Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues

Article abstract of DOI:10.1021/acs.joc.0c00125

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.

Full text of DOI:10.1021/acs.joc.0c00125

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Article
Late-Stage Conversion of a Metabolically Labile Aryl Methyl
Ether-Containing Natural Product to Fluoroalkyl Analogs
Jacob Peter Sorrentino, Brett R. Ambler, and Ryan A. Altman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00125 • Publication Date (Web): 19 Mar 2020
Downloaded from pubs.acs.org on March 20, 2020
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Title
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Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to
Fluoroalkyl Analogs
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Authors’ Names and Addresses
Jacob P. Sorrentino,†,@ Brett R. Ambler,†,§,@ Ryan A. Altman†,*
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†Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States
§Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point,
Pennsylvania 19486, United States
@Equal Contributions
Corresponding author’s email address
raaltman@ku.edu
Table of Contents/Abstract Graphic
O
H3C
EtO
N
H
N
H
1 Step
3 Steps
1 Step
CF2H
HBr
OSO2RF
OH
OCH3
5 Steps
2 Steps
1 Step
CF2Me
OCF2H
OCF3
2 Steps
• Metabolically labile Ar–OMe → stable fluoroalkyl analogs
• Sufficient quantities for biological evaluation
R1 = CF3
R1
• Challenge fluorination strategies on natural product-like scaffold
CF2CF3
ABSTRACT
We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogs through
late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short
synthetic sequences exploits a combination of both modern and traditional methods, and demonstrates that
some recently reported methods do not always work as well as desired on a natural product-like scaffold.
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Nonetheless, reaction optimization can deliver sufficient quantities of each target analog for medicinal
chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern
organofluorine transformations, which should encourage the continued search for improved reactions.
Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of
fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based
analog.
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INTRODUCTION
The physicochemical and biophysical perturbations imparted by fluorine and fluorinated
substituents on small molecule therapeutics1–4 have inspired the development of many new synthetic
methods capable of accessing fluorinated functional groups.4–7 However, most of these methods are
demonstrated on simple substrates that lack the complexity of real-life therapeutic candidates. Even fewer
of these methods are demonstrated on natural products and/or natural product-derived scaffolds, which have
a longstanding history for providing therapeutically relevant biological activities.8,9 Thus, the ability to
exploit many of these new methods for developing next-generation fluorinated therapeutics remains, in
many cases, uncertain. To push the limits of and to probe the medicinal chemistry potential of several
recently published methods, we herein test these reactions within the context of natural product-based drug
discovery, and demonstrate that, though not all reactions perform as anticipated, insightful organic
troubleshooting and optimization improves many of these transformations. Further, we demonstrate that
some classical reactions and synthetic sequences still outcompete modern organofluorine transformations,
which should encourage the continued search for new robust and efficient reactions. Overall, this work
provides a roadmap for medicinal chemists and chemical biologists to deliver a series of fluoroalkyl analogs
of a single target molecule through late-stage functionalization.
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Figure 1: Metabolism of Aryl Methyl Ethers
A Metabolism of Aryl Methyl Ethers
H
H
H
H
HO
OH
H
O
H
O
H
O
7
8
9
P450
P450
decomp.
–CH2O
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B Relative Stability Against P450 Mediated O-Dealkylation
F
D
H
F
F
D
D
H
H
O
O
O
>>
>
C Fluorinated Aryl Methyl Ether Mimetics
H3C
N
H
OCF3
OCF2H
CF3
OCH3
CF2H
CF2CF3
CF2CH3
To bridge the gap between methodology and application towards natural product-based drug
development, we selected aryl methyl ethers due to both their presence in many biologically active natural
products,10,11 as well as their well-documented metabolic liabilities.12,13 Specifically, aryl methyl ethers
commonly undergo rapid metabolism in the liver by P450 enzymes leading to short in vivo half-lives.12,13
This three-step mechanism involves: 1) abstraction of a hydrogen atom to generate a radical, 2) oxidation
of the radical to form a formyl hemiacetal, and 3) decomposition to release formaldehyde and phenol
(Figure 1A). To prevent or slow the oxidation of aryl methyl ethers, medicinal chemists have exploited
several strategies, including the substitution of weak C–H bonds with stronger C–D or C–F bonds that can
improve metabolic stability (Figure 1B).2,14,15 In the former case, the replacement of the weaker C–H bond
with stronger C–D bonds slows the initial C–H abstraction, in turn slowing the overall metabolic
process.14,16–18 In contrast, the introduction of fluorinated groups presents P450 enzymes with substructures
that are not subject to the mechanistic steps of the O-dealkylation process, and that might not be recognized
by the P450’s active site.3,19 Such fluorinated substructures might include fluoroalkyl ethers and fluoroalkyl
groups that present considerably distinct properties relative to the methyl ether substructure (Figure 1C).
Even further, considering the metabolic liability and potential for fluoroalkyl groups to stabilize the
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molecule against liver metabolism, the ability to synthetically convert the aryl methyl ether to a series
fluoroalkyl analogs at the late stage of a synthesis (Figure 1) would provide a valuable roadmap for
medicinal chemists to modify therapeutic candidates, including those derived from natural products.
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As a prototypical example, dextromethorphan (DXM) is an aryl methyl ether containing active
pharmaceutical ingredient that acts as a cough suppressant through agonism of the 1 receptor.20–22 This
approved drug bears the aryl methyl ether group that undergoes rapid in vivo metabolism through O-
dealkylation by CYP2D6 21,23 to produce the psychoactive phenolic metabolite dextrorphan (DXO). 21,23
21
This metabolite antagonizes the NMDA receptor and has opioid activity,
which combined cause
dissociative sedation and lead to recreational use, particularly amongst adolescents.24 Thus, for DXM,
introduction of the aforementioned fluoroalkyl groups might deliver analogs bearing improved in vivo
pharmacokinetic properties, as well as minimal abuse potential. Considering the natural product-like
complexity of DXM, the conversion of the parent compound into fluoroalkyl analogs presents a formidable
synthetic challenge on which to test modern synthetic methods. Herein, we present a series of synthetic
strategies for accessing six fluoroalkyl functional groups with an emphasis placed on late-stage
functionalization with minimal steps. In many cases, we exploit recently reported methods that do not
always work as well as desired on this natural product-like scaffold, though through organic chemistry
optimization, sufficient quantities of each target analog can be obtained for biological evaluation. Overall,
this work provides a template for medicinal chemists to follow for delivering a cluster of fluoroalkyl analogs
from a single analog bearing Ar–OH or Ar–OMe groups.
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RESULTS AND DISCUSSION
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Scheme 1: Preparation of Phenol 425
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O
O
O
H3C
N
N
Me
EtO
N
EtO
N
H
H
H
H
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i. NH4OH wash
i. MeOH, Reflux
BBr3
ii. Ac–Cl
K2CO3
DCE, Reflux
ii. Ethyl Chloroformate
NEt3, CHCl3
0 to 70 °C
CH2Cl2, 0 °C to rt
•HBr
OCH3
OCH3
OCH3
3
OH
87% (5 steps)
1
2
4
Considering the goal of delivering fluoroalkyl analogs of DXM in the fewest possible steps, we
exploited a late-stage functionalization strategy as opposed to de novo synthesis of each analog. Considering
the potential incompatibilities of the basic amine with reaction conditions, this group was masked as a
carbamate, which could be reduced back to the tertiary methylamine at a late stage of the synthesis using
LiAlH4. Additionally, this strategy would allow for late-stage installation of alternate substituents of the N-
atom. As such, all analogs in this series were prepared from the commercially available salt, DXM•HBr 1
(Scheme 1). To convert DXM•HBr to the carbamate, we followed a previously published procedure,25 in
which the salt (1) was neutralized with NH4OH, and the free base was reacted with acetyl chloride to
produce amide 2. Cleavage of 2 in refluxing methanol generated a secondary amine, which was
subsequently protected as an ethyl carbamate (3). Finally, O-dealkylation of the methyl ether using BBr3
afforded phenol 4,25 which served as a key synthetic intermediate for all subsequent reaction sequences.
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Scheme 2: Synthesis of Aryl Difluoromethyl Ether Analog 5
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7
O
EtO
N
H
8
“:CF2”
9
Conditions
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OCF2H
5
OH
4
Difluorocarbene Precursor
Conditions
Yield
O
F
KOH
56%
51%
42%
P
F
EtO
EtO
MeCN/H2O, 0 °C to rt
Br
O
F
F
K2CO3
DMF/H2O, 100 °C
ONa
Br
F
Ph3P
O
F
o-Xylene, 90 °C
O
Ar–OCF2H: Several reagents successfully converted phenol 4 to Ar–OCF2H (5) in synthetically
useful yields. These reactions function by generating free “:CF2,” which formally inserts into phenolic O–
–
H bonds by nucleophilic addition of the phenolate to :CF2 to generate Ar–OCF2 and subsequent
protonation. Initial screening on small scales demonstrated that multiple :CF2-generating reagents
performed similarly giving the desired product in 42–56% yield (Scheme 2).26–31 Ultimately, the use of
diethyl bromodifluoromethyl-phosphonate26 delivered Ar–OCF2H 5 in 56% yield.
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Scheme 3: Synthesis of Aryl Trifluoromethyl Ether Analog 6
5
6
TMSCF3, AgOTf, 2-Fluoropyridine
Selectfluor, NFSI, CsF
7
8
PhCF3/PhMe, rt
45% (Inseparable Mixture)
9
CH3
Route A
N
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•2 BF4
N
O
F
1. AgBF4
DCM, rt
2. H2, Pd/C
MeOH, rt
Selectfluor
EtO
N
H
DBH
HF-Pyridine
NaH, CS2
Then MeI
Route C
H/Br
CH2Cl2
–78 to 0 °C
49% (3 steps)
DMF, rt
87%
PhO2S
SO2Ph
N
OCF3
6
O
SMe
OCF2X
F
OH
4
9
NFSI
S
X = F, Br
8
Route B
Me
SF3
Me
SbCl3, Fluolead
Route D
tBu
DCM, 65 °C
54%
Fluolead
BrCF2CO2K
NaH
AgF2, AgF
2,6-Difluoropyridine
F
F
1,4-Dioxane, 60 °C
78%
ACN, rt
25%
O
HO
O
7
Ar–OCF3: Despite the many recently developed strategies to convert phenols to aryl
trifluoromethyl ethers,32–36 few of these methods have been demonstrated on complex natural product-like
substrates. Direct conversion of phenols to aryl trifluoromethyl ethers has been reported utilizing TMSCF3,
silver, and oxidants such as NFSI or Selectfluor.35,37 When applied to DXM-derived phenol 4, these
conditions formed the desired Ar–OCF3 (6, 45% 19F NMR, Scheme 3, Route A); however, the concurrent
formation of ArCF3 derived side products restricted purification.37 Attempts to optimize the reaction (e.g.
adjustment of time, temperature, reagent equivalents, and use of related reagents) were unsuccessful, and
thus, we evaluated other strategies. Subsequent effort explored Ag-mediated decarboxylative fluorination
reactions,34,35 though these sequences also provided only low yields of products (Scheme 3, Route B).
Specifically, alkylation of phenol 4 with potassium bromodifluoroacetate proceeded smoothly to provide
acid 7 (78% yield), which was then subjected to Ag-mediated decarboxylation using SelectFluor II or AgF2
as oxidants and sources of fluorine. Though both systems provided Ar–OCF3 product 6, yields were poor
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(12–25% 19F NMR yield) and difluoromethylether 5 (Ar–OCF2H) was formed as a major side product.
Further, routine optimization of the system, including screening of decarboxylation initiators, fluorinating
reagents, solvents, and temperatures did not improve the yield of 6 beyond 25%.
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Ultimately, oxidative desulfurization-fluorination reactions of methyl xanthates delivered the
desired aryl trifluoromethyl ether.38,39 In practice, reaction of phenol 4 with NaH, CS2, and MeI afforded
methyl xanthate 8 (87% yield), which was subjected to oxidative desulfurization-fluorination using 1,3-
dibromo-5,5-dimethylhydantoin (DBH) and HF-pyridine (Scheme 3, Route C).38,39 This reaction afforded
a mixture of several inseparable products (9), including the desired product (Ar–OCF3), aryl
bromodifluoromethyl ether (Ar–OCF2Br), and aryl bromide adducts derived from both ethers. This
complex mixture of products (9) was resolved to provide the desired Ar–OCF3 product (6) by (1) treating
the mixture with AgBF4 to convert the Ar–OCF2(Br/F) ether to a mixture of desired Ar–OCF3 and the aryl
40
bromide adducts,
and subsequently (2) promoting reductive dehalogenation of the Ar–Br using
Pd/C/H2(g). Ultimately, this sequence afforded desired product 6 in 49% yield over three steps (Scheme 3,
Route C).41 While this strategy delivered an initial batch of material, more modern conditions involving use
of the new Fluolead42 combined with SbCl3 cleanly converted xanthate 8 to Ar–OCF3 6 in 54% yield
(Scheme 3, Route D). These conditions negated the formation of the brominated side products generated
using DBH/HF-pyridine, and improved the overall yield, while also reducing the number of synthetic steps
(3 vs. 1).42 Overall, this sequence highlights how continued reagent development enhances discovery
chemistry.
Scheme 4: Synthesis of Perfluorinated Alkyl Analogs 12 and 13
O
B2Pin2
10 mol% Pd(dppf)Cl2
12 mol% dppf, KOAc
EtO
N
H
Tf2O, Pyridine
(phen)CuRF
DMF, 50 °C
1,4-Dioxane, 80 °C
68%
CH2Cl2, 0 °C to rt
97%
OTf
10
Bpin
11
RF
OH
4
RF = 12, CF3, 53%
13, CF2CF3, 43%
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Ar–CF3 and Ar–CF2CF3: Aryl fluoroalkyl analogs 12 and 13 were obtained from phenol 4 in a 3-
step synthetic sequence using (phen)CuCF3 and (phen)CuCF2CF3 as key reagents (Scheme 4).43
Specifically, phenol 4 was first converted into triflate 10 (97% yield), and subsequent Pd-catalyzed
borylation43 afforded pinacol boronic ester 11 (68% yield). Finally, reaction of 11 with the copper-based
perfluoroalkylating reagents provided desired fluoroalkyl analogs 12 (53% yield) and 13 (43% yield)
without need to further optimize the reaction conditions.43
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Scheme 5: Synthesis of Difluoromethyl Analog 15
A Synthesis of Difluoromethyl Analog 15
1. (vinyl)Sn(nBu)
SF3
DAST
5 mol% Pd(PPh3)4
N
CH2Cl2, 0 °C to rt
68%
Me Me
DAST
2. OsO4, NaIO4
50% (2 steps)
CF2H
15
OTf
10
O
H
14
B Generation of [Ag]CF2H In Situ
OtBu
TMSCF2H
(SIPr)AgCl
(SIPr)AgOtBu
(SIPr)AgCF2H
C Redesigned Synthesis of Difluoromethyl Analog 15
D Cross-coupling with Ar–ONf
10 mol% Pd(dba)2, 20 mol% dppf
10 mol% Pd(dba)2, 20 mol% dppf
40 mol% (SIPr)AgCl
40 mol% (SIPr)AgCl
TMSCF2H, NaOtBu
TMSCF2H, NaOtBu
PhMe, 80 °C, 6 h
PhMe, 80 °C, 6 h
61%
10%
CF2H
15
CF2H
15
OTf
ONf
16
10
Ar–CF2H: Reaction sequences based off of both classical (Scheme 5A) and modern cross-coupling
reactions (Scheme 5C, D) delivered Ar–CF2H analog 15.44–46 In one sequence, triflate 10 was cross-coupled
with tributyl(vinyl)tin to generate a styrene, and subsequent oxidative cleavage of the alkene using OsO4
and NaIO4 delivered benzaldehyde 14 (50% yield over 2 steps).47,48 Deoxyfluorination of 14 using
diethylaminosulfur trifluoride (DAST) afforded Ar–CF2H analog 15 (68% yield).49
Alternatively, optimization of a metal-catalyzed cross-coupling strategy using aryl sulfonates and
TMS–CF2H as a difluoromethyl source provided direct access to Ar–CF2H analog 15. Initially, conditions
were adapted from Pd-catalyzed difluoromethylation reactions of aryl halides,45,46 which required in situ
generation of (SIPr)AgCF2H, generated by reacting (SIPr)AgCl with TMSCF2H and NatOBu, to stabilize
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the nucleophile (Scheme 5B). However, using these conditions, triflate-based electrophile 10 did not
successfully generate the desired product in synthetically useful yields (10% yield), as the conditions
hydrolyzed the substrate to generate phenol 4 as the major product (Scheme 5C). Control experiments
confirmed that conversion of triflate to phenol was facilitated by NaOtBu, and further routine optimization
of time, temperature, loading of catalyst and reagents failed to substantially improve the reaction. Further
optimization was conducted using a model substrate [(1,1'-biphenyl)-4-yl trifluoromethanesulfonate] on
which standard conditions generated product in low yield (18% 19F NMR yield), though portion wise
addition of triflate over 5 h increased yields of Ar–CF2H product (29% 19F NMR yield). Moreover, addition
of the model triflate via syringe pump over 18 h further improved the yield of product (53% 19F NMR
10
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yield).
Additionally,
use
of
stochiometric
preformed
(SIPr)AgCF2H46
instead
of
(SIPr)AgCl/TMSCF2H/NaOtBu avoided hydrolysis of the triflate, but did not improve the yield (50% 19F
NMR yield) versus slow addition. Unfortunately, when applied to triflate 10, the slow addition strategy
19
only modestly improved the yield of Ar–CF2H product (~40% F NMR yield). To resolve this problem,
use of the more stable aryl nonafluorobutanesulfonate50,51 (Ar–ONf, 16), effectively suppressed hydrolysis,
and after minor optimization, provided the highest yield of product 15 (61%) without requiring a slow
addition technique or preforming transition metal complexes (Scheme 5D).51
Scheme 6: Synthesis of Difluoroethyl Analog 18
1. MeMgBr
THF, 0 °C
Deoxo-Fluor
2. DMP, NaHCO3
CH2Cl2, 0 °C to rt
73% (2 steps)
PhMe, 85 °C
41%
CF2Me
18
O
H
O
Me
14
17
SF3
N
MeO
OMe
Deoxo-Fluor
Ar–CF2CH3: A 3-step sequence converted benzaldehyde to 1,1-difluoroethyl analog 18. Initially,
addition of MeMgBr to benzaldehyde 14 and oxidation of the resulting alcohol with Dess-Martin
periodinane afforded aryl methyl ketone 17 (73% yield; Scheme 6). Subsequent deoxyfluorination of 17
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with Deoxo-Fluor delivered difluorinated product 18 (41% yield),49 though we are optimistic that other
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recently published mild deoxyfluorination reagents might also perform this transformation.44,52
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Scheme 7: Reduction of Ar–Rf and Ar–ORf Products to Afford DXM Analogs
O
10
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15
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Analog
RF
Yield
H3C
.
EtO
N
N
.
H
H
19
OCF3
OCF2H
CF3
CF2H
CF2CF3
CF2CH3
86%
20
21
22
23
24
84%
68%
80%
90%
72%
LiAlH4
THF
0 °C to rt
RF
RF
Reduction to Amine: All analogs in the series were deprotected by reduction of the carbamate with
LiAlH4 to give products 1924 68–90% yield (Scheme 7). After reverse phase LC purification, products
were isolated in freebase form in >95% HPLC purity. Pharmacological analysis of these analogs will be
reported in future work.
CONCLUSION
Scheme 8: Synthetic Roadmap to Fluorinated DXM Analogs
O
H3C
N
H
EtO
N
H
1) B2pin2, cat. Pd(dppf)Cl2
68%
Tf2O, Pyridine
97%
3 Steps
87%
2) (phen)CuRF
HBr
R1
R1 = 12, CF3, 53%
OTf
10
OCH3
1
OH
4
13, CF2CF3, 43%
1) (vinyl)Sn(nBu),
cat. Pd(PPh3)4
2) OsO4, NaIO4
50% (2 steps)
1) FSO2C4F9, NEt3
2) cat. Pd(dba)2, dppf,
cat. (SIPr)AgCl, KOtBu,
TMSCF2H
(EtO)2P(O)CF2Br, KOH
56%
1) CS2, MeI, NaH
2) SbCl3, Fluolead
47% (2 steps)
44% (2 steps)
1) MeMgBr
2) Dess-Martin periodinane
3) Deoxo-Fluor
30% (3 steps)
OCF2H
OCF3
CF2H
15
CHO
14
CF2Me
18
5
6
The synthetic roadmap presented above enables conversion of aryl methyl ethers and phenols into
fluoroalkyl analogs through late-stage functionalization of DXM, a natural product-derived FDA-approved
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therapeutic (Scheme 8). This set of short synthetic sequences enables access to sufficient quantities of each
target analog for initial pharmacological and PK studies, as well as backup strategies for some less reliable
reactions. Overall, the project provides a valuable synthetic template for medicinal chemists to access a
range of fluorinated therapeutic candidates, both synthetic and natural product-derived, at a late stage of a
synthesis, which avoids time- and material-consuming de novo synthesis of each analog. Further, each
fluoroalkyl analog likely possessing distinct physicochemical and possibly pharmacological properties
relative to the original Ar–OMe-derived compound. On the DXM scaffold, such physicochemical
perturbations imparted by the fluoroalkyl groups, as well as pharmacodynamic properties of the new
analogs will be reported separately in due course.
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EXPERIMENTAL SECTION
General Information: Air- and moisture-sensitive reactions were carried out in oven-dried one-dram vials
sealed with PTFE-lined septa or glassware sealed with rubber septa under an atmosphere of dry nitrogen.
PTFE syringes equipped with stainless-steel needles were used to transfer air- and moisture-sensitive liquid
reagents. Reactions were stirred using teflon-coated magnetic stir bars, and elevated temperatures were
maintained using thermostat-controlled heating mantles. Organic solvents were removed using a rotary
evaporator with a diaphragm vacuum pump. Thin-layer analytical chromatography was performed on silica
gel UNIPLATE Silica Gel HLF UV254 plates, and spots were visualized by quenching of ultraviolet light
(λ = 254 nm). Purification of products was accomplished by automated flash column chromatography on
silica gel (VWR Common Silica Gel 60ꢀÅ, 40–60ꢀμm). Unless otherwise noted, reagents were purchased
from various commercial sources and used as received. NMR spectra were recorded on a Bruker DRX 500
MHz (1H at 500 MHz, 19F at 471 MHz, 2H at 61 MHz) or a Bruker AVIIIHD 400 MHz (13C at 126 MHz)
nuclear magnetic resonance spectrometer. 1H NMR spectra were calibrated against the peak of the residual
CHCl3 (7.26 ppm) or residual (CH3)2SO (2.50 ppm) in the solvent. 19F NMR spectra were calibrated against
the peak of the internal standard using CFCl3 (0.00 ppm). 13C NMR spectra were calibrated against the peak
of CDCl3 (77.2 ppm) or (CD3)2SO (39.5 ppm). NMR data are represented as follows: chemical shift (ppm),
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multiplicity (sꢀ=ꢀsinglet, dꢀ=ꢀdoublet, tꢀ=ꢀtriplet, qꢀ=ꢀquartet, pꢀ=ꢀpentet, mꢀ=ꢀmultiplet), coupling constant in
Hertz (Hz), integration. To resolve carbamate rotamers, 1H and 13C NMR spectra for compounds 3–15, 17,
and 18 were measured at 343 K. High-resolution mass determinations were obtained by electrospray
ionization (ESI) on a Waters LCT Premier™ mass spectrometer. Infrared spectra were measured on a
Perkin Elmer Spectrum Two Fourier Transform Infrared Spectrometer by drying samples on a diamond
ATR sample base plate. Uncorrected melting points were measured on a Thomas Hoover Uni-melt
Capillary Melting Point apparatus.
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(4bS,8aS,9S)-ethyl
carboxylate (3)
3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-
Dextromethorphan hydrobromide hydrate 1 (3.70 g, 10.0 mmol) was dissolved in CHCl3 (0.10 L) and
washed with a saturated aqueous solution of ammonia (2 x 50 mL). The organic solution was dried over
Na2SO4, filtered, and the solvent was removed in vacuo. The resulting oil was transferred to a 100 mL
Schlenk flask and K2CO3 (5.53 g, 40.0 mmol) and anhydrous DCE (50 mL) were added. The flask was
attached to a reflux condenser and acetyl chloride (4.3 mL, 40 mmol) was injected dropwise. The flask was
placed in a 70 °C oil bath and the mixture was heated for 4 h. The reaction was allowed to cool to rt, the
mixture was filtered through a pad of celite, and the pad was washed with DCE (2 x 10 mL). The solvent
was removed in vacuo, and the resulting oil was dissolved in MeOH (25 mL). The flask was attached to a
reflux condenser, and placed in a 70 °C oil bath. After heating for 30 min, the reaction was cooled to 23
°C, and the solvent was removed in vacuo. The resulting oil was dissolved in DCM (100 mL) and washed
with a saturated aqueous solution of ammonia (50 mL). The organic solution was dried over Na2SO4,
filtered, and the solvent was removed in vacuo. The resulting oil was transferred to a 100 mL Schlenk flask
and CHCl3 (50 mL) and NEt3 (7.0 mL, 50 mmol) were injected. The flask was attached to a reflux condenser
and placed in a 0 °C ice bath. Ethyl chloroformate (2.9 mL, 30 mmol) was injected dropwise and the flask
was removed from the ice bath. The flask was placed in a 70 °C oil bath for 6 h and then cooled to rt. The
organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo. Chromatographic
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purification (hexanes : EtOAc, 1:0 → 9:1) provided 3.09 g (94%) of the title compound as a faint yellow
oil. 1H NMR (500 MHz, DMSO-d6, 343 K) δ 7.03 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.74 (dd, J
= 8.4, 2.6 Hz, 1H), 4.21 (s, 1H), 3.77 (s, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.04 (dd, J = 18.0, 6.0 Hz, 1H),
2.68–2.55 (m, 1H), 2.38 (d, J = 13.7 Hz, 1H), 1.62 (td, J = 9.3, 4.7 Hz, 2H), 1.56–1.41 (m, 3H), 1.38–1.23
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(m, 3H), 1.22–1.13 (m, 1H), 0.97 (qd, J = 12.8, 3.8 Hz, 1H). C NMR (126 MHz, DMSO-d6, 343 K) δ
158.0, 154.8, 139.6, 128.5, 127.6, 111.4, 110.5, 54.7, 51.7, 49.3, 43.1, 40.7, 37.6, 36.8, 35.5, 30.6, 25.9,
25.5, 21.4. IR (film) 2996, 2930, 2855, 1697, 1609, 1568, 1495, 1447, 1435, 1408, 1366, 1327, 1298, 1271,
1242, 1188, 1163, 1128, 1098, 1065, 1040, 1009, 853, 768 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for
C20H28NO3 330.2069; Found 330.2083 (4.2 ppm).
(4bS,8aS,9S)-ethyl
carboxylate (4)
3-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-
Aryl methyl ether 3 (3.1 g, 9.4 mmol) was added to a 250 mL round bottom flask, which was sealed with a
rubber septum, and evacuated and backfilled with N2 (3x). Anhydrous DCM (30 mL) was injected, and the
flask was placed in a 0 °C ice bath. A solution of BBr3 (1.0 M in DCM, 30 mL, 30 mmol) was injected
dropwise over a 10 min period. The reaction mixture was allowed to warm to rt and stirred for 1 h. The
mixture was cooled to 0 °C, and a saturated aqueous solution of NaHCO3 (50 mL) was slowly added over
a 10 min period. The mixture was stirred for 1 h, diluted with DCM (50 mL), and the organic solution was
washed with H2O (75 mL), and brine (75 mL). The organic solution was dried over Na2SO4, filtered, and
the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) provided
2.75 g (93%) of the title compound as a colorless solid. 1H NMR (500 MHz, DMSO-d6, 343 K) δ 8.85 (s,
1H), 6.90 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.2, 2.3 Hz, 1H), 4.20 (s, 1H), 3.73 (d,
J = 11.2 Hz, 1H), 3.61 (s, 3H), 3.00 (dd, J = 17.9, 5.9 Hz, 1H), 2.53 (d, J = 17.8 Hz, 2H), 2.29 (d, J = 13.2
Hz, 1H), 1.65–1.56 (m, 2H), 1.51 (td, J = 12.9, 5.2 Hz, 2H), 1.44 (d, J = 12.4 Hz, 1H), 1.39–1.13 (m, 5H),
1.00 (qd, J = 12.7, 3.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 155.8, 154.9, 139.3, 128.4, 125.6,
113.3, 111.3, 51.7, 49.4, 43.2, 40.8, 37.7, 36.6, 35.6, 30.6, 25.9, 25.5, 21.5. IR (film) 3325, 3019, 2982,
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2932, 2857, 1661, 1611, 1582, 1495, 1435, 1377, 1348, 1331, 1314, 1298, 1273, 1234, 1186, 1165, 1140,
1101, 1020, 990, 963, 912, 868, 837, 812, 772, 731 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C19H26NO3
316.1913; Found 316.1901 (3.8 ppm).
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(4bS,8aS,9S)-ethyl
3-(difluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-
phenanthrene-11-carboxylate (5)
KOH (1.12 g, 20.0 mmol) and H2O (5.0 mL) were added to a 50 mL round bottom flask, and the solution
was cooled to 0 °C. MeCN (5 mL) and phenol 4 (315 mg, 1.00 mmol) were added to the mixture.
Diethyl(bromodifluoromethyl)phosphonate (0.4 mL, 2.0 mmol) was injected and the mixture was allowed
to warm to 23 °C and stirred for 1 h. The mixture was diluted with Et2O (50 mL), and then washed with
H2O (50 mL) and brine (50 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) provided 204 mg (56%) of
1
the title compound as a colorless oil. H NMR (500 MHz, DMSO-d6, 343 K) δ 7.18 (d, J = 8.4 Hz, 1H),
7.12 (t, J = 70.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 5.8, 1.5 Hz, 1H), 4.25 (s, 1H), 3.76 (d, J =
11.2 Hz, 1H), 3.62 (s, 3H), 3.09 (dd, J = 18.3, 6.0 Hz, 1H), 2.66 (d, J = 18.4 Hz, 1H), 2.39 (d, J = 13.8 Hz,
1H), 1.76–1.43 (m, 6H), 1.40–1.24 (m, 4H), 1.16 (dtd, J = 16.5, 13.1, 11.6, 8.5 Hz, 1H), 0.94 (qd, J = 12.8,
3.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 154.8, 149.6 (t, J = 3.0 Hz), 140.0, 132.8, 129.1,
116.2, 116.1 (t, J = 257.8 Hz), 115.6, 51.8, 49.1, 42.9, 40.5, 37.5, 36.9, 35.2, 30.7, 25.8, 25.3, 21.3. 19F
NMR (376 MHz, CDCl3) δ –80.29 (d, J = 74.3 Hz). IR (film) 2982, 2930, 2859, 1694, 1611, 1580, 1495,
1427, 1377, 1327, 1296, 1267, 1236, 1184, 1169, 1128, 1099, 1042, 990, 964, 914, 880, 839, 812, 768,
729, 667 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C20H26F2NO3 366.1881; Found 366.1895 (3.8 ppm).
(4bS,8aS,9S)-ethyl
3-(((methylthio)carbonothioyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-
(epiminoethano)phenanthrene-11-carboxylate (8)
In a N2-filled glovebox, NaH (14 mg, 0.60 mmol) and DMF (1.0 mL) were added to a 10 mL round bottom
flask. The flask was removed from the glovebox, attached to a Schlenk line (N2), and placed in a 0 °C ice
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bath. A solution of phenol 4 (0.20 g, 0.50 mmol) in DMF (1.0 mL) was injected, and the reaction mixture
was allowed to warm to 23 °C and stirred for 1 h. CS2 (60 L, 1.0 mmol) was injected, and the mixture was
stirred for 1 h. Next, MeI (0.11 mL, 1.8 mmol) was injected, and the mixture was stirred for 14 h. The
reaction was quenched with 1 N HCl (5 mL), and diluted with Et2O (15 mL). The mixture was washed with
1 N HCl (2 x 15 mL), H2O (15 mL), and brine (15 mL). The organic solution was dried over Na2SO4,
filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 →
4:1) afforded the title compound as a colorless oil (0.175 g, 87%). 1H NMR (500 MHz, DMSO-d6, 343 K)
δ 7.24 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.3, 2.4 Hz, 1H), 4.28 (s, 1H), 4.09 (d, J
= 7.0 Hz, 2H), 3.80 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J = 19.1, 5.4 Hz, 1H), 2.72 (s, 3H), 2.37 (d, J =
13.7 Hz, 1H), 1.70 (dt, J = 12.7, 3.2 Hz, 1H), 1.65 (d, J = 12.7 Hz, 1H), 1.59 (td, J = 13.1, 5.4 Hz, 2H),
1.55–1.46 (m, 4H), 1.34 (ddd, J = 16.8, 13.1, 6.3 Hz, 4H), 1.22 (t, J = 7.0 Hz, 4H), 0.99 (qd, J = 12.9, 3.9
Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 215.3, 154.4, 152.8, 140.3, 134.3, 128.9, 118.9, 118.6,
60.2, 49.0, 42.8, 40.4, 37.4, 37.0, 35.3, 31.9, 25.8, 25.4, 21.3, 19.1, 14.2. IR (film) 2980, 2930, 2857, 1694,
1682, 1607, 1582, 1493, 1464, 1454, 1427, 1375, 1327, 1296, 1269, 1234, 1173, 1157, 1099, 1044, 990,
964, 914, 814, 768, 731 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C21H28NO3S2 406.1511; Found
406.1504 (1.7 ppm).
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(4bS,8aS,9S)-ethyl
3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-
phenanthrene-11-carboxylate (6)
Conditions A: 1,3-Dibromo-5,5-dimethylhydantoin (1.56 g, 5.45 mmol) was added to a 10 mL round
bottom flask. DCM (1.0 mL) was injected, and the solution was cooled to –78 °C. HF•Pyridine (0.4 mL)
and a solution of xanthate 8 (762 mg, 1.88 mmol) in DCM (1.0 mL) were injected. The reaction mixture
was allowed to warm to 0 °C and stirred for 1 h. The mixture was poured over a saturated aqueous solution
of NaHCO3 (20 mL) and extracted with Et2O (2 x 20 mL). The combined organic solution was dried over
Na2SO4, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc,
1:0 → 9:1) afforded a mixture of the title compound 6, bromoaryl trifluoromethyl ether, and aryl
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bromodifluoromethyl ether 9 as a colorless oil (445 mg). The material was dissolved in DCM (2.0 mL) and
AgBF4 (389 mg, 0.0200 mmol) was added. The mixture was stirred at 23 °C for 1 h and filtered through
celite. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded a mixture of title compound
and bromoaryl trifluoromethyl ether as a colorless oil (0.410 g). The material was dissolved in MeOH (2.0
mL) and 10% Pd/C (40.0 mg) was added. The system was flushed with N2 and then evacuated and backfilled
with H2 (3x). The mixture was stirred at 23 °C for 16 h, filtered through a pad of celite, and diluted with
EtOAc (30 mL). The solution was washed with H2O (30 mL) and brine (30 mL). The organic solution was
dried over Na2SO4, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes
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: EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil (353 mg, 49%). H NMR (500 MHz,
DMSO-d6, 343 K) δ 7.26 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.27 (s, 1H), 4.08 (s,
2H), 3.78 (d, J = 9.8 Hz, 1H), 3.13 (dd, J = 18.4, 6.1 Hz, 1H), 2.69 (d, J = 18.5 Hz, 1H), 2.45 (s, 1H), 2.40
(d, J = 14.1 Hz, 1H), 1.69 (d, J = 12.6 Hz, 1H), 1.66–1.45 (m, 4H), 1.45–1.30 (m, 3H), 1.21 (t, J = 6.9 Hz,
3H), 1.11 (q, J = 13.3 Hz, 1H), 0.93 (qd, J = 12.9, 3.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ
155.2, 148.0, 141.9, 136.1, 130.3, 120.7 (q, J = 255.6 Hz), 118.7, 118.4, 61.1, 49.7, 43.6, 41.2, 38.2, 37.8,
36.0, 31.6, 26.6, 26.1, 22.0, 15.0. 19F NMR (376 MHz, CDCl3) δ –57.86. IR (film) 3024, 2980, 2932, 2860,
1693, 1609, 1582, 1489, 1454, 1427, 1375, 1327, 1296, 1258, 1236, 1223, 1161, 1099, 1022, 989, 972,
914, 849, 837, 816, 768 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C20H25F3NO3 384.1787; Found
384.1799 (3.1 ppm). Conditions B: Xanthate 8 (40 mg, 0.10 mmol) and Fluolead (125 mg, 0.500) were
added to a 5 mL fluoropolymer vessel equipped with a 3-way adaptor and evacuated and backfilled with
N2 (3x). DCM (0.50 mL) was injected, and the solution was cooled to 0 °C. A solution of SbCl3 (1.1 mg,
0.0050 mmol) in DCM (0.20 mL) was injected. The reaction stirred at 0 °C for 10 min before heating to 65
°C for 20 h. The reaction was then allowed to cool to 23 °C and NaF (40 mg, 1.00 mmol) was added into
the vessel. The mixture was then filtered through a pad of celite, and 1N aqueous NaOH (1.0 mL) was
added. The mixture was then stirred for 30 min. The mixture was diluted in DCM (10 mL) and washed with
H2O (30 mL) and brine (30 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
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removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound
5
6
as a colorless oil (19 mg, 54%).
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2-(((4bS,8aS,9S)-11-(ethoxycarbonyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-
yl)oxy)-2,2-difluoroacetic acid (7)
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Phenol 4 (0.630 g, 2.00 mmol) was added to a 25 mL Schlenk flask (N2). 1,4-Dioxane (10 mL) was injected.
NaH (0.050 mg, 2.2 mmol) in 1,4-dioxane (1.3 mL) was injected dropwise and stirred for 30 min.
BrCF2CO2K (0.468 mg, 2.20 mmol) in 1,4-dioxane (2 mL) was injected into the mixture. The mixture was
placed in a 110 °C oil bath for 18 h. The mixture was then allowed to cool to 23 °C and 1N HCl (10 mL)
was added. The mixture was then extracted with DCM (10 x 2 mL), and the combined organic extracts
were dried over Na2SO4, filtered, and the solvent was removed in vacuo. Chromatographic purification
1
(hexanes : EtOAc, 1:0 → 0:1) afforded the title compound as a colorless solid (0.640 g, 78%). H NMR
(500 MHz, DMSO-d6, 343 K) δ 7.18 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.3, 2.0 Hz,
1H), 4.24 (s, 1H), 3.76 (d, J = 10.3 Hz, 1H), 3.62 (s, 3H), 3.10 (dd, J = 18.4, 6.0 Hz, 1H), 2.66 (d, J = 18.4
Hz, 1H), 2.46 (s, 1H), 2.34 (d, J = 13.9 Hz, 1H), 1.67 (dt, J = 12.7, 3.1 Hz, 1H), 1.62 (d, J = 12.8 Hz, 1H),
1.59–1.54 (m, 1H), 1.54–1.44 (m, 3H), 1.42–1.28 (m, 4H), 1.13 (qt, J = 13.2, 3.2 Hz, 2H), 0.94 (qd, J =
12.9, 3.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 160.8 (t, J = 39.1 Hz), 155.6, 148.9 (t, J = 2.5
Hz), 141.1, 134.5, 129.8, 119.1, 118.4, 116.2 (t, J = 272.2 Hz), 52.6, 49.9, 43.6, 41.3, 40.9, 38.3, 37.7, 36.1,
31.6, 26.6, 26.1, 22.0. IR (film) 2930, 2859, 1773, 1632, 1436, 1238, 1172, 1103, 1019, 913, 737 cm–1.
HRMS (ESI) m/z: [M - H]- Calcd for C21H25F2NO5 408.1628; Found 408.1650 (5.4 ppm).
(4bS,8aS,9S)-ethyl
3-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(ep-
iminoethano)phenanthrene-11-carboxylate (10)
Phenol 4 (1.58 g, 5.00 mmol) was added to a 50 mL Schlenk flask (N2). DCM (25.0 mL) and pyridine
(0.810 mL, 10.0 mmol) were injected, and the solution was cooled to 0 °C. Trifluoromethanesulfonic
anhydride (1.0 mL, 6.0 mmol) was injected dropwise over a 10 min period. The mixture was allowed to
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warm to 23 °C and stirred for 1 h. The reaction was quenched with 1N HCl (10 mL), and the mixture was
diluted with DCM (50 mL). The organic solution was washed with 1N HCl (50 mL), H2O (50 mL), and
brine (50 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Chromatographic purification (hexanes : EtOAc, 1:0 → 17:3) afforded the title compound as a colorless
solid (2.17 g, 97%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ 7.34 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24
(dd, J = 8.5, 2.6 Hz, 1H), 4.28 (s, 1H), 4.15–4.00 (m, 2H), 3.79 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J =
18.7, 6.0 Hz, 1H), 2.40 (d, J = 14.0 Hz, 2H), 1.71 (dt, J = 12.6, 3.2 Hz, 1H), 1.60 (td, J = 13.1, 5.4 Hz, 2H),
1.56–1.46 (m, 3H), 1.36 (dtt, J = 16.5, 7.6, 3.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.09 (qt, J = 13.2, 3.2 Hz,
1H), 0.91 (qd, J = 12.9, 3.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 155.2, 148.7, 142.5, 137.9,
130.7, 119.0, 118.8 (q, J = 321.9 Hz), 118.8, 61.1, 49.6, 43.4, 41.10, 38.1, 38.0, 36.0, 31.7, 26.5, 26.1, 21.9,
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15.0. F NMR (376 MHz, CDCl3) δ –72.79. IR (film) 2988, 2932, 2861, 1699, 1607, 1580, 1489, 1447,
1424, 1368, 1327, 1298, 1267, 1234, 1211, 1142, 1099, 1036, 1009, 990, 949, 926, 910, 899, 878, 870,
829, 766, 700, 637, 608 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C20H25F3NO5S 448.1406; Found
448.1388 (4.0 ppm).
(4bS,8aS,9S)-ethyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-
(epiminoethano)phenanthrene-11-carboxylate (11)
In a N2-filled glovebox, aryl triflate 10 (1.7 g, 3.7 mmol), bis(pinacolato)diboron (1.1 g, 4.5 mmol),
Pd(dppf)Cl2 (0.27 g, 0.37 mmol), 1,1′-ferrocenediyl-bis(diphenylphosphine) (0.25 g, 0.45 mmol), and
potassium acetate (1.1 g, 11 mmol) were added to a 100 mL pressure vessel. 1,4-Dioxane (37 mL) was
injected, and the vessel was sealed with a PTFE cap. The vessel was removed from the glovebox and placed
in an 80 °C oil bath, and the mixture was stirred for 16 h. The reaction was cooled to 23 °C and diluted with
EtOAc (50 mL). The mixture was washed with H2O (100 mL) and brine (100 mL). The layers were
separated, and the organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Chromatographic purification (hexanes : EtOAc, 9:1 → 4:1) afforded the title compound as a colorless
solid (1.1 g, 68%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ 7.34 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24
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(dd, J = 8.5, 2.6 Hz, 1H), 4.28 (s, 1H), 4.15–4.00 (m, 2H), 3.79 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J =
18.7, 6.0 Hz, 1H), 2.40 (d, J = 14.0 Hz, 2H), 1.71 (dt, J = 12.6, 3.2 Hz, 1H), 1.60 (td, J = 13.1, 5.4 Hz, 2H),
1.56 – 1.46 (m, 3H), 1.36 (dtt, J = 16.5, 7.6, 3.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.09 (qt, J = 13.2, 3.2
Hz, 1H), 0.91 (qd, J = 12.9, 3.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 155.2, 148.7, 142.5,
137.9, 130.7, 119.0, 118.8 (q, J = 321.9 Hz), 118.8, 61.1, 49.6, 43.4, 41.10, 38.1, 38.0, 36.0, 31.7, 26.5,
26.1, 21.9, 15.0. IR (film) 3040, 2978, 2932, 2859, 1697, 1609, 1505, 1427, 1415, 1404, 1389, 1371, 1348,
1327, 1312, 1296, 1285, 1266, 1233, 1219, 1190, 1167, 1146, 1103, 1022, 990, 964, 914, 864, 847, 827,
768, 735, 689, 667 cm–1. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H36BNO4Na 448.2635; Found 448.2638
(0.7 ppm).
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(4bS,8aS,9S)-ethyl 3-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-
11-carboxylate (12)
Aryl boronic ester 11 (0.21 g, 0.50 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (0.19 g,
0.60 mmol) were added to a 15 mL resealable vial. DMF (5.0 mL) was injected, and air was bubbled through
the mixture for 5 min. The vial was sealed with a PTFE-lined cap and placed in a 50 °C oil bath for 18 h.
The reaction was cooled to 23 °C, diluted with Et2O (20 mL), and filtered through SiO2 (washed with 2 x
20 mL Et2O). The solvent was removed in vacuo. Chromatographic purification (hexanes : Et2O, 1:0 →
9:1) afforded the title compound as a faint yellow oil (98 mg, 53%). 1H NMR (500 MHz, DMSO-d6, 343
K) δ 7.59 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.78 (d, J = 10.2 Hz, 1H),
3.63 (s, 3H), 3.20 (dd, J = 18.9, 5.9 Hz, 1H), 2.77 (d, J = 18.9 Hz, 1H), 2.45 (dd, J = 23.7, 13.3 Hz, 2H),
1.73 (dt, J = 12.6, 3.1 Hz, 1H), 1.62 (dt, J = 12.9, 6.4 Hz, 2H), 1.57–1.46 (m, 2H), 1.37 (qt, J = 13.1, 3.6
Hz, 3H), 1.08 (qt, J = 13.2, 3.3 Hz, 1H), 0.91 (qd, J = 12.9, 4.0 Hz, 1H). 13C NMR (126 MHz, DMSO-d6,
343 K) δ 155.6, 141.9, 140.6, 129.5, 128.1 (q, J = 31.4 Hz), 125.0 (q, J = 271.8 Hz), 122.8 (q, J = 4.0 Hz),
122.6 (q, J = 4.2 Hz), 52.7, 49.7, 43.7, 41.2, 38.1, 37.7, 35.9, 32.2, 31.0, 26.5, 26.1, 22.0. 19F NMR (376
MHz, CDCl3) δ –62.2 (s). IR (film) 3011, 2982, 2932, 2860, 1693, 1464, 1427, 1418, 1375, 1352, 1325,
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1308, 1298, 1265, 1232, 1221, 1190, 1163, 1146, 1123, 1099, 1086, 1022, 989, 945, 914, 896, 825, 798,
770, 729 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C20H25F3NO2 368.1837; Found 368.1839 (0.5 ppm).
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(4bS,8aS,9S)-ethyl 3-(perfluoroethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-
11-carboxylate (13)
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Aryl boronic ester 11 (43 mg, 0.10 mmol) and (1,10-phenanthroline)(pentafluoroethyl)copper(I) (44 mg,
012 mmol) were added to a 1 dram vial. DMF (1.0 mL) was injected and air was bubbled through the
mixture for 5 min. The vial vas sealed with a PTFE-lined cap and placed in a 50 °C oil bath for 36 h. The
reaction was cooled to 23 °C, diluted with Et2O (10 mL), and filtered through SiO2 (washed with 2 x 10
mL Et2O). The solvent was removed in vacuo. Chromatographic purification (hexanes : Et2O, 1:0 → 9:1)
afforded the title compound as a faint yellow oil (18 mg, 43%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ
7.53 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.79 (d, J = 11.0 Hz, 1H), 3.63
(s, 3H), 3.21 (dd, J = 18.9, 5.8 Hz, 1H), 2.78 (d, J = 18.9 Hz, 1H), 2.44 (d, J = 13.9 Hz, 2H), 1.74 (d, J =
12.7 Hz, 1H), 1.62 (dt, J = 12.7, 5.9 Hz, 2H), 1.57–1.46 (m, 2H), 1.46–1.24 (m, 4H), 1.05 (q, J = 13.2 Hz,
1H), 0.90 (qd, J = 12.7, 3.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 155.6, 142.1 (t, J = 1.9 Hz),
140.7, 129.6, 126.0 (t, J = 23.7 Hz), 123.8 (t, J = 6.6 Hz), 123.7 (t, J = 6.9 Hz), 119.5 (qt, J = 270.5, 40.2
Hz), 114.0 (tq, J = 254.5, 37.8 Hz), 52.7, 49.7, 43.7, 41.3, 38.1, 37.7, 35.9, 32.1, 31.0, 26.5, 26.1, 21.9. 19F
NMR (376 MHz, CDCl3) δ –84.8 (s, 3F), –114.6 (s, 2F). IR (film) 2986, 2932, 1261, 1699, 1472, 1456,
1418, 1375, 1327, 1298, 1265, 1206, 1136, 1126, 1098, 1003, 943, 914, 893, 818, 770, 743 cm–1. HRMS
(ESI) m/z: [M + Na]+ Calcd for C21H24F5NO2Na 440.1625; Found 440.1624 (0.2 ppm).
(4bS,8aS,9S)-ethyl
carboxylate (14)
3-formyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-
In a N2-filled glovebox, Pd(PPh3)4 (112 mg, 0.100 mmol), LiCl (617 mg, 15.0 mmol), and 2,6-di-tert-butyl-
4-methylphenol (5.0 mg) were added to a 100 mL pressure vessel. Aryl triflate 10 (2.17 g, 4.80 mmol) was
dissolved in 1,4-dioxane (25 mL) and transferred to the vessel. Tributyl(vinyl)tin (1.5 mL, 5.0 mmol) was
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injected and the vessel was sealed with a PTFE cap. The vessel was removed from the glovebox and placed
in a 110 °C oil bath for 3 h. The reaction was cooled to 23 °C, pyridine (1.0 mL) and HF•pyridine (0.50
mL) were injected, and the mixture was stirred for 24 h. The mixture was diluted with Et2O (50 mL) and
washed with 1N HCl (50 mL), H2O (50 mL), and brine (50 mL). The organic solution was dried over
Na2SO4, filtered, and the solvent was removed in vacuo. The residue was dissolved in Et2O (50 mL) and
stirred for 1 h with crushed NaOH (0.5 g), CsF (1 g), and SiO2 (4 g). The solvent was removed in vacuo,
and chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded (4bS,8aS,9S)-ethyl 3-vinyl-
6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (Styrene) as a colorless
oil (1.17 g, 74%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ 9.98 (s, 1H), 7.88 (s, 1H), 7.68 (dd, J = 7.8, 1.5
Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 4.29 (s, 1H), 4.08 (dq, J = 11.5, 6.7 Hz, 2H), 3.78 (dd, J = 13.6, 4.2 Hz,
1H), 3.21 (dd, J = 19.2, 6.0 Hz, 1H), 2.76 (d, J = 19.2 Hz, 1H), 2.44 (t, J = 11.4 Hz, 1H), 1.72 (dt, J = 12.6,
3.1 Hz, 1H), 1.62 (td, J = 12.9, 5.3 Hz, 2H), 1.58–1.46 (m, 2H), 1.44–1.30 (m, 3H), 1.20 (t, J = 7.0 Hz, 3H),
1.13 (dddd, J = 16.6, 13.2, 8.4, 3.4 Hz, 1H), 0.92 (qd, J = 12.9, 3.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6,
343 K) δ 193.0, 155.2, 144.4, 140.5, 135.9, 129.5, 128.0, 126.8, 61.1, 49.7, 43.8, 41.4, 38.1, 37.7, 35.9,
32.7, 26.6, 26.2, 22.1, 15.0. IR (film) 3086, 3042, 2980, 2930, 2857, 1694, 1632, 1564, 1499, 1427, 1375,
1327, 1296, 1269, 1234, 1215, 1186, 1169, 1150, 1099, 1022, 990, 907, 853, 826, 768, 735 cm–1. HRMS
(ESI) m/z: [M + Na]+ Calcd for C21H27NO2Na 348.1939; Found 348.1938 (0.3 ppm).
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The intermediate styrene (0.49 g, 1.5 mmol) was added to a 50 mL round bottom flask. THF (12 mL) and
H2O (4.0 mL) were injected, and the flask was sealed with a rubber septum. A solution of OsO4 (ca. 0.020
mL, 4% in H2O) was injected, and the reaction mixture was stirred for 10 min. The septum was removed,
and NaIO4 (1.1 g, 5.3 mmol) was slowly added. The flask was resealed with a septum, and the mixture was
stirred for 90 min. The flask was placed in a 0 °C ice bath, Na2S2O3 was added, and the mixture was stirred
for 30 min. The mixture was diluted with EtOAc (0.050 L), and washed with H2O (50 mL) and brine (50
mL). The organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) afforded the title compound as a colorless oil
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(0.33 g, 68%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ 7.35 (s, 1H), 7.27 (dd, J = 7.9, 1.4 Hz, 1H), 7.10
(d, J = 7.9 Hz, 1H), 6.72 (dd, J = 17.6, 10.9 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H),
4.25 (s, 1H), 4.18–3.97 (m, 2H), 3.76 (dd, J = 13.3, 3.9 Hz, 1H), 3.26–2.99 (m, 1H), 2.64 (d, J = 18.6 Hz,
1H), 2.48 (s, 1H), 1.69–1.41 (m, 5H), 1.41–1.27 (m, 3H), 1.20 (t, J = 6.9 Hz, 3H), 1.15 (ddd, J = 16.4, 8.3,
3.4 Hz, 1H), 0.97 (qd, J = 12.8, 3.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6, 343 K) δ 155.2, 139.4, 137.5,
136.5, 136.2, 128.8, 124.8, 123.8, 113.5, 61.0, 49.9, 44.1, 41.6, 38.3, 37.5, 36.1, 32.1, 26.7, 26.3, 22.2, 15.0.
IR (film) 3007, 2978, 2930, 2856, 2721, 1693, 1601, 1570, 1464, 1425, 1389, 1375, 1325, 1296, 1267,
1236, 1211, 1188, 1165, 1148, 1099, 1080, 1020, 914, 824, 768, 731 cm–1. HRMS (ESI) m/z: [M + H]+
Calcd for C20H26NO3 328.1913; Found 328.1906 (2.1 ppm).
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(4bS,8aS,9S)-ethyl 3-(difluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-
11-carboxylate (15)
Conditions A: Aldehyde 14 (33 mg, 0.10 mmol) was added to a 1 dram vial, which was sealed with a PTFE
cap, and evacuated and backfilled with N2 (3x). DCM (0.1 mL) was injected, and the vial was placed in a
0 °C ice bath. DAST (26 μL, 0.2 mmol) was injected, and the reaction mixture was allowed to warm to 23
°C and stir for 16 h. The mixture was diluted with DCM (15 mL) and washed with H2O (15 mL) and brine
(15 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil
(24 mg, 68%). 1H NMR (500 MHz, DMSO-d6, 343 K) δ 7.50 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.27 (d, J =
7.9 Hz, 1H), 6.94 (t, J = 56.2 Hz, 1H), 4.27 (s, 1H), 4.07 (dt, J = 11.5, 5.7 Hz, 2H), 3.77 (dd, J = 13.6, 4.4
Hz, 1H), 3.17 (dd, J = 18.7, 5.9 Hz, 1H), 2.71 (d, J = 18.7 Hz, 1H), 2.45 (d, J = 13.7 Hz, 2H), 1.70 (dt, J =
12.6, 3.2 Hz, 1H), 1.65–1.54 (m, 2H), 1.55–1.44 (m, 2H), 1.36 (ddd, J = 21.5, 10.8, 7.4 Hz, 3H), 1.20 (t, J
= 7.0 Hz, 3H), 1.11 (qt, J = 13.2, 3.3 Hz, 1H), 0.93 (qd, J = 12.9, 3.9 Hz, 1H). 13C NMR (126 MHz, DMSO-
d6, 343 K) δ 155.2, 140.0, 139.9 (t, J = 2.3 Hz), 133.1 (t, J = 22.0 Hz), 129.1, 123.4 (t, J = 6.5 Hz), 123.3
(t, J = 6.0 Hz), 115.7 (t, J = 235.8 Hz), 61.2, 49.8, 43.9, 41.4, 38.1, 37.6, 36.0, 32.2, 26.6, 26.2, 22.1, 15.0.
IR (film) 3004, 2980, 2930, 2858, 1693, 1425, 1373, 1350, 1327, 1298, 1269, 1221, 1188, 1169, 1148,
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1099, 1022, 989, 914, 825, 771, 733 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C20H26F2NO2 350.1932;
Found 350.1920 (3.4 ppm). Conditions B: In a N2-filled glovebox, nonaflate 16 (180 mg, 0.30 mmol),
Pd(dba)2 (17 mg, 0.030 mmol), 1,1′-ferrocenediyl-bis(diphenylphosphine) (33 mg, 0.060 mmol),
[SIPr]AgCl (63 mg, 0.12 mmol), sodium tert-butoxide (57 mg, 0.60 mmol), and toluene (3 mL) were added
to 15 mL vial. The vessel was sealed with a PTFE cap and removed from the glovebox. TMSCF2H (0.10
mL, 0.72 mmol) was injected, and the reaction mixture was placed in a 110 °C oil bath for 18 h. The mixture
was then filtered through celite, diluted with EtOAc (15 mL) and washed with H2O (15 mL) and brine (15
mL). The organic solution was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil
(64 mg, 61%).
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ethyl
(4bS,8aS,9S)-3-(((perfluorobutyl)sulfonyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-
(epiminoethano)phenanthrene-11-carboxylate (16)
Phenol 4 (0.63 g, 2.00 mmol) was added to a 50 mL round bottom flask (N2). DCM (10 mL) and
triethylamine (0.42 mL, 3.0 mmol) were injected, and the solution was cooled to 78 °C. Perfluoro-1-
butanesulfonyl fluoride (0.50 mL, 3.0 mmol) was injected dropwise over a 10 min period. The mixture was
warmed to 23 °C and stirred for 18 h. The reaction was quenched with 1N HCl (5.0 mL), and the mixture
was diluted with DCM (25 mL). The organic solution was washed with 1N HCl (25 mL), H2O (25 mL),
and brine (25 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was removed in
vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 16:4) afforded the title compound as a
colorless solid (0.771 g, 72%). The NMR data are reported as a 58:42 rotameric ratio at room temperature
in CDCl3. 1H NMR for the major rotamer (500 MHz, CDCl3) δ 7.17 (s, 1H), 7.17 (s, 1H), 4.45 (s, 1H), 3.82
(d, J = 14.0 Hz, 1H), 3.69 (s, 3H3.13 (d, J = 6.6 Hz, 0H), 2.77 (s, 1H), 2.55 (dt, J = 25.2, 13.5 Hz, 1H), 2.32
(d, J = 14.0 Hz, 1H), 1.81–1.48 (m, 5H), 1.45–1.27 (m, 5H), 0.99 (qd, J = 12.9, 3.9 Hz, 1H). 13C{1H} NMR
for the major rotamer (126 MHz, CDCl3) δ 156.2, 149.0, 142.3, 137.2, 130.1, 118.9, 118.7, 117.2 (qtt, J =
282.5, 32.4, 6.1 Hz), 114.9 (ttt, J = 292.9, 35.5, 5.3 Hz), 109.9 (tp, J = 266.6, 28.5 Hz), 108.5 (ttq, J = 268.4,
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39.2, 32.48 Hz), 52.7, 49.5, 43.6, 41.5, 41.2, 38.1, 38.1, 36.5, 31.8, 26.5, 26.3, 21.8. 1H NMR for the minor
rotamer (500 MHz, CDCl3) δ 7.17 (s, 1H), 7.17 (s, 1H), 4.29 (s, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.72 (s,
3H), 3.17 (d, J = 6.0 Hz, 1H), 2.73 (s, 1H), 2.55 (dt, J = 25.2, 13.5 Hz, 1H), 2.32 (d, J = 14.0 Hz, 1H), 1.81–
1.48 (m, 5H), 1.45–1.27 (m, 5H), 0.99 (qd, J = 12.9, 3.9 Hz, 1H). 13C{1H} NMR for the minor rotamer (126
MHz, CDCl3) δ 156.0, 149.0, 142.3, 137.0, 130.0, 118.9, 118.7, 117.2 (qtt, J = 282.5, 32.4, 6.1 Hz), 114.9
(ttt, J = 292.9, 35.5, 5.3 Hz), 109.9 (tp, J = 266.6, 28.5 Hz), 108.5 (ttq, J = 268.4, 39.2, 32.48 Hz), 52.8,
49.8, 43.7, 41.5, 41.2, 38.1, 38.0, 36.5, 32.1, 26.6, 26.3, 21.8. 19F NMR (470 MHz, CDCl3) δ –81.1 (t, J =
9.8 Hz), –109.4 (t, J = 14.2 Hz), (–121.3)–(–121.4) (m), (–126.3)–(–126) (m). IR (film) 2934, 2861, 1698,
1448, 1426, 1236, 1206, 1144 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C23H25F9NO5S 598.1310; Found
598.1334 (4.0 ppm).
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(4bS,8aS,9S)-ethyl
carboxylate (17)
3-acetyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-
Aldehyde 14 (130 mg, 0.40 mmol) was added to a 25 mL round bottom flask, which was sealed with a
rubber septum, and evacuated and backfilled with N2 (3x). THF (4.0 mL) was injected, and the flask was
placed in a 0 °C ice bath. A solution of MeMgBr (3.0 M in Et2O, 0.14 mL, 0.42 mmol) was injected
dropwise, and the mixture was allowed to warm to 23 °C and stir for 2 h. The reaction was quenched with
saturated NaHCO3 solution (15 mL) and diluted with EtOAc (25 mL). The organic solution was washed
with 1N HCl (25 mL), H2O (25 mL), and brine (25 mL). The organic solution was dried over Na2SO4,
filtered, and the solvent was removed in vacuo. Flash column chromatography (hexanes : EtOAc, 1:0 →
3:1) afforded a mixture of benzylic alcohol diastereomers as a faint yellow oil (120 mg), which was
subjected to the next step without further purification. The benzylic alcohol (120 mg, 0.35 mmol) and
NaHCO3 (59 mg, 0.71 mmol) were added to a 25 mL round bottom flask. DCM (3.5 mL) was injected, and
the flask was placed in a 0 °C ice bath. Dess-Martin periodinane (180 mg, 0.42 mmol) was added, and the
flask was sealed with a rubber septum. The reaction was stirred for 1 h, after which the mixture was allowed
to warm to 23 °C. The reaction was then stirred an additional 1 h, and then quenched with saturated solutions
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of NaHCO3 (5 mL) and Na2S2O3 (5 mL). After stirring for 15 min, the mixture was diluted with DCM (25
mL) and washed with H2O (25 mL) and brine (25 mL). The organic solution was dried over Na2SO4,
filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 →
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4:1) afforded the title compound as a faint yellow oil (0.10 g, 73% over 2 steps). H NMR (500 MHz,
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DMSO-d6, 343 K) δ 7.88 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.20–4.05
(m, 2H), 3.78 (dd, J = 13.6, 4.2 Hz, 1H), 3.22–3.16 (m, 1H), 2.74 (d, J = 19.0 Hz, 1H), 2.56 (s, 3H), 2.47–
2.39 (m, 1H), 1.71 (dt, J = 12.8, 3.0 Hz, 1H), 1.65–1.45 (m, 4H), 1.44–1.31 (m, 3H), 1.21 (t, J = 6.9 Hz,
3H), 1.14 (ddt, J = 16.4, 13.2, 6.7 Hz, 1H), 0.92 (qd, J = 12.9, 3.8 Hz, 1H). 13C NMR (126 MHz, DMSO-
d6, 343 K) δ 198.0, 155.2, 142.7, 139.8, 136.4, 128.9, 126.3, 125.7, 61.1, 49.7, 43.9, 41.4, 38.1, 37.7, 36.0,
32.4, 26.9, 26.6, 26.2, 22.1, 15.0. IR (film) 2980, 2930, 2859, 1694, 1682, 1603, 1566, 1454, 1424, 1416,
1373, 1354, 1327, 1298, 1263, 1231, 1190, 1171, 1150, 1101, 1022, 990, 859, 945, 916, 826, 768, 731, 646
cm–1. HRMS (ESI) m/z: [M + Na]+ Calcd for C21H27NO3Na 364.1889; Found 364.1875 (3.8 ppm).
(4bS,8aS,9S)-ethyl
3-(1,1-difluoroethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-
phenanthrene-11-carboxylate (18)
Ketone 17 (0.14 g, 0.41 mmol) was transferred to a 1 dram screw-top vial, which was capped with a PTFE
septum. The vial was evacuated and backfilled with N2 (3x), and a solution of bis(2-
methoxyethyl)aminosulfur trifluoride (50% wt in PhMe, 1.0 mL, ca. 2.2 mmol) was injected. The reaction
was placed in an 85 °C heating plate and stirred for 18 h. The mixture was cooled to rt and poured into a
saturated aqueous solution of NaHCO3 (20 mL). The aqueous layer was extracted with DCM (3 x 10 mL),
and then the combined organic solution was washed with brine (30 mL). The organic solution was dried
over MgSO4, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes :
EtOAc, 1:0 → 9:1) afforded the title compound as a yellow oil (62 mg, 41%). 1H NMR (500 MHz, DMSO-
d6, 343 K) δ 7.45 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.12–4.02 (m,
2H), 3.77 (dd, J = 13.5, 4.1 Hz, 1H), 3.16 (dd, J = 18.7, 5.9 Hz, 2H), 2.70 (d, J = 18.7 Hz, 1H), 2.47 (d, J
= 14.1 Hz, 2H), 1.97 (t, J = 18.7 Hz, 3H), 1.75–1.67 (m, 1H), 1.65–1.45 (m, 4H), 1.37 (tdd, J = 13.4, 9.0,
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3.4 Hz, 3H), 1.20 (t, J = 6.9 Hz, 3H), 1.12 (qt, J = 13.1, 3.1 Hz, 1H), 0.93 (qd, J = 12.9, 3.8 Hz, 1H). 13C
NMR (126 MHz, DMSO-d6, 343 K) δ 155.22, 139.71, 138.85, 136.34 (t, J = 26.2 Hz), 128.82, 122.87 (t, J
= 237.3 Hz), 122.54 (t, J = 5.8 Hz), 121.96 (t, J = 6.0 Hz), 61.05, 49.76, 43.92, 41.40, 38.18, 37.66, 36.03,
32.04, 26.57, 26.18, 25.59 (t, J = 29.3 Hz), 22.08, 15.04. 19F NMR (376 MHz, CDCl3) δ (–86.56)–(–86.87)
(m). IR (film) 2980, 2930, 2859, 1694, 1464, 1454, 1428, 1418, 1375, 1327, 1294, 1265, 1233, 1190, 1191,
1150, 1130, 1103, 1022, 990, 928, 914, 897, 824, 797, 768, 735 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd
for C21H28F2NO2 364.2088; Found 364.2076 (3.3 ppm).
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(4bS,8aS,9S)-11-methyl-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-
ethano)phenanthrene (19)
LiAlH4 (18 mg, 0.47 mmol) was added to a 10 mL round bottom flask. THF (0.50 mL) was injected and
the suspension was cooled to 0 °C. A solution of carbamate 6 (0.06 g, 0.16 mmol) in THF (1.0 mL) was
injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture
was cooled to 0 °C, and 1N NaOH (3 mL) was injected dropwise. Et2O (3 mL) was injected, and the mixture
was stirred for 1 h. The mixture was diluted with Et2O (20 mL) and washed with a saturated aqueous
solution of NH3 (2 x 20 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
removed in vacuo to afford the title compound (45 mg, 86%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
δ 7.12 (dt, J = 8.3, 1.0 Hz, 1 H), 7.09–7.07 (m, 1 H), 6.99–6.95 (m, 1 H), 3.03 (d, J = 18.5 Hz, 1 H), 2.83
(dd, J = 5.8, 3.1 Hz, 1 H), 2.61 (dd, J = 18.5, 5.8 Hz, 1 H), 2.45 (ddd, J = 12.0, 4.7, 1.7 Hz, 1 H), 2.40 (s, 3
H), 2.32 (dq, J = 13.7, 2.7 Hz, 1 H), 2.03 (td, J = 12.4, 3.3 Hz, 1 H), 1.85 (dt, J = 12.9, 3.0 Hz, 1 H), 1.77
(td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.61 (m, 1 H), 1.58–1.51 (m, 1 H), 1.47–1.16 (m, 5 H), 1.07 (qd, J = 12.8,
3.8 Hz, 1 H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.9 (q, J = 1.8 Hz), 142.6, 136.5, 128.9, 120.5 (q, J =
256.2 Hz), 118.1, 118.0, 57.7, 47.0, 45.1, 42.8, 42.0, 37.4, 36.5, 26.7, 26.5, 23.6, 22.0. 19F NMR (376 MHz,
CDCl3) δ –57.9. IR (film) 3026, 2928, 2859, 2799, 1611, 1578, 1493, 1449, 1429, 1379, 1256, 1225, 1155,
1121, 1099, 1055, 909, 880, 849, 816, 689 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C18H23F3NO
326.1732; Found 326.1742 (3.1 ppm).
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(4bS,8aS,9S)-3-(difluoromethoxy)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-
ethano)phenanthrene (20)
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LiAlH4 (11 mg, 0.30 mmol) was added to a 5 mL round bottom flask. THF (0.25 mL) was injected, and the
suspension was cooled to 0 °C. A solution of carbamate 5 (37 mg, 0.10 mmol) in THF (0.75 mL) was
injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture
was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et2O (2 mL) was injected, and the mixture
was stirred for 1 h. The mixture was diluted with Et2O (10 mL) and washed with a saturated aqueous
solution of NH3 (2 x 10 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
removed in vacuo to afford the title compound (26 mg, 84%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
δ 7.10 (dt, J = 8.3, 0.9 Hz, 1 H), 7.00 (d, J = 2.6 Hz, 1 H), 6.88 (dd, J = 8.3, 2.5 Hz, 1 H), 6.48 (t, J = 74.5
Hz, 1 H), 3.02 (d, J = 18.4 Hz, 1 H), 2.82 (dd, J = 5.8, 3.1 Hz, 1 H), 2.60 (dd, J = 18.4, 5.8 Hz, 1 H), 2.44
(ddd, J = 12.0, 4.9, 1.9 Hz, 1 H), 2.40 (s, 3 H), 2.35–2.29 (m, 1 H), 2.03 (td, J = 12.3, 3.3 Hz, 1 H), 1.84
(dt, J = 12.8, 3.2 Hz, 1 H), 1.76 (td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.62 (m, 1 H), 1.57–1.50 (m, 1 H), 1.46–
1.29 (m, 4 H), 1.24 (qt, J = 13.2, 3.2 Hz, 1 H), 1.08 (qd, J = 12.7, 3.9 Hz, 1 H). 13C{1H} NMR (126 MHz,
CDCl3) δ 150.0 (t, J = 2.7 Hz), 142.8, 135.2, 129.0, 116.8, 116.7, 116.4 (t, J = 258.6 Hz), 57.8, 47.2, 45.3,
43.0, 42.1, 37.5, 36.7, 26.8, 26.6, 23.7, 22.2. 19F NMR (376 MHz, CDCl3) δ –80.0 (d, J = 7.4 Hz, 1 F), –
80.2 (d, J = 7.2 Hz, 1 F). IR (film) 3019, 2928, 2857, 2799, 1611, 1578, 1493, 1474, 1449, 1431, 1379,
1356, 1294, 1275, 1225, 1128, 1044, 961, 893, 853, 816, 762, 723, 638 cm–1. HRMS (ESI) m/z: [M + H]+
Calcd for C18H24F2NO 308.1826; Found 308.1831 (1.6 ppm).
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(4bS,8aS,9S)-11-methyl-3-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-
ethano)phenanthrene (21)
LiAlH4 (11 mg, 0.30 mmol) was added to a 5 mL round bottom flask. THF (0.50 mL) was injected, and the
suspension was cooled to 0 °C. A solution of carbamate 12 (67 mg, 0.10 mmol) in THF (0.50 mL) was
injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture
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was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et2O (1 mL) was injected, and the mixture
was stirred for 1 h. The mixture was diluted with Et2O (10 mL) and washed with a saturated aqueous
solution of NH3 (2 x 10 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
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removed in vacuo to afford the title compound (21 mg, 68%) as a faint yellow oil. H NMR (500 MHz,
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CDCl3) δ 7.50–7.47 (m, 1 H), 7.37–7.34 (m, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 3.09 (d, J = 18.8 Hz, 1 H), 2.85
(dd, J = 5.8, 3.1 Hz, 1 H), 2.67 (dd, J = 18.8, 5.7 Hz, 1 H), 2.49–2.39 (m, 2 H), 2.40 (s, 3 H), 1.99 (td, J =
12.4, 3.3 Hz, 1 H), 1.88 (dt, J = 12.9, 3.0 Hz, 1 H), 1.79 (td, J = 12.7, 4.8 Hz, 1 H), 1.70–1.62 (m, 1 H),
1.59–1.52 (m, 1 H), 1.49–1.30 (m, 4 H), 1.20 (qt, J = 13.3, 3.4 Hz, 1 H), 1.05 (qd, J = 12.7, 3.8 Hz, 1 H).
13C{1H} NMR (126 MHz, CDCl3) δ 142.2 (q, J = 1.1 Hz), 141.5, 128.7 (q, J = 31.8 Hz), 128.3, 124.7 (q, J
= 271.9 Hz), 122.5 (q, J = 3.8 Hz), 122.2 (q, J = 3.7 Hz), 57.7, 47.1, 45.4, 43.0, 42.1, 37.4, 36.5, 26.8, 26.6,
24.4, 22.1. 19F NMR (376 MHz, CDCl3) δ –62.1. IR (film) 3032, 2928, 2857, 2799, 1616, 1580, 1503, 1462,
1447, 1427, 1379, 1331, 1306, 1277, 1261, 1198, 1177, 1159, 1121, 1086, 1057, 1037, 895, 837, 822, 764,
735, 723 cm–1. HRMS (ESI) m/z: [M + H]+ Calcd for C18H23F3N 310.1783; Found 310.1786 (1.0 ppm).
(4bS,8aS,9S)-3-(difluoromethyl)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-
ethano)phenanthrene (22)
LiAlH4 (6.8 mg, 0.18 mmol) was added to a 5 mL round bottom flask. THF (0.3 mL) was injected, and the
suspension was cooled to 0 °C. A solution of carbamate 15 (21 mg, 0.060 mmol) in THF (0.7 mL) was
injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture
was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et2O (1 mL) was injected, and the mixture
was stirred for 1 h. The mixture was diluted with Et2O (10 mL) and washed with a saturated aqueous
solution of NH3 (2 x 5 mL). The organic solution was dried over Na2SO4, filtered, and the solvent was
removed in vacuo to afford the title compound (14 mg, 80%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
δ 7.37 (s, 1 H), 7.27–7.24 (m, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 6.61 (t, J = 56.7 Hz, 1 H), 3.07 (d, J = 18.7
Hz, 1 H), 2.84 (dd, J = 5.8, 3.1 Hz, 1 H), 2.70–2.62 (m, 1 H), 2.47–2.39 (m, 2 H), 2.40 (s, 3 H), 2.01 (td, J
= 12.3, 3.3 Hz, 1 H), 1.87 (dt, J = 12.9, 3.0 Hz, 1 H), 1.78 (td, J = 12.7, 4.8 Hz, 1 H), 1.68–1.62 (m, 1 H),
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