A Copper-Mediated Conjugate Addition Approach to Analogues of Aconitine-Type Diterpenoid Alkaloids

Article abstract of DOI:10.1021/acs.joc.8b01967

A copper-mediated conjugate addition of electron-rich aryl groups into a complex vinyl nitrile using arylmagnesium bromides is reported. The conjugate addition adducts were advanced toward the synthesis of designed aconitine-type analogues. The variation

Full text of DOI:10.1021/acs.joc.8b01967

Subscriber access provided by University of South Dakota
Note
A Copper-Mediated Conjugate Addition Approach
to Analogs of Aconitine-Type Diterpenoid Alkaloids
Nicolle A Doering, Kevin G. M. Kou, Krissada Norseeda, Jack C
Lee, Christopher J Marth, Gary M Gallego, and Richmond Sarpong
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2018
Downloaded from http://pubs.acs.org on September 15, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 25
The Journal of Organic Chemistry
A Copper-Mediated Conjugate Addition Approach to Analogs of Ac-
onitine-Type Diterpenoid Alkaloids
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
†
‡
§
ǁ
Nicolle A. Doering, Kevin G. M. Kou , Krissada Norseeda, Jack C. Lee , Christopher J. Marth , Gary M. Gallego , Rich-
mond Sarpong*
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Department of Chemistry, University of California, Berkeley, California 94720, United States
KEYWORDS. Diterpenoid alkaloids, aconitine analogs, 1,4-addition, Cu-mediated, Rh-catalyzed, ,-unsaturated nitrile
ABSTRACT: A copper-mediated conjugate addition of electron-rich aryl groups into a complex vinyl nitrile using arylmagne-
sium bromides is reported. The conjugate addition adducts were advanced toward the synthesis of designed aconitine-type
analogs. The variation in oxygenation patterns on the arene coupling partner, introduced through the current conjugate addition
approach, may ultimately provide insight into structure–activity relationships of the diterpenoid alkaloids.
Aconitine (1, Figure 1) and lappaconitine (2) elicit contrasting effects upon interaction with human voltage-gated sodium
ion channels; aconitine exposure induces persistent activation of neurons leading to cardiac arrest, whereas lappaconitine leads
to blockage of acute pain signals.1,2 These two related diterpenoid alkaloids exemplify the disparate effects of this class of
natural products on voltage-gated ion channels.3–6 Given that voltage-gated sodium (Na
), calcium (Ca ), and potassium (K )
V V V
ion channels regulate biophysical responses across the nervous, circulatory, and muscular systems, the ability to selectively
target voltage-gated sodium ion channels would have significant implications for the treatment of epilepsy, chronic pain, and
myriad other channelopathies.7
Figure 1. Selected examples of diterpenoid alkaloids.
Diterpenoid alkaloids have long been recognized for their utility in combating channelopathies, appearing in traditional
6
Chinese medicine as treatments for pain and cardiovascular disease. Today, lappaconitine (3) is approved and marketed in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
V
chan-
8
China and Russia for pain relief and arrhythmia treatment, effects which likely stem from lappaconitine blocking Na
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9
nels. On the other hand, aconitine (1) is a highly toxic Na
V
channel activator reported to be lethal to humans in doses as low
channel blocker, whereas chasmanine (4) has no known ion channel activity.4,11
V
1
0
as 1-2 mg. Talatisamine (2) is a known K
The pronounced biological effects of small changes to the periphery of these pseudoalkaloids have made the structural
origin of their bioactivities a matter of interest for over a century. Among the first to explore the structure–activity relationships
(SAR) of the diterpenoid alkaloids were Cash and Dunstan, who compared aconitine to two hydrolyzed derivatives, aconine
and 14-O-benzoylaconine.12 More recently, Tursunkhodzhaeva and co-workers probed these relationships with a larger set of
isolated diterpenoid alkaloids and their derivatives.13,14 This approach led to the identification of some key substituents on
aconitine-type and lappaconitine-type natural products that imbue them with certain biological activities, but this study was
limited by its inability to systematically vary the peripheral substituents. Not all combinations of substitution patterns are
present in the known diterpenoid alkaloids and derivatization has been limited to hydrolysis of amides and to acylation—or,
in one case, methylation—of free hydroxy groups. Furthermore, lack of site selectivity for acylation in the presence of multiple
hydroxy groups has limited the synthesis of derivatives.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Our lab has developed strategies to access several C18-, C19-, and C20-diterpenoid alkaloids.15–17 While these efforts yielded
enough material for biological assays, the syntheses are relatively long and opportunities for wide-ranging introduction of
oxygenation have been limited. In order to overcome these challenges, we explored a synthesis approach to aconitine-type
analogs that should be more amenable to systematic variation of oxygenation patterns. In designing these analogs, we generated
a set of key considerations on the basis of which structural features are conserved and which are varied across this family of
natural products (Figure 2).
Figure 2. Ring labeling and analog design considerations.
Previous SAR studies have indicated that variation in hydroxylation along the D ring have a drastic impact on the biological
activity of aconitine-type diterpenoid alkaloids.13,14 The primary emphasis of our design strategy thus focuses on varying the
substitution pattern around this ring, while maintaining selected features common to the aconitine-type natural products. To
this end, our analogs were designed to retain the A-E-F ring carbon framework, which—unlike the [3.2.1] bicycle comprised
by the C and D rings—is conserved across the majority of the atisane-derived alkaloids. The N-ethyl group and the C1 methoxy
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
group are also highly conserved within this family and thus maintained in our designs for analogs. C4 substituents, however,
differ greatly between aconitine- and lappaconitine-type diterpenoid alkaloids. To facilitate a thorough exploration of the im-
portance of the D ring substitution patterns, the C4 substituents were excluded from our present study, although these C4
substituents may be incorporated at a later stage using previously established strategies.17 Additionally, diterpenoid alkaloids
bearing a [2.2.2] bicycle as their CD ring system, a change which significantly alters the conformation of the D ring compared
to that of the aconitine system, are also known to modulate ion channels.18 Therefore, our initial studies aimed to excise C12
as this structural simplification would allow more rapid access to natural product-inspired analogs that probe the tolerability
of the binding site to modulations in polarity, shape and spatial orientation in the D ring.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
On the basis of these considerations, we targeted analogs, such as pentacycle 5 and spirocycle 6 (Figure 3). Each of these
designed targets could ultimately arise from aldehyde 7 through oxidative dearomatization strategies. Aldehyde 7, in turn,
could be taken back to primary amide 8, which itself could be derived from known vinyl nitrile 9.15 In the forward sense, this
route would begin with a conjugate addition of aryl nucleophiles into 9. Additional analogs could be accessed through variation
of the nucleophile in this step, resulting in differing oxygenation patterns on the aryl ring (see Table 1) prior to oxidative
dearomatization.
Figure 3. Retrosynthesis of two classes of aconitine analogs.
Our initial approach toward these simplified analogs was to effect a Hayashi-type19 Rh-catalyzed conjugate addition of
boronate esters into vinyl nitrile 9, following previously successful protocols from our laboratories. However, this reaction
proved to be sensitive to the electronics and substitution patterns of the arene nucleophiles. While the Rh-catalyzed method
worked well for the two previously published substrates (Table 1, 10a and 10b), the same was not true when the boronate
derived from MOM-protected p-bromophenol was used (see 10d, Method A). In the latter case, low conversion (67% recovery
of nitrile 9) was observed.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
Table 1. Scope and comparison of Rh-catalyzed and Cu-mediated methods for conjugate addition.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a) Procedure taken from previous report; see ref. 17
b) Small amounts of -CN diastereomer obtained but not characterized.
To address the poor reactivity of many substituted aryl boronate esters in the Rh(I)-catalyzed conjugate addition, we inves-
tigated an organocuprate-based strategy using copper(I) iodide and Grignard reagents (Method B). While the conditions that
were initially selected followed related precedent involving addition of alkyl cuprates into simple—and often highly acti-
vated—vinyl nitriles,20–23 high yields using structurally complex vinyl nitrile 9 were only realized after extensive optimization.
Our Cu-mediated conjugate addition method proceeded under milder conditions than the Rh-catalyzed approach and gave the
desired product (10d) with improved efficiency over the Rh-catalyzed conjugate addition conditions (see 10d, Method A).
While a mixture of diastereomers were obtained (2.8:1 d.r. at C17), the undesired -isomer could be readily epimerized using
base to the desired -isomer (vide infra). In order to facilitate syntheses of analogs related to 5 and 6 with a variety of substi-
tution patterns, we explored a series of Cu-mediated conjugate additions using various oxygenated arenes. The reaction proved
to be robust, tolerating a variety of substitution patterns, including sterically hindered arenes. While the use of o,m-disubstituted
arenes (10a) resulted in low conversion, the reaction proceeded in good to excellent yield when other doubly oxygenated arenes
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
with at least one o-substituent were used (10c, 10f, 10m). The conjugate addition also accommodated various phenols masked
as MOM ethers (10d, 10g, 10j). Additionally, the method worked in the presence of a dibromoarene (see 10i), allowing one of
the bromine atoms to be preserved as a functional handle for further derivatization.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The conjugate addition products could then be elaborated to the caged scaffold conserved between the bioactive diterpenoid
alkaloids. A synthesis of aldehyde 7 (Scheme 1) is illustrative of our approach to the common aldehyde intermediates required
to generate aconitine-type analogs. Starting from vinyl nitrile 9, conjugate addition of the cuprate derived from arylmagnesium
bromide 11 afforded 10d as a mixture of diastereomers, which were separated by flash column chromatography. The minor -
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN product (-10d) was converted to the desired -CN diastereomer (-10d) under basic conditions. The structure of nitrile
-10d and the configuration of the two newly installed stereocenters relative to the rest of the hydrindane system were unam-
biguously confirmed by X-ray crystallography.
Scheme 1. Formation of caged piperidine skeleton.
a) Substituents on the silicon atom omitted for clarity in CYLView rendering of the crystal structure of -10d.
At this stage, the ester moiety of -10d was reduced with Red-Al® and the resultant alcohol was protected as a MOM ether
to give 12. This allowed us to retain the hydroxy group as a functional handle, in contrast to our previous syntheses, where the
primary alcohol was converted to a terminal olefin.15–17 The nitrile group was then hydrated under anhydrous conditions to
afford primary amide 8. A Hofmann rearrangement of this amide afforded a primary amine, which was subsequently acetylated
to form an acetamide. In previous syntheses, a methyl carbamate had instead been installed on related substrates at this stage.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
This necessitated late-stage conversion of that carbamate into an acetamide. Strategies to do so required hydrolysis and decar-
boxylation, which generally required harsh reaction conditions. We surmised that the severe conditions for these steps would
likely be problematic in the current synthesis due to the presence of free hydroxy groups in our late-stage intermediates. Thus,
given that we would eventually require an acetamide—that would ultimately be reduced to the ethylamine present in our
designed analogs—we decided to convert amide 8 directly to an acetamide. Following acetylation, TBAF-mediated cleavage
of the TBS group gave alcohol 13. Mesylation of primary alcohol group 13 set the stage for cyclization to form piperidine 14
under basic conditions, completing the caged left-hand side of the molecule. The two MOM groups on 14 were then cleaved
and the newly revealed primary hydroxy group was oxidized under Swern conditions to give aldehyde 7.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The exploration of various cyclization modes of key intermediate 7 to the aconitine-type analogs is ongoing in our labora-
tories. Preliminary studies toward the spirocyclic analogs are particularly promising, and the desired scaffold (15) is formed
through oxidative dearomatization with PhI(OAc)
in the presence of methanol (Scheme 2).31 Efforts toward intermolecular
2
oxidative dearomatization en route to the CD-fused analogs are also underway.
Scheme 2. Oxidative dearomatization of 7 to build spirocyclic scaffold.
In summary, with a route to aldehyde 7 firmly established through our development of a robust and versatile conjugate addition
protocol, the stage is now set for the exploration of aconitine-type analogs related to spirocyclic 5 and CD-fused 6, which may
provide additional insight into the structure–activity relationship of these intriguing pseudoalkaloids.
EXPERIMENTAL SECTION
General Experimental Methods.
i) Solvents and reagents. Unless noted below, commercial reagents were used without additional purification. Tetrahydrofuran
(
THF), diethyl ether (Et
argon and dried by passing through alumina columns using argon in a Glass Contour solvent purification system. Dichloro-
methane (CH Cl ) was freshly distilled over calcium hydride under a N atmosphere prior to each use. DMSO and toluene
PhMe) were distilled over calcium hydride under a N atmosphere, degassed using freeze-pump-thaw (3 cycles), and stored
over 4 Å molecular sieves in a Schlenk flask under N . Dimethylformamide (DMF), acetone, n-BuLi solution, LiHMDS solu-
2 3
O), acetonitrile (MeCN), benzene, methanol (MeOH), and triethylamine (Et N) were sparged with
2
2
2
(
2
2
tion, Red-Al® solution, Grignard solutions, and pyridine were purchased in Sure-SealTM, AcroSealTM, or ChemSealTM bottling,
6
ACS Paragon Plus Environment

Page 7 of 25
and used directly. 1,4-Dioxane was purchased in AcroSeal bottling (99.5%, anhydrous, stabilized, over 4 Å molecular sieves)
and additionally sparged with N prior to use.
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
ii) Reaction setup, progress monitoring, and product purification. Unless otherwise noted in the experimental procedures,
reactions were carried out in flame or oven-dried glassware under a positive pressure of N in anhydrous solvents using standard
2
Schlenk techniques. Reactions run at temperatures above rt (22–23 C) were controlled by an IKA® temperature modulator
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and monitored using liquid-in-glass thermometers. Reaction progress was monitored using a combination of LC/MS analysis
(
Shimadzu LCMS-2020 (UFLC) equipped with the LC20AD solvent delivery system, a SPD-20AV prominence UV/Vis de-
tector (SPD-M20A Photo Diode Array), and a Thermo Scientific Hypersil GOLD HPLC column (5 μm particle size, 4.6 × 50
mm)) and thin-layer chromatography (TLC) on EMD Millipore silica gel plates (glass backed, extra hard layer, 60 Å, 250 μm
thickness, F254 indicator). Visualization of the developed plates was performed under UV-light (254 nm) irradiation, and
4
subsequent gentle heating with KMnO , p-anisaldehyde, or ceric ammonium molybdate stains. Purification and isolation of
products were performed via silica gel chromatography (both column and preparative thin-layer chromatography). Flash col-
umn chromatography was performed with either glass columns using Silicycle silica gel (40–63 μm particle size) or with a
Yamazen Smart S4 Flash EPCLC W-Prep 2XY (dual channel) automated flash chromatography system on prefilled, premium,
universal columns using ACS grade solvents. Organic solutions were concentrated under reduced pressure on a Heidolph
temperature-controlled rotary evaporator equipped with a dry ice/isopropanol condenser or a Büchi temperature-controlled
rotary evaporator equipped with an Ecodyst Ecochyll system.
iii) Analytical instrumentation. NMR spectral data were obtained using deuterated solvents obtained from Cambridge Isotope
Laboratories, Inc. H NMR and 13C NMR data were recorded on Bruker AVB-400, AVQ-400, AV-500, DRX-500, AV-600,
1
or AV-700 MHz spectrometers using CDCl
3 3 6 6
, CD OD, or C D , typically at 20–23 °C. Chemical shifts () are reported in ppm
relative to the residual solvent signal ( 7.26 for H NMR,  77.16 for 13C NMR in CDCl
1
). Data for H NMR spectroscopy
24
1
3
are reported as follows; chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet, bs = broad singlet, dd = doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, ddd = doublet of
doublets of doublets, dtd = doublet of triplets of doublets, dtt = doublet of triplets of triplets, ddq = doublet of doublets of
quartets, dddd = doublet of doublets of doublets of doublets, td = triplet of doublets, tt = triplet of triplets, tdd = triplet of
doublets of doublets, qd = quartet of doublets, qt = quartet of triplets), coupling constant (Hz), integration. Data for 13C NMR
spectroscopy are reported in terms of chemical shift ( ppm). IR spectroscopic data were recorded on a Bruker ALPHA FT-IR
spectrophotometer using a diamond attenuated total reflectance (ATR) accessory. Samples are loaded onto the diamond surface
either neat or as a solution in organic solvent and the data acquired after the solvent had evaporated. Mass spectral data were
obtained from the Mass Spectral Facility at the University of California, Berkeley, on a Finnigan/Thermo LTQ-FT instrument
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
(
ESI), or from the Catalysis Facility of Lawrence Berkeley National Laboratory (supported by US Department of Energy under
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
contract no. DE-AC02-05CH11231), on a PerkinElmer AxION 2 UHPLC-TOF system (ESI or APCI). Data acquisition and
processing were performed using the XcaliburTM software. X-Ray data were collected on a Bruker APEX-II CCD diffrac-
tometer with Mo-K radiation ( = 0.71073 Å) or a MicroStar-H X8 APEX-II diffractometer with Cu-K radiation ( =
1.54178 Å) (University of California, Berkeley; Supported by an NIH Shared Instrumentation Grant S10- RR027172). CYL-
view and ORTEP3 were used for graphic rendering.25,26
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of aryl bromides for conjugate additions in Table 1.
1
2 3
-bromo-4-(methoxymethoxy)benzene (S1). 4-Bromophenol (25.2 g, 145 mmol, 1.0 equiv) and K CO (30.2 g, 218 mmol, 1.5
equiv) were dissolved in acetone (200 mL, 0.67 M) at room temperature. To this stirring suspension was added MOMCl (16.5
mL, 218 mmol, 1.5 equiv) dropwise over 5 minutes. The reaction mixture was then heated in an oil bath at 60 C for 20 h. The
reaction mixture was then cooled to room temperature and concentrated in vacuo to remove acetone. The resultant wet solid
2
was dissolved in water (75 mL), then extracted with Et O (3 × 75 mL). The combined organic extracts were washed with brine
(25 mL), dried over MgSO
4
, and concentrated in vacuo. Purification by column chromatography eluting with 0–10% EtOAc
1
in hexanes gave S1 as a colorless oil (26.3 g, 121 mmol, 83%). H NMR (400 MHz, CDCl
3
)  7.38 (m, 2H), 6.92 (m, 2H), 5.15
(s, 2H), 3.47 (s, 3H). Spectroscopic data for this compound were identical to those previously reported.27
1
-bromo-3-(methoxymethoxy)benzene (S2). 3-Bromophenol (1.37 g, 8.00 mmol, 1.0 equiv) and K
2 3
CO (1.66 g, 12.0 mmol,
1
.5 equiv) were dissolved in acetone (12.0 mL, 0.67 M) at room temperature. To this stirring suspension was added MOMCl
(
0.91 mL, 12.0 mmol, 1.5 equiv) dropwise over 5 minutes. The reaction mixture was then heated in an oil bath at 60 C for 16
h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove acetone. The resultant wet
solid was dissolved in water (10 mL), then extracted with Et O (3 × 10 mL). The combined organic extracts were washed with
2
brine (5 mL), dried over MgSO
4
, and concentrated in vacuo. Purification by column chromatography eluting with 0–7% EtOAc
1
in hexanes gave S2 as a colorless oil (879 mg, 4.05 mmol, 51%). H NMR (600 MHz, CDCl
3
)  7.22 (t, J = 1.7 Hz, 1H), 7.18
–
7.08 (m, 2H), 6.97 (dt, J = 6.6, 2.5 Hz, 1H), 5.16 (s, 2H), 3.47 (s, 3H). Spectroscopic data for this compound were identical
to those previously reported.28
1
2 3
-bromo-2-(methoxymethoxy)benzene (S3). 2-Bromophenol (1.38 g, 8.00 mmol, 1.0 equiv) and K CO (1.67 g, 12.0 mmol,
1.5 equiv) were dissolved in acetone (12.0 mL, 0.67 M) at room temperature. To this stirring suspension was added MOMCl
(0.91 mL, 12.0 mmol, 1.5 equiv) dropwise over 5 minutes. The reaction mixture was then heated in an oil bath at 60 C for 16
h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove acetone. The resultant wet
solid was dissolved in water (10 mL), then extracted with Et
2
O (3 × 10 mL). The combined organic extracts were washed with
8
ACS Paragon Plus Environment

Page 9 of 25
brine (5 mL), dried over MgSO
The Journal of Organic Chemistry
4
, and concentrated in vacuo. Purification by column chromatography eluting with 0–7% EtOAc
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
in hexanes gave S3 as a colorless oil (1.13 g, 5.21 mmol, 65%). H NMR (600 MHz, CDCl
3
)  7.55 (dd, J = 7.9, 1.6 Hz, 1H),
7
.25 (td, J = 7.6, 1.6 Hz, 1H), 7.15 (dd, J = 8.3, 1.5 Hz, 1H), 6.89 (td, J = 7.6, 1.5 Hz, 1H), 5.25 (s, 2H), 3.53 (s, 3H).
Spectroscopic data for this compound were identical to those previously reported.29
1
2 3
,3-dibromo-5-(methoxymethoxy)benzene (S4). 3,5-Dibromophenol (1.37 g, 5.44 mmol, 1.0 equiv) and K CO (1.18 g, 8.16
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol, 1.5 equiv) were dissolved in acetone (8.0 mL, 0.67 M) at room temperature. To this stirring suspension was added
MOMCl (0.41 mL, 8.16 mmol, 1.5 equiv) dropwise over 5 minutes. The reaction mixture was then heated in an oil bath at 60

C for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to remove acetone. The
resultant wet solid was dissolved in water (5 mL), then extracted with Et O (3 × 5 mL). The combined organic extracts were
2
washed with brine (5 mL), dried over MgSO
4
, and concentrated in vacuo. Purification by column chromatography eluting with
1
0
–7% EtOAc in hexanes gave S4 as a colorless oil (1.17 g, 3.95 mmol, 73%). H NMR (600 MHz, CDCl
3
)  7.30 (t, J = 1.6
Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 5.14 (s, 2H), 3.47 (s, 3H). Spectroscopic data for this compound were identical to those
previously reported.30
General procedure for copper conjugate additions using aryl bromides (method 1).
Aryl bromide (0.527 mmol, 4.0 equiv) and magnesium (14.0 mg, 0.580 mmol, 4.4 equiv) were dissolved in THF (1 mL, 0.53
M with respect to aryl bromide) and heated in an oil bath at 50 C for 45 min or until the magnesium turnings had mostly
dissolved. The reaction mixture was then allowed to cool to room temperature and then placed in an ice/water bath. The solution
was then transferred via syringe to a chilled vial containing copper(I) iodide (50.0 mg, 0.263 mmol, 2.0 equiv) and stirred
vigorously in the ice bath for 25 min. At this point, vinyl nitrile 9 (50.0 mg, 0.132 mmol, 1.0 equiv) was added as a solution in
THF (0.5 mL, 0.26 M). The reaction mixture was removed from the ice bath, sealed with a TeflonTM cap, and heated in an oil
bath at 45 C and held at this temperature for 20 h. The reaction mixture was then allowed to cool to room temperature,
quenched with MeOH (0.25 mL), diluted with NH
4
Cl (saturated aqueous, 5 mL), and extracted with EtOAc (3 × 5 mL). The
SO , and concentrated in vacuo.
combined organic extracts were washed with brine (3 × 2 mL), dried over Na
2
4
General procedure for copper conjugate additions using commercial Grignard reagents (method 2).
2
Commercial Grignard solution (0.527 mmol, 4.0 equiv) was diluted to 0.53 M in THF in a sealed 1 dram vial under N and
cooled in an ice/water bath. The solution was then transferred via syringe to a chilled vial containing copper(I) iodide (50.0
mg, 0.263 mmol, 2.0 equiv) and stirred vigorously in the ice bath for 25 min. At this point, vinyl nitrile 9 (50.0 mg, 0.132
mmol, 1.0 equiv) was added as a solution in THF (0.5 mL, 0.26 M). The reaction mixture was removed from the ice bath,
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
sealed with a TeflonTM cap, and heated in an oil bath at 45 C for 20 h. The reaction mixture was then allowed to cool to room
temperature, quenched with MeOH (0.25 mL), diluted with NH Cl (saturated aqueous, 5 mL), and extracted with EtOAc (3 ×
mL). The combined organic extracts were washed with brine (3 × 2 mL), dried over Na SO , and concentrated in vacuo.
Page 10 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
5
2
4
2-methoxy-3-OMOM tricycle (10a). Prepared according to method 1. Purification by column chromatography (eluting with
1
60–100% CH
(600 MHz, CDCl
2H), 4.04 (ddd, J = 11.6, 8.7, 2.9 Hz, 1H), 3.98 (s, 1 H), 3.94 (s, 3H), 3.74 (s, 3H), 3.52 (s, 3H), 3.44 (s, 3H), 3.40 (dd, J = 7.4,
.3, 2H), 3.25 (d, J = 8.4 Hz, 1H), 3.11 (ddd, J = 13.3, 9.0, 4.9 Hz, 1H), 2.40 (q, J = 12.5 Hz, 1H), 2.09 (ddd, J = 13.8, 4.9, 2.2
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10a (trace amounts) as a colorless oil in <5% yield. H NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
)  7.03 (dd, J = 8.1, 1.2 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.88 (dd, J = 7.7, 1.1 Hz, 1H), 5.23 – 5.18 (m,
2
Hz, 1H), 2.00 (dtt, J = 11.8, 7.4, 4.5, 1H), 1.63 (ddd, J = 12.3, 9.1, 3.0 Hz, 1H), 1.47 – 1.32 (m, 3H), 0.88 (s, 9H), 0.02 (s, 3H),
0.01 (s, 3H). Spectroscopic data for this compound were identical to those previously reported.15
−
3
,5-dimethoxy tricycle (10b). Prepared according to method 1. Run with modified equivalents of reagents (6.0 equiv of Gri-
gnard solution, 5.0 equiv of CuI). Purification by column chromatography (eluting with 60–100% CH Cl /hexanes, then 1–5%
2
2
Et
2
O/CH
2
Cl
2
) provided -10b and -10b in 76% combined yield.
1

-10b. Isolated as a colorless oil (37.1 mg, 0.0717 mmol, 58%). H NMR (500 MHz, CDCl
3
)  6.42 (d, J = 2.2 Hz, 2H), 6.33
(
t, J = 2.2 Hz, 1H), 3.97 (bs, 1H), 3.79 (s, 6H), 3.73 (s, 3H), 3.68 (ddd, J = 11.4, 8.4, 2.8 Hz, 1H), 3.43 (s, 3H), 3.42 (s, 1H),
3.41 (s, 1H), 3.08 (d, J = 8.4 Hz, 1H), 3.00 (ddd, J = 13.6, 8.9, 4.8 Hz, 1H), 2.41 (q, J = 12.6 Hz, 1H), 2.12 – 2.06 (m, 1H),
2.02 ‒ 1.95 (m, 1H), 1.74 (ddd, J = 12.4, 9.0, 2.9 Hz, 1H), 1.50 – 1.27 (m, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).
Spectroscopic data for this compound were identical to those previously reported.15
1

-10b. Isolated as a pale yellow oil (11.6 mg, 0.0224 mmol, 18%). H NMR (600 MHz, CDCl
3
)  6.43 (d, J = 2.2 Hz, 2H),
6
9
1
.34 (t, J = 2.2 Hz, 1H), 3.92 (s, 1H), 3.82 – 3.77 (m, 1H), 3.78 (s, 6H), 3.78 (s, 3H), 3.64 (d, J = 9.7 Hz, 1H), 3.49 (dd, J =
.8, 7.4 Hz, 1H), 3.43 (dd, J = 9.9, 7.3 Hz, 1H), 3.37 (s, 3H), 3.22 (ddd, J = 13.6, 8.9, 5.3 Hz, 1H), 2.28 (td, J = 13.0, 11.5 Hz,
H), 2.15 (tdd, J = 12.0, 7.3, 4.7 Hz, 1H), 2.07 (dq, J = 14.4, 3.0 Hz, 1H), 1.86 (ddd, J = 12.5, 9.0, 3.1 Hz, 1H), 1.41 – 1.34
(
m, 1H), 1.31 (qd, J = 13.1, 2.9 Hz, 1H), 1.19 (dddd, J = 14.9, 13.3, 3.7, 1.8 Hz, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H);
13C NMR (151 MHz, CDCl
)  172.7, 160.9, 145.0, 119.2, 106.7, 99.1, 79.6, 66.6, 63.1, 57.3, 55.4, 53.0, 46.1, 44.8, 41.4, 38.1,
3
3
1
2.3, 26.1, 25.4, 18.4, 16.4, −5.2; IR (thin film): 2950, 2930, 2900, 2856, 2237, 1738, 1596, 1460, 1250, 1205, 1153, 1105,
-1
+
43 6
085, 835, 775 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752; found 540.2743.
2,5-dimethoxy tricycle (10c). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10c and -10c in 93% combined yield.
10
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1

-10c. Isolated as a colorless oil (44.3 mg, 0.0856 mmol, 28%). H NMR (600 MHz, CDCl
3
)  6.78 (d, J = 8.8 Hz, 1H), 6.77
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
d, J = 3.0 Hz, 1H), 6.73 (dd, J = 8.8, 3.0 Hz, 1H), 3.97 (q, J = 1.8 Hz, 1H), 3.87 (ddd, J = 11.9, 8.7, 3.2 Hz, 1H), 3.79 (s, 3H),
.76 (s, 3H), 3.74 (s, 3H), 3.44 (s, 3H), 3.42 (d, J = 8.7 Hz, 1H), 3.41 – 3.38 (m, 2H), 3.16 (ddd, J = 13.3, 9.1, 4.9 Hz, 1H),
2.31 (q, J = 12.3 Hz, 1H), 2.09 (dq, J = 14.0, 3.0 Hz, 1H), 1.96 (tt, J = 11.5, 3.8 Hz, 1H), 1.71 (ddd, J = 12.4, 9.1, 3.3 Hz, 1H),
3
1
3
1.47 – 1.32 (m, 3H), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); C NMR (151 MHz, CDCl
3
)  173.6, 153.7, 151.5, 133.5, 120.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
116.0, 112.2, 111.9, 77.2, 66.6, 60.6, 57.0, 55.9, 55.9, 52.8, 46.1, 44.0, 42.7, 38.4, 32.1, 26.1, 25.0, 18.4, 16.8, −5.3; IR (thin
-
1
+
film): 2950, 2931, 2896, 2856, 2237, 1728, 1501, 1248, 1223, 1101, 1080, 1048, 835, 775 cm ; HRMS (ESI) m/z [M+Na] :
calc’d for C28 NNaSi 540.2752, found 540.2749.
43 6
H O
1

-10c. Isolated as a colorless oil (19.3 mg, 0.0372 mmol, 65%). H NMR (600 MHz, CDCl
d, J = 8.8 Hz, 1H), 6.74 (dd, J = 8.8, 2.9 Hz, 1H), 4.12 (ddd, J = 11.4, 9.9, 2.9 Hz, 1H), 3.91 (p, 1.5 Hz, 1H), 3.80 (s, 3H),
.79 – 3.75 (m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.54 (dd, J = 9.9, 7.0 Hz, 1H), 3.45 (dd, J = 9.9, 7.5 Hz, 1H), 3.39 (s, 3H), 3.17
ddd, J = 13.5, 8.4, 4.9 Hz, 1H), 2.21 (td, J = 13.1, 11.2 Hz, 1H), 2.12 (tdd, J = 12.0, 7.3, 4.8 Hz, 1H), 2.07 (dq, J = 14.7, 3.3
3
)  6.87 (d, J = 3.0 Hz, 1H), 6.78
(
3
(
Hz, 1H), 1.93 (ddd, J = 12.3, 8.7, 3.1 Hz, 1H), 1.42 – 1.29 (m, 2H), 1.19 (tdd, J = 14.7, 4.2, 2.0 Hz, 1H), 0.91 (s, 9H), 0.07 (s,
13
3
5
1
5
H), 0.07 (s, 3H); C NMR (151 MHz, CDCl
3
)  172.9, 153.7, 151.8, 131.9, 119.4, 115.0, 111.9, 111.2, 79.8, 66.8, 62.9, 57.5,
6.0, 55.9, 52.9, 43.8, 41.1, 39.4, 38.2, 29.7, 26.1, 25.6, 18.5, 16.6, −5.2; IR (thin film): 2952, 2928, 2855, 2234, 1739, 1591,
-1
+
43 6
496, 1250, 1219, 1106, 1087, 1054, 837, 776 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752, found
40.2747.
4-OMOM tricycle (10d). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10d and -10d in 90% combined yield from 1.23 g (3.24 mmol) of
nitrile 9.
1

-10d. Isolated as a colorless oil (1.10 g, 2.13 mmol, 66%). H NMR (500 MHz, CDCl
3
)  7.20 – 7.17 (m, 2H), 7.00 – 6.96
(
m, 2H), 5.21 – 4.93 (m, 2H), 3.97 (bs, 1H), 3.73 (s, 3H), 3.70 (ddd, J = 11.4, 8.3, 2.7 Hz, 1H), 3.47 (s, 3H), 3.45 – 3.37 (m,
H), 3.43 (s, 3H), 3.03 (ddd, J = 13.5, 9.1, 4.5 Hz, 1H), 3.02 (d, J = 8.4 Hz, 1H), 2.43 (td, J = 13.1, 11.5 Hz, 1H), 2.09 (dq, J
2
=
12.9, 2.7, 2.2 Hz, 1H), 2.00 (dtd, J = 10.7, 6.2, 3.5 Hz, 1H), 1.72 (ddd, J = 12.4, 9.0, 2.9 Hz, 1H), 1.47 – 1.32 (m, 3H), 0.89
(
s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (126 MHz, CDCl
3
)  173.3, 156.2, 139.1, 128.0, 120.1, 116.8, 94.6, 77.1, 66.2,
6
2
0.4, 57.1, 56.1, 52.9, 48.7, 47.8, 43.4, 38.2, 33.1, 26.0, 24.8, 18.4, 16.6, −5.26, −5.29; IR (thin film): 2951, 2929, 2897, 2856,
-1
+
43 6
240, 1731, 1511, 1462, 1237, 1079, 1005, 815, 776 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752,
found 540.2757.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
-10d. Isolated as a colorless oil, which slowly solidified overnight at rt (394 mg, 0.761 mmol, 24%). H NMR (600 MHz,
CDCl )  7.19 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.16 (qd, J = 6.8, 1.2 Hz, 2H), 3.92 (bs, 1H), 3.83 – 3.76 (m, 1H),
.78 (s, 3H), 3.64 (d, J = 9.7 Hz, 1H), 3.49 – 3.41 (m, 2H), 3.74 (s, 3H) 3.37 (s, 3H), 3.25 (ddd, J = 13.6, 8.8, 5.4 Hz, 1H), 2.32
q, J = 12.8 Hz, 1H), 2.15 (qd, J = 12.1, 6.7 Hz, 1H), 2.07 (dt, J = 14.6, 3.4 Hz, 1H), 1.82 (ddd, J = 12.4, 8.8, 2.8 Hz, 1H), 1.39
Page 12 of 25
1

1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
3
(
–
1
1.16 (m, 3H), 0.91 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (151 MHz, CDCl
3
)  172.8, 156.4, 136.4, 129.5, 119.3,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16.3, 94.6, 79.6, 66.5, 63.1, 57.3, 56.1, 53.0, 45.1, 44.9, 41.4, 38.0, 32.9, 26.1, 25.4, 18.4, 16.4, −5.22, −5.24; IR (thin film):
-1
+
2951, 2929, 2856, 2233, 1739, 1512, 1462, 1248, 1153, 1103, 1006, 836, 776 cm ; HRMS (ESI) m/z [M+Na] : calc’d for
28 43 6
C H O
NNaSi 540.2752, found 540.2756.

-10d from -10d. -10d (366.9 mg, 0.709 mmol, 1.0 equiv) and K
MeOH (7.0 mL, 0.1 M) and heated in an oil bath at 80 °C for 1 h. The reaction mixture was allowed to cool to room temperature,
at which time it was quenched with NH Cl (saturated aqueous, 5 mL), concentrated in vacuo to remove MeOH, and then
extracted with CH Cl (3 × 4 mL). The combined organic extracts were washed with brine (2 mL), dried over Na SO , and
2 3
CO (147.0 mg, 1.06 mmol, 1.5 equiv) were dissolved in
4
2
2
2
4
concentrated in vacuo to give a yellow oil. Purification by column chromatography (eluting with 5–35% EtOAc/hexanes)
provided -10d as a colorless oil (321.2 mg, 0.620 mmol, 88%).
4
-methoxy tricycle (10e). Prepared according to method 2. Run with modified equivalents of reagents (6.0 equiv of Grignard
solution, 5.0 equiv of CuI). Purification by column chromatography (eluting with 60–100% CH Cl /hexanes, then 1–5%
Et O/CH Cl ) provided -10e and -10e in 88% combined yield.
2
2
2
2
2
1
-10e. Isolated as a colorless oil (37.7 mg, 0.0773 mmol, 59%). H NMR (500 MHz, CDCl )  7.22 (d, J = 8.7 Hz, 2H), 6.87
3
(d, J = 8.6 Hz, 2H), 4.00 (bs, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.72 (ddd, J = 11.3, 8.4, 2.9 Hz, 1H), 3.46 (s, 3H), 3.49 – 3.39
(m, 2H), 3.07 (ddd, J = 13.3, 8.7, 4.8 Hz, 1H), 3.05 (d, J = 8.4 Hz, 1H), 2.47 (td, J = 12.9, 11.7 Hz, 1H), 2.12 (dq, J = 12.7,
2.6, 2.1 Hz, 1H), 2.03 (qd, J = 7.2, 2.7 Hz, 1H), 1.75 (ddd, J = 12.2, 8.9, 2.9 Hz, 1H), 1.52 – 1.31 (m, 3H), 0.93 (s, 9H), 0.06
(s, 3H), 0.04 (s, 3H).; 13C NMR (126 MHz, CDCl
)  173.3, 158.5, 137.8, 127.9, 120.1, 114.3, 77.0, 66.1, 57.0, 55.4, 52.8,
3
4
1
8.6, 47.8, 43.3, 38.1, 33.1, 26.0, 24.8, 18.3, 16.5, −5.3, −5.4; IR (thin film): 2948, 2928, 2855, 2238, 1736, 1612, 1514, 1435,
-1
+
41 5
250, 1106, 1077, 834, 809, 778 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C27H O NNaSi 510.2646, found 510.2648.
1

-10e. Isolated as a pale yellow oil (18.7 mg, 0.0383 mmol, 29%). H NMR (500 MHz, CDCl
3
)  7.23 – 7.13 (m, 2H), 6.92 –
6
3
.67 (m, 2H), 3.91 (bs, 1H), 3.83 – 3.75 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.64 (d, J = 9.7 Hz, 1H), 3.46 (d, J = 7.4 Hz, 2H),
.37 (s, 3H), 3.26 (ddd, J = 13.6, 8.8, 4.9 Hz, 1H), 2.33 (td, J = 13.1, 11.0 Hz, 1H), 2.15 (tdd, J = 12.3, 7.4, 4.9 Hz, 1H), 2.07
(
dq, J = 14.9, 3.4 Hz, 1H), 1.82 (ddd, J = 12.3, 8.8, 3.0 Hz, 1H), 1.38 – 1.24 (m, 2H), 1.19 (dddd, J = 14.4, 12.2, 4.8, 2.0 Hz,
12
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
H), 0.92 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (151 MHz, CDCl
)  172.8, 158.6, 135.1, 129.4, 119.4, 114.0, 79.6,
6.5, 63.1, 57.3, 55.3, 53.0, 45.03, 44.98, 41.4, 38.0, 32.9, 26.1, 25.4, 18.4, 16.4, −5.22, −5.24; IR (thin film): 2950, 2930,
1
6
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
+
899, 2856, 2234, 1738, 1612, 1514, 1462, 1249, 1179, 1102, 1085, 835, 775 cm ; HRMS (ESI) m/z [M+Na] : calc’d for
27 41 5
C H O
NNaSi 510.2646, found 510.2645.
2
,4-dimethoxy tricycle (10f). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10f and -10f in 82% combined yield.
1
-10f. Isolated as a colorless oil (35.3 mg, 0.0682 mmol, 52%). H NMR (600 MHz, CDCl
3
)  7.08 (d, J = 8.3 Hz, 1H), 6.44
(
(
d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.3, 2.4 Hz, 1H), 3.97 (bs, 1H), 3.84 (td, J = 8.6, 4.3 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73
s, 3H), 3.43 (s, 3H), 3.40 (d, J = 7.4 Hz, 2H), 3.35 (d, J = 8.5 Hz, 1H), 3.16 (ddd, J = 13.3, 9.0, 5.0 Hz, 1H), 2.29 (q, J = 12.3
Hz, 1H), 2.08 (ddd, J = 12.4, 5.2, 2.2 Hz, 1H), 1.96 (tdd, J = 11.7, 7.5, 4.7 Hz, 1H), 1.70 (ddd, J = 12.3, 9.0, 3.2 Hz, 1H), 1.46
–
1
1.28 (m, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (151 MHz, CDCl
)  173.7, 160.1, 158.2, 129.8, 124.9,
3
20.8, 104.1, 99.2, 77.3, 66.5, 60.5, 57.0, 55.5, 55.3, 52.7, 45.6, 44.2, 42.6, 38.4, 31.9, 26.1, 25.0, 18.4, 16.8, −5.3; IR (thin
-1
film): 2950, 2930, 2892, 2856, 2237, 1730, 1613, 1507, 1463, 1257, 1209, 1102, 1083, 1038, 836, 776 cm ; HRMS (ESI) m/z
+
[
M+Na] : calc’d for C28
H
43
O
6
NNaSi 540.2752, found 540.2762.
1
-10f. Isolated as a colorless oil (20.7 mg, 0.0400 mmol, 30%). H NMR (600 MHz, CDCl )  7.20 (d, J = 8.3 Hz, 1H), 6.46
3
(dd, J = 8.3, 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.05 (ddd, J = 11.8, 9.8, 2.8 Hz, 1H), 3.90 (p, J = 1.4 Hz, 1H), 3.82 (s, 3H),
3.79 (s, 3H), 3.75 (s, 3H), 3.74 (d, J = 9.8 Hz, 1H), 3.53 – 3.44 (m, 2H), 3.38 (s, 3H), 3.21 (ddd, J = 13.5, 8.4, 5.6 Hz, 1H),
2.22 (td, J = 13.1, 11.1 Hz, 1H), 2.12 (ddd, J = 14.4, 7.1, 1.9 Hz, 1H), 2.06 (dq, J = 14.5, 3.2 Hz, 1H), 1.93 (ddd, J = 12.8, 8.5,
2
.8 Hz, 1H), 1.36 – 1.31 (m, 2H), 1.18 (dtd, J = 16.9, 6.0, 1.9 Hz, 1H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (151
MHz, CDCl )  173.0, 159.9, 158.4, 128.2, 123.3, 119.7, 104.2, 98.7, 79.8, 66.7, 62.8, 57.5, 55.5, 55.4, 52.9, 43.9, 41.1, 38.5,
8.1, 29.9, 26.1, 25.6, 18.5, 16.6, −5.2; IR (thin film): 2952, 2933, 2904, 2856, 2238, 1739, 1613, 1587, 1464, 1290, 1252,
3
3
1
-1
+
43 6
103, 1085, 836, 776 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752, found 540.2748.
3
-OMOM tricycle (10g). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10g and -10g in 98% combined yield.
1
-10g. Isolated as a colorless oil (46.2 mg, 0.0892 mmol, 68%). H NMR (600 MHz, CDCl
3
)  7.25 – 7.21 (m, 1H), 6.92 (s,
2
H), 6.91 (d, J = 2.1 Hz, 1H), 5.19 (d, J = 6.8 Hz, 1H), 5.15 (d, J = 6.8 Hz, 1H), 3.97 (p, J = 1.3 Hz, 1H), 3.74 (s, 3H), 3.71
ddd, J = 11.4, 8.4, 2.9 Hz, 1H), 3.48 (s, 3H), 3.45 – 3.38 (m, 2H), 3.43 (s, 3H), 3.08 (d, J = 8.4 Hz, 1H), 3.03 (ddd, J = 13.6,
9.0, 4.9 Hz, 1H), 2.44 (td, J = 13.0, 11.5Hz, 1H), 2.09 (dq, J = 13.8, 2.4, 2.0 Hz, 1H), 2.00 (dtd, J = 16.1, 7.4, 4.9 Hz, 1H),
(
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
3
1

2
.74 (ddd, J = 12.3, 9.0, 2.8 Hz, 1H), 1.49 – 1.30 (m, 3H), 0.89 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); C NMR (151 MHz, CDCl )
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
173.3, 157.8, 147.3, 130.2, 120.2, 112.0, 115.5, 114.3, 94.6, 77.1, 66.2, 60.5, 57.1, 56.2, 52.9, 49.3, 47.4, 43.4, 38.2, 33.0,
6.0, 24.8, 18.3, 16.6, –5.27, –5.30; IR (thin film): 2953, 2929, 2897, 2855, 2240, 1731, 1584, 1462, 1452, 1249, 1150, 1078,
-
1
+
43 6
1020, 981, 834, 774 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752, found 540.2749.
1
-10g. Isolated as a colorless oil (20.8 mg, 0.0402 mmol, 30%). H NMR (600 MHz, CDCl
3
)  7.25 – 7.21 (m, 1H), 6.95 (dt,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 7.7, 1.2 Hz, 1H), 6.92 (ddd, J = 5.2, 2.7, 1.7 Hz, 2H), 5.17 (s, 2H), 3.92 (t, J = 2.5 Hz, 1H), 3.81 (ddd, J = 11.8, 9.9, 2.9
Hz, 1H), 3.78 (s, 3H), 3.66 (d, J = 9.7 Hz, 1H), 3.50 – 3.43 (m, 2H), 3.48 (s, 3H), 3.37 (s, 3H), 3.24 (ddd, J = 13.6, 9.1, 5.2 Hz,
1
8
H), 2.31 (td, J = 13.1, 11.0 Hz, 1H), 2.15 (dtd, J = 12.0, 7.3, 3.7 Hz, 1H), 2.07 (dq, J = 14.5, 3.3 Hz, 1H), 1.86 (ddd, J = 12.4,
.9, 3.0 Hz, 1H), 1.40 – 1.28 (m, 2H), 1.19 (dddd, J = 14.9, 13.1, 4.2, 2.0 Hz, 1H), 0.91 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13
C
NMR (151 MHz, CDCl
3
)  172.7, 157.4, 144.6, 129.7, 121.8, 119.1, 116.8, 114.8, 94.7, 79.6, 66.5, 63.1, 57.3, 56.1, 53.0, 45.8,
4
1
4.8, 41.5, 38.1, 32.5, 26.1, 25.4, 18.4, 16.4, –5.23, –5.24; IR (thin film): 2951, 2928, 2898, 2856, 2238, 1739, 1609, 1585,
-1
+
43 6
462, 1249, 1151, 1080, 1025, 1009, 835, 775, 729 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752,
found 540.2752.
3
-methoxy tricycle (10h). Prepared according to method 2. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10h and -10h in 92% combined yield from 1.26 mmol of nitrile 9.
1
-10h. Isolated as a colorless oil (430 mg, 0.882 mmol, 70%). H NMR (600 MHz, CDCl
3
)  7.24 (t, J = 7.9 Hz, 1H), 6.87
(dt, J = 7.6, 1.2 Hz, 1H), 6.81 (t, J = 2.1 Hz, 1H), 6.77 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.97 (bs, 1H), 3.81 (s, 3H), 3.73 (s, 3H),
3.71 (ddd, J = 11.3, 8.4, 2.9 Hz, 1H), 3.43 (s, 3H), 3.47 – 3.37 (m, 2H), 3.08 (d, J = 8.3 Hz, 1H), 3.03 (ddd, J = 13.6, 8.9, 4.8
Hz, 1H), 2.44 (td, J = 13.1, 11.6 Hz, 1H), 2.09 (dq, J = 14.1, 3.1 Hz, 1H), 2.00 (dtd, J = 16.0, 7.5, 4.9 Hz, 1H), 1.76 (ddd, J =
1
1
1
2.3, 9.0, 2.8 Hz, 1H), 1.48 – 1.33 (m, 3H), 0.89 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (151 MHz, CDCl
3
)  173.3,
60.1, 147.3, 130.1, 120.0, 119.1, 113.0, 112.2, 77.1, 66.3, 60.5, 57.1, 55.4, 52.9, 49.4, 47.5, 43.4, 38.2, 33.0, 26.0, 24.8, 18.4,
-1
6.6, –5.26, –5.28; IR (thin film): 2951, 2929, 2897, 2857, 2239, 1732, 1600, 1463, 1255, 1119, 1084, 1051, 837, 777 cm ;
+
HRMS (ESI) m/z [M+Na] : calc’d for C27
H
41
O
5
NNaSi 510.2646, found 510.2647.
1

-10h. Isolated as a colorless oil (132 mg, 0.271 mmol, 22%). H NMR (600 MHz, CDCl
3
)  7.24 (d, J = 7.9 Hz, 1H), 6.88
(
(
dt, J = 7.5, 1.2 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.78 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.92 (bs, 1H), 3.85 – 3.78 (m, 1H), 3.80
s, 3H), 3.78 (s, 3H), 3.66 (d, J = 9.8 Hz, 1H), 3.46 (qd, J = 9.9, 7.4 Hz, 2H), 3.37 (s, 3H), 3.25 (ddd, J = 13.6, 8.9, 5.0 Hz,
1
8
9
H), 2.31 (td, J = 13.1, 11.0 Hz, 1H), 2.15 (tdd, J = 12.3, 7.6, 4.9 Hz, 1H), 2.08 (dq, J = 14.1, 2.9 Hz, 1H), 1.87 (ddd, J = 12.4,
.8, 3.0 Hz, 1H), 1.39 – 1.35 (m, 1H), 1.31 (qd, J = 12.9, 3.0 Hz, 1H), 1.20 (dddd, J = 14.8, 12.8, 4.0, 2.0 Hz, 1H), 0.91 (s,
H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (151 MHz, CDCl
ACS Paragon Plus Environment
)  172.7, 159.7, 144.5, 129.6, 120.7, 119.2, 114.6, 112.4, 79.6,
3
14

Page 15 of 25
The Journal of Organic Chemistry
6
6.6, 63.1, 57.3, 55.3, 53.0, 45.9, 44.8, 41.5, 38.1, 32.5, 26.1, 25.4, 18.4, 16.4, −5.2; IR (thin film): 2951, 2930, 2856, 2359,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
+
1737, 1602, 1462, 1422, 1257, 1230, 1105, 1086, 1053, 837, 813, 803,778 cm ; HRMS (ESI) m/z [M+Na] : calc’d for
27 41 5
C H O
NNaSi 510.2646, found 510.2639.
3
-bromo-5-OMOM tricycle (10i). Prepared according to method 1. Purification by column chromatography (eluting with 60–
00% CH Cl /hexanes, then 1–5% Et O/CH Cl ) provided 10i (39.8 mg, 0.0667 mmol) as an inseparable mixture of diastere-
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
omers (2.3:1 :-10i) in 49% combined yield. IR (thin film): 2953, 2930, 2895, 2857, 2241, 1732, 1602, 1568, 1462, 1451,
-
1
+
6
437, 1256, 1152, 1083, 1026, 1007, 838, 776 cm ; HRMS (APCI) m/z [M+H] : calc’d for C28H Si 598.2017, found
4381BrNO
1
5
98.2020.
1

-10i. H NMR (600 MHz, CDCl
3
)  7.10 (dd, J = 2.3, 1.7 Hz, 1H), 7.04 (t, J = 1.6 Hz, 1H), 6.85 (t, J = 1.9 Hz, 1H), 5.17 (d,
J = 6.9 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 3.98 – 3.95 (m, 1H), 3.75 (s, 3H), 3.67 (ddd, J = 11.5, 8.5, 3.0 Hz, 1H), 3.47 (s, 3H),
3
2
1
1
.47 – 3.44 (m, 1H), 3.42 (s, 3H), 3.40 – 3.33 (m, 1H), 3.04 (d, J = 8.5 Hz, 1H), 3.00 (ddd, J = 13.3, 8.9, 4.9 Hz, 1H), 2.48 –
.37 (m, 1H), 2.09 (dq, J = 13.8, 3.0 Hz, 1H), 2.03 – 1.98 (m, 1H), 1.71 (ddd, J = 12.4, 9.0, 2.9 Hz, 1H), 1.48 – 1.41 (m, 1H),
13
.34 (tt, J = 10.7, 3.5 Hz, 2H), 0.90 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); C NMR (151 MHz, CDCl
3
)  173.1, 158.4, 148.8,
23.1, 120.2, 119.7, 117.8, 114.7, 94.6, 77.0, 66.1, 60.4, 57.1, 56.3, 53.0, 49.1, 47.2, 43.2, 38.1, 32.9, 26.1, 24.8, 18.4, 16.5, –
5.25, –5.28.
1
-10i. H NMR (600 MHz, CDCl
3
)  7.23 (tdd, J = 7.3, 2.0, 0.8 Hz, 1H), 6.92 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.20 (d, J =
6
3
2
1
1
5
.8 Hz, 1H), 5.15 (d, J = 6.8 Hz, 1H), 3.98 – 3.95 (m, 1H), 3.74 (s, 3H), 3.71 (ddd, J = 11.5, 8.6, 3.0 Hz, 1H), 3.48 (s, 3H),
.47 – 3.44 (m, 1H), 3.43 (s, 3H), 3.40 – 3.33 (m, 1H), 3.08 (d, J = 8.3 Hz, 1H), 3.00 (ddd, J = 13.3, 8.9, 4.9 Hz, 1H), 2.48 –
.37 (m, 1H), 2.09 (dq, J = 13.8, 3.0 Hz, 1H), 2.03 – 1.98 (m, 1H), 1.74 (ddd, J = 12.4, 9.0, 2.9 Hz, 1H), 1.48 – 1.41 (m, 1H),
1
3
.37 (tt, J = 10.7, 3.5 Hz, 2H), 0.89 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); C NMR (151 MHz, CDCl )  173.3, 157.8, 147.4,
3
30.2, 123.4, 120.0, 115.5, 114.3, 94.6, 77.1, 66.2, 60.5, 57.1, 56.2, 52.9, 49.3, 47.4, 43.4, 38.2, 33.1, 26.0, 24.8, 18.4, 16.6, –
.26, –5.29.
2
-OMOM tricycle (10j). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10j and -10j in 76% combined yield.
1

-10j. Isolated as a colorless oil (36.3 mg, 0.0701 mmol, 53%). H NMR (600 MHz, CDCl
3
)  7.22 (dd, J = 7.6, 1.7 Hz, 1H),
7
.19 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.11 (dd, J = 8.3, 1.2 Hz, 1H), 6.95 (td, J = 7.4, 1.2 Hz, 1H), 5.25 (d, J = 6.9 Hz, 1H), 5.23
(d, J = 6.9 Hz, 1H), 4.01 (ddd, J = 11.6, 8.6, 3.0 Hz, 1H), 3.99 (dd, J = 3.2, 1.6 Hz, 1H), 3.72 (s, 3H), 3.50 (s, 3H), 3.45 (s,
3H), 3.42 (d, J = 7.3 Hz, 2H), 3.30 (d, J = 8.4 Hz, 1H), 3.15 (ddd, J = 13.4, 8.8, 4.9 Hz, 1H), 2.38 (q, J = 12.4 Hz, 1H), 2.13 –
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
2
3
5
.07 (m, 1H), 1.98 (dq, J = 12.1, 5.9 Hz, 1H), 1.76 (ddd, J = 12.2, 8.9, 3.0 Hz, 1H), 1.48 – 1.32 (m, 3H), 0.89 (s, 9H), 0.03 (s,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
H), 0.02 (s, 3H); C NMR (151 MHz, CDCl
3
)  173.6, 155.0, 133.2, 128.8, 128.3, 122.1, 120.5, 114.2, 94.4, 77.2, 66.6, 60.6,
7.0, 56.3, 52.8, 44.79, 44.76, 43.0, 38.4, 32.0, 26.0, 25.0, 18.4, 16.8, –5.2, –5.3; IR (thin film): 2952, 2929, 2895, 2856, 2239,
-1
+
43 6
1728, 1492, 1471, 1249, 1077, 1000, 835, 775, 753 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C28H O NNaSi 540.2752,
found 540.2748.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1

-10j. Isolated as a colorless oil (15.5 mg, 0.0299 mmol, 23%). H NMR (600 MHz, CDCl
3
)  7.33 (dd, J = 7.7, 1.6 Hz, 1H),
7
.21 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.10 (dd, J = 8.3, 1.2 Hz, 1H), 7.00 (td, J = 7.5, 1.2 Hz, 1H), 5.25 (d, J = 6.6 Hz, 1H), 5.20
(
d, J = 6.6 Hz, 1H), 4.17 (td, J = 11.2, 2.7 Hz, 1H), 3.93 (p, J = 1.3 Hz, 1H), 3.78 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H), 3.52 (s,
3
1
H), 3.54 – 3.47 (m, 2H), 3.40 (s, 3H), 3.23 (ddd, J = 13.5, 8.5, 4.9 Hz, 1H), 2.26 (td, J = 13.2, 11.1 Hz, 1H), 2.18 – 2.09 (m,
H), 2.08 (dq, J = 14.4, 3.1 Hz, 1H), 1.99 (ddd, J = 12.1, 8.4, 2.7 Hz, 1H), 1.39 – 1.30 (m, 2H), 1.20 (ddd, J = 17.1, 10.4, 4.3
Hz, 1H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (151 MHz, CDCl
19.4, 114.0, 95.0, 79.8, 66.7, 62.9, 57.4, 56.3, 52.9, 43.7, 41.3, 38.9, 38.1, 29.9, 26.1, 25.5, 18.5, 16.6, –5.18, –5.20; IR (thin
)  172.9, 155.4, 131.4, 128.4, 127.8, 122.0,
3
1
-1
film): 2951, 2928, 2896, 2855, 2236, 1739, 1492, 1457, 1249, 1231, 1082, 1003, 836, 776, 754 cm ; HRMS (ESI) m/z
+
[
M+Na] : calc’d for C28
H
43
O
6
NNaSi 540.2752, found 540.2746.
2-methoxy tricycle (10k). Prepared according to method 2. Purification by column chromatography (eluting with 60–100%
CH
2
Cl
2
/hexanes, then 1–5% Et
2
O/CH
2
Cl
2
) provided -10k and -10k in 57% combined yield from 200 mg (0.527 mmol) of
nitrile 9.
1

-10k. Isolated as a colorless oil (110. mg, 0.223 mmol, 42%). H NMR (600 MHz, CDCl
3
)  7.22 (td, J = 7.6, 1.7 Hz, 1H),
7
1
.19 (dd, J = 7.6, 1.6 Hz, 1H), 6.89 (td, J = 7.5, 1.0 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.97 (t, J = 2.1 Hz, 1H), 3.92 (ddd, J =
1.7, 8.5, 3.1 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H), 3.41 (dd, J = 7.4, 1.3 Hz, 2H), 3.38 (d, J = 8.5 Hz, 1H), 3.18
(
ddd, J = 13.3, 8.9, 4.9 Hz, 1H), 2.32 (q, J = 12.3 Hz, 1H), 2.09 (dq, J = 12.4, 2.5, 1.8 Hz, 1H), 1.97 (dtt, J = 11.8, 7.6, 4.5 Hz,
H), 1.75 (ddd, J = 12.3, 9.0, 3.2 Hz, 1H), 1.46 – 1.31 (m, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (151 MHz,
1
CDCl
3
)  173.7, 157.3, 132.4, 129.3, 128.3, 120.8, 120.7, 111.0, 77.3, 66.5, 60.6, 57.0, 55.3, 52.8, 45.7, 44.1, 42.7, 38.3, 31.8,
2
6.0, 25.0, 18.4, 16.8, −5.2; IR (thin film): 2951, 2930, 2856, 2239, 1730, 1601, 1494, 1462, 1247, 1102, 1082, 837, 776, 753
-1
+
cm ; HRMS (ESI) m/z [M+Na] : calc’d for C27
H
41
O
5
NNaSi 510.2646, found 510.2653.
1

-10k. Isolated as a colorless oil (37.7 mg, 0.0773 mmol, 15%). H NMR (600 MHz, CDCl
3
)  7.31 (dd, J = 7.7, 1.6 Hz, 1H),
7
.23 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 4.13 (ddd, J = 11.4, 9.7, 2.7
Hz, 1H), 3.92 (t, J = 2.9 Hz, 1H), 3.85 (s, 3H), 3.78 (d, J = 9.7 Hz, 1H), 3.75 (s, 3H), 3.54 – 3.46 (m, 2H), 3.40 (s, 3H), 3.23
(ddd, J = 13.5, 8.5, 4.9 Hz, 1H), 2.24 (td, J = 13.1, 11.0 Hz, 1H), 2.13 (dt, J = 14.0, 7.4 Hz, 1H), 2.07 (dq, J = 14.5, 3.3 Hz,
16
ACS Paragon Plus Environment

Page 17 of 25
H), 1.99 (ddd, J = 12.2, 8.5, 2.8 Hz, 1H), 1.37 – 1.30 (m, 2H), 1.23 – 1.15 (m, 1H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H);
13C NMR (151 MHz, CDCl
)  172.8, 157.3, 130.6, 128.1, 127.5, 120.5, 119.3, 110.3, 79.6, 66.5, 62.6, 57.3, 55.3, 52.7, 43.5,
1.0, 38.8, 37.9, 29.5, 25.9, 25.4, 18.3, 16.4, −5.38, −5.39; IR (thin film): 2950, 2930, 2857, 2235, 1740, 1494, 1463, 1244,
The Journal of Organic Chemistry
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4
-
1
+
41 5
1103, 1086, 1056, 1033, 837, 776, 752 cm ; HRMS (ESI) m/z [M+Na] : calc’d for C27H O NNaSi 510.2646, found 510.2641.
2
,6-dimethoxy tricycle (10m). Prepared according to method 1. Purification by column chromatography (eluting with 60–100%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
CH
2
Cl
2
/hexanes, then 1–5% Et
)  7.16 (t, J = 8.3 Hz, 1H), 6.54 (d, J = 8.3 Hz, 2H), 4.48 (ddd, J = 11.9, 10.2, 3.5 Hz, 1H), 3.90 (t, J = 2.5
Hz, 1H), 3.80 (s, 6H), 3.79 (s, 3H), 3.56 – 3.43 (m, 3H), 3.40 (s, 3H), 3.35 (dd, J = 9.9, 7.9 Hz, 1H), 2.14 – 1.98 (m, 3H), 1.91
ddd, J = 12.2, 9.2, 3.5 Hz, 1H), 1.40 (dq, J = 11.6, 3.6 Hz, 1H), 1.32 (qd, J = 13.1, 3.0 Hz, 1H), 1.18 (tdd, J = 13.5, 3.8, 1.9
Hz, 1H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (151 MHz, CDCl
)  173.1, 158.9, 128.3, 120.30, 118.5, 104.3,
0.2, 67.2, 63.5, 57.5, 55.7, 52.8, 43.1, 40.9, 38.6, 34.8, 31.0, 26.1, 25.8, 18.5, 16.9, –5.17, –5.22; IR (thin film): 2951, 2931,
2 2 2
O/CH Cl ) provided -10m as a single diastereomer (52.4 mg, 0.101 mmol, 83%). H NMR
(
600 MHz, CDCl
3
(
3
8
2
-1
+
895, 2856, 2237, 1739, 1594, 1474, 1594, 1474, 1249, 1102, 838, 775 cm ; HRMS (ESI) m/z [M+Na] : calc’d for
28 43 6
C H O
NNaSi 540.2752, found 540.2746.
Synthesis of aldehyde 7 from ester -10d.
2 2
Alcohol derived from ester -10d (S5). Ester -10d (1.732 g, 3.34 mmol, 1.0 equiv) was dissolved in CH Cl (33 mL, 0.1 M)
and cooled in an ice/water bath. Red-Al® solution (3.4 mL, 11.7 mmol, 3.5 equiv, 70 wt% in PhMe) was added dropwise over
5 min. The reaction mixture was stirred in the bath for 1 h, then allowed to warm gradually to room temperature over 2.25 h.
The reaction mixture was then diluted with THF (25 mL), at which point it was cooled in an ice/water bath again and quenched
by the serial addition of H
2
O (88 L), NaOH (2.0 M aqueous, 88 L), and H O (3 × 88 L). The reaction mixture was allowed
2
to warm gradually to room temperature over 12 h, then filtered over a plug of CeliteTM, which was rinsed with THF (25 mL),
then EtOAc (50 mL). The combined organic filtrates were concentrated in vacuo to give a colorless oil. Purification by column
1
chromatography (eluting with 17–37% EtOAc/hexanes) provided alcohol S5 as a clear gum (1.365 g, 2.79 mmol, 83%). H
NMR (700 MHz, C
ddd, J = 11.4, 8.4, 2.7 Hz, 1H), 3.33 (dd, J = 14.8, 7.0 Hz, 1H), 3.32 (dd, J = 14.8, 7.0 Hz, 1H), 3.28 (s, 3H), 3.24 (d, J = 11.1
Hz, 1H), 3.20 (s, 1H), 3.15 (s, 3H), 3.06 (d, J = 8.5 Hz, 1H), 2.52 (ddd, J = 13.4, 8.6, 4.7 Hz, 1H), 2.39 (q, 12.4 Hz, 1H), 1.79
1.71 (m, 2H), 1.70 (dq, J = 14.8, 3.1 Hz, 1H), 1.63 (ddd, J = 12.2, 8.7, 2.7 Hz, 1H), 1.34 (qd, J = 13.4, 3.4 Hz, 1H), 1.22 (dd,
J = 13.3, 3.5 Hz, 1H), 1.01 (tt, J = 12.9, 2.3 Hz, 1H), 0.97 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (176 MHz, C
) 
56.7, 140.5, 128.3, 121.5, 117.0, 94.5, 78.0, 66.8, 63.5, 56.9, 55.8, 55.5, 48.2, 45.8, 39.7, 37.8, 34.3, 26.1, 24.3, 18.5, 17.4,
6 6
D )  7.21 (dd, J = 8.2, 1.2 Hz, 2H), 7.05 (dd, J = 8.7, 1.0 Hz, 2H), 4.86 (qd, J = 6.9, 1.0 Hz, 2H), 3.80
(
–
6
D
6
1
1
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
-1
+
−
5.3; IR (thin film): 3474, 2952, 2929, 2890, 2857, 2234, 1511, 1250, 1088, 1007, 836, 776 cm ; HRMS (ESI) m/z [M+Na] :
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
calc’d for C27H43NNaO Si 512.2803, found 512.2806.
MOM ether 12. Alcohol S5 (2.60 g, 5.30 mmol, 1.0 equiv) was dissolved in PhMe (26 mL, 0.2 M) in a round-bottomed flask.
DIPEA (3.70 mL, 21.2 mmol, 4.0 equiv) was added to the stirring mixture, followed by MOMCl (1.60 mL, 21.2 mmol, 4.0
equiv). The flask was fitted with a reflux condenser and heated in an oil bath at 70 C for 12 h. The reaction mixture was then
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
allowed to cool to room temperature, at which point it was quenched by the addition of NaHCO
3
(saturated aqueous, 20 mL)
4
SO ,
and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na
2
filtered, and concentrated in vacuo to provide MOM ether 12 as an orange oil (2.84 g, 5.30 mmol, >99% crude yield), which
1
was advanced without further purification. H NMR (500 MHz, C
6
D
6
)  7.22 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H),
4
3
.91 – 4.69 (m, 2H), 4.30 (bs, 2H), 3.83 (ddd, J = 11.4, 8.4, 2.7 Hz, 1H), 3.34 – 3.29 (m, 1H), 3.30 (s, 3H), 3.31 – 3.25 (m,
H), 3.21 (d, J = 9.9 Hz, 1H), 3.13 (s, 3H), 3.12 (s, 1H), 3.10 (s, 3H), 2.57 (ddd, J = 13.4, 8.6, 4.8 Hz, 1H), 2.39 (q, J = 12.3
Hz, 1H), 1.76 (qt, J = 7.3, 3.6 Hz, 1H), 1.71 – 1.63 (m, 1H), 1.66 (t, J = 3.7 Hz, 1H), 1.33 (qd, J = 13.0, 2.4 Hz, 1H), 1.14 (dd,
13
J = 13.4, 3.5 Hz, 1H), 1.08 – 0.97 (m, 1H), 0.95 (s, 9H), 0.01 (s, 3H), −0.01 (s, 3H); C NMR (126 MHz, C
6
D
6
)  156.7, 140.5,
1
28.2, 120.9, 117.0, 96.5, 94.4, 78.0, 68.9, 66.5, 57.0, 55.5, 55.1, 54.4, 48.3, 46.8, 40.6, 37.8, 34.0, 26.1, 24.2, 18.4, 17.3, −5.3;
-1
+
IR (thin film): 2950, 2929, 2889, 2856, 2235, 1732, 1610, 1511, 1151, 1080, 1039, 833, 774 cm ; HRMS (ESI) m/z [M+Na] :
calc’d for C29 Si 556.3065, found 556.3077.
H
47NNaO
6
Amide 8. MOM ether 12 (1.34 g, 2.51 mmol, 1.0 equiv) and Rh(PPh
3
)
3
Cl (234.5 mg, 0.251 mmol, 10 mol%) were dissolved
for 15
in PhMe (5.0 mL, 0.5 M) in a round-bottomed flask. Acetaldoxime (3.8 mL, 62.8 mmol, 25 equiv) was sparged with N
2
min, then added to the flask, which was then fitted with a reflux condenser. The reaction mixture was heated to 120 C and
held at this temperature for 14 h, at which point it was allowed to cool to room temperature, mixed with silica (10 mL), and
concentrated carefully in vacuo. This mixture was then loaded directly onto a column for purification. Purification by column
chromatography (eluting with 1–70% EtOAc/hexanes) provided amide 8 as an amorphous white solid (974 mg, 1.77 mmol,
1
7
6
1
3
0% over 2 steps, 81% based on recovered 12). H NMR (500 MHz, C
6
D
6
)  7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H),
.15 (bs, 1H), 6.13 (s, 1H), 4.86 (s, 2H), 4.37 (d, J = 6.4 Hz, 1H), 4.32 (d, J = 6.5 Hz, 1H), 4.16 (ddd, J = 10.7, 8.0, 2.3 Hz,
H), 3.89 (d, J = 9.5 Hz, 1H), 3.66 (t, J = 2.9 Hz, 1H), 3.44 (d, J = 9.6 Hz, 1H), 3.43–3.36 (m, 1H), 3.40 (t, J = 7.1 Hz, 1H),
.19 (s, 3H), 3.18 (s, 1H), 3.13 (s, 3H), 3.09 (s, 3H), 2.62 (ddd, J = 13.0, 8.2, 4.8 Hz, 1H), 2.52 (q, J = 12.1 Hz, 1H), 1.91 (ddq,
J = 15.8, 7.1, 4.1 Hz, 1H), 1.77 (dq, J = 14.1, 2.9 Hz, 1H), 1.66 (ddd, J = 11.6, 6.9, 2.4 Hz, 1H), 1.47 (qd, J = 13.1, 3.4 Hz,
H), 1.27 (ddd, J = 12.8, 6.4, 2.8 Hz, 1H), 1.16 (tt, J = 13.5, 2.7 Hz, 1H), 0.98 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
1
(
6 6
126 MHz, C D )  174.8, 156.2, 143.6, 128.6, 117.0, 96.6, 94.5, 77.4, 71.6, 66.9, 61.4, 56.6, 55.5, 55.2, 53.5, 45.4, 42.3, 38.2,
18
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
3
4.0, 26.2, 24.3, 18.5, 17.8, −5.27, −5.29; IR (thin film): 3500–3300, 2950, 2930, 2889, 2821, 1673, 1510, 1153, 1089, 836,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
+
7
776 cm ; HRMS (ESI) m/z [M+H] : calc’d for C29H50NO Si 552.3351, found 552.3360.
Alcohol 13. Amide 8 (719 mg, 1.30 mmol, 1.0 equiv) was dissolved in MeCN (8.7 mL, 0.15 M) in a round-bottomed flask
open to air. PhI(OAc) (548 mg, 1.70 mmol, 1.3 equiv) was added and the reaction mixture was stirred vigorously for 5 min,
at which point KOH (365 mg, 6.51 mmol, 5.0 equiv) was added as a solution in H O (4.3 mL, 0.30 M with respect to amide
). The reaction mixture was capped loosely and stirred at room temperature for 6 h. The resulting pink-orange solution was
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
diluted with H
2
O (5 mL) and concentrated in vacuo to remove the MeCN. The aqueous material was extracted with EtOAc (3
SO , filtered, and concentrated
×
10 mL); then the combined organic extracts were washed with brine (5 mL), dried over Na
2
4
in vacuo. Amine S6 was obtained as a pink oil, which was then azeotropically dried with benzene (3 × 5 mL). Amine S6 was
advanced without further purification.
Amine S6 (700 mg) was dissolved in CH
5.0 equiv) was added, followed by Ac O (0.37 mL, 3.91 mmol, 3.0 equiv). Each addition was performed dropwise over 5 min
by syringe. The reaction mixture was allowed to warm gradually to room temperature over 16 h, at which time it was quenched
with NaHCO (10 mL) and extracted with CH Cl (3 × 10 mL). The combined organic extracts were dried over Na SO
filtered, and concentrated in vacuo to give acetamide S7 as an orange oil, which was advanced without further purification.
2 2
Cl (13 mL, 0.1 M), then cooled in an ice/water bath. Pyridine (0.53 mL, 6.58 mmol,
2
3
2
2
2
4
,
Acetamide S7 (740 mg, 1.31 mmol, 1.0 equiv) was dissolved in THF (13 mL, 0.1 M) in a round-bottomed flask open to air.
TBAF solution (2.6 mL, 2.62 mmol, 2.0 equiv, 1 M in THF) was added and the reaction mixture stirred for 15 h. The crude
reaction mixture was concentrated in vacuo to give a brown oil. Purification by column chromatography (eluting with 5–55%
1
acetone/CH
2
Cl
2
) provided alcohol 13 (445 mg, 0.985 mmol, 75% over 3 steps) as a white gum. H NMR (500 MHz, C
6
D
6
, 343
K)*  7.33 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 5.42 (d, J = 10.1 Hz, 1H), 5.09 (t, J = 9.4 Hz, 1H), 4.88 (s, 2H), 4.76
d, J = 6.5 Hz, 1H), 4.66 (d, J = 6.2 Hz, 1H), 3.42 (dd, J = 16.5, 10.0 Hz, 2H), 3.33 (s, 3H), 3.29 (d, J = 7.6 Hz, 1H), 3.24 (t, J
= 8.5 Hz, 1H), 3.16 (s, 3H), 2.94 (bs, 1H), 2.91 (s, 3H), 2.69 – 2.57 (m, 1H), 2.33 (q, J = 12.6 Hz, 1H), 1.75 (d, J = 15.5 Hz,
(
1
3
1H), 1.62 (s, 3H), 1.56 (t, J = 10.7 Hz, 1H), 1.36 – 1.26 (m, 2H), 1.20 (t, J = 12.6 Hz, 1H), 1.06 – 0.95 (m, 1H); C NMR (126
MHz, C , 343 K)  168.2, 156.5, 140.9, 128.4, 117.1, 98.0, 95.0, 78.4, 70.4, 66.3, 62.6, 55.5, 55.4, 55.1, 52.5, 50.8, 38.7,
38.4, 33.0, 24.2, 23.2, 17.7; IR (thin film): 3375, 2932, 2889, 2824, 1651, 1509, 1232, 1150, 1044, 919, 830 cm ; HRMS (ESI)
6
D
6
-1
+
1
7
m/z [M+Na] : calc’d for C24H37NNaO 474.2462, found 474.2451. * H NMR peaks did not fully coalesce at 343 K, so peaks
are reported for major rotamer at that temperature.
2 2 3
Piperidine 14. Alcohol 13 (445 mg, 0.984 mmol, 1.0 equiv) was dissolved in CH Cl (10. mL, 0.1 M). Et N (0.69 mL, 4.92
mmol, 5.0 equiv) was added via syringe, followed by MsCl (120 L, 1.48 mmol, 1.5 equiv). The reaction mixture was stirred
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
at room temperature for 3.5 h, then quenched by the addition of brine (10 mL). The solution was extracted with CH Cl (3 ×
2 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
10 mL) and the combined organic extracts were dried over Na
2 4
SO , filtered, and concentrated in vacuo to give mesylate S8 as
a pale brown foam (530 mg), which was advanced without further purification.
Mesylate S8 (530 mg, 0.984 mmol, 1.0 equiv) was dissolved in DMF (10. mL, 0.1 M). KH (59.2 mg, 1.48 mmol, 1.5 equiv)
was added and the reaction mixture was heated in an oil bath at 50 C for 15 h. At this point, conversion was judged to be
incomplete (by TLC and LCMS analysis) and additional KH (39.0 mg, 0.984 mmol, 1.0 equiv) was added after allowing the
reaction mixture to cool to room temperature. The reaction mixture was returned to the oil bath and heated at 50 °C for 2 h.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The reaction mixture was cooled to room temperature, diluted with brine (10 mL) and H
2
O (90 mL), and extracted with EtOAc
SO , filtered, and concentrated in
Cl ) provided piperidine
(
3 × 25 mL). The combined organic extracts were washed with brine (5 mL), dried over Na
2
4
vacuo to give a yellow oil. Purification by column chromatography (eluting with 45–70% acetone/CH
2
2
1
1
4 (366 mg, 0.844 mmol, 86% over 2 steps) as a white gum. H NMR (500 MHz, C
6
D
6
, 343 K)  7.09–6.97 (m, 4H), 4.87 (d,
J = 1.1 Hz, 2H), 4.54 (d, J = 14.3 Hz, 1H), 4.29 (s, 1H), 4.29 – 4.22 (m, 1H), 4.23 (s, 1H), 3.62 (dd, J = 10.2, 7.5, 1H), 3.36
d, J = 9.7 Hz, 1H), 3.14 (dd, J = 17.0, 7.9 Hz, 1H), 3.14 (s, 3H), 3.08 (s, 3H), 3.05 (s, 3H), 3.02 (d, J = 9.7 Hz, 1H), 2.82 (dd,
(
J = 14.5, 4.6 Hz, 1H), 2.27 (s, 3H), 2.26 (bs, 1H), 2.18 (dt, J = 13.2, 6.5 Hz, 1H), 1.84 – 1.78 (m, 1H), 1.73 (dd, J = 13.4, 9.8
Hz, 1H), 1.69 – 1.63 (m, 1H), 1.65 – 1.58 (m, 1H), 1.38 (t, J = 4.1 Hz, 1H), 1.26 (td, J = 14.1, 5.5 Hz, 1H); 13C NMR (126
6 6
MHz, C D , 343 K)  167.2, 156.3, 137.5, 127.5, 116.9, 97.0, 95.0, 77.4, 66.5, 64.8, 56.6, 55.6, 55.1, 53.0, 47.5, 42.1, 41.1,
-1
33.5, 33.0, 30.1, 24.3, 22.1; IR (thin film): 2923, 2897, 2863, 2818, 1631, 1511, 1422, 1016, 916, 513 cm ; HRMS (ESI) m/z
+
[M+Na] : calc’d for C24
H
35NNaO
6
456.2357, found 456.2346.
Aldehyde 7. Piperidine 14 (79.0 mg, 0.182 mmol, 1.0 equiv) was dissolved in THF (1.4 mL, 75 mM) in a round-bottomed flask
left open to air. A 6N HCl aqueous solution (0.84 mL, 5.0 mmol, 28 equiv) was added and the reaction mixture was stirred at
room temperature for 28 h, at which point it was concentrated in vacuo to remove THF. The aqueous phase was diluted with
brine (5 mL) and extracted with CH
2 2 2 4
Cl (3 × 5 mL). The combined organic extracts were dried over Na SO , filtered, and
concentrated in vacuo to give diol S9 a white solid (52 mg, 0.151 mmol, 84% crude yield), which was advanced without further
-1
+
purification. IR (thin film): 3288, 2966, 2930, 2818, 1609, 1515, 1452, 1264, 1105, 830 cm ; HRMS (ESI) m/z [M+Na] :
calc’d for C20 368.1832, found 368.1825.
H
27NNaO
4
Diol S9 (52.0 mg, 0.151 mmol, 1.0 equiv) was suspended in CH
was added and the resulting suspension was cooled in a dry ice/acetone bath at −78 C. Oxalyl chloride (26 L, 0.303 mmol,
.0 equiv) was added dropwise and the reaction mixture was maintained at −78 C for 75 min. Et N (210 L, 1.51 mmol, 10.
equiv) was then added via syringe and the solution was maintained at −78 C for 45 min. The light yellow solution was removed
2 2
Cl (4.0 mL, 37 mM). DMSO (75 L, 1.05 mmol, 7.0 equiv)
2
3
20
ACS Paragon Plus Environment

Page 21 of 25
from the bath and stirred at room temperature for 1 h, at which point it was quenched with NH
and brine (5 mL). Upon extraction with CH Cl (3 × 5 mL), the combined organic extracts were dried over Na
The Journal of Organic Chemistry
4
Cl (saturated aqueous, 15 mL)
SO , filtered,
) provided aldehyde
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
4
2 2
and concentrated in vacuo. Purification by column chromatography (eluting with 0–40% acetone/CH Cl
1
7 (30.0 mg, 0.0874 mmol, 58%) as a colorless oil. H NMR (700 MHz, C
6
D
6
)*  9.37 (s, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.82
(d, J = 8.4 Hz, 2H),4.93 (bs, 1H), 4.32 (d, J = 14.3 Hz, 1H), 3.53 (dd, J = 10.3, 6.8 Hz, 1H), 3.42 (dd, J = 9.9, 6.1 Hz, 1H),
3.21 (d, J = 1.5 Hz, 3H), 3.06 (dd, J = 14.4, 5.3 Hz, 1H), 2.56 (t, J = 4.9 Hz, 1H), 2.33 (d, J = 1.4 Hz, 3H), 2.21 (dt, J = 13.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
1
8
1
*
.3 Hz, 1H), 2.03 (td, J = 6.5, 3.4 Hz, 1H), 1.98 (dd, J = 14.3, 9.6 Hz, 1H), 1.92 – 1.89 (m, 1H), 1.86 (q, J = 5.2, 4.7 Hz, 1H),
1
3
.56 – 1.50 (m, 1H), 1.47 (qd, J = 12.3, 4.9 Hz, 1H); C NMR (176 MHz, C
6 6
D )  206.9, 169.1, 154.9, 131.5, 128.8, 115.9,
0.4, 65.2, 62.2, 56.5, 47.6, 41.7, 41.4, 32.5, 30.8, 29.1, 24.1, 22.4; IR (thin film): 3252, 2958, 2934, 2856, 2358, 1717, 1613,
-1
+
4
591, 1514, 1450, 1260, 1090, 1027, 799 cm ; HRMS (ESI) m/z [M+H] : calc’d for C20H26NO 344.1856, found 344.1855.
Rotameric mixture (3:1 ratio of rotamers at 298 K); peaks reported for major rotamer.
Dienone 15. Aldehyde 7 (23.0 mg, 0.0670 mmol, 1.0 equiv) and NaHCO
in MeOH (3.0 mL, 22 mM), then sonicated until dissolution was nearly complete. The mixture was cooled in an ice/water bath
at 0 C before PhI(OAc) (22.6 mg, 0.0702 mmol, 1.04 equiv) was added. The reaction mixture was allowed to warm gradually
to room temperature over 3.5 h, at which point H O (0.5 mL) was added and the mixture concentrated in vacuo to remove
MeOH. The resulting residue was diluted with H O (1.0 mL) and extracted with EtOAc (3 × 1 mL). The combined organic
extracts were washed with brine (0.5 mL), dried over Na
TLC (eluting with 20–50% acetone/CH Cl
(600 MHz, C
J = 10.4, 2.0 Hz, 1H), 4.90 (s, 1H), 4.21 (d, J = 14.4 Hz, 1H), 4.16 (s, 1H), 3.27 (dd, J = 10.9, 7.0 Hz, 1H), 3.21 (s, 3H), 3.00
3
(23.4 mg, 0.279 mmol, 4.0 equiv) were suspended
2
2
2
2
SO
4
, filtered, and concentrated in vacuo. Purification by preparatory
1
2
2
) provided dienone 15 (13.0 mg, 0.0348 mmol, 52%) as a colorless oil. H NMR
6
6
D )* 6.62 (dd, J = 10.4, 3.2 Hz, 1H), 6.56 (dd, J = 10.4, 3.2 Hz, 1H), 6.03 (dd, J = 10.4, 2.0 Hz, 1H), 5.98 (dd,
(
s, 3H), 2.68 (dd, J = 13.7, 6.2 Hz, 1H), 2.14 (dd, J = 7.2, 4.7 Hz, 1H), 2.01 (s, 3H), 2.00 – 1.95 (m, 1H), 1.68 – 1.61 (m, 1H),
.50 (dq, J = 13.3, 2.9 Hz, 1H), 1.40 – 1.33 (m, 2H), 1.23 (dt, J = 7.5, 3.3 Hz, 1H), 1.10 (t, J = 8.5 Hz, 2H); 13C NMR (126
1
MHz, C
6 6
D )  183.7, 168.2, 148.9, 147.6, 128.6, 128.5, 103.8, 78.4, 74.9, 58.1, 56.8, 56.3, 52.5, 48.9, 41.3, 37.6, 32.5, 29.6,
-1
2
9.4, 24.1, 22.4; IR (thin film) 2932, 2828, 1720, 1671, 1629, 1450, 1378, 1251, 1194, 1135, 1090, 948 cm ; HRMS (ESI)
+
5
m/z [M+H] : calc’d for C21H28NO 374.1962, found 374.1942. *Rotameric mixture (4:1 ratio of rotamers at 298 K); peaks
reported for major rotamer.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
1
13
H and C NMR spectra for all new compounds (PDF)
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
X-ray crystallographic data for compound -10d (CCDC 1859315) (CIF)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
AUTHOR INFORMATION
Corresponding Author
*
Email: rsarpong@berkeley.edu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Present Addresses
†Department of Chemistry, University of California, Riverside, California 92521, United States
‡World Wide Medicinal Chemistry, Groton Laboratories, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, United States
§The University of Chicago Law School, 1111 East 60th Street, Chicago, IL 60637, United States
ǁDepartment of Chemistry, Pfizer Pharmaceuticals, La Jolla Laboratories, 10770 Science Center Drive, La Jolla, CA 92121,
United States
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
R.S. is grateful to the National Institutes of Health (NIGMS R01 086374) for funding this work. We are thankful to the NSF
GRFP for graduate fellowships to N.A.D. (DGE 1106400) and C.J.M., and to the Chulabhorn Graduate Institute for financial
support to K.N. K.G.M.K. acknowledges NSERC for a postdoctoral fellowship. G.M.G. thanks the NIH for a graduate fellow-
ship (5F31GM095238). We thank A. DiPasquale (UC Berkeley) for solving the crystal structure of -10d, supported by the
NIH Shared Instrumentation Grant (S10RR027172).
REFERENCES
(
(
(
1) Wang, F.-P.; Chen, Q.-H.; Liu, X.-Y. Diterpenoid alkaloids. Nat. Prod. Rep. 2010, 27, 529–570.
2) Wang, X.-W.; Xie, H. Alkaloids of Chinese Aconitum plants. Drugs Future 1999, 24, 877–892.
3) Wang, F.-P.; Chen, Q.-H.; Liang, X.-T. The C18-diterpenoid alkaloids. In The Alkaloids: Chemistry and Biology; Cordell,
G. A., Ed.; Academic Press: San Diego, 2009; Vol. 67, pp 1−78.
4) Wang, F.-P.; Chen, Q.-H. The C19-diterpenoid alkaloids. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press: San Diego, 2010; Vol. 69, pp 1−577.
5) Wang, F.-P.; Liang, X.-T. C20-diterpenoid alkaloids. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed. Aca-
demic Press: San Diego, 2002; Vol. 59, pp 1−280.
(
(
(
6) Ameri, A. The effects of Aconitum alkaloids on the central nervous system. Prog. Neurobiol. 1998, 56, 211-235.
22
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
(
7) Camerino, D. C.; Tricarico, D.; Desaphy, J. F. Ion channel pharmacology. Neurotherapeutics 2007, 4, 184–198.
1
2
3
(8) Vakhitova, Yu. V.; Farafontova, E. I.; R. Yu. Khisamutdinova; Yunusov, V. M.; Tsypysheva, I. P.; Yunusov, M. S. A study
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of the mechanism of the antiarrhythmic action of allapinin. Russ. J. Bioorg. Chem. 2013, 39, 92–101.
(9) Wright, S. N. Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine. Mol. Phar-
macol. 2001, 59, 183–192.
(10) Fujita, Y.; Terui, K.; Fujita, M.; Kakizaki, A.; Sato, N.; Oikawa, K.; Aoki, H.; Takahashi, K.; Endo, S. Five cases of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aconite poisoning: toxicokinetics of aconitines. J. Anal. Toxicol. 2007, 31, 132–137.
(
11) Song, M.-K.; Liu, H.; Jiang, H.-L.; Yue, J.-M.; Hu, G.-Y.; Chen, H.-Z. Discovery of talatisamine as a novel specific
+
blocker for the delayed rectifier K channels in rat hippocampal neurons. Neuroscience 2008, 155, 469–475.
(
12) Cash, J. T.; Dunstan, W. R. The pharmacology of aconitine, diacetyl-aconitine, benzaconine, and aconine, considered
in relation to their chemical constitution. Phil. Trans., B, 1898, 190, 239–393.
13) Tursunkhodzhaeva, F. M.; Dzhakhangirov, F. N.; Salimov, B .T. Diterpenoid alkaloids as antidotes to aconitine-type
neurotoxin poisoning. Structure–activity relationship. Chem. Nat. Compd. 2016, 52, 849–852.
14) Dzhakhangirov, F. N.; Tursunkhodzhaeva, F. M.; Sultankhodzhaev, M. N.; Salimov, B. T. Spasmolytic activity of
diterpenoid alkaloids and their derivatives. Structure–activity relationship. Chem. Nat. Compd. 2013, 49, 702–706.
15) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Network-
(
(
(
analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 2015, 528, 493–498.
(16) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A. G.; Sarpong, R. Synthesis of denu-
datine diterpenoid alkaloids: cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine. J. Am. Chem. Soc.
2
016, 138, 10830–10833.
17) Kou, K. G. M.; Kulyk, S.; Marth, C. J.; Lee, J. C.; Doering, N. A.; Li, B. X.; Gallego, G. M.; Lebold, T. P.; Sarpong, R.
A unifying synthesis approach to the C18-, C19-, and C20-diterpenoid alkaloids. J. Am. Chem. Soc. 2017, 139, 13882–13896.
18) Jin, S.-S.; Guo, Q.; Xu, J.; Yu, P.; Liu, J.-H.; Tang, Y.-Q. Antiarrhythmic ionic mechanism of Guanfu base A—Selective
inhibition of late sodium current in isolated ventricular myocytes from guinea pigs. Chi. J. Nat. Med. 2015, 13, 361–367.
19) Takaya, Y.; Ogasawara, M.; Hayashi, T. Rhodium-catalyzed asymmetric 1,4-addition of arylboron compounds generated
in situ from aryl bromides. Tetrahedron Lett. 1999, 40, 6957–6961.
20) Kung, L.-K.; Tu, C.-H.; Shia, K.-S.; Liu, H.-J. Palladium(II) acetate mediated oxidative cyclization of -unsaturated α-
cyano ketones. A facile methylenecyclopentane annulation process. Chem. Commun. 2003, 2490–2491.
21) Fleming, F. F.; Gudipati, S. Alkenenitriles: Zn–Cu promoted conjugate additions of alkyl iodides in water. Org. Lett.
2006, 8, 1557–1559.
(
(
(
(
(
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
(
22) Majetich, G.; Casares, A. M.; Chapman, D.; Behnke, M. Chemoselectivity in the conjugate addition of allylsilane to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Michael acceptors. Tetrahedron Lett. 1983, 24, 1909–1912.
(23) Fleming, F. F.; Wang, Q. Unsaturated nitriles: Conjugate additions of carbon nucleophiles to a recalcitrant class of
acceptors. Chem. Rev. 2003, 103, 2035–2078.
(
24) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. NMR chemical shifts of common laboratory solvents as trace impurities. J.
Org. Chem. 1997, 62, 7512–7515.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
(
25) CYLview, 1.0b, Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org).
26) Farrugia, L. J. WinGX and ORTEP for Windows: an update. J. Appl. Cryst. 2012, 45, 849–854.
27) Gu, W.; She, X.; Pan, X.; Yang, T.-K. Enantioselective syntheses of (S)- and (R)-8,9-dihydroxydihydromagnolol. Tet-
rahedron: Asymmetry 1998, 9, 1377–1380.
28) Neufeind, S.; Hülsken, N.; Neudörfl, J.-M.; Schlörer, N.; Schmalz, H.-G. Total synthesis of cylco-mumbaistatin ana-
logues through anionin homo-Fries rearrangement. Chem. Eur. J. 2011, 17, 2633–2641.
29) Deguchi, J.; Sasaki, T.; Hirasawa, Y.; Kaneda, T.; Kusumawati, I.; Shirota, O.; Morita, H. Two novel heterocycles,
(
(
cassibiphenols A and B from the flowers of Cassia siamea. Tetrahedron Lett. 2014, 55, 1362–1365.
(30) Komatsu, H.; Oi, W.; Naritani, K.; Takaishi, K.; Uchiyama, M.; Muranaka, A.; Maeda, H. Formation of cyclic and
polymeric structures from zwitterions. Chem. Eur. J. 2013, 19, 6956–6960.
(
31) Stereochemistry at the acetal carbon was determined by nOe correlations, most notably between the acetal proton and
the methinyl proton adjacent to the amide moiety (see SI for further details).
24
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
For Table of Contents Only:
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
ACS Paragon Plus Environment