisomer. Removal of the tosyl group from 58 with Mg/MeOH23
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and subsequent N-methylation of the resulting secondary amine 59 led to (±)-alstoscholarisine B
(2) whose NMR spectra matched those reported for the natural product.5a
Syntheses of (±)-Alstoscholarisines A and E. The total syntheses of the remaining two
alstoscholarsines lacking the C16 carboxyl group utilized the key bridged intermediate ester 39. In
our first approach, reduction of the methyl ester with lithium aluminum hydride cleanly provided
alcohol 60, which was then protected as the TBS ether 61 (Scheme 14). This compound underwent
an ene reaction with DEAD in refluxing toluene to afford the desired (E)-allylic hydrazine
derivative 62 in 53% yield, along with some of the compound 63 (43%) where reaction with the
DEAD had also occurred at C3 of the indole (3.8:1 mixture of diastereomers). Attempts to convert
6
3 to the desired ene product 62 by heating in xylenes only led to decomposition.
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Cleavage of the double bond of 62 using the previously applied two-step sequence was
uneventful and provided the requisite axial aldehyde 64 (Scheme 15). However, at this stage an
unforeseen problem arose: all attempts to remove the TBS protecting group of 64 using TBAF
inexplicably led to the exclusive formation of the ring-opened product 65. A similar result was
observed on attempting to remove the TBS group with HCl. It is notable that the compound
analogous to 65 was never detected in the system bearing a C16 carbomethoxyl group (Cf. Scheme
1
1).
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This problem could be mitigated by simply changing the order of steps. Therefore, the TBS
group in ene product 62 was first removed with TBAF to yield alcohol 66 (Scheme 16). Cleavage
of the alkene could then be effected by the usual two-step dihydroxylation/oxidative cleavage
protocol, leading to the desired axial aldehyde 67. Upon treatment with DBU, this aldehyde was
transformed to lactol 68 along with some of the ring-opened product 65. Without purification, this
mixure was converted to lactol acetate 69 using acetic anhydride (34% yield from axial aldehyde
6
7) along with the acetylated ring-opened product 70 (37%). It should be noted that in the
7
Bihelovic/Ferjancic synthesis of alstoscholarisine A, treatment of an axial aldehyde like 67, but
bearing an N-methyl rather than an N-tosyl group, with DBU led to the lactol corresponding to 68
in a similar yield (35%). However, no mention was made by these authors regarding the formation
of a ring-opened product such as 65.
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In a similar vein, the ester group in propenyl compound 51 could be reduced with lithium
aluminum hydride to afford the corresponding alcohol 71 (Scheme 17). The double bond in this
intermediate could then be cleaved as usual to afford the axial aldehyde, which without purification
was converted to lactol acetate 69 (31%) along with the ring-opened derivative 70 (33%).
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A synthesis of alstoscholarisine E (5) could be executed from lactol acetate 69, which was
first exposed to TMS-triflate and trimethylaluminum in methylene chloride at -78 °C, affording
tetrahydropyran 72 in good yield as a single stereoisomer (Scheme 18). It should be pointed out
that to effect a clean reaction, this step requires a lower temperature than the methylation of the
corresponding lactol acetate substrate 49 bearing an ester moiety at C16, which is done at room
temperature (Cf. Scheme 12). The tosyl group could be removed from intermediate 72 using
Mg/MeOH, and the resulting amine 73 was N-methylated to afford (±)-alstoscholarisine E (5)
which had proton and carbon NMR spectra as described for natural material.5a
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The construction of alstoscholarisine A (1) utilized δ-lactone 74. Thus, using ene product
66, it was possible to effect double bond cleavage as usual, followed by aldehyde epimerization
with DBU to produce a mixture of lactol 68 and ring-opened product 65, which was not purified
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(
Scheme 19). Further oxidation of this crude mixture with TEMPO/PhI(OAc)2, as had previously
been done with the lactol 48 which contains a carbomethoxyl group (Cf. Scheme 10), indeed gave
the desired lactone 74 (32% from alkene 66) but also produced some of the unexpected tetracyclic
dialdehyde 75 as one stereoisomer (27% from 66, stereochemistry not determined). However,
lactone 74 could be obtained in somewhat better yield by effecting the same sequence with
propenyl derivative 71 (see Experimental Section).
We believe that compound 75 arises from cyclization of sulfonamide 65 via a Hofmann-
Loffler-Freytag process, which has precedent in related systems, but not with this combination of
reagents.26 An interesting question here is how an initial sulfonamide radical derived from
substrate 65 is produced under these conditions. We speculate that the TEMPO is first oxidized by
2
7
PhI(OAc) to form an oxoammonium species that undergoes nucleophilic attack at oxygen by
2
the sulfonamide nitrogen. The resulting intermediate could then undergo N-O bond homolysis to
reform TEMPO along with the sulfonamide radical.
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Reaction of lactone 74 with methyllithium afforded hemiketal 76, which upon treatment
with trimethylsilyl triflate/triethylsilane in methylene chloride at -78 °C led to the tetrahydropyran
7
7 as a single stereoisomer in 72% yield (Scheme 20). Finally, removal of the tosyl group of 77
produced amine 78 and subsequent N-methylation yielded (±)-alstoscholarisine A (1) having
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spectra as reported for the natural product.5a
CONCLUSION
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8
In summary, we have devised a divergent strategy for construction of alstoscholarisines
A-E. Bridged aminal ester 38, which acts as a pivotal intermediate in this approach, is prepared in
five steps via an initial Michael addition of the readily available indole-2-acetic acid methyl ester
enolate 19 with the α,β-unsaturated-N-sulfonyllactam 16 to form the C15, C16 bond of the
alkaloids. This step is followed by a one-pot C-allylation/decarboxylation at C20 and then a
selective partial reduction of the N-acylsulfonamide functionality to a N,O-hemiacetal 37 that can
be cyclized under acidic conditions via an N-sulfonyliminium ion to form aminal 38. This
intermediate proved to be central for the construction of the five alkaloids.
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6
EXPERIMENTAL SECTION
General Methods. All non-aqueous reactions were carried out in oven- or flame-dried
glassware under an atmosphere of argon. All reagents were purchased from commercial vendors
and used as received, unless otherwise specified. Anhydrous tetrahydrofuran (THF),
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dichloromethane (CH
2
Cl ), toluene (PhMe), and acetonitrile (MeCN) were obtained from a solvent
2
purification system (Glass Contour). Reactions were stirred magnetically and monitored by thin
layer chromatography (TLC) with 250 μm EMD 60 F254 precoated silica gel plates. Flash
chromatographic separations were performed using silica gel (240-400 mesh). FT-IR spectra were
recorded on a Thermo-Nicolet FT-IR spectrometer equipped with a diamond ATR accessory.
NMR spectral data were recorded on Bruker DPX-300 or AVANCE III HD 500 (Prodigy BBO
cryoprobe) spectrometers. Proton and carbon-13 NMR chemical shifts are reported relative to
1
13
chloroform for H and C NMR (δ 7.26 and 77.16, respectively), acetone (δ 2.05 and 20.94,
respectively), or methanol (δ 3.31 and 49.00, respectively). High resolution mass spectra were
recorded on a time-of-flight (TOF) mass spectrometer.
General Procedure for Selenide Synthesis. A 1.0 M solution of LiHMDS in THF (2.2
equiv) was added dropwise to a -78 °C solution of lactam 10 in THF (0.072 M) and the solution
was stirred at -78 °C for 1 h. The appropriate alkyl chloroformate (1.2 equiv) was added and the
mixture was stirred at -78 °C for 1 h, after which a solution of PhSeBr (1.1 equiv) in THF (1.75
M) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min and at rt for 1.5 h,
diluted with sat. NH
4
Cl and extracted twice with EtOAc. The combined organic layers were
SO and concentrated in vacuo. The residue was purified by
washed with brine, dried over Na
2
4
flash chromatography on silica gel to provide the selenide.
Methyl 2-Oxo-3-(phenylselanyl)-1-tosylpiperidine-3-carboxylate (11). Prepared by the
general procedure using the following quantities: lactam 10 (1.816 g, 7.17 mmol), 1.0 M LiHMDS
in THF (15.8 mL, 15.8 mmol), methyl chloroformate (0.66 mL, 812 mg, 8.60 mmol), and PhSeBr
(1.861 g, 7.89 mmol). The product was purified by flash chromatography on silica gel (gradient
15% to 25% EtOAc in hexanes) to provide selenide 11 (1.378 g, 35%) as a pale yellow solid. IR
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-1
1
(
neat) 2952, 1729, 1688, 1351, 1167 cm ; H NMR (300 MHz, CDCl
3
) δ 7.94 (d, J = 8.3 Hz, 2H),
7.55 (d, J = 7.0 Hz, 2H), 7.46-7.25 (m, 5H), 3.96-3.75 (m, 2H), 3.65 (s, 3H), 2.48 (s, 3H), 2.31-
1
3
2
1
.20 (m, 1H), 2.03-1.89 (m, 2H), 1.86-1.71 (m, 1H); C NMR (75 MHz, CDCl ) δ 170.2, 167.3,
3
45.4, 138.8, 135.8, 130.4, 129.8, 129.4, 126.5, 55.9, 53.9, 46.5, 32.0, 22.2, 21.8; HRMS (ESI-
1
1
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+
TOF) m/z: [M + H] Calcd for C20
H
22NO SSe 468.0384; found 468.0360.
5
Benzyl 2-Oxo-3-(phenylselanyl)-1-tosylpiperidine-3-carboxylate (12). Prepared by the
general procedure using the following quantities: lactam 10 (1.505 g, 5.94 mmol), 1.0 M LiHMDS
in THF (13.0 mL, 13.0 mmol), benzyl chloroformate (1.02 mL, 1.220 g, 7.13 mmol), and PhSeBr
(1.541 g, 6.53 mmol). The product was purified by flash chromatography on silica gel (20% EtOAc
in hexanes) to provide selenide 12 (1.810 g, 56%) as white needles. IR (neat) 2980, 1727, 1692,
-1
1
1
352, 1168 cm ; H NMR (300 MHz, CDCl
3
) δ 7.93 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H),
7.41-7.17 (m, 10H), 5.10 (s, 2H), 3.85-3.70 (m, 2H), 2.40 (s, 3H), 2.28-2.15 (m, 1H), 2.02-1.83
1
3
(
m, 2H), 1.77-1.61 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 168.7, 166.6, 144.7, 138.2, 135.2, 134.8,
1
2
29.7, 129.2, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 127.8, 125.7, 67.6, 55.5, 45.7, 31.2, 21.5,
+
1.0; HRMS (ESI-TOF) m/z: [M + H] Calcd for C26
H
26NO SSe 544.0697; found 544.0687.
5
Allyl 2-Oxo-3-(phenylselanyl)-1-tosylpiperidine-3-carboxylate (13). Prepared by the
general procedure using the following quantities: lactam 10 (16.08 g, 63.4 mmol), 1.0 M LiHMDS
in THF (140 mL, 140 mmol), allyl chloroformate (8.0 mL, 9.072 g, 75.2 mmol), and PhSeBr (16.47
g, 69.8 mmol). The product was purified by flash chromatography on silica gel (gradient 20% to
2
2
5% EtOAc in hexanes) to provide selenide 13 (22.10 g, 71%) as pale yellow needles. IR (neat)
-1 1
956, 1728, 1699, 1353, 1170 cm ; H NMR (300 MHz, CDCl ) δ 7.93 (d, J = 8.2 Hz, 2H), 7.55
3
(d, J = 7.1 Hz, 2H), 7.44-7.23 (m, 5H), 5.71 (ddt, J = 5.5, 9.5, 15.2 Hz, 1H), 5.27 (d, J = 15.2 Hz,
1
H), 5.16 (d, J = 9.5 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H), 3.92-3.79 (m, 2H), 2.45 (s, 3H), 2.22 (dt,
13
J = 4.9, 13.4 Hz, 1H), 2.02-1.89 (m, 2H), 1.82-1.69 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 168.8,
1
66.7, 144.9, 138.3, 135.3, 130.8, 129.8, 129.3, 128.8, 128.8, 125.9, 118.7, 66.6, 55.6, 46.0, 31.4,
+
21.6, 21.3; HRMS (ESI-TOF) m/z: [M + H] Calcd for C22
H
24NO SSe 494.0540; found 494.0535.
5
General Procedure for Formation of α,β-Unsaturated Lactams. The selenide was
dissolved in CH Cl (0.05 M) and the solution was cooled to 0 °C. Solid m-CPBA (73%, 2.0 equiv)
2
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was added and the reaction mixture was stirred at 0 °C for 1 h, and was diluted with sat. Na
2
S
2
O .
3
The organic layer was washed sequentially with sat. NaHCO
3
and water, and dried over Na
2
SO .
4
The solution was concentrated in vacuo to provide the crude Michael acceptor, which was used
directly in the next step. For characterization purposes, a sample was purified by flash
chromatography on silica gel.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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8
9
0
Methyl 2-Oxo-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate (14). Prepared by the
general procedure using the following quantities: selenide 11 (981 mg, 2.10 mmol) and m-CPBA
(73%, 1.04 g, 725 mg of m-CPBA, 4.20 mmol) provided crude Michael acceptor 14 (601 mg, 92%)
as a yellow oil. A sample was purified by flash chromatography on silica gel (45% EtOAc in
hexanes) to provide unsaturated lactam 14 as a colorless oil. IR (neat) 2952, 1740, 1687, 1346,
-1
1
1
164 cm ; H NMR (300 MHz, CDCl
3
) δ 7.92 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 4.3 Hz, 1H), 7.30
(d, J = 8.2 Hz, 2H), 4.10 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.65 (td, J = 4.4, 6.4 Hz, 2H), 2.41 (s,
1
3
3
4
3
H); C NMR (75 MHz, CDCl
3
) δ 163.8, 159.6, 151.1, 145.0, 135.8, 129.6, 129.2, 128.8, 52.7,
+
3.5, 25.6, 21.8; HRMS (ESI-TOF) m/z: [M + H] Calcd for C14
H
16NO S 310.0749; found
5
10.0742.
Benzyl 2-Oxo-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate (15). Prepared by the
general procedure using the following quantities: selenide 12 (2.54 g, 4.68 mmol) and m-CPBA
73%, 2.21 g, 1.62 g of m-CPBA, 9.36 mmol) provided crude Michael acceptor 15 (1.78 g, 99%)
(
as a yellow oil. A sample was purified by flash chromatography on silica gel (35% EtOAc in
hexanes) to provide unsaturated lactam 15 as a colorless oil. IR (neat) 2952, 1739, 1690, 1360,
-1 1
1
167 cm ; H NMR (500 MHz, CDCl
3
) δ 7.94 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 4.4 Hz, 1H), 7.37-
7
.28 (m, 7H), 5.20 (s, 2H), 4.09 (t, J = 6.4 Hz, 2H), 2.64 (td, J = 4.4 Hz, 6.4 Hz, 2H), 2.42 (s, 3H);
13C NMR (125 MHz, CDCl
) δ 162.7, 159.4, 150.8, 145.1, 135.8, 135.4, 129.6, 129.2, 128.8,
3
+
1
28.7, 128.5, 128.4, 67.3, 43.5, 25.6, 21.8; HRMS (ESI-TOF) m/z: [M + H] Calcd for
C
20
H
20NO S 386.1062; found 386.1048.
5
Allyl 2-Oxo-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate (16). Prepared by the
general procedure using the following quantities: selenide 13 (13.17 g, 26.74 mmol) and m-CPBA
73%, 12.00 g, 9.23 g of m-CPBA, 53.5 mmol) provided crude Michael acceptor 16 (8.96 g, 100%)
as a yellow oil. A sample was purified by flash chromatography on silica gel (30% EtOAc in
(
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hexanes) to provide unsaturated lactam 16 as a colorless oil. IR (neat) 2952, 1732, 1692, 1356,
-1 1
1165 cm ; H NMR (300 MHz, CDCl
3
) δ 7.95 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 4.3 Hz, 1H), 7.33
(d, J = 8.2 Hz, 2H), 5.92 (ddt, J = 5.7, 10.9, 17.4 Hz, 1H), 5.34 (d, J = 17.4 Hz, 1H), 5.25 (d, J =
1
0.9 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 2.68 (td, J = 6.4, 4.3 Hz, 2H), 2.44
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
(
s, 3H); C NMR (75 MHz, CDCl
3
) δ 162.6, 159.4, 150.9, 145.1, 135.7, 131.5, 129.6, 129.2,
+
128.8, 119.0, 66.1, 43.4, 25.6, 21.7; HRMS (ESI-TOF) m/z: [M + H] Calcd for C16
H
18NO S
5
3
36.0906; found 336.0893.
tert-Butyl 2-(2-Methoxy-2-oxoethyl)-3-methyl-1H-indole-1-carboxylate (18). Indole ester
17 (9.41 g, 46.3 mmol) was dissolved in CH Cl (200 mL) and the solution was cooled to 0 °C.
A solution of Boc O (10.61 g, 48.6 mmol) in CH Cl (20 mL) was added, followed by DMAP
5.94 g, 48.6 mmol). The reaction mixture was stirred at 0 °C for 20 min and concentrated in vacuo.
1
1
2
2
2
2
2
(
The residue was purified by flash chromatography on silica gel (7.5% EtOAc in hexanes) to
provide Boc-protected indole 18 (12.63 g, 90%) as a white solid. IR (neat) 2983, 2939, 1741, 1713,
-1 1
1
460, 1355, 1333, 1165 cm ; H NMR (300 MHz, CDCl
3
) δ 8.19 (d, J = 8.0 Hz, 1H), 7.53 (d, J =
1
3
7
.6 Hz, 1H), 7.41-7.27 (m, 2H), 4.11 (s, 2H), 3.77 (s, 3H), 2.28 (s, 3H), 1.73 (s, 9H); C NMR
(75 MHz, CDCl
3
) δ 170.8, 150.6, 135.7, 130.2, 128.6, 124.1, 122.4, 118.4, 116.4, 115.5, 83.8,
+
5
1.9, 32.9, 28.1, 8.6; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C17
H
21NO Na 326.1368; found
4
3
26.1335.
General Procedure for Michael Reactions. A solution of LiHMDS (1.0 M in THF, 1.32
equiv) was added dropwise to a -78 °C solution of indole ester 18 (1.2 equiv) in THF (0.08 M) and
the reaction mixture was stirred at -78 °C for 1 h. A solution of the crude Michael acceptor (1.0
equiv) in THF (0.31 M) was added and the reaction mixture was stirred at -78 °C for 10 min. The
reaction mixture was diluted with sat. NH
organic layers were washed with brine, dried over Na
was purified by flash chromatography on silica gel to provide the Michael adduct.
4
Cl and extracted twice with EtOAc. The combined
2
SO , and concentrated in vacuo. The residue
4
tert-Butyl
2-(1-(3-((Methyloxy)carbonyl)-2-oxo-1-tosylpiperidin-4-yl)-2-methoxy-2-
oxoethyl)-3-methyl-1H-indole-1-carboxylate (20). Prepared by the general procedure using the
following quantities: LiHMDS (1.0 M in THF, 0.46 mL, 0.46 mmol), indole ester 18 (127 mg,
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2
2
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2
2
2
2
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5
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5
5
5
6
0
.418 mmol), and crude Michael acceptor 14 (107.7 mg, 0.348 mmol). The product was purified
by flash chromatography on silica gel (gradient 20% to 25% EtOAc in hexanes) to provide Michael
adduct 20 (121 mg, 57%) as a colorless oil (complex mixture of inseparable stereoisomers). IR
-1 1
(
neat) 2951, 1724, 1455, 1356, 1168, 1134 cm ; H NMR (300 MHz, CDCl
.57-7.18 (m, 5H), 4.71-3.83 (m, 2H), 3.80-3.35 (m, 7.3 H), 3.21-3.07 (m, 0.7H), 2.90 (s, 0.7H),
2.70-2.58 (m, 0.3H), 2.45 (s, 1.5H), 2.43 (s, 1.5H), 2.22 (s, 1.5H), 2.19 (s, 0.5H), 2.13 (s, 1H),
3
) δ 8.05-7.80 (m, 3H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1
3
2
1
1
.02-1.90 (m, 1H), 1.76-1.60 (m, 1H), 1.71 (s, 9H); C NMR (75 MHz, CDCl ) δ 171.9, 171.5,
3
71.3, 171.2, 169.2, 168.6, 167.6, 166.5, 166.1, 165.7, 165.4, 150.9, 150.7, 144.9, 144.9, 135.5,
35.4, 135.2, 135.1, 130.5, 130.1, 130.0, 129.9, 129.9, 129.4, 129.3, 129.3, 128.7, 128.6, 128.6,
124.8, 124.8, 124.7, 122.8, 122.8, 122.7, 119.1, 118.8, 188.6, 118.5, 118.4, 115.8, 84.7, 84.6, 84.6,
5
2
6.8, 54.3, 52.9, 52.7, 52.2, 52.1, 52.0, 46.4, 46.0, 45.5, 44.8, 44.6, 43.5, 37.0, 36.5, 36.4, 28.2,
+
8.1, 28.0, 25.8, 25.4, 23.2, 21.6, 21.6, 9.3, 9.2, 9.0; HRMS (ESI-TOF) m/z: [M + H] Calcd for
C
31
H
37
N
2
9
O S 613.2220; found 612.2227.
tert-Butyl
2-(1-(3-((Benzyloxy)carbonyl)-2-oxo-1-tosylpiperidin-4-yl)-2-methoxy-2-
oxoethyl)-3-methyl-1H-indole-1-carboxylate (21). Prepared by the general procedure using the
following quantities: LiHMDS (1.0 M in THF, 0.81 mL, 0.81 mmol), indole ester 18 (244 mg,
0
.805 mmol), and crude Michael acceptor 15 (259 mg, 0.671 mmol). The product was purified by
flash chromatography on silica gel (gradient 20% to 25% EtOAc in hexanes) to provide Michael
adduct 21 (316 mg, 68%) as a colorless oil (complex mixture of inseparable stereoisomers). IR
-1 1
(neat) 2975, 1725, 1358, 1327, 1162 cm ; H NMR (300 MHz, CDCl
3
) δ 8.08-7.71 (m, 3H), 7.59-
.80 (m, 10H), 5.32-5.06 (m, 1H), 4.98-4.50 (m, 1H), 4.30-3.72 (m, 3H), 3.69-3.52 (m, 3H), 3.51-
.37 (m, 0.5 H), 3.15-2.88 (m, 0.5 H), 2.68-2.33 (m, 4H), 2.25-2.06 (m, 3H), 2.01-1.86 (m, 1H),
6
3
13
1.76-1.45 (m, 10H); C NMR (75 MHz, CDCl
3
) δ 173.4, 171.3, 168.6, 168.3, 166.4, 166.0, 165.8,
1
1
1
51.0, 150.8, 144.9, 135.6, 135.4, 135.3, 134.9, 131.0, 130.2, 130.0, 129.9, 129.7, 129.4, 129.4,
28.7, 128.6, 128.5, 128.1, 127.9, 127.8, 127.7, 127.1, 124.9, 124.8, 124.7, 122.9, 119.4, 118.8,
18.7, 118.5, 118.3, 116.1, 115.8, 84.8, 84.7, 68.0, 67.4, 67.1, 66.3, 66.0, 60.4, 57.1, 54.4, 52.2,
52.2, 46.1, 45.5, 44.7, 44.5, 42.7, 36.9, 36.6, 33.5, 29.0, 28.2, 25.9, 22.0, 21.7, 21.5, 10.4, 9.3, 9.0,
+
8
.8; HRMS (ESI-TOF) m/z: [M + H] Calcd for C37
H
41
N
2
9
O S 689.2533; found 689.2509.
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tert-Butyl
2-(1-(3-((Allyloxy)carbonyl)-2-oxo-1-tosylpiperidin-4-yl)-2-methoxy-2-
oxoethyl)-3-methyl-1H-indole-1-carboxylate (22). Prepared by the general procedure using the
following quantities: LiHMDS (1.0 M in THF, 35.5 mL, 35.5 mmol), indole ester 18 (9.73 g, 32.1
mmol), and crude Michael acceptor 16 (8.96 g, 26.74 mmol). The product was purified by flash
chromatography on silica gel (gradient 20% to 30% EtOAc in hexanes) to provide Michael adduct
22 (11.80 g, 69%) as a white foam (complex mixture of inseparable stereoisomers). IR (neat) 2976,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
2
939, 1725, 1452, 1357, 1162, 1131 cm ; H NMR (300 MHz, CDCl
d, J = 7.4 Hz, 0.5H), 7.45 (d, J = 7.5 Hz, 0.5H), 7.41-7.18 (m, 4H), 5.90-5.67 (m, 0.4H), 5.34-
.10 (m, 1H), 4.95-4.81 (m, 0.6H), 4.75-4.35 (m, 2H), 4.33-3.10 (m, 8H), 2.50-2.40 (m, 3H), 2.32-
3
) δ 8.02-7.80 (m, 3H), 7.52
(
5
13
1.90 (m, 4H), 1.75-1.58 (m, 10H); C NMR (75 MHz, CDCl
3
) δ 171.4, 168.5, 168.1, 166.5, 166.0,
65.7, 151.0, 150.8, 145.0, 135.6, 135.3, 131.4, 131.1, 130.2, 130.1, 129.9, 129.5, 129.4, 129.4,
28.8, 128.7, 124.9, 124.9, 124.8, 122.8, 119.3, 118.9, 118.8, 118.4, 118.3, 116.0, 115.9, 84.8,
1
1
84.7, 66.3, 66.1, 54.4, 52.3, 52.2, 46.1, 45.6, 44.8, 44.6, 36.9, 36.6, 36.5, 28.3, 28.2, 25.9, 21.8,
+
9
.4, 9.1; HRMS (ESI-TOF) m/z: [M + H] Calcd for C33
H
39
N
2
9
O S 639.2376; found 639.2366.
tert-Butyl
2-(1-(2-Hydroxy-3-(methoxycarbonyl)-tosylpiperidin-4-yl)-2-methoxy-2-
oxoethyl)-3-methyl-1H-indole-1-carboxylate (23). A 1.0 M solution of DIBALH in PhMe (0.40
mL, 0.40 mmol) was added dropwise to a -78 °C solution of N-sulfonyllactam 20 (81.9 mg, 0.134
mmol) in CH
by sequential addition of H
was warmed to rt and stirred for 30 min, after which MgSO
filtered through a Celite pad. The filtrate was washed with a saturated aqueous solution of
Rochelle’s salt (20 mL), dried over Na SO , and concentrated in vacuo. The residue was purified
2
Cl
2
(13 mL). The reaction mixture was stirred at -78 °C for 1 h, and was quenched
O (0.02 mL), 15% NaOH (0.02 mL), and H O (0.04 mL). The mixture
was added and the suspension was
2
2
4
2
4
by flash chromatography on silica gel (25% EtOAc in hexanes) to provide hemiaminal 23 (53.8
mg, 65%) as a colorless oil (complex mixture of inseparable stereoisomers). IR (neat) 3485, 2950,
-1
1
1
724, 1454, 1325, 1227, 1158, 1133 cm ; H NMR (300 MHz, CDCl
d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.57-7.47 (m, 1H), 7.38-7.23 (m, 4H), 5.97 (s, 0.6H),
5.85 (s, 0.4H), 4.80 (d, J = 8.5 Hz, 0.5H), 4.20-4.08 (m, 0.5H), 3.75 (s, 1H), 3.64-3.38 (m, 7H),
3
) δ 8.07-7.90 (m, 1H), 7.78
(
3
1
.27-2.92 (m, 2H), 2.84 (s, 0.5H), 2.62 (d, J = 11.4 Hz, 0.5H), 2.43 (s, 3H), 2.37-2.20 (m, 3H),
13
.98-1.83 (m, 1H), 1.68 (s, 9H), 1.51-1.42 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 174.4, 172.6,
172.2, 171.1, 150.7, 143.7, 143.6, 136.5, 136.1, 135.5, 131.8, 131.0, 130.3, 130.1, 129.7, 129.5,
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
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5
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5
5
5
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1
28.1, 127.6, 127.5, 124.6, 124.3, 122.8, 122.6, 118.7, 115.9, 84.5, 84.4, 78.1, 77.4, 52.7, 52.5,
52.1, 51.8, 51.7, 47.8, 44.9, 43.5, 39.8, 32.7, 32.2, 28.7, 28.3, 28.2, 25.1, 21.6, 9.3; HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C31
H
38
N
2
9
O SNa 637.2196; found 637.2174.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl
tetrahydropyridine-3-carboxylate (25). Hemiaminal 23 (202 mg, 0.329 mmol) was dissolved in
CH Cl (3.0 mL) and TFA (3.0 mL) was added. The solution was stirred at rt for 10 min and
carefully diluted with sat. NaHCO (100 mL). The mixture was extracted with CH Cl (2 × 50 mL)
and the combined organic layers were dried over Na SO and concentrated in vacuo. The residue
4-(2-Methoxy-1-(3-methyl-1H-indol-2-yl)-2-oxoethyl)-1-tosyl-1,4,5,6-
2
2
3
2
2
2
4
was purified by flash chromatography on silica gel (30 % EtOAc in hexanes) to provide vinylogous
carbamate 25 (120.4 mg, 74%) as a white foam (1.5:1 mixture of diastereomers). For
characterization purposes, the two isomers were separated by flash chromatography on silica gel
(50% Et
2
O in hexanes).
Less polar isomer (major): white powder, IR (neat) 3404, 2951, 1728, 1712, 1622, 1459,
-1 1
1
356, 1269, 1166, 1107 cm ; H NMR (500 MHz, CDCl
8.2 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.12 (t,
J = 8.0 Hz, 1H), 7.04 (t, J = 7.1 Hz, 1H), 3.92-3.88 (m, 1H), 3.80-3.77 (m, 1H), 3.63 (s, 3H), 3.40-
3
) δ 8.66 (s, 1H), 7.88 (s, 1H), 7.71 (d, J
=
3
1
1
2
4
.35 (m, 1H), 3.18 (td, J = 3.4, 12.9 Hz, 1H), 3.11 (s, 3H), 2.46 (s, 3H), 1.96 (s, 3H), 1.88-1.82 (m,
13
H), 1.71-1.63 (m, 1H); C NMR (125 MHz, CDCl
3
) δ 173.0, 166.6, 145.0, 135.8, 135.3, 134.4,
30.3, 129.6, 128.4, 127.8, 127.3, 122.1, 119.2, 118.6, 110.8, 109.3, 52.4, 51.5, 46.6, 39.3, 33.8,
+
3.9, 21.8, 8.5; HRMS (ESI-TOF) m/z: [M + H] Calcd for C26
H
29
N
2
O S 497.1746; found
6
97.1734.
More polar isomer (minor): white powder IR (neat) 3391, 2950, 1730, 1704, 1622, 1439,
-1 1
1352, 1273, 1165, 1097 cm ; H NMR (500 MHz, CDCl
8.1 Hz, 2H), 7.35-7.29 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (t, J =
.5 Hz, 1H), 3.90 (d, J = 6.7 Hz, 1H), 3.81 (s, 3H), 3.67 (s, 3H), 3.56 (br d, J = 11.6 Hz, 1H), 3.30
3
) δ 8.80 (s, 1H), 8.06 (s, 1H), 5.49 (d, J
=
7
1
3
(
t, J = 5.8 Hz, 1H), 2.43 (s, 3H), 1.91 (s, 3H), 1.85 (d, J = 14.2 Hz, 1H), 1.54-1.46 (m, 1H); C
NMR (125 MHz, CDCl ) δ 173.2, 167.4, 144.8, 136.7, 136.0, 134.1, 130.2 128.5, 128.0, 127.0,
22.3, 119.2, 118.7, 111.0, 110.4, 108.8, 52.5, 51.8, 46.0, 39.3, 33.6, 23.2, 21.8, 8.8; HRMS (ESI-
3
1
+
TOF) m/z: [M + H] Calcd for C26
H
29
N
2
6
O S 497.1746; found 497.1763.
2
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Page 29 of 64
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Methyl
6-Methyl-12-oxo-2-tosyl-2,3,4,4a,5,12-hexahydroindolo[1,2-
b][2,7]naphthyridine-5-carboxylate (27). Vinylogous carbamate 25 (34.9 mg, 0.0751 mmol) was
dissolved in MeCN (7.5 mL) and K CO (260 mg, 1.88 mmol) was added. The suspension was
2
3
refluxed for 6 h, cooled to rt and filtered through a Celite pad. The filtrate was concentrated in
vacuo and the residue was purified by flash chromatography on silica gel (25% EtOAc in hexanes)
to provide indole lactam 27 (22.1 mg, 68%) as a white solid. IR (neat) 2951, 1735, 1683, 1610,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1 1
1
455, 1367, 1348, 1166 cm ; H NMR (500 MHz, CDCl
3
) δ 8.51 (d, J = 8.1 Hz, 1H), 8.29 (s, 1H),
7
.74 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.39-7.32 (m, 3H), 7.30-7.26 (m, 1H), 4.18 (d,
J = 5.8 Hz, 1H), 4.02 (dt, J = 3.3, 12.3 Hz, 1H), 3.53 (s, 3H), 3.07 (td, J = 2.5, 12.3 Hz, 1H), 2.95
(dtd, J = 1.9, 5.4, 11.5 Hz, 1H), 2.43 (s, 3H), 2.22 (s, 3H), 2.20-2.13 (m, 1H), 1.65-1.59 (m, 1H);
13C NMR (125 MHz, CDCl
3
) δ 169.5, 161.6, 144.9, 136.0, 135.3, 134.6, 130.5, 130.3, 128.1,
1
27.4, 125.2, 123.7, 118.6, 116.5, 114.6, 108.9, 52.4, 43.2, 42.0, 32.4, 25.2, 21.8, 8.5; HRMS (ESI-
+
TOF) m/z: [M + H] Calcd for C25
H
25
N
2
5
O S 465.1484; found 465.1481.
tert-Butyl 2-(1-(3-((Benzyloxy)carbonyl)-3-(hydroxymethyl)-2-oxo-1-tosylpiperidin-4-yl)-
2
-methoxy-2-oxoethyl)-3-methyl-1H-indole-1-carboxylate (28). Michael adduct 21 (606 mg, 0.88
mmol) was dissolved in a mixture of dioxane (8.8 mL) and 37% aqueous formaldehyde (5.6 mL,
.26 g of HCHO, 75 mmol), and Et N (0.74 mL, 534 mg, 5.28 mmol) was added. The solution
was stirred at rt for 16 h, and was diluted with sat. NH Cl (50 mL). The mixture was extracted
with EtOAc (2 × 50 mL) and the combined organic layers were washed with brine (50 mL), dried
over Na SO , and concentrated in vacuo. The residue was purified by flash chromatography on
2
3
4
2
4
silica gel (gradient 30% to 35% EtOAc in hexanes) to provide aldol adduct 21 (423 mg, 67%) as
a white foam (complex mixture of inseparable stereoisomers). IR (neat) 3514, 2977, 1723, 1455,
-1 1
1357, 1328, 1164 cm ; H NMR (300 MHz, CDCl
3
) δ 8.15-7.73 (m, 4H), 7.59-7.08 (m, 9H), 5.26-
4
2
1
.97 (m, 2H), 4.60-4.51 (m, 1H), 4.39-4.30 (m, 1H), 4.15-3.98 (m, 2H), 3.70-3.53 (m, 4H), 2.47-
13
.32 (m, 4H), 2.25-2.06 (m, 3H), 1.76-1.48 (m, 11H); C NMR (75 MHz, CDCl
3
) δ 174.1, 169.8,
68.5, 151.0, 144.6, 135.8, 134.7, 134.6, 130.4, 130.1, 129.8, 129.2, 128.6, 128.5, 128.4, 127.4,
127.1, 124.9, 122.9, 119.0, 118.7, 115.7, 84.8, 67.6, 66.2, 66.0, 63.7, 62.9, 52.8, 45.8, 42.7, 37.0,
+
2
7
8.3, 28.1, 23.8, 22.0, 21.7, 21.5, 8.9; HRMS (ESI-TOF) m/z: [M + H] Calcd for C38
H
43
N
2
10
O S
19.2638; found 719.2627.
2
9
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