Development of a β-C-H Bromination Approach toward the Synthesis of Jerantinine e

Article abstract of DOI:10.1021/acs.joc.7b01095

The development of an asymmetric and highly convergent three-component synthesis of the functionalized ABC ring system of the Aspidosperma alkaloid jerantinine E is reported. The presented synthetic strategy relies on our recently developed method for the one-pot β-C-H bromination of enones, which allows for rapid construction of the tricyclic tetrahydrocarbazolone core via a palladium-catalyzed amination and oxidative indole formation. Moreover, a secondary amine building block that contains all carbon atoms of the D and E ring of the natural product could be installed in three additional steps.

Full text of DOI:10.1021/acs.joc.7b01095

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Article
Development of a #-C–H Bromination Approach
Towards the Synthesis of Jerantinine E
Tatjana Huber, Teresa A. Preuhs, Christa K. G. Gerlinger, and Thomas Magauer
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Jun 2017
Downloaded from http://pubs.acs.org on June 16, 2017
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Development of a β-C–H Bromination Approach Towards the Syn-
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thesis of Jerantinine E
Tatjana Huber,1,† Teresa A. Preuhs,1,† Christa K. G. Gerlinger,2 and Thomas Magauer*,1,3
1Department of Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany. 2Faculty of Chemistry, University of
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Konstanz, 78457 Konstanz, Germany. Institute of Organic Chemistry and Center for Molecular Biosciences, University of
Innsbruck, 6020 Innsbruck, Austria.
*E-mail: thomas.magauer@uibk.ac.at
ABSTRACT: The development of an asymmetric and highly convergent three-component synthesis of the functionalized ABC
ring system of the Aspidosperma alkaloid jerantinine E is reported. The presented synthetic strategy relies on our recently devel-
oped method for the one-pot β-C–H bromination of enones, which allows for rapid construction of the tricyclic tetrahydrocarbazo-
lone core via a palladium-catalyzed amination and oxidative indole formation. Additionally, a secondary amine building block that
contains all carbon atoms of the D and E ring of the natural product could be installed in further three steps.
Introduction
Monoterpenoid indole alkaloids have been attractive targets for synthetic chemists for several decades and many of their unique
skeletons have been synthesized in the past.1 In addition to their daunting structural complexity, a variety of biological activities
and medicinal applications have been reported, including anticancer (e.g. jerantinine E, vinblastine, brucine)2 and insecticidal (e.g.
aspidophytine)3 activities (Figure 1A). The Aspidosperma alkaloid subfamily consists of more than 250 different members and
biosynthetically originates from the condensation of tryptamine with a rearranged secologanin-derived C9 or C10 terpene unit.4 The
secondary metabolites jerantinine A–G (Figure 1B) were isolated in 2008 from leaf extracts of the Malayan plant Tabernaemontana
corymbosa and exhibit cytotoxic effects against vincristine-sensitive and vincristine-resistant epidermoid carcinoma cell lines (IC50
= 0.68–2.55 µM).2a In 2013, Waser reported the first synthesis of the Aspidosperma alkaloid jerantinine E (1) in 17 steps,5 and dis-
closed its antiproliferative activity against several human-derived breast and lung cancer cell lines (IC50 = 1.0−6.0 M) mediated by
inhibition of tubulin polymerization.
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Figure 1. A) Naturally occurring indole alkaloids and B) structures of jerantinines A−G
In the course of our studies towards novel methods for the site-selective functionalization of ,-unsaturated compounds,6 we iden-
tified several monoterpenoid indole alkaloids that could be retrosynthetically traced back to a β-halogenated enone. Despite signifi-
cant advances made in the functionalization of ,-unsaturated compounds in recent years,7 only two examples for the direct -
halogenation of enones are known.8 The syntheses of Aspidosperma alkaloids by Desmaële9 and Qiu10 both require multistep se-
quences relying on prefunctionalized vinylogous thioesters for the preparation of the crucial β-enaminone subunit common to sev-
eral Aspidosperma alkaloids (Scheme 1A). We could circumvent these rather inefficient transformations by our two-step sequence
starting from simple enones (Scheme 1B). Herein, we describe a convergent synthesis of the ABC ring system of the oxygenated
indole alkaloid jerantinine E (1) employing our recently developed protocol for the one-pot β-C−H bromination of enones.6
Scheme 1. Methods for the Preparation of Functionalized β-Enaminones for the Synthesis of Aspidosperma alkaloids
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Results and Discussion
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Our retrosynthetic analysis of 1 was guided by the proposed use of β-bromo enone 11 (Figure 1B) as a general entry to polycyclic
indole alkaloids. Identification of this subunit in jerantinine E (1) inspired the strategy illustrated in Scheme 2A. In our analysis,
tetracycle 12 would to arise from the sequential diastereoselective alkylation of the tetrahydrocarbazolone 13 with iodide 14 and
ethyl iodide. For the construction of the D-ring of 1, we envisioned a sequence that would be initiated by the reduction of the ketone
and subsequent acid-mediated elimination of the alcohol followed by in situ addition of the free amine to the resultant vinylogous
iminium ion 19 (Scheme 2B).11 The tetrahydrocarbazolone 13 was traced back to 3,4-dimethoxyaniline (15) and β-bromo enone 16
which in turn could be accessed via β-C−H bromination of the parent enone.
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Scheme 2. A) Initial Retrosynthetic Analysis of Jerantinine E (1) and B) Envisioned Cascade Reaction for the Construction
of the D-Ring
In an initial attempt to synthesize jerantinine E (1), we targeted racemic intermediate 12. The synthesis started with our previously
reported preparation of tetrahydrocarbazolone rac-13, prepared in 3 steps from enone 21 utilizing a β-C–H bromination, a palladi-
um-catalyzed amination with 3,4-dimethoxyaniline (15), and oxidative indole formation (Scheme 3).6 Finally, tetrahydrocarbazo-
lone rac-13 was Boc-protected to give 22 in good yield (88%). To examine the introduction of secondary amine 14, we performed
first alkylation with 1-chloro-3-iodopropane as a model electrophile. Treatment of 22 with lithium bis(trimethylsilyl)amide
(LHMDS) and an excess of 1-chloro-3-iodopropane followed by nucleophilic displacement of the chloride provided azide 23. Un-
fortunately, alkylation of 23 by treatment with LHMDS and ethyl iodide did not give the desired product. Instead, the elimination of
the benzyl ether to give alkene 24 was observed,12 which was prone to aromatization upon exposure to traces of acid.
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Scheme 3. Synthesis of Tetrahydrocarbazolone 22 and Alkylation with a Model Electrophile
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Since 23 underwent undesired elimination under basic alkylation conditions, we contemplated exchange of the CH2OBn moiety for
a protected hydroxy group in γ-position of the enone. Our revised retrosynthetic analysis featured the synthesis of a modified,
asymmetric tetrahydrocarbazolone core structure which could be constructed from 3,4-dimethoxyaniline (15), secondary amine
building block 14 and enantiopure β-bromo enone 27 (Scheme 4). The stereocenter of the latter component was planned to direct
the sequential introduction of the side chains and enable the asymmetric total synthesis of jerantinine E (1).
Scheme 4. Revised Retrosynthetic Analysis of Jerantinine E (1)
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We began our endeavor with the synthesis of known chiral alcohol 29, itself derived from 1,4-cyclohexanedione monoethylene
acetal (28) in four steps.13 Protection of 29 as its para-methoxybenzyl ether (PMB) using Dudley’s reagent II (2-(4-
methoxybenzyloxy)-4-methylquinoline)14 furnished 30. Enone 30 was then subjected to our conditions for one-pot β-C−H bromina-
tion, which includes (1) Umpolung of the enone by hydrazone formation with tert-butyl carbazate (tert-butoxycarbonyl hydrazide),
(2) selective β-C−H bromination with N-bromosuccinimide (NBS) followed by addition of triethylamine to isomerize the allyl
bromide and (3) hydrolysis of the hydrazone moiety, to afford 27 in 57% yield on a 340 mg scale (Scheme 5). Palladium-catalyzed
amination with 3,4-dimethoxyaniline (15) employing Buchwald’s SPhos 2nd generation precatalyst15 followed by an oxidative in-
dole formation16 using palladium acetate and copper acetate furnished 32. It is noteworthy that careful monitoring of the C−H acti-
vation reaction proved to be crucial to avoid over-oxidation and subsequent hydrolysis of the PMB ether with extended reaction
times. Benzyl protection of the tetrahydrocarbazolone 32 provided 33,17 whose structure could be validated by single-crystal X-ray
diffraction.18
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Having developed a short and efficient synthesis of key intermediate 33, the stage was set for the installation of the quaternary
stereocenter as the crucial handle to construct the DE ring system of jerantinine E (1). However, in sharp contrast to the results
obtained for the alkylation of 22, direct alkylation of 33 with ethyl iodide was not feasible under a variety of conditions. The use of
LHMDS, LDA or LDA/HMPA only led to recovered starting material. The exact influence of the substituent at the γ-position of the
ketone and the protecting groups (Bn and PMB) on the alkylation is unclear.
Scheme 5. Synthesis of Tetrahydrocarbazolone 33
To overcome this poor reactivity, we investigated the acylation of 33. Surprisingly, exposure of 33 to LHMDS and Mander’s rea-
gent19 (methyl cyanoformate) at –78 °C followed by alkylation with sodium hydride and ethyl iodide, proceeded cleanly and fur-
nished 34 in good yields (Scheme 6). Next, we attempted to convert 34 to 35 by means of a decarboxylation using lithium chloride
in aqueous dimethylformamide and subsequent reaction using acrylonitrile as a reactive model electrophile. Although traces of the
decarboxylated product were observed, we were unable to detect any of the conjugate addition product.
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Scheme 6. Attempted Formation of the Quaternary Stereocenter
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Based on the successful alkylation of the β-keto ester with ethyl iodide, we decided to investigate the alkylation of 33 using iodide
14. Thus, the Boc-protected amine building block 14 was synthesized as illustrated in Scheme 7A. Alkylation of commercially
available tert-butyl N-allylcarbamate (36) with literature known iodide 37 under standard conditions (NaH, DMF) afforded 38 in
good yield (80%).20 Hydroboration of 38 with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by oxidative workup using aqueous
hydrogen peroxide furnished alcohol 39. The latter was then transformed into iodide 14, employing Appel's conditions (I2, PPh3,
imH). With iodide 14 and tricyclic key intermediate 33 in hand, we were poised to examine the challenging fragment coupling.
Acylation of 33 followed by reaction of the β-keto ester with sodium hydride and iodide 14 furnished the quaternary stereocenter in
40 in good yield (Scheme 7B). Thus, the introduction of the secondary amine building block could be accomplished in an efficient
manner. The methyl ester of 40 could then be transformed to the ethyl group of the natural product at a later stage of the synthesis.
Scheme 7. A) Preparation of the Boc-Protected Amine Building Block 14 and B) Introduction of the Quaternary Stereocen-
ter
For the construction of the D-ring of 1 (see Scheme 1B), we first tried to selectively reduce 40 using sodium borohydride (Scheme
8A). Since these conditions turned out to be ineffective and no conversion was observed, we opted for more forcing conditions. As
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direct reduction of 40 with lithium aluminum hydride could not be considered due to concomitant reduction of the Boc protecting
group, 40 was treated with 4 M hydrochloric acid in 1,4-dioxane to remove the Boc protecting group (Scheme 8B). Unfortunately
under these conditions, deprotection of the Boc group and elimination of the PMB ether occurred, giving compound 42 as the major
product. Exposure of the crude reaction mixture to lithium aluminium hydride followed by treatment with either 1 M aqueous hy-
drochloric acid or Rochelle’s salt did not afford any detectable amounts of tetracycle 43. Attempts to remove the Boc group under
basic conditions (K2CO3, DMSO/H2O, 65 °C; DIBAL-H, CH2Cl2, 23 °C) without affecting the PMB group were unsuccessful and
only complex product mixtures were obtained.
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Scheme 8. Attempted Closure of the D-Ring of Jerantinine E
In order to avoid these undesired pathways in the functionalization of 40, we decided to replace the methyl with an allyl ester, and
set the quaternary stereocenter in a subsequent diastereoselective palladium-catalyzed decarboxylative allylation reaction.21 The
obtained allyl group could then be converted to the ethyl group in further three steps.22 We anticipated that stereochemical outcome
of the allylation step could to be controlled by the stereocenter at C16. To obtain the desired stereochemistry in the decarboxylative
allylation reaction, we prepared ent-33 according to the route described above.23
For the incorporation of the allyl ester, we examined the conditions shown in Table 1. Initially, the acylation reaction of ent-33
with sodium hydride (1.1 equiv) and commercially available allyl chloroformate (1.2 equiv) at –78 °C resulted in no product for-
mation. Surprisingly, treatment of ent-33 with lithium diisopropylamide (LDA, 1.2 equiv) and allyl chloroformate (1.2 equiv) re-
sulted in the formation of the di-acylated product 45 (entry 2). Extensive screening using a variety of lithium amide bases and allyl
chloroformate or allyl 1H-imidazole-1-carboxylate failed to provide β-keto ester 44 and only formation of the di-acylated product
was observed (entry 3–7). Based on our previous findings that acylation of 44 works best with methyl cyanoformate, we investigat-
ed the use of allyl cyanoformate. This modification resulted in the formation of β-keto ester 44 for the first time (entry 8, 42%).
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Further optimization of the reaction conditions by variation of lithium amide bases and solvents revealed that the use of LHMDS
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(1.5 equiv) in the presence of hexamethylphosphoramide (HMPA, 2 equiv) is crucial to reproducibly obtain 44 in good yield (70%).
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Table 1. Screen of Conditions for the Acylation of ent-29a
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entry base
X
product: yieldb
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CN 44: 42%
CN 44: 62%
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LHMDS
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LHMDS, HMPA CN 44: 70%
aAll reactions were performed on a 0.02 mmol scale in THF (c = 0.02 M) with 1.1–1.2 equiv of base and 1.2 equiv of electrophile.
bYields of isolated products. The reaction was performed at 0 °C. The reactions were monitored by H NMR spectroscopy. The
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yields were not determined. 2 equiv of HMPA were used as additive. LiTMP = lithium 2,2,6,6-tetramethylpiperidide, LTBTA =
lithium tert-butyltritylamide, im = 1-imidazoyl.
Finally, treatment of 44 with LHMDS, HMPA and iodide 14 resulted in the smooth formation of β-keto ester 46 (Scheme 9). Oth-
er alkylation conditions explored (Cs2CO3, MeCN; NaH, DMF; KHMDS, THF) were inferior. Unfortunately, initial attempts to
induce the palladium-catalyzed decarboxylative allylation reaction (Pd(PPh3)4 or Pd2(dba)3, (S)-t-Bu-PHOX)24 only resulted in
decarboxylation without incorporation of the allyl group. A more exhaustive screen of ligands is currently under way in our labora-
tories and should ultimately allow us to complete the total synthesis of jerantinine E.
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Scheme 9. Successful Alkylation with Building Block 14
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Conclusion
We have reported a synthetic route towards the total synthesis of the Aspidosperma alkaloid jerantinine E (1). The presented strat-
egies rely on an efficient one-pot β-C–H bromination protocol to provide the C-ring subunit of the target structure. A palladium-
catalyzed amination reaction was used to further functionalize the β-bromo enones and oxidative indole formation enabled for-
mation of the tricyclic ABC tetrahydrocarbazolone fragment of jerantinine E (1). Our initial strategy to construct the functionalized
tricyclic key intermediate of the natural product was hampered by the base-mediated elimination of the benzyl ether at C16 of the
C-ring. Starting from a γ-hydroxylated enone instead, we were able to prepare highly functionalized precursor 46. The overall se-
quence to the functionalized tetrahydrocarbazolone core of 1 proceeds in eleven linear steps from commercially available ketone 28
and the secondary amine component 14. The latter contains all carbon atoms of the D and E rings of the natural product. The pre-
sented strategy is amenable to rapid modification to give a variety of tetrahydrocarbazolone structural motifs.
Experimental Section
General Methods. All reactions were performed in oven-dried or flame-dried glassware fitted with rubber septa under a positive pressure of
argon unless otherwise stated. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from benzophenone and sodium prior to use.
Dichloromethane (CH2Cl2), triethylamine (NEt3), and N,N-diisopropylamine (DIPA) were distilled from CaH2 prior to use. Commercially
available N-bromosuccinimide (NBS) was purified by recrystallization from water.25 All other reagents and solvents were purchased from
commercial suppliers and were used without further purification. The reactions were magnetically stirred and monitored by NMR spec-
troscopy or analytical thin-layer chromatography (TLC). The TLC plates were visualized by exposure to ultraviolet light (UV, 254 nm)
and exposure to either an aqueous solution of ceric ammoniummolybdate (CAM) or an aqueous solution of potassium permanganate
(KMnO4) followed by heating with a heat gun. 1H NMR and 13C NMR spectra were measured in CDCl3 or CD2Cl2. Proton chemical shifts
are expressed in parts per million (δ scale) and are calibrated using residual undeuterated solvent as an internal reference. Additionally to
1H and 13C NMR measurements, 2D NMR techniques such as homonuclear correlation spectroscopy (COSY), heteronuclear single quan-
tum coherence (HSQC) and heteronuclear multiple bond coherence (HMBC) were used to assist signal assignment. Infrared (IR) spectra
were recorded on an FT-IR spectrometer. IR data is reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were
obtained by electrospray ionization (ESI) or electron ionization (EI) using a sector field mass spectrometer. Melting points (M.p.) were
determined on a B-450 melting point apparatus from BÜCHI Labortechnik AG. Optical rotations were recorded on a Perkin Elmer 241 or
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Anton Paar MCP 200 polarimeter with a sodium lamp and are reported as follows: [훂]퐓퐃[°퐂](c [g/100 mL], solvent). X-ray structural anal-
yses were performed on a diffractometer using Mo-Kα radiation (λ = 0.71073 Å, graphite monochromator).
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Preparation of Azide 19
N-Boc-tetrahydrocarbazolone 22. To a solution of tetrahydrocarbazolone rac-136 (80 mg, 0.22 mmol, 1 equiv) in tetrahydrofuran (2.74
mL) was added sodium hydride (13 mg, 0.3 mmol, 1.5 equiv, 60% dispersion in mineral oil) at 0 °C. After 30 min, di-tert-butyl dicar-
bonate (72 mg, 0.3 mmol, 1.5 equiv) was added and the solution was allowed to warm to 23 °C. After 1.5 h, the solution was diluted with
saturated aqueous ammonium chloride solution (10 mL) and diethyl ether (10 mL). The layers were separated and the aqueous layer was
extracted with diethyl ether (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10
mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude
product was purified by flash column chromatography on silica gel (40% ethyl acetate in hexanes) to afford 22 as a white solid (90 mg,
88%). TLC (25% ethyl acetate in hexane): Rf = 0.38 (UV, CAM). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.71 (s, 1H), 7.34–7.24 (m,
5H), 4.60 (d, J = 12.1 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.09–4.02 (m, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.78 (dd, J = 9.2, 3.8 Hz, 1H), 3.62
(app t, J = 9.1 Hz, 1H), 2.72 (ddd, J = 17.4, 14.4, 5.2 Hz, 1H), 2.52–2.42 (m, 2H), 2.33–2.22 (m, 1H), 1.67 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 196.0, 149.7, 149.4, 147.9, 147.6, 138.1, 130.3, 128.5, 127.9, 127.9, 118.6, 117.9, 102.9, 99.3, 85.5, 73.2, 69.4, 56.3, 56.2, 34.8,
33.9, 28.2, 25.4. IR (Diamond-ATR, neat) ṽmax: 2937, 1736, 1660, 1550, 1493, 1475, 1453, 1369, 1307, 1251, 1209, 1134 cm−1. HR-MS
(EI): calcd for (C27H31O6N)+: 465.2146, found: 465.2150.
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Azide 23. N-Boc-tetrahydrocarbazolone 22 (12 mg, 0.026 mmol, 1 equiv) was dissolved in tetrahydrofuran (0.3 mL) and 1-chloro-3-
iodopropane (21.1 mg, 0.10 mmol, 4.00 equiv) was added. The solution was cooled to 0 °C and a solution of lithium
bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 36 µL, 0.036 mmol, 1.40 equiv) was added dropwise over 6 min. After 2 h, the reaction
mixture was allowed to warm to 23 °C. After 1 h, the reaction mixture was diluted with diethyl ether (5 mL), one drop of acetic acid was
added and the resulting suspension was filtered through a fritted glass funnel (Por. 4). The filter cake was rinsed with diethyl ether (10
mL). The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel (20% ethyl acetate in
hexanes) to afford the chloride as a colorless oil (8.8 mg, d:r = 5:1). No separation of the two diastereomers could be achieved and the
diastereomeric mixture was used for the next step.
The chloride was dissolved in N,N-dimethylformamide (0.16 mL) and sodium azide (5.3 mg, 0.08 mmol, 5.00 equiv) was added. The
reaction mixture was stirred at 50 °C for 2 h and then the temperature was increased to 75 °C. After 5 h, heating was ceased and the reac-
tion mixture was diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with
ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), the washed
solution was dried over sodium sulfate and the dried solution was filtered. The filtrate was concentrated. The crude product was purified by
flash column chromatography on silica gel (25% ethyl acetate in hexanes) to afford 23 as a yellow oil (7.5 mg, 53% over 2 steps, d.r. =
5:1). The major diastereomer could be separated by flash column chromatography. TLC (25% ethyl acetate in hexanes): Rf = 0.48 (UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.70 (s, 1H), 7.37–7.25 (m, 5H), 4.63 (d, J = 12.2 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H),
4.09–4.04 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.80 (dd, J = 9.1, 3.9 Hz, 1H), 3.63 (t, J = 9.1 Hz, 1H), 3.33 (t, J = 7.0 Hz, 2H), 2.67 (ddd, J
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= 17.9, 8.3, 4.7 Hz, 1H), 2.52 (ddd, J = 13.4, 4.7, 2.1 Hz, 1H), 2.11–1.99 (m, 2H), 1.76–1.70 (m, 2H), 1.67 (s, 9H), 1.48–1.43 (1H). 13C
NMR (100 MHz, CDCl3) δ 197.4, 149.7, 148.8, 147.9, 147.6, 138.0, 130.5, 128.6, 128.0, 128.0, 118.7, 117.8, 102.8, 99.4, 85.6, 73.3, 69.5,
56.3, 56.2, 51.9, 41.5, 35.2, 31.1, 28.2, 26.9, 26.7. IR (Diamond-ATR, neat) ṽmax: 2930, 2096, 1737, 1654, 1476, 1371, 1309, 1206, 1141,
1105 cm−1. HR-MS (ESI): calcd for (C30H37O6N4)+ (M+H)+: 549.2713, found: 549.2706.
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Preparation of Tetrahydrocarbazolone 33
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(S)-4-[(4-Methoxyphenyl)oxy]cyclohex-2-en-1-one (30). To a suspension of (S)-4-hydroxycyclohex-2-en-1-one (29)26 (2.30 mg, 20.5
mmol, 1 equiv), magnesium oxide (1.66 g, 41.0 mmol, 2.00 equiv, vacuum-dried) and Dudley reagent II14 (11.5 g, 41.0 mmol, 2.00 equiv)
in α,α,α-trifluorotoluene (200 mL) was added dropwise methyl triflate (4.64 mL, 41.0 mmol, 2.00 equiv) at 0 °C. Upon completion of the
addition, the reaction mixture was allowed to warm to 23 °C. After 75 min, ethyl acetate (40 mL) was added and the suspension was fil-
tered through a fritted glass funnel. The filter cake was rinsed with ethyl acetate (2×20 mL). The filtrate was washed with water (50 mL)
and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residual
yellow oil was purified by flash column chromatography on silica gel (9% to 14% ethyl acetate in hexanes) to afford 30 as a colorless oil
(2.60 mg, 55%). The obtained characterization data were in full agreement with those values reported in the literature.27
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(S)-3-Bromo-4-[(4-methoxyphenyl)oxy]cyclohex-2-en-1-one (27). (S)-4-[(4-Methoxyphenyl)oxy]cyclohex-2-en-1-one (30) (340 mg,
1.46 mmol, 1 equiv) was added to a mixture of sodium sulfate (643 mg, 4.53 mmol, 3.10 equiv) and tert-butyl carbazate (203 mg, 1.54
mmol, 1.05 equiv) in degassed 1,2-dichloroethane (1.2 mL) in a pressure flask. The resulting suspension was heated to 85 °C. After 4.5 h,
the orange mixture was allowed to cool to 23 °C. Dichloromethane (4.4 mL) was added, the solution was cooled to 0 °C and recrystallized
N-bromosuccinimide (274 mg, 1.54 mmol, 1.05 equiv) was added. After 1 h at 0 °C, triethylamine (427 μL, 3.07 mmol, 2.10 equiv) was
added in one portion. The resulting orange solution was stirred for 24 h at 23 °C. Acetone-water (v/v = 9:2, 6.1 mL) and Amberlyst 15
(1.76 g) were added and the yellow suspension was heated to 50 °C. After 12 h, the reaction mixture was allowed to cool to 23 °C and then
was diluted with dichloromethane (3 mL). The crude mixture was dried over sodium sulfate, the dried solution was filtered and the filtrate
was concentrated. The residual yellow oil was purified by flash column chromatography on silica gel (14% ethyl acetate in hexanes) to
afford 27 as a yellow oil (261 mg, 57%). TLC (20% ethyl acetate in hexane): Rf = 0.32 (UV, CAM). 1H NMR (400 MHz, CDCl3) δ 7.36–
7.31 (m, 2H), 6.94–6.87 (m, 2H), 6.48 (s, 1H), 4.68 (s, 2H), 4.26 (t, J = 4.7 Hz, 1H), 3.81 (s, 3H), 2.72–2.61 (m, 1H), 2.36 (dt, J = 16.9, 5.6
Hz, 1H), 2.23–2.14 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 195.9, 159.7, 149.4, 133.8, 129.8, 129.4, 114.0, 76.0, 72.6, 55.4, 33.2, 28.0.
IR (Diamond-ATR, neat) ṽmax: 2934, 2836, 1682, 1611, 1513, 1464, 1331, 1302, 1278, 1247, 1174, 1084 cm-1. HR-MS (EI): calcd for
79
(C14H15 BrO3)+: 310.0199, found: 310.0200. [훼]25089 = –46.4 (c = 1.0 ∙ 10 g ∙ mL−1, CH2Cl2).
Enaminone 31. To an oven-dried pressure tube were added chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-
biphenyl-2-yl) palladium(II) (126 mg, 0.18 mmol, 0.10 equiv), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (72 mg, 0.18 mmol,
0.10 equiv), sodium tert-butoxide (252 mg, 2.63 mmol, 1.50 equiv), 3,4-dimethoxyaniline (15) (402 mg, 2.63 mmol, 1.50 equiv) and tolu-
ene (12 mL). (S)-3-Bromo-4-[(4-methoxyphenyl)oxy]cyclohex-2-en-1-one (27) (545 mg, 1.75 mmol, 1 equiv) was added and the dark red
suspension was heated to 80 °C for 18 h. The reaction mixture was allowed to cool to 23 °C and was filtered through a short plug of celite.
The filter cake was rinsed with dichloromethane (30 mL). The filtrate was concentrated and the residual red oil was purified by flash col-
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umn chromatography on silica gel (1% methanol in dichloromethane) to afford 31 as a brown foam (474 mg, 77%). TLC (2% methanol in
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dichloromethane): Rf = 0.22 (UV, CAM). H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.3 Hz, 2H), 6.98 (s, 1H), 6.94 (d, J = 8.3 Hz, 2H),
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6.80 (d, J = 8.5 Hz, 1H), 6.69 (dd, J = 8.5, 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.39 (s, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 11.2
Hz, 1H), 4.41 (dd, J = 11.4, 4.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.60–2.40 (m, 2H), 2.34 (ddd, J = 17.2, 13.4, 4.6 Hz, 1H),
1.99 (qd, J = 11.9, 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.1, 162.0, 159.9, 149.5, 147.3, 130.7, 129.9, 129.1, 116.8, 114.3, 111.5,
108.5, 97.9, 74.1, 71.4, 56.2, 56.1, 55.5, 35.1, 27.7. IR (Diamond-ATR, neat) ṽmax: 3250, 2393, 1611, 1581, 1500, 1463, 1235, 1196, 1172,
1026 cm−1. HR-MS (EI): calcd for (C22H25NO5)+: 383.1727, found: 383.1727. [훼]25089 = +12.8 (c = 0.31 ∙ 10 g ∙ mL−1, CH2Cl2).
Tetrahydrocarbazolone 32. A solution of enaminone 31 (485 mg, 1.26 mmol, 1 equiv) in N,N-dimethylformamide (16 mL) was added to
an oven-dried pressure tube containing palladium(II) acetate (28.4 mg, 0.13 mmol, 0.10 equiv), copper(II) acetate (689 mg, 3.79 mmol,
3.00 equiv) and potassium carbonate (524 mg, 3.79 mmol, 3.00 equiv). The resulting green-brown mixture was placed in a preheated oil
bath at 140 °C. After 1 h, the reaction mixture was allowed to cool to 23 °C and the dark solution was filtered through a short plug of
celite. The filter cake was rinsed with dichloromethane (40 mL). The filtrate was concentrated. The residual black oil was purified by flash
column chromatography on silica gel (50% to 66% ethyl acetate in hexanes) to afford 32 as a grey solid (275 mg, 57%). TLC (1% metha-
nol in dichloromethane): Rf = 0.12 (UV, CAM). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 6.89 (d,
J = 8.3 Hz, 2H), 6.83 (s, 1H), 4.88 (dt, J = 8.8, 3.2 Hz, 1H), 4.75 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H),
3.80 (s, 3H), 2.75 (dt, J = 15.5, 4.0 Hz, 1H), 2.60–2.46 (m, 2H), 2.29–2.10 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 193.7, 159.6, 148.7,
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147.8, 146.9, 130.1, 129.8, 129.7, 117.5, 114.2, 112.8, 103.1, 94.8, 71.0, 70.8, 56.3, 56.2, 55.4, 36.3, 30.5. IR (Diamond-ATR, neat) ṽmax
:
3294, 2949, 1626, 1585, 1540, 1513, 1466, 1340, 1295, 1247, 1135 cm-1. HR-MS (EI): calcd for (C22H23NO5)+: 381.1571, found:
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381.1570. M.p. 196−199 °C. [훼]
= –1.4 (c = 1.0 ∙ 10 g ∙ mL−1, CH2Cl2).
N-Benzyltetrahydrocarbazolone 33. Tetrahydrocarbazolone 32 (203 mg, 0.532 mmol, 1 equiv) was dissolved in N,N-dimethylformamide
(2.7 mL) and the solution was cooled to 0 °C. Sodium hydride (25.5 mg, 0.639 mmol, 1.20 equiv, 60% dispersion in mineral oil) was
added and the suspension was stirred for 1 h at 0 °C. Benzyl bromide (76 µL, 0.639 mmol, 1.20 equiv) was added and the reaction mixture
was allowed to warm to 23 °C. After 2 h, saturated aqueous ammonium chloride solution (5 mL) and ethyl acetate (5 mL) were added, the
layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with
saturated aqueous sodium chloride solution (10 mL), the washed solution was dried over sodium sulfate and the dried solution was filtered.
The filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (60% ethyl acetate in hexanes)
to afford 33 as a slightly beige solid (224 mg, 89%). Crystals that were suitable for X-Ray diffraction analysis were obtained by crystalliza-
1
tion from dichloromethane. TLC (50% ethyl acetate in hexanes): Rf = 0.22 (UV, KMnO4). H NMR (400 MHz, CD2Cl2) δ 7.67 (s, 1H),
7.27–7.22 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.95 (dd, J = 6.7, 2.8 Hz, 2H), 6.84–6.76 (m, 2H), 6.64 (s, 1H), 5.22 (q, J = 16.7 Hz, 2H), 4.76
(t, J = 3.6 Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 4.43 (d, J = 11.1 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 2.88 (ddd, J = 16.4, 11.8,
4.4 Hz, 1H), 2.57–2.49 (m, 1H), 2.41 (dt, J = 16.6, 4.2 Hz, 1H), 2.26 (ddt, J = 15.0, 11.7, 4.0 Hz, 1H). 13C NMR (100 MHz, CD2Cl2) δ
194.2, 160.0, 148.7, 147.8, 146.7, 137.1, 132.1, 130.3, 130.2, 129.3, 128.1, 126.7, 117.6, 114.3, 113.7, 103.8, 94.4, 71.1, 67.5, 56.6, 56.5,
55.8, 47.9, 34.3, 27.9. IR (Diamond-ATR, neat) ṽmax: 2943, 1700, 1647, 1558, 1540, 1513, 1483, 1444, 1303, 1270, 1248, 1173, 1106
cm−1. HR-MS (ESI): calcd for (C29H29NO5)+: 471.2046, found: 471.2054. M.p. 139−144 °C. [훼]25089 = –6.4 (c = 1.0 ∙ 10 g ∙ mL−1, CH2Cl2).
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Preparation of Tetrahydrocarbazolone 34
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Tetrahydrocarbazolone 34. N-Benzyltetrahydrocarbazolone 33 (49 mg, 0.10 mmol, 1 equiv) in tetrahydrofuran (0.5 mL) was added
dropwise to a solution of lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 0.12 mL, 0.12 mmol, 1.2 equiv) and hexa-
methylphosphoramide (36 µL, 0.20 mmol, 2.0 equiv) in tetrahydrofuran (0.5mL) at –78 °C. After 1 h, methyl cyanoformate (12 µL, 0.15
mmol, 1.5 equiv) was added in one portion and the solution was slowly allowed to warm to 23 °C. After 20 h, the solution was diluted with
saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10
mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude
product was purified by flash column chromatography on silica gel (50% ethyl acetate in hexanes) to afford the β-keto ester as a red oil (40
mg, 73%) containing minor impurities. The β-keto ester was used without additional purification for the next step.
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Sodium hydride (2.5 mg, 62 µmol, 1.5 equiv, 60% suspension in mineral oil) was added a solution of the β-keto ester (22 mg, 41 µmol, 1
equiv) in N,N-dimethylformamide (0.4 mL) at 0 °C. After 1 h, ethyl iodide (13 µL, 0.16 mmol, 4.0 equiv) was added, the reaction flask
was covered with aluminum foil and the reaction mixture was allowed to warm to 23 °C. After 20 h, the reaction mixture was diluted with
saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (3×10 mL). The organic layers were washed with saturated aqueous sodium chloride solution (10 mL) and the
washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product was
purified by flash column chromatography on silica gel (40% ethyl acetate in hexanes) to afford 34 as a brown oil (12 mg, 52%, dr = 4:1).
All characterization data refers to the major diastereomer shown in the scheme. TLC (50% ethyl acetate in hexanes): Rf = 0.40 (UV,
CAM). 1H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.26–7.24 (m, 3H), 7.16–7.11 (m, 2H), 6.98–6.92 (m, 2H), 6.81–6.78 (m, 2H), 6.59 (s,
1H), 5.42–5.29 (m, 2H), 5.21 (dd, J = 7.7, 5.4 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 11.0 Hz, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.76
(s, 3H), 3.66 (s, 3H), 3.05 (dd, J = 13.3, 5.3 Hz, 1H), 2.29 (dd, J = 13.9, 7.5 Hz, 1H), 2.24 (dd, J = 13.2, 7.8 Hz, 1H), 2.09 (dd, J = 14.1, 7.3
Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 189.7, 172.5, 159.6, 148.1, 147.3, 146.2, 136.5, 132.4, 129.8, 128.9,
127.7, 126.3, 117.8, 114.0, 112.7, 103.4, 93.8, 70.5, 68.9, 58.9, 56.3, 55.4, 52.7, 48.3, 36.0, 28.2, 9.4. IR (Diamond-ATR, neat) ṽmax: 2936,
2252, 1726, 1648, 1483, 1441, 1246, 1162, 1029 cm−1, HR-MS (EI): calcd. for (C33H35NO7)+: 557.2408, found: 557.2403.
Synthesis of the Tertiary Amine Building Block 14
((2-Iodoethoxy)methyl)benzene (37). 2-Benzyloxyethanol (5.00 g, 32.9 mmol, 1 equiv) was dissolved in dichloromethane (95 mL) and
triphenylphosphine (12.9 g, 49.3 mmol, 1.50 equiv) and imidazole (3.36 g, 49.3 mmol, 1.50 equiv) were added. Iodine (12.5 g, 49.3 mmol,
1.5 equiv) was carefully added in three portions and the yellow suspension was stirred at 23 °C. After 18 h, aqueous sodium thiosulfate
solution (1 M, 100 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and
the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL). The washed solution was dried over
sodium sulfate and the dried solution was filtered. The filtrate was concentrated. The crude product was purified by flash column chroma-
tography on silica gel (5% ethyl acetate in hexanes) to afford 37 (8.00 g, 93%) as a colorless oil. The obtained characterization data were in
full agreement with those values reported in the literature.20
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Tert-Butyl N-allyl-N-(2-benzyloxyethyl) carbamate (38). Tert-Butyl allylcarbamate (36) (3.14 g, 20.0 mmol, 1 equiv) was dissolved in
N,N-dimethylformamide (66 mL) and was added dropwise to a suspension of sodium hydride (1.20 g, 30.0 mmol, 1.50 equiv, 60% disper-
sion in mineral oil) in N,N-dimethylformamide (100 mL) at 0 °C. After 45 min, ((2-iodoethoxy)methyl)benzene (37) (6.81 g, 26.0 mmol,
1.30 equiv) was added dropwise. The reaction mixture then was allowed to warm to 23 °C. After 16 h, the reaction mixture was carefully
diluted with ammonium chloride solution (200 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200
mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude
product was purified by flash column chromatography on silica gel (10% ethyl acetate in hexanes) to afford 38 as a colorless oil (4.65 g,
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80%). TLC (33% ethyl acetate in hexanes): Rf = 0.83 (UV, CAM). H NMR (400 MHz, CD2Cl2) δ 7.38–7.25 (m, 5H), 5.79 (dddd, J =
17.7, 9.8, 6.0, 5.2 Hz, 1H), 5.15–5.06 (m, 2H), 4.51 (s, 2H), 3.88 (br s, 2H), 3.58 (t, J = 5.9 Hz, 2H), 3.39 (br s, 2H), 1.42 (s, 9H). 13C
NMR (100 MHz, CD2Cl2) δ 155.8, 139.3, 135.2, 128.8, 128.0, 128.0, 116.3, 116.0, 79.8, 73.4, 69.4, 51.3, 50.7, 46.9, 28.7. IR (Diamond-
ATR, neat) ṽmax: 2976, 2930, 2861, 1690, 1477, 1454, 1405, 1365, 1244, 1173, 1150, 1103, 1029 cm−1. HR-MS (ESI): calcd for
(C17H26NO3)+ (M+H)+: 292.1913, found: 292.1909.
Tert-Butyl N-(3-hydroxypropyl)-N-(2-benzyloxyethyl) carbamate (39). Tert-Butyl N-allyl-N-(2-benzyloxyethyl) carbamate (38) (3.1 g,
10.6 mmol, 1 equiv) was dissolved in tetrahydrofuran (5.6 mL) and a solution of 9-borabicyclo[3.3.1]nonane (0.5 M solution in tetrahydro-
furan, 29.8 mL, 14.9 mmol, 1.40 equiv) was added at 0 °C. After 3 h at 0 °C, the reaction mixture was allowed to warm to 23 °C. After 16
h, aqueous sodium hydroxide solution (10 wt.%, 4.9 mL) and aqueous hydrogen peroxide solution (30 wt.%, 4.9 mL) were added dropwise
and the reaction was heated to 50 °C. After 2 h, heating was ceased and the solution was allowed to cool to 23 °C. The reaction mixture
was saturated with sodium carbonate and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were
washed with saturated aqueous sodium chloride solution and the washed solution was dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (33% ethyl acetate
in hexanes) to afford 39 as a colorless oil (1.64 g, 50%). TLC (9% ethyl acetate in hexanes): Rf = 0.10 (UV, KMnO4). 1H NMR (400 MHz,
CDCl3) δ 7.39–7.27 (m, 5H), 4.51 (s, 2H), 3.80 (t, J = 7.1 Hz, 1H), 3.67–3.31 (m, 8H), 1.87–1.59 (m, 2H), 1.42 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 157.1, 138.1, 128.6, 127.9, 127.7, 80.4, 73.3, 68.8, 58.4, 47.3, 43.9, 30.7, 28.5. IR (Diamond-ATR, neat) ṽmax: 3444, 2974,
2866, 1688, 1667, 1479, 1454, 1413, 1366, 1246, 1166, 1139, 1103 cm-1. HR-MS (ESI): calcd for (C17H28NO4)+ (M+H)+: 310.2018, found:
310.2015.
Tert-Butyl N-(3-iodopropyl)-N-(2-benzyloxyethyl) carbamate (14). Iodine (541 mg, 2.13 mmol, 1.20 equiv) was added to a solution of
triphenylphosphine (559 mg, 2.13 mmol, 1.20 equiv) and imidazole (145 mg, 2.13 mmol, 1.20 equiv) in dichloromethane (17.5 mL) at 0
°C. After 15 min, a solution of tert-butyl N-(3-hydroxypropyl)-N-(2-phenoxyethyl) carbamate (39) (550 mg, 1.78 mmol, 1 equiv) in di-
chloromethane (3.5 mL) was added dropwise. Upon completion of the addition, the yellow suspension was allowed to warm to 23 °C.
After 3 h, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL). The layers were separated and the organic layer
was washed with aqueous sodium thiosulfate solution (1 M, 40 mL) and saturated aqueous sodium chloride solution (40 mL). The washed
solution was dried over sodium sulfate, the dried solution was filtered and the filtrate was concentrated. The crude product was purified by
flash column chromatography on silica gel (10% ethyl acetate in hexanes) to afford 14 as a yellow oil (592 mg, 79%). TLC (20% ethyl
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acetate in hexanes): Rf = 0.68 (UV, KMnO4). H NMR (400 MHz, CDCl3) δ 7.41–7.25 (m, 5H), 4.52 (s, 2H), 3.68–3.51 (m, 2H), 3.49–
3.37 (m, 2H), 3.34 (t, J = 7.0 Hz, 2H), 3.18–3.08 (m, 2H), 2.18–1.98 (m, 2H), 1.47 (s, 5H), 1.41 (s, 4H). 13C NMR (100 MHz, CDCl3, ~1:1
rotamer ratio, asterisk denotes signals of the second rotamer) δ 155.6, 138.3, *138.3, 132.5, *132.4, *128.6, 128.6, *127.8, 127.7, 80.0,
*79.8, 73.2, 69.1, *69.0, 49.2, *47.9, 47.6, 40.6, 32.7, *32.5, 28.6, *28.6. IR (Diamond-ATR, neat) ṽmax: 2974, 1671, 1477, 1465, 1454,
1409, 1366, 1241, 1156, 1114 cm−1. HR-MS (ESI): calcd for (C17H27NO3I)+ (M+H)+: 420.1036, found: 420.1034.
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Tetrahydrocarbazolone 40. N-Benzyltetrahydrocarbazolone 33 (50 mg, 0.11 mmol, 1 equiv) was dissolved in tetrahydrofuran (1.1 mL)
and was added dropwise to a solution of lithium diisopropylamide (0.5 M in tetrahydrofuran, 320 µL, 0.16 mmol, 1.50 equiv; freshly
prepared) at –78 °C. After 1 h, methyl cyanoformate (17 µL, 0.21 mmol, 2.00 equiv) was added in one portion and the solution was slowly
allowed to warm to 23 °C. After 14 h, the red solution was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and ethyl
acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic
layers were washed with saturated aqueous sodium chloride solution (10 mL) and the washed solution was dried over sodium sulfate. The
dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel
(50% ethyl acetate in hexanes) to afford β-keto ester as an orange oil (43 mg, d.r. = 2.5:1) which contained minor impurities. The β-keto
ester was used without additional purification for the next step. To a suspension of sodium hydride (4.9 mg, 0.12 mmol, 1.5 equiv, 60%
suspension in mineral oil) in N,N-dimethylformamide (0.4 mL) was added a solution of β-keto ester (43 mg, 0.08 mmol, 1 equiv) in N,N-
dimethylformamide (0.8 mL) at 0 °C. After 30 min, tert-butyl N-(3-iodopropyl)-N-(2-phenoxyethyl) carbamate (14) (136 mg, 0.33 mmol,
4.00 equiv) was added, the reaction flask was covered with aluminum foil and the reaction mixture was allowed to warm to 23 °C. After 20
h, the reaction mixture was diluted with saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL). The layers
were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layers were washed with saturated aqueous
sodium chloride solution (10 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated. The crude product was purified by flash column chromatography on silica gel (25% to 50% ethyl acetate in hexanes) to
afford 40 as a yellow solid (54 mg, 60% over 2 steps). Partial separation of the diastereomeric mixture could be achieved by flash column
chromatography on silica gel (25% ethyl acetate in hexanes). All characterization data refers to the major diastereomer shown in the
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scheme. TLC (50% ethyl acetate in hexanes): Rf = 0.28 (UV, CAM). H NMR (400 MHz, CDCl3, 50 °C) δ 7.79 (s, 1H), 7.34–7.27 (m,
5H), 7.27–7.21 (m, 3H), 7.15–7.11 (m, 2H), 6.96–6.92 (m, 2H), 6.81–6.78 (m, 2H), 6.60 (s, 1H), 5.34 (q, J = 16.5 Hz, 2H), 5.19 (dd, J =
7.9, 5.4 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.51 (s, 2H), 4.44 (d, J = 11.2 Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.63 (s, 3H),
3.64–3.55 (m, 2H), 3.42 (t, J = 5.9 Hz, 2H), 3.36–3.25 (m, 3H), 3.02 (dd, J = 13.2, 5.5 Hz, 1H), 2.28–2.11 (m, 2H), 2.02 (td, J = 13.3, 12.6,
4.7 Hz, 1H), 1.63 (ddt, J = 31.4, 13.1, 6.2 Hz, 2H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3, 50 °C) δ 189.3, 172.5, 159.8, 155.7, 148.4,
147.7, 146.3, 138.7, 136.6, 132.6, 129.9, 128.9, 128.5, 127.7, 126.4, 118.2, 114.2, 112.8, 103.9, 94.4, 79.5, 73.3, 70.5, 69.1, 69.0, 58.4,
56.5, 56.4, 55.5, 52.6, 48.5, 47.4, 36.8, 32.5, 28.7, 28.6. IR (Diamond-ATR, neat) ṽmax: 2935, 1727, 1689, 1658, 1650, 1513, 1494, 1483,
1452, 1365 cm−1. HR-MS (ESI): calcd for (C48H57N2O10)+: 821.4013, found: 821.4008. [훼]25089 = –3.6 (c = 0.5 ∙ 10 g ∙ mL−1, CH2Cl2).
Preparation of Amine 42
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Amine 42. Tetrahydrocarbazolone 40 (13.5 mg, 16.4 µmol, 1 equiv) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M,
0.1 mL) at 23 °C. After 2 h, the reaction mixture was diluted with saturated aqueous potassium carbonate solution (5 mL) and ethyl acetate
(5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were
dried over sodium sulfate, the dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column
chromatography on silica gel (4% to 8% methanol in dichloromethane) to afford 41 (9.6 mg, quant.) which contained minor impurities.
The product was used without additional purification for the next step. HR-MS (ESI): calcd for (C35H39N2O6)+ (M+H)+: 583.2808, found:
583.2805.
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Preparation of Allyl Cyanoformate
Allyl cyanoformate. Trimethylsilyl cyanide (1.98 g, 20.0 mmol, 1 equiv) was added to a suspension of allyl chloroformate (2.41 g, 20.0
mmol, 1 equiv) and 1,4-diazabicyclo[2.2.2]octane (12.30 mg, 0.110 mmol, 0.005 equiv) at 0 °C. The solution was allowed to warm to
23 °C. After 12 h, 1,4-diazabicyclo[2.2.2]octane was removed by filtration to afford allyl cyanoformate as a yellow oil (1.80 g, 81%). The
product was used without further purification for the next step. The obtained characterization data were in full agreement with those values
reported in the literature.28
Preparation of Diacylated Tetrahydrocarbazolone 45
Diacylated tetrahydrocarbazolone 45. N-Benzyltetrahydrocarbazolone 33 (92 mg, 0.19 mmol, 1 equiv) was dissolved in tetrahydrofuran
(2 mL) and was added dropwise to a solution of lithium diisopropylamide (freshly prepared from diisopropylamine (0.036 mL, 0.25 mmol,
1.3 equiv) and n-butyl lithium (2.3 M in hexanes, 0.10 mL, 0.23 mmol, 1.2 equiv)) in tetrahydrofuran (3 mL) at –78 °C. After 1 h, allyl
chloroformate (0.041 mL, 0.39 mmol, 2.0 equiv) was added in one portion. The solution was allowed to warm to 23 °C. After 18 h, the
reaction was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium
chloride solution (10 mL) and dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The crude mate-
rial was purified by flash column chromatography on silica gel (50% ethyl acetate in hexanes) to afford 45 as a yellow oil (30 mg, 24 %).
TLC (50% ethyl acetate in hexanes): Rf = 0.60 (UV, CAM). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.27–7.20 (m, 3H), 7.19–7.10 (m,
2H), 6.87–6.78 (m, 4H), 6.59 (s, 1H), 5.94 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.80 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.36 (dq, J = 17.2, 1.6
Hz, 1H), 5.27–5.02 (m, 5H), 4.79–4.71 (m, 3H), 4.66 (d, J = 11.2 Hz, 1H), 4.64–4.50 (m, 2H), 4.37 (d, J = 11.2 Hz, 1H), 3.94 (s, 3H), 3.80
(s, 3H), 3.77 (s, 3H), 3.28 (dd, J = 14.5, 3.7 Hz, 1H), 2.99 (dd, J = 14.4, 3.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 185.1, 168.4, 168.1,
159.7, 148.4, 147.5, 144.9, 136.0, 132.0, 131.5, 130.5, 128.9, 127.9, 126.1, 118.7, 118.4, 117.6, 113.9, 112.1, 103.4, 93.6, 70.5, 66.8, 66.8,
65.1, 64.8, 56.3, 56.2, 55.4, 47.5, 34.0. IR (Diamond-ATR, neat) ṽmax: 2936, 1731, 1658, 1611, 1542, 1514, 1485, 1443, 1272, 1247, 1164,
1075, 1029 cm−1. HR-MS (ESI): calcd for (C37H38NO9)+ (M+H)+: 640,2547, found: 640.2542.
Preparation of Tetrahydrocarbazolone 46
Tetrahydrocarbazolone 46. N-Benzyltetrahydrocarbazolone ent-33 (10 mg, 0.020 mmol, 1 equiv) was
dissolved in tetrahydrofuran (0.5 mL) and hexamethylphosphoramide (0.040 mL, 0.040 mmol, 2.00 equiv)
was added. A solution of lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 0.30 mL, 0.30 mmol, 1.5
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equiv) was added dropwise at −78 °C. After 1 h, allyl cyanoformate (4.71 mg, 0.04 mmol, 2.00 equiv) was added in one portion. The
solution was allowed to warm to 23 °C. After 13 h, the reaction was diluted with saturated aqueous sodium bicarbonate solution (2 mL)
and ethyl acetate (2 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined
organic layers were washed with saturated aqueous sodium chloride solution (2 mL) and dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The crude material was purified by flash column chromatography on silica gel (50% ethyl acetate
in hexanes) to afford β-keto ester 44 as a beige foam, which contained minor impurities. 44 was used without additional purification for the
next step. To a solution of β-keto ester 44 (12 mg, 0.020 mmol, 1 equiv) and carbamate 7 (36.2 mg, 0.080 mmol, 4.0 equiv) in tetrahydro-
furan (0.5 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 0.04 mL, 0.040 mmol, 2.0 equiv) dropwise over 15
minutes at −78 °C. The solution was allowed to warm to 23 °C. After 12 h, the reaction mixture was diluted with ethyl acetate (2 mL) and
saturated aqueous sodium bicarbonate solution (2 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate
(3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL) and dried over sodium
sulfate. The dried solution was filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography
on silica gel (25% to 50% ethyl acetate in hexanes) to afford 46 as a yellow oil (4.0 mg, 33 % over 2 steps). TLC (50% ethyl acetate in
hexanes): Rf = 0.21 (UV, CAM). Protons of diastereotopic methylene groups are reported as HA and HB, where HA is the more downfield
shifted proton. In cases were resonances overlap or cannot be unambiguously assigned to a single proton or carbon atom, multiple as-
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signments are listed (e.g. the 13C assignment “130.0 (PMB, Bn)” indicates that the resonance at 130.0 is either PMB or Bn). H NMR
(400 MHz, CDCl3,) δ 7.80 (s, 1H, H-4), 7.35−7.27 (m, 4H, Bn), 7.26−7.22 (m, 4H, Bn), 7.16−7.10 (m, 2H, PMB), 6.91−6.89 (m, 2H, Bn),
6.81−6.76 (m, 2H, PMB), 6.59 (s, 1H, H-9), 5.78 (ddt, 3J22/23 = 17.2, 3J22/23 = 10.4, 3J22/21 = 5.5 Hz, 1H, H-22), 5.40 (d, 2JHA/HB = 16.6 Hz,
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1H, Bn), 5.28 (d, 2JHA/HB = 16.6 Hz, 1H, Bn), 5.20−5.06 (m, 3H, H-12, H-23), 4.68 (app t, 2JHA/HB = 11.0 Hz, 1H, PMB), 4.54 (d, J21/22
=
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5.5 Hz, 2H, H-21), 4.51 (s, 2H, Bn), 4.42 (d, JHA/HB = 11.0 Hz, 1H, PMB), 3.94 (s, 3H, H-6), 3.78 (s, 3H, PMB), 3.76 (s, 3H, H-7),
3.63−3.52 (m, 2H, H-19), 3.41 (br s, 2H, H-18), 3.31 (br s, 2H, H-17), 3.03 (t, 3J13/12 = 12.7 Hz, 1H, HA-13), 2.31−2.09 (m, 3H, HB-13, H-
15), 1.66−1.56 (m, 2H, H-16), 1.43 (app d, J = 10.0 Hz, 9H, Boc). 13C NMR (100 MHz, CDCl3, asterisks denotes rotamer peaks) δ 189.3
(C-1), 171.5 (C-20), 159.6 (PMB), 155.7 (Boc), 155.5* (Boc), 148.1 (C-8), 147.3 (C-5), 146.1 (C-11), 145.9* (C-11), 138.5 (Bn), 136.4
(Bn), 132.4 (C-10), 131.7 (C-22), 130.0 (PMB, Bn), 129.8 (PMB, Bn), 129.2 (PMB), 128.9 (Bn), 128.5 (Bn), 127.6 (Bn), 126.2 (Bn),
118.5 (C-3, C-23), 117.7 (C-3, C-23), 114.0 (PMB), 112.7 (C-2), 103.3 (C-4), 93.7 (C-9), 79.5 (Boc), 73.1 (Bn), 70.3 (PMB), 69.0 (C-12),
68.7 (C-19), 65.9 (C-21), 58.3 (C-14), 56.3 (C-6), 56.2 (C-7), 55.4 (PMB), 48.2 (Bn), 47.2 (C-17), 47.0 (C-18), 36.5 (C-13), 32.3 (C-15),
32.1* (C-15), 28.6 (Boc), 24.2 (C-16), 23.7* (C-16). IR (Diamond-ATR, neat) ṽmax: 2932, 1728, 1689, 1513, 1453, 1411, 1365, 1248,
1163, 1103, 1067, 1029 cm−1. HR-MS (ESI): calcd for (C50H59N2O10)+: (M+H)+: 847.4170, found: 847.4155.
ASSOCIATED CONTENT
SUPPORTING INFORMATION
Experimental procedures, X-ray crystallographic data for 33, NMR spectra of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-Mail: thomas.magauer@uibk.ac.at
Author Contributions
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†These authors contributed equally to this work.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We gratefully acknowledge financial support from the Funds of the Chemical Industry (Sachkostenzuschuss and Dozentenpreis to
T. M.), the German Research Foundation (Emmy Noether Fellowship, SFB 749 and SFB TRR 152 to T. M.) and the German Na-
tional Academic Foundation (Fellowship to T. H.). We thank Dr. Peter Mayer (LMU Munich) for X-ray structure analysis and Dr.
Benjamin Marsh, Dr. Klaus Speck and Dr. Bryan Matsuura for helpful discussions during the preparation of this manuscript. We
thank Alexander Schweiger for assistance with the preparation of 33.
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(18) CCDC 1547827 contains the supplementary crystallographic data for compound 33. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/
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(23) Analytical data were in full agreement with those reported for 33.
(24) Gartshore, C. J.; Lupton, D. W Angew. Chem. Int. Ed. 2013, 52, 4113−4116.
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