Development of a Flexible and Robust Synthesis of Tetrahydrofuro[3,4- b]furan Nucleoside Analogues

Article abstract of DOI:10.1021/acs.joc.0c02969

In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derive

Full text of DOI:10.1021/acs.joc.0c02969

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Article
Development of a Flexible and Robust Synthesis of
Tetrahydrofuro[3,4‑b]furan Nucleoside Analogues
David A. Candito,* Yingchun Ye, Ryan V. Quiroz, Michael H. Reutershan, David Witter,
Surendra B. Gadamsetty, Hongming Li, Josep Saurí, Sebastian E. Schneider, Yu-hong Lam,
and Rachel L. Palte
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Supporting Information
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ABSTRACT: In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to
access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an
alkenol derived from D-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in
a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the
desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the
pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31−48% yield. Compound 1.1-C
was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a
PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15
nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate
drug discovery programs.
conformation and reduce metabolism by blocking hotspots
or altering binding to CYP enzymes.1c,d As part of a systematic
effort to explore the SAR of 5,5-bicyclic nucleoside analogues,
a tetrahydrofuro[3,4-b]furan target was envisioned. It was
hypothesized that the additional oxygen atom in the core
would lower the LogP, which could lead to reduced
metabolism, a cleaner off target profile, and potentially
improved solubility.2 There is a wealth of literature around
the synthesis of conformationally constrained bicyclic nucleo-
side analogues. As is often the case, there were no-known
examples with the substitution pattern we required.1c,d
INTRODUCTION
■
Protein-aRginine-MethyTransferase-5 (PRMT5) is a type-II
methyl transferase that catalyzes the transfer of a methyl group
from the cofactor S-adenosyl methionine (SAM) to the
guanidino groups of arginine residues on histone and
nonhistone proteins. Methylation is an important posttransla-
tional modification in cell signaling and regulation. PRMT5 is
known to be implicated in a number of diverse cellular
functions, and it has emerged as a promising therapeutic target
for the treatment of cancer.1a,b
As part of a lead optimization effort to develop high-quality
PRMT5 inhibitors, we were initially inspired by the natural co-
factor SAM and used this scaffold as a starting point to develop
a series of SAM-competitive inhibitors (Figure 1, PDB ID:
7L1G). By joining the 5′- and 3′-carbons of SAM in a ring, a
series of 5,5-bicyclic analogues were developed. Conforma-
tionally restricted nucleoside analogues can potentially
improve binding by locking groups into a bioactive
Received: January 5, 2021
Published: March 23, 2021
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© 2021 American Chemical Society
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kcal/mol favoring the S-configuration over the R-configuration
at C6. Furthermore, we were interested in the conformational
strain of the ligand in the bioactive conformation. Using a QM-
based procedure (Supporting Information), the S-configura-
tion was favored by 1 kcal/mol over the R-configuration. The
energy values should not be taken as absolute; rather, they
suggest a preference for the (S)-isomer. Given this stereo-
chemical preference, our synthetic strategy would ideally
deliver the desired isomer selectively.
Retrosynthetically, we envisioned a late-stage glycosylation
of triol 1.2 (Scheme 1), which would allow us to readily
explore SAR around the nucleobase. The problem was now
reduced to finding a flexible synthesis of intermediate 1.3. We
explored three main strategies toward the synthesis of this key
intermediate. Strategy 1 employed a palladium-catalyzed
Suzuki−Miyaura cross-coupling to install the aryl group in a
modular fashion. Borylations of exocyclic enol ethers are scarce
in literature;3 however, combined with some of the existing
precedent and previous experience with a similar system, we
felt that this was a viable approach.2 Furthermore, we surmised
that the electronics of the enol ether and the concavity of the
molecule would provide the desired organoborane intermedi-
ate with the desired stereochemistry at C6. Strategy 2 was
viewed as a complementary approach, whereby the aryl ring
would be introduced earlier in the sequence by a Sonogashira
reaction. Here, the key would be finding a reduction, which
was highly selective and left the aryl bromide untouched, a
challenging proposition. Finally, strategy 3 was envisioned
whereby a palladium-catalyzed carboetherification would be
employed to forge both the tetrahydrofuran ring and aryl-
carbon bond in a single operation.4 Strategy 3 was clearly the
most attractive route on paper; however, given the short
timelines in the drug discovery space, multiple strategies were
pursued in parallel.
The synthesis of key intermediate 1.5 began from readily
available glucofuranose derivative 1.9 (Scheme 2). Dess−
Martin oxidation followed by vinyl Grignard addition stereo-
selectively produced 1.11. The protection of the tertiary
alcohol to provide 1.12 was necessary for the success of
subsequent chemistry. A benzyl-protecting group was chosen
due to its common use in sugar chemistry and for its stability,
which would allow for flexibility in the choice of conditions
downstream. One of the acetonides was selectively cleaved
with dilute sulfuric acid to provide 1.13. A sequence of diol
oxidative cleavage, alkynylation, ozonolysis, and reduction was
effective in producing intermediate 1.16 on a multigram scale.
The ozonolysis is noteworthy, as the olefin in 1.13 was
uniquely hindered and failed to undergo dihydroxylation. With
this key intermediate in hand, we could explore strategies to
introduce the aryl ring and forge the second B-ring.
Figure 1. Inspiration and the design of tetrahydrofuro[3,4-b]furan
PRMT5 Inhibitors.
Furthermore, our objective was to develop a synthetic
approach capable of allowing for diversification, which required
a different chemistry strategy than targeting a single
compound. Herein, we describe our efforts toward enabling
the synthesis of tetrahydrofuro[3,4-b]furan nucleoside ana-
logues in the context of a PRMT5 inhibitor program.
RESULTS AND DISCUSSION
■
From previous studies, it was known that the 3-bromoquinolin-
2-amine fragment was a privileged motif that made several key
contacts with the protein,2 so we needed to ensure that the
chemistry we employed would be capable of installing that
fragment. Another key consideration was the stereochemistry
at C6. Both C6-stereoisomers of our target were docked into
the receptor of PRMT5, the resulting poses were refined using
MM-GBSA, allowing a flexible minimization for the ligand and
the receptor sidechains within 5 Å of the ligand (Figure 2, see
the Supporting Information for detailed methods). This
resulted in a MMGBSA ΔG binding score difference of 9.02
The cyclization of alkynols has been accomplished via a
number of methods, including metal-catalyzed cyclization,
halogenation, and Brønsted acid or base-catalyzed cyclization.5
A limited exploration of gold and silver salts revealed that the
silver-mediated cyclization performed well to provide the
desired product 1.5 in 80% isolated yield.5a,b It was found that
the quality of the silver carbonate is important for this
transformation as variability was observed with different
batches of reagent. It is also noteworthy that the enol ether
1.5 was found to be a stable colorless solid, which could be
handled under ambient conditions and stored for an
appreciable time at −20 °C. The key Suzuki−Miyaura
reactions failed to provide the desired product 1.17; rather,
Figure 2. Docking and prediction of stereochemistry at C6.
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Scheme 1. Retrosynthesis
Scheme 2. Evaluation of Strategy 1
Scheme 3. Evaluation of Strategy 2
1.20 as an 85:15 mixture of Z:E isomers. We then went on to
explore the reduction of the exocyclic enol ether. This was a
very challenging feat as we required a selective reduction that
would reduce a hindered electron-rich olefin in the presence of
a heterocyclic aryl bromide. Several conditions were surveyed
such as Pd/C, Rh/alumina, PtO4, Crabtree’s catalyst,
Wilkinson’s catalyst, diimide reduction, cobalt-mediated hydro-
gen atom transfer,7b and polar reduction with TFA/HSiEt3.7
However, most of the methods returned the starting material
or afforded dehalogenated product 1.23 without reduction of
the double bond. We then investigated a rhodium Josiphos
catalyst system under higher pressures, which was able to
cleanly afford product 1.22 in 95% LCAP in screening
experiments. Scale up of the hit resulted in a 53% isolated
yield of 1.22 as a 1:1 mixture of isomers at C6. Given the
reluctance of the olefin to reduce under a number of alternate
conditions, the reactivity of this catalyst system is truly
remarkable. While this method could be useful in cases where
both isomers at C6 are of interest and for compounds lacking a
bromide substituent, it failed to meet our requirements, so we
went on to explore an alternate strategy.
the ring-opened product 1.18 was formed in 12% LCAP (LC-
area percent).6 The formation of this byproduct is likely due to
ring opening of the boronate species competing with
transmetalation to the aryl palladium(II) species and is
shown in Scheme 2.6 Additional catalysts were screened, and
the equivalents of 9-BBN were adjusted, but the desired
product was not observed in all cases. While it is conceivable
that with careful and thorough optimization, conditions could
be found to affect a rapid transmetalation onto palladium and
avoid ring opening; we felt that pursuing alternate strategies
would be more fruitful.
Finally, strategy 3 was inspired by the work of J. P Wolfe and
co-workers who had done extensive work to develop
intramolecular palladium-catalyzed carboetherification and
carboaminations, whereby a carbon−carbon bond and
carbo−heteroatom bond are formed in the same operation.4
The mechanism is believed to proceed via coordination of the
pendant alkoxide to the aryl palladium(II) intermediate,
We turned our attention to strategy 2 (Scheme 3).
Sonogashira reaction with 1.16 under standard conditions
provided a good yield of 1.19, which could be cyclized under
the same silver-mediated conditions used previously to afford
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followed by a syn-insertion and reductive elimination (Figure
Scheme 4. Evaluation of Strategy 3
3).4
Table 1. Carboetherification of 1.8
Figure 3. DFT transition structures for diastereoselective ring closure.
To get a sense for the diastereoselectivity, we computed the
migratory insertion transition states (TSs) leading to the major
(TS-a) and the minor (TS-b) diastereomer, using PPh3 to
model the monodentate coordination of dpe-phos and a
methoxy group to model the benzyloxy group on the substrate.
The energy difference between TS-a and TS-b of 1.3 kcal/mol
predicted a diastereoselectivity of 7:1. The minor TS is slightly
higher in energy due to more-eclipsing interactions associated
with the alkene C−C bond and O−Pd bond involved in
migratory insertion, as indicated by the torsional angles
between these two partial bonds (−18° in the major TS vs
−5° in the minor TS). The relatively small energy difference
does not allow for a prediction to be made with confidence;
however, encouraged by the models, we went forward to test
out this strategy.
The key alkenyl alcohol 1.8 was made by altering the
strategy shown in scheme 2 and diverting intermediate 1.12.
Beginning from intermediate 1.12, a sequence of ozonolysis,
reduction, acetonide deprotection, and diol cleavage cleanly
provided 1.26 as a mixture of cyclic acetals. Finally, olefination
with methyltriphenylphosphonium bromide generated 1.8 in
excellent overall yield (Scheme 4).
a
Isolated yield of the major isomer, stereochemistry as drawn.
Determined by H NMR. Single isomer or alternate isomer not
b
c
1
detected.
Scheme 5. End-Game Glycosylation
Gratifyingly, under standard conditions reported by the
Wolfe group,4f reaction of 1.8 with 3-bromo-7-iodo-N-(4-
methoxybenzyl)quinolin-2-amine delivered the desired prod-
uct 1.3-A in 64% yield and 9.1:1 dr in favor of the desired
isomer, in good agreement with the predicted diastereose-
lectivity. The efficiency and functional group tolerance of this
reaction were truly remarkable. We explored additional
couplings with model substrates to inform on whether aryl
bromides would also be suitable coupling partners and
demonstrate that other aryl halides could be employed
(Table 1). In general, aryl iodides and bromides can be
used, and the selectivity is good, in line with studies from the
Wolfe group.4 Importantly, this reaction could be performed
on a gram scale to provide ample amounts of intermediate 1.3-
A for further chemistry exploration and analogue synthesis.
Having found an efficient strategy to forge the B-ring and
install our requisite aryl group, we proceeded to explore the
end game of the synthesis (Scheme 5). Deprotection of 1.3-A
was accomplished under the action of boron trichloride. The
DMB-group on the aniline was reluctant to cleave and required
warming to 0 °C. Despite a clean reaction profile, the recovery
of the triol was only 32% yield likely due to its high polarity
and aqueous solubility. Despite the lower yield, this chemistry
could readily be scaled and provided enough material to go
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(3aR,5R,6aS)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one (1.10). DMP
(61.6 g, 145 mmol, 1.5 equiv) was added in portions to a solution of
diacetone-D-glucose (25 g, 97 mmol, 1.0 equiv) in DCM (300 mL) at
0 °C. The reaction was then warmed to room temperature and stirred
overnight. The reaction was then cooled to 0 °C, and a saturated
solution of sodium bicarbonate was added (100 mL) followed by a
saturated solution of sodium sulfite (100 mL). The reaction was
stirred for 30 min at room temperature, and the layers were separated.
The aqueous layers were extracted with DCM (1 × 200 mL); the
combined organic layers were then dried over sodium sulfate, filtered,
and concentrated under reduced pressure to afford 1.10 (24.7 g, 99%
yield) as a yellow oil. This material was used in the next step without
forward. With intermediate 1.2-A in hand, we could begin to
study the late-stage glycosylation. In general, the glycosylation
of nucleosides remains a challenge in the field. Often harsh
conditions are necessary, and yields can be low and substrate
specific.1b,8 We explored a number of different methods on
related scaffolds, including the more traditional Vorbruggen
̈
glycosylation. In many cases, low yields and multiple
byproducts were observed. It was found that Mitsunobu
conditions adapted from the work of Hocek, Mahrwald, and
co-workers proved to be the most general and efficient
approach for installing the base on these scaffolds.9 It is
thought that activation of the anomeric alcohol leads to
displacement by the 2′-hydroxyl group of the ribose, yielding
an epoxide intermediate; the backside attack guarantees the
stereochemistry at the anomeric carbon. In general, moderate-
to-low yields of the final nucleosides were obtained. It
appeared that blocking the 3-position can provide a boost in
yield likely because it discourages reaction at the 3-position of
the pyrrolopyrimidine.
1
further purification. H NMR (400 MHz, DMSO-d6) δ 6.09 (d, J =
4.2 Hz, 1H), 4.57−4.51 (m, 2H), 4.32−4.25 (m, 1H), 4.01−3.93 (m,
1H), 3.89−3.82 (m, 1H), 1.35 (s, 6H), 1.25 (s, 6H). 13C{1H} NMR
(101 MHz, DMSO) δ 209.8, 113.0, 109.2, 102.5, 78.5, 76.6, 75.7,
63.9, 27.2, 27.0, 25.9, 25.0. HRMS (ESI) m/z: does not ionize as
parent.[α]1D5 + 23° (c = 0.1, MeOH).
(3aR,5R,6R,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1.11).
A 500 mL three-necked flask with a stir bar, temperature probe,
dropping funnel, and septum was heated with a heat gun under
vacuum; the glassware was cooled to room temperature and charged
with 1.10 (20 g, 77 mmol, 1.0 equiv) and toluene (309 mL). The
solution was cooled to 0 °C, and vinylmagnesium chloride (58 mL,
1.6 M in THF, 93 mmol, 1.2 equiv) was added dropwise at such a rate
that the temperature did not exceed 5 °C. After the addition was
complete, the reaction was warmed to room temperature and stirred
for 3 h. The mixture was quenched with saturated aqueous
ammonium chloride (250 mL) and then diluted with EtOAc (500
mL). The layers were separated, and the organic layer was washed
with brine (2 × 250 mL), dried over sodium sulfate, filtered, and
concentrated under reduced pressure to afford 1.11 as a colorless
solid (18 g, 81% yield). This material was used in the next step
without further purification. 1H NMR (400 MHz, DMSO-d6) δ 5.86−
5.77 (m, 1H), 5.70 (dd, J = 17.1, 11.0 Hz, 1H), 5.38 (d, J = 17.2 Hz,
1H), 5.28−5.24 (m, 1H), 5.21 (d, J = 10.8 Hz, 1H), 4.22−4.09 (m,
1H), 4.08−4.02 (m, 1H), 4.03−3.94 (m, 1H), 3.82−3.63 (m, 2H),
1.49 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO) δ 136.7, 115.4, 111.5, 107.4, 103.3, 82.7, 81.0,
79.3, 73.5, 64.2, 26.6, 26.3, 26.2, 25.0. HRMS (ESI) m/z: [M + Na] +
calcd for C14H22NaO6 309.1314, found 309.1328. [α]2D0 + 101° (c =
0.126, MeOH).
Despite the lower yields of the glycosylation, enough
material could be made for biological testing. For example,
compound 1.1-C was submitted to our PRMT5-MEP50
biochemical assay, which is a direct measurement of the
methylation activity of the enzyme complex on a short peptide
substrate derived from the N-terminus of H4 histone. The
biochemical IC50 was determined to be 0.8 nM, whereas the
C6-diastereomer was 4-fold less potent, consistent with
modeling predictions. Compound 1.1-C also showed potent
cellular activity in our cellular target engagement assay and our
Z138 cell proliferation assays (see the Supporting Information)
where it was found to have 3 and 15 nM potency values,
respectively. Given the potency of these compounds and their
mechanism of action, extreme care was taken when handling
compounds such as 1.1-A−C to limit exposure.
CONCLUSIONS
■
In conclusion, in the context of a program to identify PRMT5
inhibitors, our search led us to develop a flexible and robust
synthetic strategy to access tetrahydrofuro[3,4-b]furan nucleo-
side analogues bearing aryl moieties at the 5′-position. The key
to the success of this approach was the implementation of a
Wolfe carboetherification reaction and a late stage glyco-
sylation under Mitsunobu conditions. It is conceivable that,
through modification of the intermediates or chemistry
outlined herein, others can achieve novel scaffolds with
substituents and properties tailored to their unique purpose.
(3aR,5R,6R,6aR)-6-(Benzyloxy)-5-((R)-2,2-dimethyl-1,3-diox-
olan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]-
dioxole (1.12). A solution of 1.11 (18.0 g, 62.8 mmol, 1.0 equiv) in
THF (165 mL) was cooled to 0 °C, and sodium hydride (6.28 g, 157
mmol, 2.5 equiv) was added in portions. The reaction was stirred for
30 min at 0 °C and then for 30 min at room temperature. Then, TBAI
(2.32 g, 6.28 mmol, 0.1 equiv) was added followed by benzyl bromide
(14.9 mL, 125 mmol, 2 equiv), and the reaction was stirred at room
temperature overnight. The mixture was cooled to 0 °C and quenched
with a saturated ammonium chloride solution (200 mL). The mixture
was diluted with EtOAc (200 mL), and the layers were separated. The
combined organic layers were washed with brine (2 × 200 mL), dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica (0−100% EtOAc/hexanes) to afford 1.12 as a colorless solid
EXPERIMENTAL SECTION
■
All reagents and solvents were purchased from commercial sources
and used without further purification. Reactions were monitored by
LCMS or thin-layer chromatography (TLC) on silica gel and
visualized with UV light (254 nm). Flash chromatography was
performed using prepacked RediSep Rf silica gel columns on a
Teledyne Isco CombiFlash Rf automated chromatography system;
column volumes are abbreviated as CV. All chemical shifts (δ) are
reported in parts per million (ppm) and referenced to residual
protium or the carbon resonance of the NMR solvent, respectively.
Data are represented as follows: chemical shift, multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
brs = broad singlet), coupling constants (J) in Hertz (Hz),
integration. HRMS data was collected on a Waters Acquity I Class
UPLC with Xevo G2 XS Q Tof HRMS. The following compounds
have previously been reported: 1.9−1.1410 and 1.24.11
1
(17.2 g, 73% yield) H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.5
Hz, 2H), 7.37−7.32 (m, 2H), 7.31−7.26 (m, 1H), 5.89 (dd, J = 18.0,
11.4 Hz, 1H), 5.85 (d, J = 3.6 Hz, 1H), 5.49 (d, J = 11.4 Hz, 1H),
5.32 (d, J = 18.0 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.65 (d, J = 3.6
Hz, 1H), 4.63 (d, J = 11.4 Hz, 1H), 4.34 (d, J = 5.7 Hz, 1H), 4.19
(dd, J = 5.9 Hz, 1H), 4.01−3.94 (m, 2H), 1.64 (s, 3H), 1.45 (s, 3H),
1.41 (s, 3H), 1.36 (s, 3H). 13C{1H} NMR (101 MHz, CD3CN) δ
139.9, 136.4, 129.1, 128.3, 128.2, 119.7, 118.3, 113.3, 109.2, 105.5,
85.8, 83.1, 81.9, 74.8, 67.6, 66.6, 27.1, 26.8, 26.8, 25.4. HRMS (ESI)
m/z: [M + Na] + calcd for C21H28O6Na 399.1784, found 399.1788.
[α]2D0 + 142° (c = 0.197, MeOH).
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(R)-1-((3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-6-
vinyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol
(1.13). Sulfuric acid (5% v/v, 0.348 mL, 6.53 mmol, 0.4 equiv) was
added to a solution of 1.12 (6.15 g, 16.34 mmol) in acetonitrile (82
mL) at room temperature. The reaction was stirred at room
temperature for 3.75 h and monitored by TLC. The mixture was
quenched with aqueous sodium hydrogen carbonate (saturated, 50
mL) and extracted with IPA/CHCl3 (4 × 100 mL). The combined
organic fractions were dried over sodium sulfate, filtered, and
concentrated under reduced pressure to afford 1.13 (5.50 g, 100%
yield). This material was used in the next step without further
stain) and 1H NMR were used to monitor the reaction. A small
aliquot was removed and concentrated, 1H NMR showed 90%
conversion. The reaction was re-cooled to −78 °C, and ozone was
passed through for another 10 min and then purged with air. The
reaction was allowed to reach room temperature, diluted with DCM
(20 mL), and washed with saturated sodium bicarbonate solution (1
× 30 mL); the organic layer was dried over sodium sulfate, filtered,
and concentrated. The crude was diluted with MeOH (20 mL), and
sodium borohydride (366 mg, 9.67 mmol) was added at 0 °C. The
reaction was warmed to room temperature and stirred for 3 h. TLC
indicated complete consumption of the starting material. The reaction
was quenched by the addition of NaOH solution (1 M, 10 mL),
stirred for 5 min, diluted with EtOAc (50 mL), and washed with brine
(3 × 50 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel RediSep Gold 40 g eluting with EtOAc/
hexane (0% to 100%) to give 1.16 (581 mg, 99% yield) as a colorless
1
purification. H NMR (400 MHz, acetonitrile-d3) δ 7.46−7.25 (m,
5H), 6.03 (dd, J = 18.1, 11.5 Hz, 1H), 5.80 (d, J = 3.6 Hz, 1H), 5.53
(d, J = 11.5 Hz, 1H), 5.38 (d, J = 18.1 Hz, 1H), 4.80 (d, J = 3.7 Hz,
1H), 4.62 (d, J = 11.0 Hz, 1H), 4.56 (d, J = 11.0 Hz, 1H), 4.03 (d, J =
8.5 Hz, 1H), 3.66−3.51 (m, 2H), 3.51−3.39 (m, 1H), 2.80 (d, J = 4.1
Hz, 1H), 2.72−2.66 (m, 1H), 1.55 (s, 3H), 1.37 (s, 3H). 13C
NMR{1H} (101 MHz, CD3CN) δ 139.6, 136.2, 129.2, 128.6, 128.4,
119.5, 113.4, 105.3, 86.7, 81.8, 80.8, 71.4, 68.1, 64.7, 27.1, 26.8.
HRMS (ESI) m/z: [M + Na] + calcd for C18H24O6Na 359.1471,
found 359.1473. [α]2D0 + 181° (c = 0.280, MeOH).
1
wax. H NMR (400 MHz, DMSO-d6) δ 7.43−7.30 (m, 4H), 7.31−
7.22 (m, 1H), 5.79 (d, J = 3.7 Hz, 1H), 5.16 (t, J = 5.3 Hz, 1H), 4.89
(d, J = 3.7 Hz, 1H), 4.85 (d, J = 11.3 Hz, 1H), 4.69 (d, J = 11.3 Hz,
1H), 4.63 (d, J = 2.0 Hz, 1H), 4.01 (dd, J = 12.4, 5.4 Hz, 1H), 3.63−
3.55 (m, 2H), 1.49 (s, 3H), 1.31 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO) δ 138.8, 128.0, 127.4, 127.3, 111.8, 103.9, 84.3, 79.2, 78.0,
77.8, 71.0, 67.6, 61.7, 26.7, 26.3. HRMS (ESI) m/z: [M + Na] + calcd
for C17H20O5Na 327.1208, found 327.1199. [α]2D0 + 274° (c = 0.292,
MeOH).
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-6-
vinyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (1.14).
A solution of sodium periodate (2.42 g, 11.3 mmol, 1.4 equiv) in
water (25 mL) was cooled to 0 °C, a solution of 1.13 (2.72 g, 8.09
mmol, 1 equiv) in MeOH (25 mL) was added dropwise, and then the
internal temperature was kept below 5 °C. The reaction was stirred
for 1 h at 0 °C and then warmed to room temperature and stirred for
1.5 h. TLC indicated complete conversion. The reaction was cooled
to 0 °C, ethylene glycol (2 mL, 36 mmol, 4.4 equiv) was added, the
reaction was stirred for 5 min, a saturated sodium sulfite solution (50
mL) was added, and the mixture was allowed to warm to room
temperature. The mixture was diluted with EtOAc (100 mL) and
washed with brine (3 × 200 mL); the organic extracts were dried over
sodium sulfate, filtered, and concentrated. This provided 1.14 as a
yellow oil (2.5 g, 100% yield). This material was used without further
purification. 1H NMR (300 MHz, chloroform-d) δ 9.60 (s, 1H),
7.50−7.24 (m, 5H), 5.99 (d, J = 3.4 Hz, 1H), 5.80 (dd, J = 17.7, 11.2
Hz, 1H), 5.52 (d, J = 11.2 Hz, 1H), 5.43 (d, J = 17.7 Hz, 1H), 4.76−
4.61 (m, 4H), 1.64 (s, 3H), 1.42 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 198.1, 138.0, 133.5, 128.5, 127.8, 127.6, 120.3, 113.9, 105.2,
86.3, 85.7, 81.8, 67.5, 27.2, 26.8. HRMS (ESI) m/z: [M + Na] + calcd
for C17H20O5Na 327.1208, found 327.1209. [α]1D4 + 71° (c = 0.12,
MeOH).
(3aR,4aR,7aR,7bR)-7a-(Benzyloxy)-2,2-dimethyl-5-
methylenehexahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]dioxole
(1.5). Silver carbonate (1.25 g, 4.52 mmol, 1.27 equiv) and 1.16 (1.08
g, 3.56 mmol, 1 equiv) in dry toluene (18 mL) were heated to 80 °C
overnight in an oil bath. TLC indicated complete conversion. The
reaction was filtered through a pad of Celite with DCM and
concentrated. The residue was purified by column chromatography
on silica gel RediSep gold 40 g, eluting with EtOAc/isohexane (0% to
1
100%) to provide 1.5 (855 mg, 80% yield) as a colorless solid. H
NMR (400 MHz, DMSO-d6) δ 7.39−7.31 (m, 4H), 7.32−7.23 (m,
1H), 6.02 (d, J = 2.6 Hz, 1H), 4.81 (d, J = 2.7 Hz, 1H), 4.70−4.62
(m, 2H), 4.62−4.49 (m, 2H), 4.33 (s, 1H), 4.23 (s, 1H), 3.88 (d, J =
10.9 Hz, 1H), 1.53 (s, 3H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 160.2, 137.9, 128.2, 127.5, 127.5, 112.3, 106.4, 91.1,
86.4, 83.6, 77.9, 72.3, 67.1, 26.9, 26.9. HRMS (ESI) m/z: [M + H] +
calcd for C17H21O5 305.1389, found 305.1382. [α]2D0 + 80° (c = 0.153,
MeOH).
((3aR,5R,6R,6aR)-6-(Benzyloxy)-5-((3-bromo-2-((4-
methoxybenzyl)amino)quinolin-7-yl)ethynyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)methanol
(1.19). 3-Bromo-7-iodo-N-(4-methoxybenzyl)quinolin-2-amine (933
mg, 1.99 mmol, 1.1 equiv), 1.16 (550 mg, 1.81 mmol, 1 equiv),
cuprous iodide (17.2 mg, 0.090 mmol, 0.05 equiv), and bis-
(triphenylphosphine)palladium(II) dichloride (127 mg, 0.181 mmol,
0.1 equiv) were charged in a 20 mL microwave vial, the vial was
evacuated and backfilled with argon (3×), and tetrahydrofuran (7
mL) was added followed by diisopropylamine (0.386 mL, 2.71
mmol). The reaction was stirred at room temperature overnight. The
residue was purified by column chromatography on silica gel RediSep
Gold 12 g prepacked, eluting with EtOAc/hexane (0% to 100%) to
(3aR,5R,6R,6aR)-6-(Benzyloxy)-5-ethynyl-2,2-dimethyl-6-
vinyltetrahydrofuro[2,3-d][1,3]dioxole (1.15). Dimethyl (1-
diazo-2-oxopropyl)phosphonate (10% in MeCN, 25 mL, 10 mmol,
1.2 equiv) was added to a solution of 1.14 (2.6 g, 8.5 mmol, 1.0
equiv) and potassium carbonate (2.36 g, 17.1 mmol, 2 equiv) in
MeOH (57 mL) at room temperature. The reaction was monitored
by LCMS, and upon completion, the reaction was diluted with EtOAc
(250 mL) and washed with saturated sodium bicarbonate solution (3
× 250 mL). The organic layer was dried over sodium sulfate, filtered,
and concentrated. This provided 1.15 as a colorless solid (2.6 g, 100%
1
yield). This material was used without further purification. H NMR
(400 MHz, DMSO-d6) δ 7.42−7.19 (m, 5H), 6.00 (dd, J = 18.0, 11.4
Hz, 1H), 5.83 (d, J = 3.5 Hz, 1H), 5.59 (d, J = 11.4 Hz, 1H), 5.53 (d,
J = 18.0 Hz, 1H), 4.90 (d, J = 3.5 Hz, 1H), 4.69 (d, J = 1.8 Hz, 1H),
4.55−4.43 (m, 2H), 3.60 (d, J = 1.9 Hz, 1H), 1.51 (s, 3H), 1.34 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 138.0, 134.5, 128.1,
127.4, 120.2, 112.0, 103.9, 84.5, 79.5, 78.8, 78.2, 72.2, 66.5, 26.5, 26.2.
HRMS (ESI) m/z: [M + Na] + calcd for C18H20O4Na 323.1259,
found 323.1259. [α]2D0 + 295° (c = 0.242, MeOH).
((3aR,5R,6R, 6aR)-6-(Benzyloxy)-5-ethynyl-2, 2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)methanol
(1.16). A solution of 1.15 (581 mg, 1.93 mmol, 1 equiv) and pyridine
(0.47 mL, 5.8 mmol, 3 equiv) in DCM (20 mL) was cooled to −78
°C, and a stream of ozone (Triogen Lab 2B ozone generator, using
compressed air) was passed through for 10 min. The vessel was
purged with air and warmed to room temperature. TLC (vanillin
1
provide 1.19 (807 mg, 69% yield) as a yellow solid. H NMR (400
MHz, chloroform-d) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.32−7.22 (m, 3H),
7.21−7.14 (m, 4H), 7.13−7.04 (m, 3H), 6.72 (d, J = 8.5 Hz, 2H),
5.69 (d, J = 3.7 Hz, 1H), 5.54−5.44 (m, 1H), 5.00 (s, 1H), 4.74−4.65
(m, 2H), 4.61 (d, J = 3.8 Hz, 1H), 4.59−4.52 (m, 2H), 4.03 (dd, J =
12.3, 5.2 Hz, 1H), 3.74 (dd, J = 12.3, 7.6 Hz, 1H), 3.63 (s, 3H), 1.48
(s, 3H), 1.23 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.2,
152.6, 146.4, 138.6, 138.5, 131.1, 130.3, 129.5, 128.6, 128.0, 127.8,
126.8, 125.6, 124.5, 123.0, 114.2, 113.2, 109.4, 104.3, 89.5, 85.2, 84.1,
80.4, 71.5, 68.1, 62.6, 55.5, 45.6, 27.1, 26.6. HRMS (ESI) m/z: [M +
H] + calcd for C34H34N2O6Br 645.1600, found 645.1596. [α]D15
163° (c = 0.233, MeOH).
+
7-((Z)-((3aR, 4aR, 7aR, 7bR)-7a-(Benzyloxy)-2, 2-
dimethyltetrahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]dioxol-5-
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(4aH)-ylidene)methyl)-3-bromo-N-(4-methoxybenzyl)-
quinolin-2-amine (1.20). Silver carbonate (9.36 g, 34.0 mmol, 3
equiv) and 1.19 (8.7 g, 11.3 mmol, 1 equiv) in dry toluene (139 mL)
were heated to 110 °C overnight in an oil bath. The reaction was
filtered, and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel eluting
with EtOAc/hexanes (0 to 100%) to provide 1.20 (4.6 g, 57% yield,
85:15 Z:E) of 1.20 as a white solid. (Z-Major isomer) 1H NMR (499
MHz, DMSO-d6) δ 8.28 (s, 1H), 7.75 (s, 1H), 7.62−7.53 (m, 1H),
7.44−7.21 (m, 6H), 7.15−7.06 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H),
6.09 (d, J = 3.6 Hz, 1H), 5.78 (s, 1H), 4.95−4.83 (m, 2H), 4.75−4.56
(m, 5H), 4.19 (d, J = 11.1 Hz, 1H), 3.70 (s, 3H), 3.37 (s, 1H), 1.59
(s, 3H), 1.37 (d, J = 9.7 Hz, 3H). (Major isomer) 13C{1H} NMR
(126 MHz, DMSO) δ 158.1, 155.4, 152.2, 146.4, 138.5, 137.8, 136.9,
132.2, 128.9, 128.7, 128.1, 127.6, 127.5, 123.9, 122.9, 122.2, 113.6,
113.5, 112.4, 106.9, 106.5, 102.9, 90.1, 85.8, 77.8, 74.0, 67.2, 55.0,
43.7, 27.0, 26.9. HRMS (ESI) m/z: [M + H] + calcd for
C34H34N2O6Br 645.1600, found 645.1610. [α]1D6.5 + 140° (c =
0.115, MeOH).
7 - ( ( ( 3 a R , 4 a R , 7 a R , 7 b R ) - 7 a - ( B e n z y l o x y ) - 2 , 2 -
dimethylhexahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]dioxol-5-yl)-
methyl)-N-(4-methoxybenzyl)quinolin-2-amine (1.22). Catalyst
preparation: A 50 mL three-necked round-bottomed flask was
charged with rac-tBuJosiphos (0.378 g, 0.697 mmol) and bis(1,5-
cyclooctadiene)rhodium (I) BF4 (0.283 g, 0.697 mmol); the vessel
was evacuated and backfilled with argon (3×), and DCM (20 mL)
was added. The solution was stirred for 1 h and then concentrated.
The residue was dissolved in DCM (3 mL), and MTBE (3 mL) was
added causing precipitation. The slurry was stirred for 15 min, filtered,
and washed with MTBE (3 × 3 mL). The solid was dried under a
stream of nitrogen on the filter to provide a [Rh(tBuJosiphos)NBD]-
BF4 precatalyst (600 mg, 104% yield). A steel reactor was charged
with the rac-[Rh(tBuJosiphos)NBD]BF4 precatalyst (600 mg, 50 mol
%), 1.20 (1.0 g, 1.4 mmol), and TFE:DCE (40 mL, 3:1). The
reaction was stirred under 30 atm of hydrogen at room temperature
for 3 days. The mixture was filtered, and the solid was washed with
MeCN (2 × 10 mL); the filtrate was concentrated, and the residue
was purified by reverse-phase HPLC (HP-Flash, MeCN/H2O/1%
NH4HCO3). This provided 1.22 (465 mg, 53% yield, dr = 1:1) as a
yellow solid.
The vessel was purged with air and warmed to room temperature. The
reaction was cooled to −78 ° C, and ozone was passed through for
another 10−15 min. The vessel was purged with air and warmed to 0
°C. The crude was diluted with MeOH (20 mL), and sodium
borohydride (502 mg, 13.3 mmol, 5 equiv) was added at 0 °C. The
reaction was stirred at this temperature for 3 h. The reaction was
quenched by the addition of NaOH solution (1 M, 50 mL), stirred for
5 min, and diluted with EtOAc (200 mL). The organic layer was
washed with brine (3 × 50 mL), dried over sodium sulfate, filtered,
and concentrated under reduced pressure to afford 1.24 as a colorless
solid (1.1 g, 100% yield). This material was used in the next step
1
without further purification. H NMR (300 MHz, chloroform-d) δ
7.47−7.25 (m, 5H), 5.78 (d, J = 3.9 Hz, 1H), 4.76 (s, 2H), 4.51 (d, J
= 3.9 Hz, 1H), 4.40 (dd, J = 6.4 Hz, 1H), 4.20 (d, J = 6.8 Hz, 1H),
4.15−4.02 (m, 2H), 3.92 (dd, J = 11.7, 4.5 Hz, 1H), 3.81 (dd, J =
11.8, 5.5 Hz, 1H), 3.14−3.00 (m, 1H), 1.62 (s, 3H), 1.46 (s, 3H),
1.38 (s, 3H), 1.37 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.7,
128.3, 127.7, 127.6, 112.9, 110.0, 104.2, 84.8, 82.1, 80.2, 73.8, 67.3,
66.9, 61.4, 27.1, 26.8, 26.4, 24.9. HRMS (ESI) m/z: [M + Na] + calcd
for C20H28O7Na 403.1733, found 403.1731. [α]1D5 + 28° (c = 0.094,
MeOH).
(R)-1-((3aR,5R,6R,6aR)-6-(Benzyloxy)-6-(hydroxymethyl)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-
diol (1.25). Sulfuric acid (1.2 mL, 5% v/v aqueous solution, 1.1
mmol, 0.4 equiv) was added to a solution of 1.24 (1.1 g, 2.8 mmol, 1
equiv) in MeCN (30 mL) at room temperature, and the reaction was
stirred for 2 h. The reaction was made basic with a minimal amount of
sodium hydroxide (1 mL, 2 mmol, 2 M), and then magnesium sulfate
was added. The slurry was filtered and concentrated under reduced
pressure to afford 1.25 as a yellow oil (800 mg, 84% yield). This
1
material was used crude without further purification. H NMR (400
MHz, acetonitrile-d3) δ 7.42 (d, J = 7.5 Hz, 2H), 7.39−7.32 (m, 2H),
7.32−7.26 (m, 1H), 5.69 (d, J = 3.8 Hz, 1H), 4.75 (d, J = 10.5 Hz,
1H), 4.60 (d, J = 10.5 Hz, 1H), 4.43 (d, J = 3.8 Hz, 1H), 3.97−3.87
(m, 2H), 3.86−3.78 (m, 2H), 3.66 (ddd, J = 26.5, 15.0, 5.2 Hz, 3H),
3.57−3.47 (m, 1H), 2.75−2.67 (m, 1H), 1.53 (s, 3H), 1.32 (s, 3H).
13C{1H} NMR (101 MHz, CD3CN) δ 139.8, 129.2, 128.7, 128.4,
113.2, 104.8, 86.2, 81.3, 80.1, 71.8, 67.5, 64.6, 60.0, 27.0, 26.8. HRMS
(ESI) m/z: [M + Na] + calcd for C17H24O7Na 363.1420, found
363.1426. [α]1D7 + 67° (c = 0.099, MeOH).
( 3 a R , 4 a S , 7 a R , 7 b R ) - 7 a - ( B e n z y l o x y ) - 2 , 2 -
dimethylhexahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]dioxol-5-ol
(1.26). A solution of sodium periodate (277 mg, 1.30 mmol, 1.4
equiv) in water was cooled to 0 °C; then a solution of 1.25 (315 mg,
0.925 mmol, 1.0 equiv) in MeOH (2 mL) was added dropwise. The
reaction was stirred for 1 h at 0 °C and then warmed to room
temperature and stirred overnight. The reaction was cooled to 0 °C,
and ethylene glycol (1 mL, 17.9 mmol) was added. The reaction was
stirred for 5 min, saturated sodium sulfite (50 mL) was added, and
then the reaction was warmed to room temperature. The mixture was
diluted with EtOAc (100 mL), and the organic layer was washed with
brine (3 × 200 mL), dried over sodium sulfate, filtered, and
concentrated under reduced pressure to afford 1.26 as a colorless
solid (251 mg, 88% yield, 1.8:1 mixture at acetal carbon). This
material was used without further purification. (spectra recorded as
observed) 1H NMR (400 MHz, chloroform-d) δ 7.46−7.30 (m), 6.02
(d, J = 3.4 Hz), 5.95 (d, J = 3.6 Hz), 5.37 (d, J = 14.3 Hz), 4.81 (d, J =
10.6 Hz), 4.75 (d, J = 10.6 Hz), 4.67 (dd, J = 5.8, 3.6 Hz), 4.61 (d, J =
10.6 Hz), 4.57 (s), 4.56−4.48 (m), 4.14 (d, J = 10.6 Hz), 3.88 (d, J =
11.6 Hz), 3.85−3.76 (m), 3.06 (bs, 1H), 1.66 (s), 1.46 (s), 1.43 (s).
13C{1H} NMR (101 MHz, CDCl3) δ 137.6, 128.6, 128.1, 127.9,
Isomer 1: 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 8.9 Hz,
1H), 7.53−7.41 (m, 4H), 7.40−7.32 (m, 2H), 7.31−7.23 (m, 3H),
7.04 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.9 Hz,
1H), 5.89 (d, J = 3.6 Hz, 1H), 4.84 (s, 1H), 4.74−4.59 (m, 3H), 4.55
(s, 2H), 4.47 (s, 1H), 4.41 (d, J = 10.7 Hz, 1H), 4.34−4.25 (m, 1H),
3.73 (s, 3H), 3.61 (d, J = 10.7 Hz, 1H), 3.04 (dd, J = 13.6, 7.9 Hz,
1H), 2.95 (dd, J = 13.6, 7.3 Hz, 1H), 1.51 (s, 3H), 1.35 (s, 3H).
13C{1H} NMR (101 MHz, MeOD) δ 160.3, 158.9, 149.0, 140.9,
139.8, 138.1, 132.8, 130.0, 129.3, 128.7, 128.7, 128.6, 126.3, 124.6,
123.3, 114.9, 114.2, 113.3, 108.2, 94.5, 89.9, 86.6, 80.5, 72.5, 69.1,
55.7, 45.7, 39.9, 27.5, 27.3. HRMS (ESI) m/z: [M + H] + calcd for
C34H37N2O6 569.2652, found 569.2654.
Isomer 2: 1H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.9 Hz,
1H), 7.54 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.35−7.18 (m, 7H), 7.10
(dd, J = 8.1, 1.5 Hz, 1H), 6.87−6.81 (m, 2H), 6.68 (d, J = 8.9 Hz,
1H), 5.96 (d, J = 3.5 Hz, 1H), 4.85 (s, 2H), 4.74 (d, J = 3.5 Hz, 1H),
4.62 (d, J = 10.8 Hz, 1H), 4.55 (s, 1H), 4.47 (d, J = 10.8 Hz, 1H),
4.37 (d, J = 2.3 Hz, 1H), 4.21−4.14 (m, 1H), 4.08 (d, J = 10.5 Hz,
1H), 3.88 (d, J = 10.5 Hz, 1H), 3.72 (s, 3H), 3.10−2.96 (m, 2H),
1.52 (s, 3H), 1.38 (s, 3H). 13C{1H} NMR (101 MHz, MeOD) δ
160.3, 158.9, 149.0, 141.3, 139.4, 138.1, 132.9, 130.0, 129.2, 128.8,
128.7, 128.5, 126.0, 124.6, 123.2, 114.9, 114.7, 113.3, 108.2, 94.1,
87.4, 84.2, 82.6, 74.3, 68.9, 55.7, 45.7, 36.6, 27.8, 27.4. HRMS (ESI)
m/z: [M + H] + calcd for C34H37N2O6 569.2652, found 569.2652.
((3aR,5R,6R,6aR)-6-(Benzyloxy)-5-((R)-2,2-dimethyl-1,3-di-
oxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-
yl)methanol (1.24). A solution of 1.12 (1000 mg, 2.66 mmol, 1
equiv) and pyridine (0.645 mL, 7.97 mmol, 3 equiv) in DCM (20
mL) was cooled to −78 °C, and a stream of ozone (Triogen ozonator,
using compressed air) was passed through the solution for 10 min.
127.9, 114.7, 114.2, 107.3, 106.9, 101.4, 98.7, 91.9, 91.9, 88.2, 84.8,
82.1, 80.9, 73.1, 70.0, 69.0, 68.3, 27.6, 27.5, 27.4, 27.3. HRMS (ESI)
m/z: [M + Na] + calcd for C16H20O6Na 331.1158, found 331.1155.
[α]1D7 + 48° (c = 0.106, MeOH).
((3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-
vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)methanol (1.8). Po-
tassium tert-butoxide (183 mg, 1.63 mmol, 2.0 equiv) was added in
portions to a suspension of methyltriphenylphosphonium bromide
(611 mg, 1.71 mmol, 2.1 equiv) in THF (4 mL) at room temperature.
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The reaction was stirred at room temperature for 3 h, the solution was
cooled to 0 °C, a solution of 1.26 (251 mg, 0.814 mmol, 1.0 equiv) in
THF (2 mL) was added, and then the reaction was stirred for 2 h.
The mixture was quenched with saturated aqueous ammonium
chloride (10 mL), and the mixture was extracted with EtOAc (1 × 50
mL). The combined organic layers were washed with brine (2 × 50
mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica (0−100% EtOAc/hexanes) to afford 1.8 (189 mg, 76%
yield) as a colorless solid. 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J =
7.3 Hz, 2H), 7.37−7.33 (m, 2H), 7.31−7.27 (m, 1H), 5.94 (ddd, J =
17.2, 10.8, 5.3 Hz, 1H), 5.82 (d, J = 3.9 Hz, 1H), 5.49 (dt, J = 17.3,
1.6 Hz, 1H), 5.30 (dt, J = 10.8, 1.5 Hz, 1H), 4.79 (d, J = 11.1 Hz,
1H), 4.74 (d, J = 11.1 Hz, 1H), 4.73−4.70 (m, 1H), 4.68 (d, J = 3.9
Hz, 1H), 3.80 (d, J = 12.1 Hz, 1H), 3.69 (d, J = 12.1 Hz, 1H), 1.63 (s,
3H), 1.56 (bs, 1H), 1.39 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 138.8, 132.0, 128.3, 127.6, 127.6, 118.0, 112.7, 104.1, 84.9, 80.6,
80.0, 67.9, 62.2, 26.9, 26.6. HRMS (ESI) m/z: [M + Na] + calcd for
C17H22O5Na 329.1365, found 329.1353. [α]2D0 + 48° (c = 7.085,
CHCl3).
1H), 4.56 (q, J = 11.2 Hz, 2H), 4.35 (d, J = 2.3 Hz, 1H), 4.17 (ddd, J
= 8.1, 6.0, 2.3 Hz, 1H), 4.05 (d, J = 10.6 Hz, 1H), 3.88 (d, J = 10.6
Hz, 1H), 3.15−2.96 (m, 2H), 1.50 (s, 3H), 1.36 (s, 3H). 13C{1H}
NMR (151 MHz, DMSO) δ 138.6, 136.8, 133.5, 132.2, 128.6, 128.2,
128.1, 128.0, 127.9, 127.9, 127.8, 127.6, 126.4, 125.8, 113.0, 106.8,
92.8, 86.2, 82.5, 81.0, 72.8, 67.5, 35.5, 27.7, 27.6. HRMS (ESI): [M +
Na] + calcd for C27H28O5Na 455.1829, found 455.1820. [α]1D7 + 48°
(c = 0.198, MeOH).
(3aR,4aR,5R,7aR,7bR)-7a-(Benzyloxy)-2,2-dimethyl-5-
(naphthalen-2-ylmethyl)hexahydrofuro[3′,4′:4,5]furo[2,3-d]-
1
[1,3]dioxole (1.3-B2 Minor Diaseteromer). H NMR (600 MHz,
DMSO) δ 7.89−7.83 (m, 3H), 7.69 (s, 1H), 7.51−7.44 (m, 4H),
7.43−7.38 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 5.96 (d, J = 3.7 Hz, 1H),
4.77 (d, J = 3.7 Hz, 1H), 4.75−4.64 (m, 2H), 4.40−4.36 (m, 2H),
4.26 (t, J = 7.5 Hz, 1H), 3.59 (d, J = 10.8 Hz, 1H), 3.06−2.96 (m,
2H), 1.47 (s, 3H), 1.33 (s, 3H). 13C{1H} NMR (151 MHz, DMSO) δ
139.1, 136.3, 133.6, 132.2, 128.7, 128.3, 128.2, 127.9, 127.9, 127.8,
127.7, 127.6, 126.5, 125.9, 112.6, 106.8, 93.37, 88.68, 84.91, 79.18,
71.33, 67.79, 38.67, 27.51, 27.44. HRMS (ESI) m/z: [M + Na] +
calcd for C27H28O5Na 455.1829, found 455.1817. [α]1D7 + 37° (c =
0.34, MeOH).
Carboetherification General Procedure. 7-(((3aR,4a-
R,7aR,7bR)-7a-(Benzyloxy)-2,2-dimethylhexahydrofuro[3′,4′:4,5]-
furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-
dimethoxybenzyl)quinolin-2-amine (1.3-A): A schlenk flask was
charged with 3-bromo-N-(2,4-dimethoxybenzyl)-7-iodoquinolin-2-
amine (3.3 g, 6.5 mmol, 2.0 equiv), tris(dibenzylideneacetone)-
dipalladium(0) (149 mg, 0.163 mmol, 0.05 equiv), sodium tert-
butoxide (627 mg, 6.53 mmol, 2.0 equiv), and bis(2-
diphenylphosphinophenyl)ether (176 mg, 0.326 mmol, 0.1 equiv),
the flask was evacuated and backfilled with argon (3×), and then a
solution of 1.8 (1.00 g, 3.26 mmol, 1.0 equiv) in THF (33 mL) was
added. The reaction was heated to 65 °C overnight in an oil bath. The
reaction was cooled to room temperature, diluted with EtOAc (200
mL), and washed with brine (2 × 200 mL). The organic layer was
dried with Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica (0−
100% EtOAc/hexanes) to afford 1.3-A1 as a colorless solid (1.38 g,
62% yield major 1.3-A1, 9.1:1 dr of crude mix).
3-(( (3 a R, 4 aR, 5 S , 7 aR, 7b R)-7 a-(Benzyloxy)-2, 2-
dimethylhexahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]dioxol-5-yl)-
methyl)pyridine (1.3-C). Following the general procedure, 1.3-
C(101 mg, 81% yield) was obtained. 1H NMR (500 MHz, DMSO) δ
8.47 (d, J = 1.8 Hz, 1H), 8.42 (dd, J = 4.8, 1.5 Hz, 1H), 7.68 (dt, J =
7.8, 1.7 Hz, 1H), 7.39−7.25 (m, 6H), 6.02 (d, J = 3.6 Hz, 1H), 4.85
(d, J = 3.6 Hz, 1H), 4.61−4.52 (m, 2H), 4.34 (d, J = 2.4 Hz, 1H),
4.08 (td, J = 5.6, 2.8 Hz, 1H), 4.05 (d, J = 10.6 Hz, 1H), 3.87 (d, J =
10.6 Hz, 1H), 2.97−2.81 (m, 2H), 1.51 (s, 3H), 1.36 (s, 3H).
13C{1H} NMR (126 MHz, DMSO) δ 150.6, 147.9, 138.6, 137.0,
134.7, 128.6, 128.0, 127.9, 123.8, 113.1, 106.8, 92.9, 86.1, 82.1, 80.9,
72.8, 67.5, 32.6, 27.7, 27.5. HRMS (ESI) m/z: [M + H] + calcd for
C22H26NO5 384.1811, found 384.1804. [α]1D7 + 44° (c = 0.448,
MeOH).
(3R,3aS,6aR)-6-((2-Amino-3-bromoquinolin-7-yl)methyl)-
tetrahydrofuro[3,4-b]furan-2,3,3a(4H)-triol (1.2A). Boron tri-
chloride (0.79 mL, 0.79 mmol, 5 equiv) was added to a solution of
1.3-A1 (107 mg, 0.16 mmol, 1.0 equiv) in DCM (8 mL) at −78 °C.
The reaction was stirred for 15 min, warmed to 0 °C, and then stirred
for 30 min. The reaction was quenched by the addition of THF and
saturated aqueous NHCO3 (4:1, 3 mL). The mixture was
concentrated under reduced pressure, and the crude was purified by
mass-triggered reverse-phase HPLC (MeCN/water with 0.1%
NH4OH modifier) to afford 1.2-A as a colorless solid (34 mg, 32%
yield) as a 1.25:1 mixture at the anomeric carbon. (Reported as
Isomer 1 (1.3-A1): 1H NMR (400 MHz, acetonitrile-d3) δ 8.16 (s,
1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.40−7.25 (m, 5H), 7.22
(d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 6.43 (d, J =
8.4 Hz, 1H), 6.17−6.07 (m, 1H), 5.96 (d, J = 3.1 Hz, 1H), 4.76 (d, J
= 3.1 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 4.61 (d, J = 10.8 Hz, 1H),
4.52 (d, J = 11.0 Hz, 1H), 4.36 (s, 1H), 4.21−4.12 (m, 1H), 4.07 (d, J
= 10.6 Hz, 1H), 3.88 (s, 3H), 3.87 (d, J = 9.3 Hz, 1H), 3.75 (s, 3H),
3.07−2.95 (m, 2H), 1.51 (s, 3H), 1.37 (s, 3H). 13C{1H} NMR (75
MHz, DMSO) δ 159.5, 157.8, 152.1, 146.2, 140.6, 138.5, 138.1,
128.4, 128.0, 127.4, 127.3, 126.5, 125.4, 123.9, 122.2, 119.3, 112.5,
106.9, 106.3, 104.3, 98.3, 92.2, 85.7, 81.9, 80.5, 72.3, 67.0, 55.4, 55.1,
35.1, 28.9, 27.1, 27.0. HRMS (ESI) m/z: [M + H] + calcd for
C35H38N2O7Br 677.1862, found 677.1868. [α]1D5 + 22° (c = 0.097,
MeOH).
1
observed). H NMR (400 MHz, methanol-d4) δ 8.25 (s, 1H (isomer
1 + isomer 2)), 7.59−7.44 (m, 2H (isomer 1 + isomer 2)), 7.25 (dd, J
= 7.7, 3.9 Hz, 1H (isomer 1 + isomer 2)), 5.38 (d, J = 3.8 Hz, 1H
(isomer 1)), 5.19 (d, J = 2.8 Hz, 1H (isomer 2)), 4.24 (d, J = 3.3 Hz,
1H (isomer 1)), 4.13−4.02 (m, 2H (isomer 1 + isomer 2)), 3.91 (d, J
= 9.4 Hz, 1H (isomer 1)), 3.81 (d, J = 3.8 Hz, 1H (isomer 2)), 3.69
(d, J = 2.7 Hz, 1H (isomer 2)), 3.59 (d, J = 9.5 Hz, 1H (isomer 2)),
3.50 (d, J = 9.4 Hz, 1H (isomer 1)), 3.07 (m, 2H (isomer 1 + isomer
2)). 13C{1H} NMR (101 MHz, DMSO) δ 154.4, 146.6, 140.7, 140.5,
139.0, 126.5, 124.9, 124.0, 124.0, 122.4, 105.9, 102.9, 97.6, 86.1, 86.0,
84.4, 84.0, 82.3, 82.2, 78.8, 76.2, 76.0, 75.3, 35.0, 35.0. HRMS (ESI)
m/z: [M + H]+ calcd for C16H18N2O5Br 397.0399, found 397.0395.
[α]1D5 + 65° (c = 0.28, MeOH).
End-Game Glycosylation General Procedure. Synthesis of
(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-
(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]-
furan-3,3a(4H)-diol (1.1-C): To a vial containing 1.2-A (100 mg,
0.25 mmol, 1 equiv) in anhydrous acetonitrile (4 mL) was added 1,1′-
(azodicarbonyl)dipiperidine (95 mg, 0.38 mmol, 1.5 equiv) followed
by tri-n-butylphosphine (81 mg, 0.40 mmol, 1.6 equiv) at room
temperature. The mixture was stirred for 1 h. In a separate oven-dried
vial containing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (67 mg, 0.50
mmol, 2 equiv) suspended in dry MeCN (4 mL) was added DBU (76
μL, 0.50 mmol, 2 equiv). This mixture was stirred for 1 h at room
1
Isomer 2 (1.3-A2): H NMR (300 MHz, methanol-d4) δ 8.15 (s,
1H), 7.55−7.19 (m, 7H), 7.11 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 2.2
Hz, 1H), 6.44 (dd, J = 8.3, 2.2 Hz, 1H), 5.93 (d, J = 3.7 Hz, 1H), 4.82
(s, 2H), 4.75−4.61 (m, 4H), 4.44 (d, J = 12.2 Hz, 2H), 4.36−4.26
(m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.64 (d, J = 10.8 Hz, 1H), 3.06
(dd, J = 13.9, 7.7 Hz, 1H), 2.98 (dd, J = 13.9, 7.1 Hz, 2H), 1.53 (s,
3H), 1.37 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5,
1598.0, 152.5, 147.2, 139.9, 138.4, 138.3, 130.8, 128.5, 127.8, 127.6,
126.6, 126.6, 124.1, 123.0, 119.8, 113.4, 108.1, 106.9, 104.1, 98.8,
93.4, 89.2, 85.3, 79.7, 71.9 68.3, 55.5, 55.5, 41.3, 39.0, 27.4, 27.3.
HRMS (ESI) m/z: [M + H] + calcd for C35H38N2O7Br 677.1862,
found 677.1867. [α]1D5 − 15° (c = 0.13, MeOH).
(3aR,4aR,5S,7aR,7bR)-7a-(Benzyloxy)-2,2-dimethyl-5-(naph-
thalen-2-ylmethyl)hexahydrofuro[3′,4′:4,5]furo[2,3-d][1,3]-
dioxole (1.3-B1). Following the general procedure, 1.3-B1 (73 mg,
1
52% yield) was obtained. H NMR (600 MHz, DMSO-d6) δ 7.88−
7.81 (m, 3H), 7.75 (s, 1H), 7.50−7.42 (m, 3H), 7.36−7.29 (m, 4H),
7.28−7.24 (m, 1H), 6.04 (d, J = 3.7 Hz, 1H), 4.85 (d, J = 3.6 Hz,
5149
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J. Org. Chem. 2021, 86, 5142−5151

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
temperature and was then added to the above mixture containing the
triol. The final reaction mixture was then stirred at room temperature
overnight. The reaction mixture was filtered and purified by Prep-
HPLC (MeCN/water with 0.1% TFA modifier) to afford 53 mg (33%
yield) of 1.1-C as a TFA salt. **Caution** when handling
compounds 1.1-A−C manipulations such as drying, concentrating,
or weighing of final compounds was performed in an isolator to
reduce potential exposure. A disposable lab coat over a regular lab
coat should be worn in addition to double gloves. Ensure that your
institution has the proper procedures, PPE, and equipment to handle
extremely potent compounds. 1H NMR (499 MHz, DMSO-d6) δ 9.10
(s, 1H), 8.85 (s, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.79 (d, J = 8.3 Hz,
1H), 7.57−7.50 (m, 1H), 7.46−7.42 (m, 1H), 7.19 (d, J = 3.8 Hz,
1H), 6.26 (d, J = 7.9 Hz, 1H), 4.36 (d, J = 8.0 Hz, 1H), 4.33 (d, J =
4.2 Hz, 1H), 4.13−4.08 (m, 1H), 3.96 (d, J = 9.1 Hz, 1H), 3.38 (d, J
= 9.2 Hz, 1H), 3.08−3.03 (m, 2H), 2.89 (s, 3H). 13C{1H} NMR (126
MHz, DMSO) δ 156.1, 152.5, 150.5, 145.0, 144.6, 136.2, 129.4,
127.7, 126.9, 120.1, 117.8, 117.4, 117.0, 105.7, 103.1, 88.0, 86.6, 83.4,
81.5, 75.1, 34.6, 18.4. HRMS (ESI) m/z: [M + H] + calcd for
C23H23N5O4Br 512.0933, found 512.0908.
Ryan V. Quiroz − Discovery Chemistry, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States; orcid.org/
0000-0001-6840-9636
Michael H. Reutershan − Discovery Chemistry, Merck & Co.,
Inc., Boston, Massachusetts 02115, United States
David Witter − Discovery Chemistry, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States
Surendra B. Gadamsetty − Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Hongming Li − External Capabilities, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States
Josep Saurí − Analytical Enabling Technologies, Merck & Co.,
Inc., Boston, Massachusetts 02115, United States
Sebastian E. Schneider − Computational and Structural
Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115,
United States; orcid.org/0000-0003-1233-8984
Yu-hong Lam − Computational and Structural Chemistry,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0002-4946-1487
(2R,3R,3aS,6S,6aR)-6-((2-Amino-3-bromoquinolin-7-yl)-
methyl)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol (1.1-A). Following the
glycosylation general procedure, 1.1-A (10 mg, 31% yield) was
Rachel L. Palte − Computational and Structural Chemistry,
Merck & Co., Inc., Boston, Massachusetts 02115, United
States
1
obtained. H NMR (499 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.71 (s,
1H), 8.19 (s, 2H), 8.00 (d, J = 3.7 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H),
7.49 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 3.7 Hz, 1H), 6.21
(d, J = 7.9 Hz, 1H), 4.38 (d, J = 7.9 Hz, 1H), 4.28 (d, J = 4.1 Hz, 1H),
4.12−4.06 (m, 1H), 3.95 (d, J = 9.1 Hz, 1H), 3.37 (d, J = 9.1 Hz,
1H), 3.09−2.99 (m, 2H). 13C{1H} NMR (126 MHz, DMSO) δ
152.0, 151.5, 151.3, 143.8, 139.0, 128.9, 127.8, 126.5, 121.3, 120.2,
117.9, 106.1, 100.8, 88.2, 87.2, 83.8, 82.0, 77.3, 75.1, 35.0.HRMS
(ESI) m/z: [M + H] + calcd for C22H20N5O4ClBr 532.0387, found
532.0380.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02969
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(2R,3R,3aS,6S,6aR)-6-((2-Amino-3-bromoquinolin-7-yl)-
methyl)-2-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol (1.1-B). Following
the glycosylation general procedure, 1.1-B (16 mg, 48% yield) was
D.C. would like to thank Dr. Michelle Machacek for her
contributions to this work.
1
obtained. H NMR (499 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.63 (s,
REFERENCES
■
1H), 7.77 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.42 (dd, J =
8.3, 1.1 Hz, 1H), 6.17 (d, J = 8.1 Hz, 1H), 4.31−4.25 (m, 2H), 4.12−
4.05 (m, 1H), 3.94 (d, J = 9.1 Hz, 1H), 3.36 (d, J = 9.2 Hz, 1H),
3.09−3.00 (m, 2H), 2.47−2.44 (m, 3H). 13C{1H} NMR (126 MHz,
DMSO) δ 159.3, 159.1, 152.5, 152.0, 151.1, 150.6, 144.8, 144.5,
126.8, 125.3, 120.1, 116.5, 114.9, 110.8, 105.6, 87.6, 86.0, 83.2, 81.5,
76.8, 74.8, 34.6, 11.2. HRMS (ESI): [M + H]+ calcd for
C23H22N5O4ClBr 546.0544, found 546.0529.
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ASSOCIATED CONTENT
(2) Quiroz, R. V.; Reutershan, M.H.; Schneider, S. E.; Sloman, D.;
Lacey, B. M.; Swalm, B. M; Yeung, C. S.; Gibeau, C.; Spellman, D. S.;
Rankic, D. A.; Chen, D.; Witter, D.; Linn, D.; Munsell, E.; Feng, G.;
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02969.
Modeling and computational results, biological assays,
1
copies of H NMR and 13C NMR spectra, and X-ray
crystallography (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
David A. Candito − Process Research and Development,
Merck & Co., Inc., Boston, Massachusetts 02115, United
States; orcid.org/0000-0003-4773-1647;
Email: david.candito@merck.com
Authors
Yingchun Ye − Discovery Chemistry, Merck & Co., Inc.,
Boston, Massachusetts 02115, United States
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(6) 1.18 was isolated as a minor product, and its structure was
elucidated. The isolated yield was not determined. An experiment was
conducted to test whether a hydroboration/oxidation could be
performed, and it was found that a number of different products were
formed with only minor amounts of product III, which was isolated as
a mixture with compound II. The isolated yields were not determined.
From these results, it appears that the initial borane undergoes base-
mediated elimination to provide a ring-opened olefin, which
undergoes hydroboration to yield products I, II, and IV.
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