Synthesis of stereochemically and skeletally diverse fused ring systems from functionalized C-glycosides

Article abstract of DOI:10.1021/jo4000916

A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.

Full text of DOI:10.1021/jo4000916

Article
pubs.acs.org/joc
Synthesis of Stereochemically and Skeletally Diverse Fused Ring
Systems from Functionalized C‑Glycosides
Baudouin Gerard,† Maurice D. Lee, IV, Sivaraman Dandapani, Jeremy R. Duvall, Mark E. Fitzgerald,
Sarathy Kesavan,† Jason T. Lowe,† Jean-Charles Marie, Bhaumik A. Pandya, Byung-Chul Suh,
́
Morgan Welzel O’Shea,† Michael Dombrowski, Diane Hamann, Berenice Lemercier, Tiffanie Murillo,
Lakshmi B. Akella,† Michael A. Foley, and Lisa A. Marcaurelle*,†
Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United
States
S
* Supporting Information
ABSTRACT: A diversity-oriented synthesis (DOS) strategy
was developed for the synthesis of stereochemically diverse
fused-ring systems containing a pyran moiety. Each scaffold
contains an amine and methyl ester for further diversification
via amine capping and amide coupling. Scaffold diversity was
evaluated in comparison to previously prepared scaffolds by a
shape-based principal moments of inertia (PMI) analysis.
cyclization and nucleophilic aromatic substitution (SNAr)
reactions, and bicyclic compounds 5 and 6 through intra-
molecular Mitsunobu and epoxide ring-opening reactions. All
skeletons resulting from these pathways retain functional
handles that can be utilized for solid-phase library synthesis
and future analogue development.
INTRODUCTION
■
As part of ongoing efforts to produce a stereochemically and
skeletally diverse collection of small molecules, we sought to
develop methods for the synthesis of a set of pyran-containing
fused ring systems.1 Pyrans are common subunits of natural
products and biologically relevant small molecules.2 To access
pyran-containing fused ring systems, we envisioned utilizing a
2,3-unsaturated C-glycoside scaffold (1 and 2, Figure 1)
previously reported by our group.3 Having access to all eight
stereoisomers of C-glycoside 1 and the corresponding allylic
amine 2, we aimed to develop synthetic pathways that would
yield fused bi- and tricyclic ring systems. This paper descibes
the synthesis of tricyclic compounds 3 and 4 via radical
RESULTS AND DISCUSSION
■
The benzofuran motif is present in a wide range of natural
products.4 We aimed to access a [6,5,6] benzofuran scaffold (3,
Scheme 1) starting from C-glycoside 1 via a 5-exo-trig radical
cyclization.5 This type of radical cyclization has been
successfully employed in the construction of current drugs
and numerous natural products including pregabalin6 and
morphine.7 We anticipated that the radical cyclization step
would occur by a regio- and stereoselective mode of addition
onto the alkene, providing a cis relationship between C-4 and
the newly formed stereogenic center at C-3.
The synthesis of benzofuran scaffold 3 began with an
intermolecular SNAr reaction between C-glycoside 1 and
commercially available 2-bromo-1-fluoro-4-nitrobenzene 7
(Scheme 1). This reaction proceeded in the presence of
sodium hydride in DMF with varying degrees of success (52−
78% yield) across the diastereomers to afford 8a−d. Selective
reduction of the aryl nitro group using Zn metal8 afforded the
desired aniline 9a−d in good yield. Initial attempts to effect the
Figure 1. Synthesis of fused bi- and tricyclic ring systems from a C-
glycoside template.
Received: January 15, 2013
© XXXX American Chemical Society
A
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Scheme 1. Benzofuran Formation via a 5-exo-trig Cyclization
Scheme 2. Tricyclic Lactam Formation via Intramolecular SNAr
5-exo-trig radical cyclization of 9a by treatment with excess
amounts of n-Bu3SnH and catalytic AIBN in refluxing benzene
were successful, affording the desired benzofuran 10a in 53%
yield. Concerns about toxicity and contamination by organo-tin
reagents led us to explore the possibility of utilizing a catalytic
amount of tin for the radical cyclization.9 Using catalytic
amounts of n-Bu3SnCl and AIBN in the presence of NaBH3CN
in i-PrOH10 resulted in the formation of the cyclized product
with similar efficiency as when using excess n-Bu3SnH. Notably,
we were able to perform this reaction on multigram scale for all
stereoisomers yielding >20 g of each product. Finally, removal
of the TBDPS group using HF·pyridine followed by Fmoc
protection of the aniline yielded the desired benzofuran
scaffolds 3a−d in high yield.11
molecule synthesis in general.13 We envisioned employing a
SNAr cyclization to produce a [6,8,6] tricyclic scaffold
containing an 8-membered lactam starting from allylic amine
2. Thus, amine 2 was first acylated with 2-fluoro-5-nitrobenzoyl
chloride 11 to afford amide 12 (Scheme 2). Initially we
attempted the SNAr cyclization of 12 with a “one-pot” TBDPS
deprotection/cyclization sequence using either TBAF or CsF;
however, only dimerization and decomposition was observed.
We hypothesized that the success of the intramolecular
cyclization may be affected by the conformation of the amide
bond. On the basis of observations by Smith and co-workers,14
we decided to investigate the impact of an N-alkylated amide
bond on intramolecular ring cyclization. Thus, amides 12a−d
were treated with methyl iodide in the presence of sodium
hydride in DMF to afford N-methyl amide 13a−d. Subsequent
conversion of the alkylated amides to the cyclized products was
The intramolecular SNAr reaction has been widely used in
the context of diversity-oriented synthesis (DOS)12 and small
B
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Scheme 3. Azetidine Formation via Intramolecular Mitsunobu
Scheme 4. Oxazacane Formation via Epoxide Opening/Ring-Closing Reaction
successful; however, the SNAr reaction was found to have
moderate stereochemical dependency. Upon treatment with
cesium fluoride in DMF at 40 °C, TBDPS ethers 13c,d
underwent a smooth deprotection/cyclization sequence to
produce lactams 14c,d. Meanwhile, amides 13a,b required a
two-step sequence involving TBDPS removal with HF·pyridine
followed by treatment with CsF to promote the SNAr-mediated
ring closure.1a Finally, hydrogenation of the cyclized products
14a−d15 reduced both the double bond and aryl nitro group,
which afforded the desired tricyclic scaffolds 4a−d.
We next investigated the possibility of azetidine ring
formation 1e,16 to yield the [6,4] ring system 5 through an
intramolecular Mitsunobu reaction. Starting from amines 2a,b,
the Mitsunobu precursors 16a,b were obtained in three steps
including hydrogenation, N-nosylation and TBDPS depro-
tection (Scheme 3). This material was then treated with PPh3
and DIAD leading to the formation of the desired bicyclic
azetidine 5a,b in high yield. The product was easily isolated
from the Mitsunobu byproducts, and the reaction could be
carried out on multigram scale.
Finally, a number of interesting oxazapane and/or oxazacane
ring systems were envisioned to be readily accessed through the
use of chiral intermediate 15 (Scheme 4). We chose to explore
the use of an epoxide-opening/ring-closing reaction, which
would allow for the formation of a single diastereomeric
product upon cyclization. A number of examples utilizing chiral
epoxides as synthons for the assembly of complex small
molecules, including both natural products17 and library
scaffolds,18 have been well documented. Execution of this
approach first required the incorporation of an epoxide into the
C-glycoside template.
presumably due to steric hindrance. Ultimately, this was
overcome using the (R)- or (S)-glycidol triflates (17)19
(Scheme 4). Liberation of the primary alcohol by TBDPS
deprotection gave compound 19, the precursor to the epoxide-
opening/ring-closing reaction. Previous reports of epoxide-
opening/ring-closing reactions17c have mainly focused on the
formation of smaller ring systems with varying degrees of endo/
exo selectivity. Although the 7-exo-tet cyclization20 is favored on
the basis of Baldwin’s rules, there is precedent for the 8-endo-tet
cyclization to occur under basic conditions.21 After a series of
trial experiments, we found that the endo/exo selectivity of the
Lewis-acid-mediated epoxide-opening/ring-closing reaction had
a strong dependence on the stereochemical relationship
between C-4 and C-5. With the syn configuration (19-syn,
not shown, see experimental details), mixtures of both the 7-
membered oxazapane (20) and 8-membered oxazacane ring
(6) systems were observed with selectivity ranging from 1:1 to
9:1 favoring the oxazapane depending on the stereoisomer
used. Interestingly, with the anti-configuration (19a−d), the
cyclization occurs smoothly via 8-endo-tet in the presence of
BF3·OEt2 in either CH2Cl2 or THF to give primarily the endo
product, 8-membered oxazacane 6a−d.22 The stereochemistry
at both C-1 of the pyran and of the epoxide has little impact on
the regioselectivity of the reaction. The epoxide-opening/ring-
closing reaction was run on a multigram scale with 19a−d,
obtaining acceptable yields of 6a−d while not affecting
selectivity.
In order to visualize the chemical space represented by the
pyran-containing fused-ring systems as compared to our
previously reported aldol-1a−c and azetidine-based1e pathways,
we undertook a principal moments of inertia (PMI) analysis
(Figure 2).23 Through this shape-based analysis, we were able
to visualize the differences between the three collections and
Initially, alkylation of sulfonamide 15a−d with epichlorohy-
drin proved difficult when using the all syn stereoisomer,
C
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to rt and allowed to stir for 4 h. The reaction was then quenched with
a saturated solution of aqueous ammonium chloride. DMF was
removed in vacuo, and the aqueous layer was extracted with EtOAc (3
× 200 mL). The combined organic layers were washed with brine,
dried over MgSO4 and filtered. The organic layer was concentrated
under reduced pressure, and the crude residue was purified by
chromatography on silica gel (gradient: 0−15% EtOAc in hexanes),
which provided 28.6 g (78%) of 8a as a yellow oil. [α]D20 +80.2 (c 1.1,
CHCl3). IR νmax (cm−1, film): 2930, 2856, 1740, 1582, 1519, 1478,
1343, 1272, 1113. 1H NMR (300 MHz, CDCl3): δ 8.50 (d, J = 2.7 Hz,
1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 7.76−7.63 (m, 2H), 7.64−7.52
(m, 2H), 7.50−7.23 (m, 6H), 7.14 (d, J = 9.2 Hz, 1H), 6.05−5.97 (m,
2H), 5.31 (d, J = 8.3 Hz, 1H), 4.76 (t, J = 6.1 Hz, 1H), 4.05−3.92 (m,
2H), 3.86 (d, J = 8.3 Hz, 1H), 3.74 (s, 3H), 2.74−2.59 (m, 2H), 1.05
(s, 9H). 13C NMR (125 MHz, CDCl3): δ 170.9, 159.7, 141.9, 135.5,
133.2, 133.8, 127.8, 124.9, 124.7, 113.3, 113.0, 77.6, 72.0, 70.7, 62.9,
51.9, 40.2, 26.0, 19.4. HRMS (ESI+) calcd for C31H34BrNNaO7Si [M
+ +Na]+: 662.1186. Found: 662.1181.
Methyl 2-((2R,5S,6R)-5-(2-bromo-4-nitrophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 8b. Following the above protocol, 1b (29.5 g, 67 mmol, 1.0
equiv) was treated with 2-bromo-1-fluoro-4-nitrobenzene 7 (14.7 g, 67
mmol, 1.0 equiv) and sodium hydride (3.5 g, 87 mmol, 1.3 equiv) in
DMF (890 mL). The reaction provided, after purification, 24.0 g
Figure 2. PMI analysis of pyran-containing scaffolds, along with
previously reported scaffolds from aldol- and azetidine-based pathways.
20
(56%) of 8b as a yellow oil. [α]D +49.7 (c 1.0, CHCl3). IR νmax
(cm−1, film): 2930, 2856, 1740, 1582, 1519, 1478, 1343, 1272, 1113.
1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 2.7 Hz, 1H), 8.09 (dd, J =
observed that the fused ring systems access different chemical
space than that occupied by the previously described scaffolds,
especially compared to the aldol-based pathways, which
included a variety of macrocycles.
9.1, 2.7 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.7 Hz, 2H),
7.43−7.26 (m, 6H), 7.06 (d, J = 9.1 Hz, 1H), 5.99 (q, J = 10.4 Hz,
2H), 5.10 (d, J = 5.7 Hz, 1H), 4.79 (t, J = 6.0 Hz, 1H), 3.92 (dd, J =
7.1, 10.3 Hz, 3H), 3.72 (s, 3H), 2.78 (dd, J = 15.3, 8.6 Hz, 1H), 2.57
(dd, J = 15.3, 5.6 Hz, 1H), 1.15−0.82 (m, 9H). 13C NMR (75 MHz,
CDCl3): δ 170.9, 159.4, 141.9, 135.7, 135.6, 133.2, 133.0, 132.9, 129.9,
129.6, 127.9, 124.7, 123.9, 113.1, 72.2, 70.2, 69.5, 52.1, 38.5, 26.9, 19.4.
HRMS (ESI+) calcd for C31H34BrNNaO7Si [M + Na]+: 662.1186.
Found: 662.1180.
CONCLUSIONS
■
In conclusion, we have reported the synthesis of a diverse set of
fused-ring systems containing a pyran moiety. Utilizing all
stereoisomers of a common C-glycoside intermediate, we are
able to access all possible stereoisomers of each scaffold
efficiently on multigram scale. Elaboration of these scaffolds to
libraries suitable for high-throughput screening has been
completed and will be the basis of future publications.
Methyl 2-((2S,5R,6R)-5-(2-bromo-4-nitrophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 8c. Following the above protocol, 1c (10.0 g, 22.7 mmol, 1.0
equiv) was treated with 2-bromo-1-fluoro-4-nitrobenzene 7 (5.0 g,
22.7 mmol, 1.0 equiv) and sodium hydride (1.3 g, 31.8 mmol, 1.3
equiv) in DMF (280 mL). The reaction provided, after purification,
EXPERIMENTAL SECTION
20
■
9.0 g (61%) of 8c as a yellow oil. [α]D −137.0 (c 0.9, CHCl3). IR
νmax (cm−1, film): 2930, 2856, 1740, 1582, 1519, 1478, 1343, 1272,
General Methods. All oxygen and/or moisture-sensitive reactions
were carried out under N2 atmosphere in glassware that had been
flame-dried under a vacuum (∼0.5 mmHg) and purged with N2 prior
to use. All reagents and solvents were purchased from commercial
vendors and used as received or synthesized according to the
footnoted references. 1H and 13C NMR spectra were recorded on 300
and/or 500 MHz spectrometers. All chemical shifts are reported in
parts per million (δ) referenced to residual nondeuterated solvent.
Data are reported as follows: chemical shifts, multiplicity (br = broad, s
= singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet; coupling constant(s) in Hz; integration). Unless otherwise
indicated, NMR data were collected at 25 °C. IR spectra were obtained
with an FTIR spectrometer and are reported in cm−1. Flash
chromatography was performed using 40−60 μm silica gel (60 Å
mesh) with the indicated solvent. Analytical thin layer chromatography
(TLC) was performed on 0.25 mm silica gel 60-F plates. Visualization
was accomplished with UV light and aqueous potassium permanganate
or ceric ammonium molybdate stain followed by heating. High-
resolution mass spectra were obtained using a LC−MS coupled with a
quadrupole.
1
1113. H NMR (300 MHz, CDCl3): δ 8.48 (d, J = 2.6 Hz, 1H), 8.18
(d, J = 9.1 Hz, 1H), 7.57 (dd, J = 18.8, 7.7 Hz, 4H), 7.47−7.26 (m,
6H), 7.06 (d, J = 9.1 Hz, 1H), 6.52−6.33 (m, 1H), 6.18 (d, J = 10.2
Hz, 1H), 4.90 (d, J = 4.5 Hz, 1H), 4.65 (t, J = 6.5 Hz, 1H), 4.13−4.03
(m, 1H), 4.02−3.89 (m, 2H), 3.70 (s, 3H), 2.71 (dd, J = 15.9, 7.2 Hz,
1H), 2.57 (dd, J = 16.0, 6.5 Hz, 1H), 0.95 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 170.9, 159.8, 141.4, 136.7, 135.4, 133.2, 133.1, 129.7,
129.4, 127.7, 127.6, 125.1, 124.5, 121.6, 116.0, 113.0, 112.4, 71.6, 68.8,
62.3, 51.8, 39.6, 26.7, 19.1. HRMS (ESI+) calcd for C31H34BrNNaO7Si
[M + Na]+: 662.1186. Found: 662.1194.
Methyl 2-((2R,5R,6R)-5-(2-bromo-4-nitrophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 8d. Following the above protocol, 1d (15.0 g, 34.0 mmol, 1.0
equiv) was treated with 2-bromo-1-fluoro-4-nitrobenzene 7 (7.49 g,
34.0 mmol, 1.0 equiv) and sodium hydride (1.12 g, 28.0 mmol, 1.3
equiv) in DMF (400 mL). The reaction provided, after purification,
20
11.4 g (52%) of 8d as a yellow oil. [α]D −116.2 (c 1.1, CHCl3). IR
νmax (cm−1, film): 2930, 2856, 1740, 1582, 1519, 1478, 1343, 1272,
1
1113. H NMR (300 MHz, CDCl3): δ 8.36 (d, J = 2.7 Hz, 1H), 8.08
Methyl 2-((2S,5S,6R)-5-(2-bromo-4-nitrophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 8a. To a solution of 1a (25.0 g, 57.2 mmol, 1.0 equiv) in
DMF (570 mL) was added 2-bromo-1-fluoro-4-nitrobenzene 7 (12.6
g, 57.2 mmol, 1.0 equiv). The reaction mixture was cooled to 0 °C,
and sodium hydride (2.5 g, 62.9 mmol, 1.3 equiv) was added portion-
wise over a period of 10 min. The reaction mixture was slowly warmed
(dd, J = 9.1, 2.7 Hz, 1H), 7.48 (dd, J = 13.7, 7.9 Hz, 4H), 7.50−7.20
(m, 6H), 6.94 (d, J = 9.1 Hz, 1H), 6.35−6.09 (m, 2H), 4.77 (s, 2H),
3.98 (d, J = 4.6 Hz, 2H), 3.81 (d, J = 9.7 Hz, 1H), 3.59 (s, 3H), 2.64
(dd, J = 15.1, 8.9 Hz, 1H), 2.45 (dd, J = 15.1, 5.5 Hz, 1H), 0.86 (s,
9H). 13C NMR (75 MHz, CDCl3): δ 170.9, 159.8, 141.7, 135.7, 135.6,
135.6, 133.4, 133.2, 130.0, 129.6, 128.7, 127.9 (2), 124.7, 121.6, 113.2,
D
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112.6, 71.5, 69.6, 68.8, 62.1, 52.1, 37.5, 26.9, 19.3. HRMS (ESI+) calcd
for C31H34BrNNaO7Si [M + Na]+: 662.1186. Found: 662.1195.
Methyl 2-((2S,5S,6R)-5-(4-amino-2-bromophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 9a. To a solution of 8a (27.3 g, 42.6 mmol) in THF (426
mL) and acetic acid (426 mL) was added zinc powder (41.8 g, 639
mmol, 15 equiv) in small portions at rt. The reaction mixture was
stirred at rt for 4 h. The reaction mixture was diluted with CH2Cl2,
filtered over Celite and washed with CH2Cl2. After filtration, the
solvent was removed in vacuo. The organic residue was dissolved in
CH2Cl2 (300 mL) and then washed with water (2 × 200 mL), brine
(100 mL) and dried over Na2SO4. After filtration, excess solvent was
removed in vacuo to afford a crude residue, which was purified by
chromatography on silica gel (gradient: 0−60% EtOAc in hexanes) to
provide 19.5 g (73%) of 9a as a white foamy solid. [α]D20 +59.3 (c 1.3,
CHCl3). IR νmax (cm−1, film): 2929, 2856, 1735, 1492, 1427, 1224,
NMR (75 MHz, CDCl3): δ 171.2, 147.4, 142.1, 135.8, 133.8 (2),
133.3, 129.8, 127.8 (2), 124.2, 120.1, 118.8, 115.1, 72.8, 69.9, 69.2,
62.5, 60.6, 52.0, 38.0, 27.0, 19.3. HRMS (ESI+) calcd for
C31H36BrNNaO5Si [M + Na]+: 632.1444. Found: 632.1441.
M e t h y l 2 - ( ( 1 R , 3 R , 4 a R , 9 a S )- 6 - a m i n o - 1 - ( ( ( t e r t -
butyldiphenylsilyl)oxy)methyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 10a. To a solution of 9a
(32.6 g, 53.4 mmol) in i-PrOH (530 mL) in a jacketed, 3-necked
round-bottom flask (equipped with a reflux condenser and
recirculating chiller) was added AIBN (1.7 g, 10.7 mmol) and
tributyltin chloride (2.2 mL, 8.0 mmol). The reaction mixture was
carefully degassed with Ar for 10 min prior to heating. The reaction
mixture was then heated at 85 °C and was allowed to stir for 5 min.
Simultaneously, a solution of NaBH3CN (5.0 g, 80.0 mmol) in i-PrOH
(120 mL) and a solution of AIBN (1.7g, 10.7 mmol) in benzene (120
mL) were added slowly over 2 h. After 2 h, the reaction was cooled to
rt. i-PrOH was removed in vacuo, and the residue was coevaporated
with benzene (3 × 20 mL). The crude purple solid was diluted in
EtOAc (200 mL) and extracted with a saturated solution of aqueous
ammonium chloride (2 × 100 mL). The organic layer was washed with
brine, dried with MgSO4, filtered and concentrated. The resulting
residue was diluted with MeCN (100 mL) and washed with hexanes
(2 × 60 mL). The MeCN phase was then dried in vacuo to afford a
pink residue, which was purified by chromatography on silica gel
(gradient: 0−70% EtOAc in hexanes), which provided 28.5 g (57%) of
10a as a white/pink foamy solid. [α]D20 +36.4 (c 1.1, CHCl31). IR νmax
(cm−1, film): 2930, 2856, 1736, 1488, 1428, 1217, 1112. H NMR
(300 MHz, CDCl3): δ 7.63−7.60 (m, 4H), 7.29−7.27 (m, 6H), 6.50−
6.37 (m, 3H), 4.46 (t, J = 8.7 Hz, 1H), 3.80−3.77 (m, 3H), 3.69 (m,
1H), 3.64 (s, 3H), 3.40 (m, 3H), 2.59 (dd, J = 15.4, 7.8 Hz, 1H), 2.45
(dd, J = 15.5, 5.2 Hz, 1H), 2.21 (d, J = 13.9 Hz, 1H), 1.78 (m, 1H),
0.95 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 171.5, 152.5, 140.8,
135.8 (2), 133.9, 133.7, 129.59, 129.54, 129.5, 127.6, 115.0, 111.3,
110.6, 77.6, 77.0, 70.0, 64.9, 60.5, 51.8, 40.8, 39.5, 30.3, 26.9, 19.4.
HRMS (ESI+) calcd for C31H38NO5Si [M + H]+: 532.2519. Found:
532.2516.
1
1112. H NMR (300 MHz, CDCl3): δ 7.70 (d, J = 7.8 Hz, 2H), 7.60
(d, J = 7.8 Hz, 2H), 7.44−7.26 (m, 6H), 6.90−6.79 (m, 2H), 6.53 (dd,
J = 8.7, 2.7 Hz, 1H), 6.01 (d, J = 10.3 Hz, 1H), 5.85 (d, J = 10.3 Hz,
1H), 4.92 (d, J = 7.5 Hz, 1H), 4.67 (br s, 1H), 3.97 (s, 2H), 3.76 (d, J
= 8.5 Hz, 1H), 3.69 (s, 3H), 3.50−3.13 (m, 2H), 2.71−2.40 (m, 2H),
0.99 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 171.2, 147.6, 142.0,
136.0, 135.7, 134.0, 133.6, 131.0, 129.7, 129.6, 127.7 (2), 127.1, 120.1,
118.0, 115.3, 114.3, 78.0, 71.8, 71.5, 63.4, 51.9, 40.5, 26.9, 19.5. HRMS
(ESI+) calcd for C31H36BrNNaO5Si [M + Na]+: 632.1444. Found:
632.1447.
Methyl 2-((2R,5S,6R)-5-(4-amino-2-bromophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 9b. Following the above protocol, 8b (24.0 g, 37.5 mmol, 1
equiv) was treated with zinc powder (36.8 g, 562 mmol, 15 equiv) in
THF (375 mL) and acetic acid (375 mL). The reaction provided, after
purification, 14.3 g (63%) of 9b as a white foamy solid. [α]D20 +38.6 (c
1.1, CHCl3). IR νmax (cm−1, film): 2929, 2856, 1735, 1492, 1427, 1224,
1112. 1H NMR (300 MHz, CDCl3): δ 7.64 (dd, J = 6.1, 2.0 Hz, 4H),
7.47−7.26 (m, 6H), 6.87 (dd, J = 15.2, 5.7 Hz, 2H), 6.52 (dd, J = 8.7,
2.7 Hz, 1H), 6.01 (d, J = 10.4 Hz, 1H), 5.88 (d, J = 10.3 Hz, 1H), 4.75
(br s, 2H), 3.91 (br s, 3H), 3.67 (s, 3H), 3.51 (br s, 1H), 2.78 (dd, J =
15.3, 8.8 Hz, 1H), 2.54 (dd, J = 15.3, 5.4 Hz, 1H), 0.99 (s, 9H). 13C
NMR (75 MHz, CDCl3): δ 171.4, 147.3, 142.1, 135.9, 135.8, 133.7,
133.5, 131.1, 129.7, 127.8, 126.1, 120.1, 118.3, 115.2, 114.6, 72.8, 71.2,
69.4, 63.3, 51.9, 38.6, 26.9, 19.4. HRMS (ESI+) calcd for
C31H36BrNNaO5Si [M + Na]+: 632.1444. Found: 632.1439.
M e t h y l 2 - ( ( 1 R , 3 S , 4 a R , 9 a S ) - 6 - a m i n o - 1 - ( ( ( t e r t -
butyldiphenylsilyl)oxy)methyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 10b. Following the above
protocol, 9b (15.0 g, 24.6 mmol, 1 equiv) was treated with AIBN (1.6
g, 8.9 mmol) and tributyltin chloride (1.0 mL, 3.6 mmol) followed by
NaBH3CN (2.3 g, 36.8 mmol) in i-PrOH (250 mL). The reaction
provided, after purification, 8.8 g (66%) of 10b as a white/pink foamy
Methyl 2-((2S,5R,6R)-5-(4-amino-2-bromophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 9c. Following the general reaction protocol, 8c (30.0 g, 46.8
mmol, 1 equiv) was treated with zinc powder (45.9 g, 702 mmol, 15
equiv) in THF (468 mL) and acetic acid (468 mL). The reaction
provided, after purification, 21.0 g (73%) of 9c as a white foamy solid.
[α]D20 −137.0 (c 1.0, CHCl3). IR νmax (cm−1, film): 2929, 2856, 1735,
20
solid. [α]D +54.9 (c 1.1, CHCl3). IR νmax (cm−1, film): 2930, 2856,
1736, 1488, 1428, 1217, 1112. 1H NMR (300 MHz, CDCl3): δ 7.87−
7.55 (m, 4H), 7.40 (m, 5H), 6.57 (dd, J = 15.0, 5.2 Hz, 2H), 6.46 (dd,
J = 8.3, 2.4 Hz, 1H), 4.69−4.48 (m, 1H), 4.35 (td, J = 11.4, 5.0 Hz,
1H), 4.07−3.89 (m, 2H), 3.82 (dd, J = 10.9, 5.4 Hz, 1H), 3.63 (s, 3H),
3.49−3.29 (m, 2H), 2.61 (dd, J = 15.4, 7.5 Hz, 1H), 2.38 (dd, J = 15.4,
5.6 Hz, 1H), 2.00 (ddd, J = 13.7, 5.7, 3.7 Hz, 1H), 1.49 (m 1H), 1.05
(s, 9H). 13C NMR (75 MHz, CDCl3): δ 171.6, 152.3, 140.4, 135.9,
135.8, 133.4, 133.4, 132.2, 129.8, 129.8, 127.9, 127.9, 115.2, 112.0,
110.2, 79.6, 77.5, 77.2, 77.0, 72.7, 68.2, 65.3, 51.8, 40.8, 38.9, 32.9,
27.0, 19.4. HRMS (ESI+) calcd for C31H37NNaO5Si [M + Na]+:
554.2339. Found: 554.2345.
1
1492, 1427, 1224, 1112. H NMR (300 MHz, CDCl3): δ 7.73−7.57
(m, 4H), 7.45−7.22 (m, 6H), 6.83 (dd, J = 8.5, 5.7 Hz, 2H), 6.50 (dd,
J = 8.6, 2.7 Hz, 1H), 6.00 (dd, J = 16.0, 6.8 Hz, 2H), 4.62−4.43 (m,
2H), 4.14 (dd, J = 10.2, 6.8 Hz, 1H), 3.95 (dd, J = 10.2, 6.2 Hz, 1H),
3.84 (d, J = 4.8 Hz, 1H), 3.66 (s, 3H), 3.47 (s, 2H), 2.69 (dd, J = 15.7,
7.3 Hz, 1H), 2.52 (dd, J = 15.7, 6.5 Hz, 1H), 1.03 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 171.3, 147.3, 142.1, 135.8, 134.7, 133.8, 129.7,
127.8, 124.2, 120.0, 119.3, 115.3, 115.0, 78.0, 71.8, 69.7, 63.4, 51.9,
39.9, 27.0, 19.4. HRMS (ESI+) calcd for C31H36BrNNaO5Si [M +
Na]+: 632.1444. Found: 632.1441.
M e t h y l 2 - ( ( 1 R , 3 R , 4 a S , 9a R )- 6 - a m i n o - 1 - ( ( ( t e r t -
butyldiphenylsilyl)oxy)methyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 10c. Following the above
protocol, 9c (20.0 g, 32.8 mmol, 1 equiv) was treated with AIBN (2.1
g, 13.1 mmol) and tributyltin chloride (1.3 mL, 4.9 mmol) followed by
NaBH3CN (3.1 g, 49.1 mmol) in i-PrOH (430 mL). The reaction
provided, after purification, 13.8 g (79%) of 10c as a white/pink foamy
Methyl 2-((2R,5R,6R)-5-(4-amino-2-bromophenoxy)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-2-yl)-
acetate 9d. Following the above protocol, 8d (15.0 g, 23.4 mmol, 1
equiv) was treated with zinc powder (23.0 g, 351 mmol, 15 equiv) in
THF (234 mL) and acetic acid (234 mL). The reaction provided, after
20
solid. [α]D −53.0 (c 0.9, CHCl3). IR νmax (cm−1, film): 2930, 2856,
1736, 1488, 1428, 1217, 1112. 1H NMR (300 MHz, CDCl3): δ 7.71 (t,
J = 8.0 Hz, 4H), 7.39−7.37 (m, 6H), 6.63−6.37 (m, 3H), 4.38 (d, J =
9.9 Hz, 1H), 4.03 (dt, J = 10.9, 5.6 Hz, 1H), 3.91 (m, 2H), 3.85−3.67
(m, 2H), 3.64 (s, 3H), 3.39 (s, 2H), 3.15−3.09 (m, 1H), 2.58−2.53
(dd, J = 14.9, 7.1 Hz, 1H), 2.30−2.27 (dd, J = 14.9, 5.6, 1H), 2.07−
1.89 (m, 1H), 1.27−1.18 (m, 1H), 1.05 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 171.7, 152.1, 140.2, 135.9, 135.8, 134.2, 133.8, 129.8, 129.7,
20
purification, 10.9 g (76%) of 9d as a white foamy solid. [α]D −23.9
(c, 1.1 CHCl3). IR νmax (cm−1, film): 2929, 2856, 1735, 1492, 1427,
1
1224, 1112. H NMR (300 MHz, CDCl3): δ 7.72−7.53 (m, 4H),
7.46−7.23 (m, 6H), 6.91−6.69 (m, 2H), 6.62−6.42 (m, 1H), 6.12−
5.88 (m, 2H), 4.90−4.68 (m, 1H), 4.56−4.45 (m, 1H), 4.12 (dt, J =
18.7, 7.0 Hz, 2H), 4.03−3.85 (m, 3H), 3.63 (s, 3H), 2.66 (dd, J = 15.0,
8.6 Hz, 1H), 2.47 (dd, J = 15.0, 5.6 Hz, 1H), 1.10−0.86 (m, 9H). 13C
E
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Article
127.8, 115.0, 111.5, 110.8, 78.9, 78.0, 72.1, 63.9, 51.9, 40.9, 39.5, 35.4,
27.0, 19.4. HRMS (ESI+) calcd for C31H37NNaO5Si [M + Na]+:
554.2339. Found: 554.2341.
= 8.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.62−4.53 (m, 1H), 4.48 (d, J
= 6.6 Hz, 2H), 4.30 (t, J = 6.5 Hz, 1H), 4.16 (dt, J = 16.5, 8.3 Hz, 1H),
3.87 (dd, J = 10.1, 5.5 Hz, 1H), 3.73−3.57 (m, 5H), 3.56−3.40 (m,
1H), 2.54−2.36 (m, 2H), 2.08−1.91 (m, 1H), 1.40 (m, 1H). 13C
NMR (125 MHz, DMSO-d6, 100 °C): δ 170.2, 154.1, 153.3, 143.4,
140.3, 131.7, 131.3, 127.0, 126.5, 124.5, 119.4, 119.1, 115.8, 108.4,
79.0, 71.7, 66.6, 65.1, 61.3, 50.5, 46.5, 37.3, 31.8. HRMS (ESI+) calcd
for C30H30NO7 [M + H]+: 516.2022. Found: 516.2021.
M e t h y l 2 - ( ( 1 R , 3 S , 4 a S , 9 a R ) - 6 - a m i n o - 1 - ( ( ( t e r t -
butyldiphenylsilyl)oxy)methyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 10d. Following the above
protocol, 9d (6.0 g, 9.8 mmol, 1 equiv) was treated with AIBN (0.6 g,
3.9 mmol) and tributyltin chloride (0.6 mL, 2.4 mmol) followed by
NaBH3CN (0.9 g, 14.7 mmol) in i-PrOH (130 mL). The reaction
provided, after purification, 3.2 g (61%) of 10d as a white/pink
Methyl 2-((1R,3R,4aR,9aR)-6-((((9H-fluoren-9-yl)methoxy)-
carbonyl)amino)-1-(hydroxymethyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 3c. Following the above
protocol, 10c (7.5 g, 14.1 mmol, 1 equiv) was treated with
HF·pyridine (70 wt %, 8.7 mL, 70.5 mmol) in THF (140 mL). The
crude alcohol was dissolved in 1,4-dioxane (180 mL), and 10%
aqueous NaHCO3 solution (120 mL) was added, followed by a
solution of FmocCl (7.3 g, 28.2 mmol) in 1,4-dioxane (20 mL). The
reaction provided, after filtration, 6.2 g (85%) of 3c as a white foamy
solid. [α]D20 −121.9 (c 0.8, CHCl3). IR νmax (cm−1, film): 2950, 1723,
1615, 1548, 1490, 1449, 1439, 1219, 1150, 1054. 1H NMR (500 MHz,
DMSO-d6, 100 °C): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 7.6 Hz,
2H), 7.72 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (m, 2H),
7.10 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 4.48 (d, J = 6.6 Hz,
2H), 4.39 (d, J = 6.2 Hz, 1H), 4.35−4.22 (m, 2H), 3.79−3.70 (m,
3H), 3.69−3.48 (m, 4H), 3.40−3.23 (m, 1H), 2.56−2.32 (m, 2H),
1.98 (dd, J = 13.5, 7.0 Hz, 1H), 1.03−0.98 (m, 1H). 13C NMR (125
MHz, DMSO-d6, 100 °C): δ 170.0, 153.8, 153.3, 143.5, 140.4, 133.2,
131.7, 127.1, 126.4, 124.5, 119.4, 118.9, 115.2, 108.7, 78.7, 77.1, 71.0,
65.1, 60.8, 50.5, 46.5, 38.0, 34.4. HRMS (ESI+) calcd for C30H30NO7
[M + H]+: 516.2022. Found: 516.2027.
20
amorphous solid. [α]D −92.5 (c, 0.5 CHCl3). IR νmax (cm−1, film):
2930, 2856, 1736, 1488, 1428, 1217, 1112. 1H NMR (300 MHz,
CDCl3): δ 7.76−7.71 (m, 4H), 7.43−7.41 (m, 6H), 6.61−6.50 (m,
3H), 6.46 (dd, J = 8.3, 1.7 Hz, 1H), 5.00 (d, J = 5.9 Hz, 1H), 4.10−
4.04 (m, 1H), 3.90−3.80 (m, 2H), 3.77−3.70 (m, 2H), 3.61 (s, 3H),
3.50 (s, 2H), 2.57−2.49 (dd, J = 15.7, 7.3 Hz, 1H), 2.43−2.38 (dd, J =
15.7, 5.8 Hz, 1H), 2.10−1.95 (m, 1H), 1.90−1.80 (m, 1H), 1.09 (s,
9H). 13C NMR (125 MHz, CDCl3): δ 171.4, 153.3, 140.0, 135.9,
135.8, 133.8, 133.7, 130.1, 129.8, 129.8, 127.8, 127.8, 115.8, 112.0,
109.7, 79.7, 77.5, 77.2, 77.0, 71.1, 67.4, 63.3, 51.8, 40.9, 37.9, 30.4,
27.0, 19.4. HRMS (ESI+) calcd for C31H37NNaO5Si [M + Na]+:
554.2339. Found: 554.2335.
Methyl 2-((1R,3R,4aR,9aS)-6-((((9H-fluoren-9-yl)methoxy)-
carbonyl)amino)-1-(hydroxymethyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 3a. To a solution of 10a
(6.70 g, 12.6 mmol, 1 equiv) in THF (130 mL) was added
HF·pyridine (70 wt %, 6.3 mL, 50 mmol, 4 equiv) at rt. The reaction
was monitored by LC−MS until complete conversion of the starting
material was observed. After stirring overnight, the reaction was
quenched with TMSOMe (17.3 mL, 126 mmol), and excess of solvent
was removed in vacuo to afford a crude oil, which was carried on to the
next step without purification. To a solution of crude deprotected
alcohol (3.70 g, 12.6 mmol) in dioxane (160 mL) was added a 10%
aqueous NaHCO3 solution (100 mL) until pH 6−7 was reached. The
reaction mixture was cooled to 0 °C, and a solution of FmocCl (3.59 g,
13.9 mmol) in dioxane (20 mL) was added. The reaction was
quenched with a saturated solution of aqueous ammonium chloride,
and 1,4-dioxane was removed in vacuo. The aqueous layer was
extracted with CH2Cl2 (3 × 100 mL), and the combined organic layers
were then washed with brine, separated and dried over MgSO4. After
filtration, the solvent was removed, and a crude pink solid was
obtained. The solid was triturated in cold CH2Cl2 and then filtered and
washed carefully with cold CH2Cl2 to give 4.7 g (72%) of the desired
Methyl 2-((1R,3S,4aR,9aR)-6-((((9H-fluoren-9-yl)methoxy)-
carbonyl)amino)-1-(hydroxymethyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 3d. Following the above
protocol, 10d (3.2 g, 6.0 mmol, 1 equiv) was treated with HF·pyridine
(70 wt %, 3.0 mL, 24.0 mmol) in THF (60 mL). The crude alcohol
was dissolved in dioxane (70 mL), and 10% aqueous NaHCO3
solution (80 mL) was added, followed by a solution of FmocCl (1.6
g, 6.2 mmol) in 1,4-dioxane (10 mL). The reaction provided, after
20
filtration, 2.4 g (82%) of 3d as a white foamy solid. [α]D −65.8 (c
1.0, CHCl3). IR νmax (cm−1, film): 2950, 1723, 1615, 1548, 1490, 1449,
1
1439, 1219, 1150, 1054. H NMR (500 MHz, DMSO-d6, 100 °C): δ
9.07 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 7.3 Hz, 2H), 7.43 (t,
J = 7.4 Hz, 2H), 7.36−7.31 (m, 3H), 7.11 (d, J = 8.3 Hz, 1H), 6.64 (d,
J = 8.5 Hz, 1H), 4.91 (d, J = 9.8 Hz, 1H), 4.47 (d, J = 6.7 Hz, 2H),
4.32−4.24 (m, 2H), 3.85−3.75 (m, 3H), 3.65−3.60 (m, 4H), 3.51−
3.47 (m, 1H), 2.56−2.42 (m, 4H), 2.03 (s, 1H), 1.83−1.78 (m, 1H).
13C NMR (125 MHz, DMSO-d6): δ 170.1, 155.0, 153.3, 143.4, 140.3,
20
product 3a as a white-gray amorphous solid. [α]D +94.1 (c 0.8,
CHCl3). IR νmax (cm−1, film): 2950, 1723, 1615, 1548, 1490, 1449,
1
1439, 1219, 1150, 1054. H NMR (500 MHz, DMSO-d6, 100 °C): δ
9.10 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 6.6 Hz, 2H), 7.43 (t,
J = 7.3 Hz, 2H), 7.40−7.31 (m, 3H), 7.16 (d, J = 8.3 Hz, 1H), 6.70 (d,
J = 8.5 Hz, 1H), 4.61 (t, J = 8.7 Hz, 1H), 4.54−4.46 (m, 2H), 4.31−
4.24 (m, 2H), 3.87−3.76 (m, 1H), 3.69−3.56 (m, 4H), 3.55−3.50 (m,
1H), 3.22−3.18 (m, 1H), 2.52−2.49 (m, 1H, obscured by solvent
peak), 2.19 (d, J = 14.1, 1H), 1.99−1.89 (m, 1H), 1.38−1.32 (m, 1H).
13C NMR (125 MHz, DMSO-d6, 100 °C, as a mixture of rotamers): δ
170.1, 154.4, 153.3, 143.4, 140.3, 132.2, 128.8, 128.3, 127.0, 126.6,
126.4, 124.5, 120.6, 119.4, 119.3, 115.1, 108.8, 108.4, 108.1, 77.0, 69.3,
65.2, 61.7, 50.5, 46.5, 38.0, 29.5, 29.4. HRMS (ESI+) calcd for
C30H30NO7 [M + H]+: 516.2022. Found: 516.2027.
131.4, 129.5, 127.0, 126.4, 124.5, 119.4, 119.3, 115.8, 107.6, 93.7, 70.2,
66.4, 65.1, 60.2, 50.4, 46.5, 36.5, 29.0. HRMS (ESI+) calcd for
C30H30NO7 [M + H]+: 516.2022. Found: 516.2030.
Methyl 2-((2S,5R,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-fluoro-N-methyl-5-nitrobenzamido)-5,6-dihydro-
2H-pyran-2-yl)acetate 13a. To a solution of 2a (21.0 g, 47.8 mmol,
1.0 equiv) in CH2Cl2 (480 mL) at 0 °C was added 2,6-lutidine (11.1
mL, 96.0 mmol, 2.0 equiv) followed by 2-fluoro-5-nitrobenzoyl
chloride 11 (11.7 g, 57.3 mmol, 1.2 equiv). The reaction mixture was
stirred at 0 °C for 2 h. After complete conversion (determined by LC−
MS) the reaction mixture was quenched with a saturated aqueous
solution of aqueous ammonium chloride. The organic layer was
washed with water, and the combined aqueous phases were extracted
twice with CH2Cl2, dried over MgSO4, filtered and concentrated. The
crude material was purified by chromatography on silica gel, which
provided 25.2 g of the amide (87%). The purified amide (21.0 g, 34.6
mmol, 1.0 equiv) was dissolved in dry DMF (700 mL) and neat
methyl iodide (4.3 mL, 69.2 mmol, 2.0 equiv) was added to the
solution. At 0 °C, sodium hydride (60% dispersion in mineral oil, 2.1
g, 51.9 mmol, 1.5 equiv) was added portion-wise to the mixture, over a
period of 15 min. After 2 h at 0 °C, the reaction mixture was quenched
with a saturated solution of ammonium chloride, and the layers were
separated. The aqueous phase was extracted with ether, and the
combined organic phases were washed with brine, dried with MgSO4,
Methyl 2-((1R,3S,4aR,9aS)-6-((((9H-fluoren-9-yl)methoxy)-
carbonyl)amino)-1-(hydroxymethyl)-3,4,4a,9a-tetrahydro-1H-
pyrano[3,4-b]benzofuran-3-yl)acetate 3b. Following the above
protocol, 10b (6.8 g, 12.7 mmol, 1 equiv) was treated with
HF·pyridine (70 wt %, 7.9 mL, 64.0 mmol) in THF (130 mL). The
crude alcohol was dissolved in 1,4-dioxane (160 mL), and 10%
aqueous NaHCO3 solution (100 mL) was added followed by a
solution of FmocCl (6.6 g, 25.6 mmol) in 1,4-dioxane (20 mL). The
reaction provided, after filtration, 5.84 g (89%) of 3b as a white foamy
20
solid. [α]D +89.3 (c 1.0, CHCl3). IR νmax (cm−1, film): 2950, 1723,
1615, 1548, 1490, 1449, 1439, 1219, 1150, 1054. 1H NMR (500 MHz,
DMSO-d6, 100 °C): δ 9.07 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.72 (d, J
= 7.4 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.37−7.34 (m, 3H), 7.11 (d, J
F
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filtered and concentrated to afford a crude material that was purified
by silica gel chromatography (gradient: 0−30% EtOAc in hexanes) to
afford 13a as a pale yellow oil (18.0 g, 84% yield). [α]D20 −42.7 (c 1.0,
CHCl3). IR νmax (cm−1, film): 2931, 2857, 1739, 1641, 1533, 1350,
Methyl 2-((2R,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-fluoro-N-methyl-5-nitrobenzamido)-5,6-dihydro-
2H-pyran-2-yl)acetate 13d. Compound 13d was prepared using the
above protocol starting from 2d (41.6 g, 95.0 mmol, 1.0 equiv) via
treatment with 2,6-lutidine (22.0 mL, 189.0 mmol, 2.0 equiv) and 2-
fluoro-5-nitrobenzoyl chloride 11 (23.1 g, 113.0 mmol, 1.2 equiv) in
CH2Cl2 (1000 mL), to provide 52.0 g (91%) of the amide. The
methylation was performed on 52.0 g (86.0 mmol, 1.0 equiv) of the
amide intermediate with sodium hydride (60% dispersion in mineral
oil, 4.8 g, 120.0 mmol, 1.4 equiv) and methyl iodide (10.7 mL, 171.0
mmol, 2.0 equiv) in DMF (1750 mL). The reaction provided, after
1
1112, 1097. H NMR (300 MHz, CDCl3, mixture of rotamers, ratio
4:1): δ 8.26 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 8.11 (ddd, J = 12.3, 5.3, 2.7
Hz, 1H), 7.75−7.67 (m, 2H), 7.65−7.57 (m, 1H), 7.45−7.33 (m, 6H),
7.24−7.12 (m, 2H), 6.17 (d, J = 10.0 Hz, 1H), 5.76 (ddd, J = 10.1, 5.5,
1.9 Hz, 1H), 5.25 (s, 1H), 4.62−4.41 (m, 1H), 4.01−3.86 (m, 2H),
3.78−3.70 (dd, J = 10.7, 7.4 Hz, 1H), 3.70 (s, 3H × 0.2), 3.66 (s, 3H ×
0.8), 2.95 (s, 3H × 0.2), 2.69 (br s, 3H × 0.8), 2.63−2.43 (m, 2H),
1.06 (s, 9H × 0.8), 1.00 (s, 9H × 0.2). 13C NMR (75 MHz, CDCl3): δ
170.6, 164.8, 144.5, 137.9, 135.7, 135.6, 135.4, 135.3, 133.6, 133.5,
129.7, 129.5, 129.0, 128.2, 127.7, 127.6, 127.5, 126.7, 126.6, 126.3,
126.0, 125.3, 125.2, 125.1, 123.6, 117.1, 116.8, 78.4, 71.9, 63.9, 51.8,
46.6, 39.6, 39.5, 33.6, 26.8, 26.7, 21.4, 19.3, 19.1. HRMS (ESI) calcd
for C33H37FN2NaO7Si [M + Na]+: 643.2252. Found: 643.2250.
Methyl 2-((2R,5R,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-fluoro-N-methyl-5-nitrobenzamido)-5,6-dihydro-
2H-pyran-2-yl)acetate 13b. Compound 13b was prepared using the
above protocol starting from 2b (24.2 g, 55.0 mmol, 1.0 equiv) via
treatment with 2,6-lutidine (12.8 mL, 110.0 mmol, 2.0 equiv) and 2-
fluoro-5-nitrobenzoyl chloride 11 (13.5 g, 66.1 mmol, 1.2 equiv) in
CH2Cl2 (550 mL) to provide 29.2 g (87%) of the amide. The
methylation was performed on 23.6 g (38.8 mmol, 1.0 equiv) of the
amide intermediate with sodium hydride (60% dispersion in mineral
oil, 2.2 g, 54.4 mmol, 1.4 equiv) and methyl iodide (4.8 mL, 78.0
mmol, 2.0 equiv) in DMF (650 mL). The reaction provided, after
purification, 19.1 g (79%) of 13b as a pale yellow oil. [α]D20 −96.8 (c
1.1, CHCl3). IR νmax (cm−1, film) 2926, 2852, 1736, 1640, 1532, 1349,
20
purification, 40.1 g (75%) of 13d as a yellow oil. [α]D +40.3 (c 1.0,
CHCl3). IR νmax (cm−1, film): 2931, 2857, 1737, 1643, 1533, 1349,
1111. 1H NMR (300 MHz, CDCl3, mixture of rotamers 3:2): δ 8.35−
8.02 (m, 2H), 7.75−7.65 (m, 2H), 7.52 (dd, J = 18.1, 7.2 Hz, 2H),
7.45−7.31 (m, 7H), 6.07 (br d, J = 10.3 Hz, 1H), 5.72 (br d, J = 10.2
Hz, 1H), 5.18 (s, 1H), 4.66 (br s, 1H), 3.97 (dd, J = 8.9, 4.3 Hz, 3H ×
0.4), 3.90−3.78 (m, 3H × 0.6), 3.67 (s, 3H), 2.99 (br s, 3H × 0.4),
2.79 (s, 3H × 0.6), 2.66 (dd, J = 14.4, 8.4 Hz, 1H), 2.54 (br dd, J =
14.9, 6.0 Hz, 1H), 1.07 (s, 9H × 0.6), 0.93 (s, 9H × 0.4). 13C NMR
(75 MHz, CDCl3): δ 170.8, 170.6, 164.4, 164.2, 163.0, 159.6, 144.5,
135.7, 135.6, 135.3, 133.3, 133.2, 129.9, 129.8, 129.7, 127.7, 126.8,
126.7, 125.3, 125.2, 123.9, 117.2, 116.9, 74.1, 67.2, 63.4, 51.9, 51.8,
47.6, 39.2, 32.5, 32.5, 29.1, 26.8, 26.7, 19.2, 19.1. HRMS (ESI) calcd
for C33H37FN2NaO7Si [M + Na]+: 643.2252. Found: 643.2245.
Methyl 2-((2S,4aR,12aS)-5-methyl-8-nitro-6-oxo-
2,4a,5,6,12,12a-hexahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 14a. A solution of HF·pyridine (70% by wt.
in pyridine, 11.2 mL, 90.0 mmol, 4.0 equiv) was added via syringe at 0
°C to a solution of 13a (14.0 g, 22.6 mmol, 1.0 equiv) in 250 mL
THF. Once the addition was complete, the cold bath was removed
allowing the reaction mixture to reach rt, and the mixture was stirred
until complete conversion of the starting material was observed (4 h,
LC−MS). The reaction was quenched at 0 °C with TMSOMe (24.9
mL, 180.4 mmol, 8.0 equiv), and solvent was removed in vacuo to
afford a crude material (7.87 g, 20.6 mmol, 91% yield), which was used
in the next step without further purification. A solution of the
intermediate alcohol (7.87 g, 20.6 mmol, 1.0 equiv) in DMF (700 mL)
was added via cannula at 0 °C to a flame-dried round-bottom flask
containing dry CsF (31.3 g, 206.0 mmol, 10.0 equiv). The mixture was
warmed to 40 °C overnight. The reaction was carefully quenched at 0
°C with brine (350 mL), and the compound was partitioned between
brine and ether. The aqueous layer was extracted with ether (3×), and
the combined organic phases were dried over Na2SO4, filtered and
concentrated to afford a crude material that was purified on silica gel
(gradient: 0−60% EtOAc in hexanes) to afford 14a (3.7 g, 10.2 mmol,
1
1093. H NMR (300 MHz, CDCl3, mixture of rotamers, ratio 9:2): δ
8.29−8.20 (m, 1H), 8.17−8.04 (m, 1H), 7.69 (br t, J = 6.0 Hz, 3H),
7.55 (br dd, J = 14.1, 7.2 Hz, 1H), 7.47−7.29 (m, 6H), 7.20 (t, J = 8.6
Hz, 1H), 6.18 (br d, J = 9.9 Hz, 1H), 5.90−5.73 (m, 1H), 5.21 (br s,
1H), 4.85 (br s, 1H), 3.98 (br s, 1H), 3.87 (br dd, J = 11.0, 4.0 Hz,
1H), 3.76−3.65 (m, 4H), 2.99 (s, 3H × 0.2), 2.82−2.69 (m, 1H), 2.74
(s, 3H × 0.8), 2.64−2.35 (m, 1H), 1.05 (s, 9H × 0.8), 0.97 (s, 9H ×
0.2). 13C NMR (75 MHz, CDCl3): δ 170.9, 170.6, 164.8, 164.3, 162.8,
159.4, 144.5, 135.7, 135.6, 135.5, 135.3, 134.6, 133.5, 129.8, 129.7,
129.6, 127.7, 127.6, 126.7, 126.6, 126.3, 126.0, 125.2, 125.1, 123.1,
117.2, 116.8, 72.8, 72.5, 69.9, 69.7, 63.9, 51.9, 51.7, 46.1, 36.9, 36.7,
33.5, 33.4, 26.8, 19.2, 19.1. HRMS (ESI) calcd for C33H37FN2NaO7Si
[M + Na]+: 643.2252. Found: 643.2250.
Methyl 2-((2S,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-fluoro-N-methyl-5-nitrobenzamido)-5,6-dihydro-
2H-pyran-2-yl)acetate 13c. Compound 13c was prepared using
starting from 2a (20.3 g, 46.2 mmol, 1.0 equiv) via treatment with 2,6-
lutidine (10.8 mL, 92.4 mmol, 2.0 equiv) and 2-fluoro-5-nitrobenzoyl
chloride 11 (11.3 g, 55.5 mmol, 1.2 equiv) in CH2Cl2 (460 mL). This
stereoisomer was not purified, and the crude mixture was used directly
in the next step. The methylation was performed when the crude
amide intermediate was reacted with sodium hydride (60% dispersion
in mineral oil, 3.7 g, 92.0 mmol, 2.0 equiv) and methyl iodide (28.9
mL, 462 mmol, 10.0 equiv) in THF (750 mL). The reaction provided,
after purification, 15.2 g of 13c as a pale yellow oil (53% yield over two
steps). [α]D20 +13.6 (c 1.0, CHCl3). IR νmax (cm−1, film): 2926, 2852,
1737, 1643, 1532, 1348, 1111. 1H NMR (300 MHz, CDCl3, mixture of
rotamers, ratio 1:1): δ 8.29 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H × 0.5), 8.15
(m, 3H × 0.5), 7.76−7.67 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.50 (d, J
= 6.9 Hz, 1H), 7.43−7.29 (m, 7H), 6.00 (d, J = 9.5 Hz, 1H), 5.75 (br
d, J = 9.5 Hz, 1H × 0.5), 5.65 (d, J = 10.2 Hz, 1H × 0.5), 5.25 (br d, J
= 8.2 Hz, 1H × 0.5), 4.66−4.50 (m, 1H), 4.16 (br s, 1H × 0.5), 3.88−
3.72 (m, 3H), 3.70 (s, 3H × 0.5), 3.66 (s, 3H × 0.5), 2.89 (s, 3H ×
0.5), 2.64 (s, 3H × 0.5), 2.70−2.51 (m, 1H), 2.51−2.36 (m, 1H), 1.04
(s, 9H × 0.5), 0.91 (s, 9H × 0.5). 13C NMR (75 MHz, CDCl3, mixture
of rotamers): δ 171.0, 170.7, 164.8, 159.5, 144.5, 135.8, 135.7, 135.3,
133.7, 133.5, 133.0, 129.8, 129.7, 129.6, 128.3, 127.7, 127.6, 126.9,
126.8, 126.5, 125.9, 125.3, 125.3, 125.2, 117.2, 116.9, 75.7, 75.4, 71.2,
64.0, 63.3, 51.8, 49.2, 40.1, 39.8, 32.0, 26.7, 19.3, 19.2. HRMS (ESI)
calcd for C33H37FN2NaO7Si [M + Na]+: 643.2252. Found: 643.2245.
20
50% yield) as a yellow foamy solid. [α]D −109.8 (c 1.1, CHCl3). IR
νmax (cm−1, film) 2995, 2947, 2856, 1736, 1632, 1518, 1436, 1343,
1256, 1085. 1H NMR (300 MHz, CDCl3): δ 8.39 (d, J = 2.8 Hz, 1H),
8.10 (dd, J = 9.2, 2.8 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.18 (d, J =
10.1 Hz, 1H), 6.00−5.85 (m, 1H), 4.67 (s, 1H), 4.36 (dd, J = 12.6, 4.0
Hz, 1H), 4.26 (dd, J = 12.5, 9.5 Hz, 1H), 4.06−4.00 (m, 1H), 3.96
(ddd, J = 9.4, 3.9, 2.4 Hz, 1H), 3.72 (s, 3H), 3.08 (s, 3H), 2.64 (dd, J =
15.7, 7.6 Hz, 1H), 2.55 (dd, J = 15.7, 6.1 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 170.3, 168.3, 159.0, 141.6, 135.4, 128.7, 126.3, 122.3, 121.1,
120.1, 74.8, 72.2, 65.9, 52.0, 51.9, 38.8, 32.3. HRMS (ESI) calcd for
C17H19N2O7 [M + H]+: 363.1187. Found: 363.1193.
Methyl 2-((2R,4aR,12aS)-5-methyl-8-nitro-6-oxo-
2,4a,5,6,12,12a-hexahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 14b. Compound 14b was prepared using
above protocol starting from 13b (8.5 g, 13.7 mmol, 1.0 equiv).
TBDPS deprotection was accomplished via treatment with HF·pyr-
idine (70% by wt. in pyridine, 6.8 mL, 54.8 mmol, 4.0 equiv) in THF
(150 mL), and the reaction was quenched with TMSOMe (18.8 mL,
137.0 mmol, 10.0 equiv) to afford the intermediate alcohol (4.8 g, 12.5
mmol) in 91% yield. Cyclization of the crude material (4.8 g, 12.5
mmol, 1.0 equiv) was conducted in DMF (420 mL) with CsF (19.0 g,
125.0 mmol, 10.0 equiv) at 40 °C for 5 h to afford 14b (2.8 g, 7.8
20
mmol, 63% yield) as a yellow foamy solid. [α]D −91.0 (c 1.1,
CHCl3). IR νmax (cm−1, film) 2952, 2900, 1736, 1634, 1518, 1437,
G
dx.doi.org/10.1021/jo4000916 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1343, 1306, 1257, 1104. H NMR (300 MHz, CDCl3): δ 8.39 (d, J =
Methyl 2-((2S,4aR,12aS)-8-amino-5-methyl-6-oxo-
2,3,4,4a,5,6,12,12a-octahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 4b. Compound 4b was prepared using the
above protocol starting from 14b (6.0 g, 16.4 mmol, 1.0 equiv) and
Pd/C (10 wt %, 0.4 g, 4.1 mmol, 0.3 equiv) in THF:MeOH (3:1, 165
mL). The reaction provided, after purification, 5.2 g (94%) of 4b as a
2.8 Hz, 1H), 8.10 (dd, J = 9.2, 2.9 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H),
6.21 (dd, J = 10.0, 3.0 Hz, 1H), 5.98 (ddd, J = 8.8, 6.2, 2.1 Hz, 1H),
4.81 (ddt, J = 7.7, 5.1, 2.6 Hz, 1H), 4.34−4.20 (m, 2H), 4.06−3.96 (m,
2H), 3.74 (s, 3H), 3.07 (s, 3H), 2.74 (dd, J = 15.3, 9.4 Hz, 1H), 2.56
(dd, J = 15.3, 5.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 170.4,
168.3, 156.0, 141.7, 134.9, 128.9, 126.4, 122.1, 121.2, 120.1, 70.3, 69.2,
66.3, 52.1, 51.5, 37.2, 32.1. HRMS (ESI) calcd for C17H19N2O7 [M +
H]+: 363.1187. Found: 363.1194.
20
red-brown powder. [α]D +41.2 (c 1.0, CHCl3). IR νmax (cm−1, film)
3347, 2950, 1731, 1610, 1493, 1396, 1205, 1022. 1H NMR (500 MHz,
DMSO-d6, 100 °C): δ 6.70 (d, J = 8.6 Hz, 1H), 6.65 (dd, J = 8.6, 2.5
Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 4.66 (br s, 2H), 4.17−4.04 (m, 3H),
3.98 (dd, J = 12.9, 11.0 Hz, 1H), 3.71−3.66 (m, 1H), 3.61 (s, 3H),
3.14 (s, 3H), 2.58 (dd, J = 14.9, 7.8 Hz, 1H), 2.47 (dd, J = 15.1, 5.5
Hz, 1H), 1.85 (br app t, J = 15.0 Hz, 2H), 1.58 (br d, J = 8.1 Hz, 1H),
1.46−1.37 (m, 1H). 13C NMR (125 MHz, DMSO-d6, 100 °C): δ
171.1, 169.4, 146.5, 143.7, 120.8, 118.5 (2), 114.7, 69.6, 68.8, 68.1,
57.1, 51.5, 39.4, 34.8, 28.3, 22.5. HRMS (ESI) calcd for
C17H22N2NaO5 [M + Na]+: 357.1421. Found: 357.1426.
Methyl 2-((2R,4aS,12aS)-8-amino-5-methyl-6-oxo-
2,3,4,4a,5,6,12,12a-octahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 4c. Compound 4c was prepared as described
above starting from 14c (6.3 g, 17.5 mmol, 1.0 equiv) and Pd/C (10
wt %, 0.5 g, 4.4 mmol, 0.3 equiv) in THF:MeOH (3:1, 180 mL). The
reaction provided, after purification, 5.8 g (99%) of 4c as a red-brown
powder. [α]D20 −32.0 (c 1.0, CHCl3). IR νmax (cm−1, film) 3427, 3349,
2951, 2873, 1733, 1616, 1493, 1436, 1202, 1091. 1H NMR (300 MHz,
CDCl3): δ 6.82 (d, J = 2.7 Hz, 1H), 6.79 (dd, J = 9.0 Hz, 1H), 6.69
(dd, J = 8.7, 2.8 Hz, 1H), 4.18 (dd, J = 13.8, 1.6 Hz, 1H), 4.06 (dd, J =
13.8, 1.9 Hz, 1H), 3.93−3.70 (m, 4H), 3.67 (s, 3H), 3.60 (d, J = 10.6
Hz, 1H), 3.01 (s, 3H), 2.65 (dd, J = 16.0, 7.1 Hz, 1H), 2.42 (dd, J =
16.0, 5.8 Hz, 1H), 2.02−1.75 (m, 3H), 1.39 (ddd, J = 24.3, 11.3, 5.4
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 171.5, 170.9, 149.8, 140.1,
121.7, 120.5, 120.1, 117.9, 76.4, 74.1, 68.5, 53.2, 51.8, 40.5, 30.6, 28.7,
27.0. HRMS (ESI) calcd for C17H22N2NaO5 [M + Na]+: 357.1421.
Found: 357.1419.
Methyl 2-((2S,4aS,12aS)-5-methyl-8-nitro-6-oxo-
2,4a,5,6,12,12a-hexahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 14c. Cesium fluoride (CsF, 25.0 g, 165.0
mmol, 13.1 equiv) was added in one portion at 0 °C to a solution of
13c (7.8 g, 12.6 mmol, 1.0 equiv) in DMF (1 L) under argon. The
temperature was slowly raised to 40 °C, and the mixture was stirred at
this temperature until complete conversion of the starting material was
observed (LC−MS). The reaction was carefully quenched with brine
(500 mL) at 0 °C and then partially concentrated. The crude mixture
was partitioned between Et2O and brine. The organic layers were
combined, dried over Na2SO4, filtered and concentrated. The crude
material was then purified on silica gel (gradient: 0−50% EtOAc in
hexanes) to afford 14c (3.5 g, 9.7 mmol, 77% yield) as a yellow
powder. [α]D20 −42.5 (c 1.0, CHCl3). IR νmax (cm−1, film) 2943, 2847,
1735, 1636, 1518, 1437, 1345, 1327, 1255, 1092. 1H NMR (300 MHz,
CDCl3): δ 8.52 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.1, 2.9 Hz, 1H),
7.09 (d, J = 9.1 Hz, 1H), 5.97 (dd, J = 10.3, 2.5 Hz, 1H), 5.84 (br d, J =
10.3 Hz, 1H), 4.76−4.66 (m, 1H), 4.45 (dd, J = 13.9, 2.6 Hz, 1H),
4.43−4.37 (m, 1H), 4.34 (dd, J = 13.8, 2.3 Hz, 1H), 3.80 (ddd, J =
10.0, 2.5, 2.5 Hz, 1H), 3.71 (s, 3H), 3.01 (s, 3H), 2.67 (dd, J = 16.0,
7.3 Hz, 1H), 2.52 (dd, J = 16.0, 6.4 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 170.6, 168.3, 161.2, 142.4, 132.6, 129.3, 126.7, 124.6, 122.8,
121.1, 73.3, 71.8, 69.7, 52.0, 51.8, 39.5, 29.5. HRMS (ESI) calcd for
C17H19N2O7 [M + H]+: 363.1187. Found: 363.1190.
Methyl 2-((2R,4aS,12aS)-5-methyl-8-nitro-6-oxo-
2,4a,5,6,12,12a-hexahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 14d. Treatment of 13d (6.3 g, 10.2 mmol,
1.0 equiv) with CsF (20.0 g, 132.0 mmol, 13.0 equiv) in DMF (800
mL) afforded 14d (2.7 g, 7.5 mmol, 73% yield) as a yellow foamy
Methyl 2-((2S,4aS,12aS)-8-amino-5-methyl-6-oxo-
2,3,4,4a,5,6,12,12a-octahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 4d. Compound 4d was prepared using the
above protocol starting from 14d (6.1 g, 17.0 mmol, 1.0 equiv) and
Pd/C (10 wt %, 0.5 g, 4.2 mmol, 0.3 equiv) in THF:MeOH (3:1, 170
mL). The reaction provided, after purification, 5.5 g (98%) of 4d as a
20
solid. [α]D −63.9 (c 1.2, CHCl3). IR νmax (cm−1, film) 3008, 2947,
1735, 1635, 1518, 1438, 1345, 1324, 1255, 1093. 1H NMR (300 MHz,
CDCl3): δ 8.50 (s, 1H), 8.14 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 (d, J = 9.1
Hz, 1H), 5.99 (d, J = 10.4 Hz, 1H), 5.89 (d, J = 10.5 Hz, 1H), 4.82 (br
s, 1H), 4.51−4.19 (m, 3H), 3.80 (d, J = 9.8 Hz, 1H), 3.72 (s, 3H), 2.99
(s, 3H), 2.73 (dd, J = 15.1, 9.1 Hz, 1H), 2.59 (dd, J = 15.0, 5.1 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 170.3, 168.4, 161.1, 142.2, 131.7,
129.6, 126.7, 124.7, 122.0, 120.9, 70.6, 69.2, 67.8, 52.0, 51.8, 38.4, 29.7.
HRMS (ESI) calcd for C17H19N2O7 [M + H]+: 363.1187. Found:
363.1193.
20
red-brown powder. [α]D +10.4 (c 1.0, CHCl3). IR νmax (cm−1, film)
3437, 3350, 2950, 1733, 1623, 1493, 1437, 1206, 1095. 1H NMR (300
MHz, CDCl3): δ 6.72 (dd, J = 5.7, 2.9 Hz, 2H), 6.61 (dd, J = 8.8, 2.7
Hz, 1H), 4.42−4.30 m, 1H), 4.11 (d, J = 13.6 Hz, 1H), 3.89 (d, J =
13.5 Hz, 1H), 3.72 (d, J = 3.2 Hz, 2H), 3.60 (s, 3H), 3.48 (br s, 2H),
2.95 (s, 3H), 2.76 (dd, J = 14.4, 9.1 Hz, 1H), 2.41 (dd, J = 14.5, 6.0
Hz, 1H), 1.99−1.50 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 171.1,
170.6, 149.6, 140.7, 128.4, 122.5, 120.7, 119.9, 117.4, 69.6, 69.2, 68.8,
53.8, 52.0, 36.5, 28.6, 27.6, 22.0. HRMS (ESI) calcd for
C17H22N2NaO5 [M + Na]+: 357.1421. Found: 357.1419.
Methyl 2-((2R,4aR,12aS)-8-amino-5-methyl-6-oxo-
2,3,4,4a,5,6,12,12a-octahydrobenzo[b]pyrano[3,2-f][1,5]-
oxazocin-2-yl)acetate 4a. To a solution of 14a (6.3 g, 17.5 mmol,
1.0 equiv) in THF:MeOH (3:1, 175 mL) under N2 was added
palladium on carbon (10 wt %, 0.5 g, 4.4 mmol, 0.3 equiv). The
solution was purged with H2 for 30 min, and the mixture was stirred
overnight at rt under an atmosphere of H2 (balloon). Celite was added
to the reaction mixture, and after 30 min, the crude material was
filtered through a plug of Celite and rinsed with a solution of 10%
MeOH in CH2Cl2 (50 mL). The solvents were removed in vacuo, and
the residue was purified by silica gel chromatography (gradient: 0−7%
MeOH in CH2Cl2). Aniline 4a was isolated as a red-brown powder
Methyl 2-((2R,5R,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitrophenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 15a. A solution of 2a (17.1 g, 38.9 mmol, 1.0 equiv) in
MeOH (389 mL) was degassed for 20 min by sparging with dry N2.
To the solution was added Pd(OH)2/C (20% by weight, 2.73 g, 3.89
mmol, 0.1 equiv), and the suspension was sparged with H2 for 20 min
before being placed under a static atmosphere of H2 (balloon) at rt
while stirring for 20 h. Upon completion of the reaction (LC−MS),
the mixture was filtered through Celite. The filter cake was washed
with CH2Cl2, and the filtrate was concentrated under reduced pressure
to provide 16.45 g of crude product (96%), which was used in the next
step without further purification. The crude material from above 16.45
g (37.2 mmol, 1.0 equiv) was dissolved in CH2Cl2 (372 mL) at 0 °C
(ice/water bath), and to this solution was added sequentially Et3N
(15.7 mL, 112 mmol, 3.0 equiv), DMAP (0.46 g, 3.72 mmol, 0.1
equiv) and 2-nitrobenzenesulfonyl chloride (12.38 g, 55.9 mmol, 1.5
equiv). The reaction was stirred at 0 °C for 15 min before removing
the ice bath and stirring for an additional 100 min. When the reaction
was deemed complete by LC−MS, the reaction was concentrated
under reduced pressure, and the crude residue was purified by
chromatography on silica gel (gradient: 0−40% EtOAc in hexanes),
20
(5.8 g, 17.4 mmol, 99% yield). [α]D +21.6 (c 1.0, CHCl3). IR νmax
(cm−1, film) 3434, 3347, 2950, 2895, 1732, 1612, 1494, 1436, 1201,
1045. 1H NMR (300 MHz, CDCl3): δ 6.72−6.53 (m, 3H), 4.07 (d, J =
3.0 Hz, 1H), 4.05 (s, 1H), 3.84−3.99 (m, 1H), 3.84−3.72 (m, 2H),
3.68 (s, 3H), 3.58 (br s, 2H), 3.24 (s, 3H), 2.57 (dd, J = 15.5, 7.4 Hz,
1H), 2.44 (dd, J = 15.5, 5.3 Hz, 1H), 2.18−1.96 (m, 2H), 1.96−1.76
(m, 1H), 1.77−1.61 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 171.2,
170.8, 147.6, 139.8, 121.1, 119.8, 119.5, 117.2, 78.8, 74.6, 65.2, 51.9,
50.6, 41.3, 32.1, 27.3, 24.2. HRMS (ESI) calcd for C17H22N2NaO5 [M
+ Na]+: 357.1421. Found: 357.1427.
H
dx.doi.org/10.1021/jo4000916 | J. Org. Chem. XXXX, XXX, XXX−XXX

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20
which provided 19.0 g (82%) of 15a as a yellow foamy solid. [α]D
Hz, 1H), 7.73 (dd, J = 5.7, 3.3 Hz, 2H), 5.76 (br s, 1H), 4.23−4.11 (m,
1H), 3.95−3.76 (m, 2H), 3.76−3.50 (m, 2H), 3.66 (s, 3H), 2.72 (br d,
J = 6.1 Hz, 1H), 2.61 (dd, J = 15.9, 9.4 Hz, 1H), 2.42 (dd, J = 15.9, 4.4
Hz, 1H), 1.93−1.59 (m, 3H), 1.48−1.31 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 171.9, 147.9, 134.3, 133.9, 133.1, 130.7, 125.6, 73.0,
67.1, 59.4, 52.1, 50.5, 37.9, 26.8, 25.7. HRMS (ESI) calcd for
C15H21N2O8S [M + H]+: 389.1019. Found: 389.1022.
−18.9 (c 1.0, CHCl3). IR νmax (cm−1, film): 2931 (w), 2857 (w), 1737
(m), 1540 (s), 1427 (m), 1352 (s), 1165 (s), 1111 (s). 1H NMR (300
MHz, CDCl3): δ 8.12−8.00 (m, 1H), 7.73−7.65 (m, 1H), 7.66−7.55
(m, 4H), 7.50 (dd, J = 3.4, 5.9 Hz, 2H), 7.48−7.32 (m, 6H), 5.81 (d, J
= 8.7 Hz, 1H), 3.95−3.77 (m, 2H), 3.63 (s, 3H), 3.59 (d, J = 5.6 Hz,
1H), 3.48−3.35 (m, 1H), 3.38 (dd, J = 5.9, 10.5 Hz, 1H), 2.55 (dd, J =
7.2, 15.6 Hz, 1H), 2.39 (dd, J = 5.5, 15.6 Hz, 1H), 1.88 (d, J = 13.6 Hz,
1H), 1.71 (brs, 1H), 1.63−1.46 (m, 2H), 0.99 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 171.1, 147.4, 135.4, 135.4, 135.1, 133.1, 133.1, 133.0,
132.7, 129.9, 129.6, 129.6, 127.6, 127.6, 125.1, 80.1, 74.6, 63.4, 51.6,
49.2, 40.7, 29.3, 26.6, 25.3, 19.0. HRMS (ESI) calcd for
C31H38N2NaO8SSi [M + Na]+: 649.2016. Found: 649.2012.
Methyl 2-((2S,5R,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitrophenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 15b. Compound 15b was prepared using the above
protocol from 2b (21 g, 47.7 mmol, 1.0 equiv) in MeOH (477 mL)
and Pd(OH)2/C (20% by weight, 3.35 g, 4.77 mmol, 0.1 equiv), which
provide 20.1 g of crude saturated amine (96%), which was used in the
next step without further purification. The crude material from above
(20.13 g, 45.6 mmol, 1.0 equiv) was subjected to a nosylation using
CH2Cl2 (456 mL), Et3N (19.22 mL, 137 mmol, 3.0 equiv), DMAP
(0.55 g, 4.56 mmol, 0.1 equiv) and 2-nitrobenzenesulfonyl chloride
(15.15 g, 68.4 mmol, 1.5 equiv), which provided, after purification,
Methyl 2-((1R,3R,6R)-7-((2-nitrophenyl)sulfonyl)-2-oxa-7-
azabicyclo[4.2.0]octan-3-yl)acetate 5a. To a solution of alcohol
16a (12.1 g, 31.2 mmol, 1.0 equiv) and PPh3 (16.3 g, 62.3 mmol, 2.0
equiv) in THF (312 mL) at 0 °C (ice/water bath) was added DIAD
(13.5 mL, 68.5 mmol, 2.2 equiv) dropwise over 5 min. The reaction
was stirred, slowly warming to rt over 1 h until the reaction was
deemed complete by LC−MS. The reaction mixture was concentrated
under reduced pressure, and the crude residue was purified by
chromatography on silica gel (gradient: 0−100% EtOAc in hexanes),
to afford 9.84 g (85%) of 5a as a white foamy solid. [α]D20 −108.6 (c
1.0, CHCl3). IR νmax (cm−1, film): 2952 (w), 1736 (m), 1544 (s), 1371
1
(m), 1168 (s). H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 8.0 Hz,
1H), 7.86−7.73 (m, 2H), 7.66 (d, J = 9.0 Hz, 1H), 4.28 (brs, 1H), 4.23
(t, J = 4.8 Hz, 1H), 3.93 (dd, J = 4.6, 8.5 Hz, 1H), 3.67 (s, 4H), 3.61
(d, J = 8.6 Hz, 1H), 2.58 (dd, J = 8.0, 15.8 Hz, 1H), 2.44 (dd, J = 4.8,
15.7 Hz, 1H), 2.18 (d, J = 11.6 Hz, 1H), 1.76 (dd, J = 8.5, 17.4 Hz,
2H), 1.55 (d, J = 9.4 Hz, 1H), 1.24 (t, J = 5.8 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 171.4, 148.7, 134.0, 131.6, 130.9, 129.7, 124.1, 70.6,
66.5, 60.7, 57.2, 51.6, 40.8, 25.3, 24.6. HRMS (ESI) calcd for
C15H18N2NaO7S [M + Na]+: 393.0732. Found: 393.0730.
20
23.6 g (83%) of 15b as a yellow foamy solid. [α]D +22.6 (c 1.0,
CHCl3). IR νmax (cm−1, film): 2932 (w), 2858 (w), 1736 (s), 1541 (s),
1427 (m), 1360 (s), 1168 (s), 1111 (s). 1H NMR (300 MHz, CDCl3):
δ 8.11−8.00 (m, 1H), 7.71−7.63 (m, 1H), 7.63−7.49 (m, 6H), 7.40
(dt, J = 13.7, 6.7 Hz, 6H), 5.86 (d, J = 7.8 Hz, 1H), 4.33 (t, J = 6.9 Hz,
1H), 3.85−3.72 (m, 2H), 3.61 (obscured s, 2H), 3.59 (s, 3H), 2.64
(dd, J = 14.9, 7.9 Hz, 1H), 2.41 (dd, J = 14.8, 6.5 Hz, 1H), 2.03−1.69
(m, 3H), 1.43−1.30 (m, 1H), 1.01 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 171.2, 147.8, 135.7, 135.0, 133.4, 133.1, 133.0, 132.9, 130.4,
130.0, 129.9, 127.9, 125.3, 73.0, 69.2, 63.4, 51.8, 50.5, 37.6, 26.9, 25.8,
25.2, 19.2. HRMS (ESI) calcd for C31H38N2NaO8SSi [M + Na]+:
649.2016. Found: 649.2012.
Methyl 2-((1R,3S,6R)-7-((2-nitrophenyl)sulfonyl)-2-oxa-7-
azabicyclo[4.2.0]octan-3-yl)acetate 5b. Compound 5b was
obtained following the above procedure using 16b (13.53 g, 34.8
mmol, 1.0 equiv) PPh3 (18.27 g, 69.7 mmol, 2.0 equiv), DIAD (15.1
mL, 77.0 mmol, 2.2 equiv) in THF (348 mL). Purification of the
reaction mixture afforded 11.46 g (89%) of 5b as a white foamy solid.
20
[α]D −86.2 (c 1.0, CHCl3). IR νm1ax (cm−1, film): 2952 (w), 1735
(m), 1544 (s), 1371 (m), 1168 (s). H NMR (300 MHz, CDCl3): δ
7.93 (dd, J = 7.2, 3.2 Hz, 1H), 7.75−7.64 (m, 2H), 7.64−7.56 (m,
1H), 4.56−4.39 (m, 2H), 4.31 (td, J = 6.3, 2.7 Hz, 1H), 4.05 (dd, J =
9.3, 6.2 Hz, 1H), 3.94 (dd, J = 9.3, 2.6 Hz, 1H), 3.61 (s, 3H), 2.53 (dd,
J = 15.2, 8.8 Hz, 1H), 2.38 (dd, J = 15.2, 4.9 Hz, 1H), 2.08−1.81 (m,
3H), 1.44−1.28 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 171.2, 148.5,
134.1, 131.9, 130.7, 130.5, 124.2, 67.1, 63.5, 61.9, 56.3, 51.7, 39.4, 23.4,
21.4. HRMS (ESI) calcd for C15H19N2O7S [M + H]+: 371.0913.
Found: 371.0913.
Methyl 2-((2R, 5R, 6S)-6-(hydroxymethyl)-5-(2-
nitrophenylsulfonamido)tetrahydro-2H-pyran-2-yl)acetate
16a. To a solution of 15a (21.7 g, 34.6 mmol, 1.0 equiv) in THF (173
mL) at 0 °C (ice/water bath) in a plastic bottle was added
HF·pyridine (70 wt %, 8.60 mL, 69.2 mmol, 2.0 equiv). The reaction
was stirred, slowly warming to rt overnight for 20 h. The reaction was
deemed complete by TLC and subsequently quenched with TMSOMe
(38.2 mL, 277 mmol, 8.0 equiv). The mixture was stirred for an
additional 30 min and then diluted with EtOAc and washed with
aqueous saturated copper sulfate solution (2 × 100 mL). The organic
layer was dried over MgSO4, filtered and concentrated under reduced
pressure. The crude residue was purified by chromatography on silica
gel (gradient: 0−100% EtOAc in hexanes) to provide 12.1 g (90%) of
Methyl 2-((2R,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitrophenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 15c. To allylic amine 2c (4.5 g, 10.2 mmol) under Ar was
added ethanol (100 mL) and Pd/C (10 wt %, 0.1 g, 1.0 mmol, 0.1
equiv). The solution was subsequently purged with H2 (balloon) for
10 min and left to stir under the H2 atmosphere for 16 h. The reaction
mixture was then filtered through Celite, and the filter cake was
washed with CH2Cl2 (3 × 75 mL). The filtrate was then concentrated
to give the primary amine, which was used in the next reaction without
further purification. To a solution of the saturated primary amine (4.5
g, 10.2 mmol, 1.0 equiv) in CH2Cl2 (41 mL) was added Et3N (1.7 mL,
12.2 mmol, 1.2 equiv) followed by 2-nitrobenzenesulfonyl chloride
(2.5 g, 11.2 mmol, 1.1 equiv). The reaction was stirred at rt until
analysis of the reaction mixture by LC−MS showed that all starting
material had been consumed (∼1 h). The reaction was quenched with
a saturated solution of aqueous ammonium chloride (100 mL). The
organic layer was separated, and the aqueous layer was then washed
with CH2Cl2 (2 × 100 mL). The combined organic layers were
washed with brine, dried over MgSO4 and filtered. The organic layer
was concentrated under reduced pressure, and the crude residue was
purified by chromatography on silica gel (gradient: 5−50% EtOAc in
hexanes), which provided 5.5 g (86%) of 15c as a yellow foamy solid.
20
16a as a pale yellow foamy solid. [α]D −107.9 (c 1.0, CHCl3). IR
νmax (cm−1, film): 3278 (w), 2953 (w), 1728 (m), 1541 (s), 1442 (m),
1344 (m), 1164 (s). 1H NMR (300 MHz, CDCl3): δ 8.12 (dd, J = 3.4,
5.8 Hz, 1H), 7.86 (dd, J = 3.5, 5.8 Hz, 1H), 7.80−7.73 (m, 2H), 5.83
(d, J = 9.0 Hz, 1H), 3.90−3.79 (m, 1H), 3.69 (s, 4H), 3.67−3.59 (m,
2H), 3.58−3.40 (m, 1H), 2.59 (dd, J = 7.3, 15.7 Hz, 1H), 2.43 (dd, J =
5.5, 15.8 Hz, 1H), 2.23−2.13 (m, 1H), 1.79−1.63 (m, 2H), 1.62−1.41
(m, 2H). 13C NMR (75 MHz, CDCl3): δ 171.1, 147.7, 134.5, 133.6,
132.9, 130.4, 125.3, 79.3, 74.4, 62.0, 51.7, 48.8, 40.6, 28.7, 25.4. HRMS
(ESI) calcd for C15H20N2NaO8S [M + Na]+: 411.0838. Found:
411.0844.
Methyl 2-((2S, 5R, 6S)-6-(hydroxymethyl)-5-(2-
nitrophenylsulfonamido)tetrahydro-2H-pyran-2-yl)acetate
16b. Compound 16b was prepared following the above protocol using
a solution of 15b (23.59 g, 37.6 mmol, 1.0 equiv), THF (188 mL),
HF·pyridine (70 wt %, 7.0 mL, 56.5 mmol, 1.5 equiv), TMSOMe
(41.5 mL, 300 mmol, 8.0 equiv), which provided, after purification,
13.59 g (93%) of 16b as a pale yellow foamy solid. [α]D20 +23.3 (c 1.0,
CHCl3). IR νmax (cm−1, film): 3395 (w), 2932 (w), 2857 (w), 1737
(m), 1541 (s), 1427 (m), 1360 (s), 1168 (s), 1112 (s). 1H NMR (300
MHz, CDCl3): δ 8.12 (dd, J = 5.9, 3.3 Hz, 1H), 7.84 (dd, J = 7.5, 3.8
22
[α]D +8.3 (c 1.0, CHCl3). IR νmax (cm−1, film): 3327, 2932, 2857,
1734, 1542, 1437, 1362, 1188, 1168, 1112. 1H NMR (300 MHz,
CDCl3): δ 8.10 (d, J = 6.9 Hz, 1H), 8.04−7.97 (m, 1H), 7.80−7.27
(m, 13H), 5.26 (d, J = 8.3 Hz, 1H), 4.33 (q, J = 7.1 Hz, 1H), 3.82−
3.70 (m, 2H), 3.62 (s, 3H), 3.43 (s, 1H), 3.30 (s, 1H), 2.44 (ddd, J =
I
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20.9, 15.5, 6.4 Hz, 2H), 1.96 (d, J = 12.1 Hz, 1H), 1.68 (d, J = 11.9 Hz,
1H), 1.48 (s, 1H), 1.41−1.34 (m, 2H), 0.99 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 171.5, 147.8, 135.9, 135.8, 134.89, 134.86, 133.9,
133.55, 133.48, 133.0, 132.4, 131.3, 130.6, 129.9, 129.67, 129.62,
127.9, 127.7, 127.7, 125.4, 124.9, 81.0, 76.8, 73.8, 69.1, 63.9, 51.8, 50.9,
40.8, 31.8, 30.6, 26.9, 26.7, 22.1, 19.4, 14.9. HRMS (ESI+) calcd for
C31H38N2NaO8SSi [M + Na]+: 649.2016. Found: 649.2020.
HRMS (ESI+) calcd for C34H43N2O9SSi [M + H]+: 683.2459. Found:
683.2468.
Methyl 2-((2S,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitro-N-((R)-oxiran-2-ylmethyl)phenylsulfon-
amido)tetrahydro-2H-pyran-2-yl)acetate 18c. Following the
above protocol, (S,S,S)-15d (10.0 g, 16.0 mmol, 1.0 equiv) was
treated with (S)-glycidyl triflate [(S)-17] (6.6 g, 31.9 mmol, 2.0 equiv),
cesium carbonate (20.8 g, 63.8 mmol, 4.0 equiv) in DCE (64 mL).
The reaction provided, after purification, 10.1 g (93%) of 18c as a
yellow oil. [α]D22 +3.2 (c 1.0, CHCl3). IR νmax (cm−1, film) 2931, 2857,
Methyl 2-((2S,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitrophenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 15d. Compound 15d was prepared as described above
using allylic amine (R,S,S)-2d (41.4 g, 94 mmol) and 10% Pd/C (10.0
g, 9.42 mmol, 0.1 equiv) in MeOH (942 mL). The resulting crude
amine (42.0 g, 95.0 mmol) was treated with Et3N (15.9 mL, 114
mmol, 1.2 equiv) and 2-nitrobenzenesulfonyl chloride (23.2 g, 105
mmol, 1.1 equiv) in CH2Cl2 (476 mL) to afford 54.9 g (92%) of the
1
1734, 1543, 1360, 1165, 1110, 1006. H NMR (300 MHz, CDCl3): δ
7.97 (dd, J = 7.3, 1.5 Hz, 1H), 7.71−7.57 (m, 4H), 7.57−7.46 (m,
2H), 7.45−7.28 (m, 7H), 4.43 (s, 1H), 4.06−3.93 (m, 1H), 3.92−3.66
(m, 3H), 3.62 (s, 3H), 3.49 (dd, J = 11.1, 6.6 Hz, 1H), 3.01 (dd, J =
15.8, 7.0 Hz, 1H), 2.93−2.71 (m, 2H), 2.67−2.48 (m, 2H), 2.13−1.84
(m, 2H), 1.79−1.52 (m, 2H), 1.00 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 171.5, 147.8, 135.8, 135.8, 133.8, 133.7, 133.6, 133.2, 131.7,
131.3, 129.69, 129.61, 127.69, 127.65, 124.3, 72.8, 68.9, 64.3, 55.3,
51.8, 51.3, 47.9, 46.2, 36.4, 28.3, 26.9, 22.8, 19.3. HRMS (ESI) calcd
for C34H42N2NaO9SSi [M + Na]+: 705.2278. Found: 705.2296.
Methyl 2-((2S,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitro-N-((S)-oxiran-2-ylmethyl)phenylsulfon-
amido)tetrahydro-2H-pyran-2-yl)acetate 18d. Following the
above protocol, 15d (20.1 g, 32.0 mmol, 1.0 equiv) was treated with
(R)-glycidyl triflate [(R)-17] (13.2 g, 64.0 mmol, 2.0 equiv), cesium
carbonate (41.7 g, 128.0 mmol, 4.0 equiv) in DCE (128 mL). The
reaction provided, after purification, 19.3 g (88%) 18d as a yellow oil.
22
desired amine 15d as a yellow foamy solid. [α]D −50.6 (c 1.0,
CHCl3). IR νmax (cm−1, film) 3361, 2932, 2858, 1733, 1541, 1427,
1
1361, 1166, 1111. H NMR (300 MHz, CDCl3): δ 8.13−8.01 (m,
1H), 7.86−7.77 (m, 1H), 7.65 (dd, J = 11.2, 4.3 Hz, 1H), 7.60−7.48
(m, 5H), 7.46−7.30 (m, 6H), 5.97 (d, J = 8.2 Hz, 1H), 3.99−3.65 (m,
5H), 3.62 (s, 4H), 2.42 (ddd, J = 20.9, 15.5, 6.3 Hz, 2H), 1.73 (s, 2H),
1.53 (s, 2H), 1.01 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 171.2,
147.9, 135.6, 135.5, 134.7, 133.5, 133.0, 132.9, 132.9, 130.7, 130.0,
129.9, 127.9, 127.8, 125.4, 77.0, 68.0, 61.8, 51.7, 48.8, 40.4, 26.9, 25.2,
24.3, 19.2. HRMS (ESI) calcd for C31H38N2NaO8SSi [M + Na]+:
649.2016. Found: 649.2011.
22
[α]D −74.5 (c 1.0, CHCl3). IR νmax (cm−1, film) 2931, 2857, 1736,
Methyl 2-((2R,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitro-N-((R)-oxiran-2-ylmethyl)phenylsulfon-
amido)tetrahydro-2H-pyran-2-yl)acetate 18a. To a solution of
sulfonamide 15c (6.5 g, 10.4 mmol, 1.0 equiv) in 1,2-dichloroethane
(42 mL) was added cesium carbonate (13.5 g, 41.5 mmol, 4.0 equiv)
followed by (S)-glycidyl triflate [(S)-17] (4.3 g, 20.7 mmol, 2.0 equiv).
The reaction mixture was stirred at rt until deemed completion (∼1 h)
and then quenched with 100 mL of a saturated solution of aqueous
ammonium chloride. The organic layer was separated, and the aqueous
layer was then washed with CH2Cl2 (2 × 100 mL). The combined
organic layers were washed with brine, dried over MgSO4 and filtered.
The organic layer was concentrated under reduced pressure, and the
crude residue was purified by chromatography on silica gel (gradient:
5−55% EtOAc in hexanes), which provided 6.4 g (90%) of pure 18a as
a yellow oil. [α]D22 −10.3 (c 1.0, CHCl3). IR νmax (cm−1, film): 2932,
2857, 1740, 1545, 1437, 1373, 1265, 1113. 1H NMR (300 MHz,
CDCl3): δ 7.94 (d, J = 9.0 Hz, 1H), 7.70−7.31 (m, 13H), 3.90−3.27
(m, 7H), 3.62 (s, 3H), 3.05 (dd, J = 6.1, 14.9 Hz, 1H), 2.94 (bs, 1H),
2.76 (t, J = 3.1 Hz, 1H), 2.58−2.47 (m, 2H), 2.38 (dd, J = 6.1, 17.8 Hz,
1H), 1.83−1.70 (m, 2H), 1.48−1.35 (m, 1H), 0.97 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 171.4, 147.6, 135.8, 135.7, 133.8, 131.7, 131.3,
129.6, 129.5, 127.6, 124.2, 79.6, 73.4, 63.9, 51.7, 51.3, 46.3, 40.7, 39.5,
31.5, 27.5, 26.8, 19.2. HRMS (ESI+) calcd for C34H42N2NaO9SSi [M
+ Na]+: 705.2278. Found: 705.2299.
1542, 1428, 1360, 1165, 1111. 1H NMR (300 MHz, CDCl3): δ 7.96−
7.86 (m, 1H), 7.53 (dd, J = 15.6, 6.7 Hz, 4H), 7.46−7.29 (m, 8H),
4.54−4.40 (m, 1H), 3.96 (d, J = 16.4 Hz, 1H), 3.79 (t, J = 7.9 Hz, 1H),
3.63 (s, 3H), 3.40 (d, J = 10.7 Hz, 2H), 3.17−3.02 (m, 1H), 3.02−2.77
(m, 3H), 2.62 (dd, J = 15.2, 6.6 Hz, 1H), 2.56−2.48 (m, 1H), 2.46−
2.14 (m, 2H), 2.04−1.90 (m, 2H), 1.78−1.59 (m, 1H), 0.92 (s, 9H).
13C NMR (75 MHz, CDCl3): δ 171.5, 147.4, 135.7, 133.65, 133.61,
133.4, 132.9, 131.6, 131.3, 129.8, 129.6, 127.76, 127.72, 124.3, 71.6,
69.2, 64.0, 55.0, 52.4, 51.8, 48.0, 46.4, 36.1, 28.5, 26.8, 24.8, 19.2.
HRMS (ESI) calcd for C34H43N2O9SSi [M + H]+: 683.2459. Found:
683.2444.
Methyl 2-((2R,5S,6S)-6-(hydroxymethyl)-5-(2-nitro-N-((R)-ox-
iran-2-ylmethyl)phenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 19a. To a solution of 18a (5.6 g, 8.2 mmol, 1.0 equiv) in
THF (41 mL) was added HF·pyridine (70 wt %, 6.1 mL, 49.2 mmol,
6.0 equiv) at rt. The reaction mixture was stirred at rt for 2 h. The
mixture reaction was quenched with TMSOMe (17.0 mL, 123.0 mmol,
15.0 equiv), and stirring was continued for 1 h. The solvent was then
removed under reduced pressure, and the crude residue was purified
by chromatography on silica gel (gradient: 0−5% MeOH in CH2Cl2),
22
which provided 2.8 g (77%) of 19a as a foamy solid. [α]D −22.6 (c
1.0, CHCl3). IR νmax (cm−1, film): 3436, 3350, 2933, 1689, 1609, 1450,
1
1396, 1241, 1193, 1081. H NMR (300 MHz, CDCl3): δ 8.20−8.02
(m, 1H), 7.73−7.58 (m, 3H), 4.11−3.75 (m, 4H), 3.65 (s, 3H), 3.62−
3.43 (m, 3H), 3.18−3.12 (m, 1H), 2.93−2.85 (m, 1H), 2.63−2.32 (m,
3H), 2.15−2.08 (m, 1H), 1.91−1.37 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 171.3, 134.2, 132.0, 131.9, 130.9, 124.6, 124.3, 81.2, 78.3,
75.3, 74.6, 74.1, 70.3, 62.2, 51.9, 40.7, 31.7, 31.3, 28.7, 27.7. HRMS
(ESI+) calcd for C18H25N2O9S [M + H]+: 445.1281. Found: 445.1288.
Methyl 2-((2R,5S,6S)-6-(hydroxymethyl)-5-(2-nitro-N-((S)-ox-
iran-2-ylmethyl)phenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 19b. Following the above protocol, 18b (11.0 g, 16.1
mmol, 1.0 equiv) was treated with HF·pyridine (70 wt %, 10.0 mL,
81.0 mmol, 5.0 equiv) in THF (81 mL). The reaction provided, after
purification, 6.3 g (88%) of 19b as a foamy solid. [α]D22 −62.5 (c 1.0,
CHCl3). IR νmax (cm−1, film): 3485, 2951, 2874, 1732, 1541, 1373,
Methyl 2-((2R,5S,6S)-6-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(2-nitro-N-((S)-oxiran-2-ylmethyl)phenylsulfon-
amido)tetrahydro-2H-pyran-2-yl)acetate 18b. Following the
above protocol, 15c (15.9 g, 50.8 mmol, 1.0 equiv) was treated with
(R)-glycidyl triflate [(R)-17] (10.5 g, 50.8 mmol, 2.0 equiv), cesium
carbonate (33.1 g, 102 mmol, 4.0 equiv) in 1,2-dichloroethane (100
mL). The reaction provided, after purification, 15.0 g (93%) of 18b as
a yellow oil. [α]D22 −86.8 (c 1.0, CHCl3). IR νmax (cm−1, film): 2956,
2931, 2857, 1741, 1544, 1428, 1356, 1264, 1164, 1112. 1H NMR (300
MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.4 Hz, 4H),
7.43−7.32 (m, 8H), 7.15 (d, J = 8.4 Hz, 1H), 4.41 (dd, J = 12.1, 3.2
Hz, 1H), 4.03 (dd, J = 12.1, 6.1 Hz, 1H), 3.91−3.69 (m, 2H), 3.58 (s,
3H), 3.41 (d, J = 11.2 Hz, 1H), 3.39−3.29 (m, 1H), 3.26−3.17 (m,
1H), 3.08−3.02 (m, 1H), 2.82 (dt, J = 9.0, 4.5 Hz, 2H), 2.66 (dd, J =
4.8, 2.6 Hz, 1H), 2.60−2.37 (m, 3H), 2.29−1.95 (m, 1H), 1.84 (d, J =
13.3 Hz, 1H), 1.48 (d, J = 12.4 Hz, 1H), 0.92 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 171.4, 155.0, 147.3, 135.9, 135.8, 133.7, 133.5, 132.9,
131.8, 131.4, 129.8, 129.7, 127.8, 127.7, 124.4, 80.0, 79.2, 74.1, 68.7,
63.7, 55.2, 51.9, 49.1, 47.9, 46.7, 44.73, 40.9, 31.8, 29.4, 26.8, 19.3.
1
1349, 1260, 1163. H NMR (300 MHz, CDCl3): δ 8.24−8.00 (m,
1H), 7.71−7.56 (m, 3H), 3.98 (dd, J = 16.3, 2.6 Hz, 1H), 3.88−3.76
(m, 1H), 3.64 (s, 4H), 3.61−3.39 (m, 3H), 3.19−3.11 (m, 2H), 2.96−
2.81 (m, 2H), 2.60 (dd, J = 4.5, 2.6 Hz, 1H), 2.46 (ddd, J = 20.8, 15.5,
6.5 Hz, 2H), 2.18−1.98 (m, 2H), 1.87−1.79 (m, 2H), 1.59−1.36 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 171.1, 147.7, 133.9, 133.1,
131.86, 131.83, 124.4, 78.1, 73.9, 62.0, 54.2, 51.8, 51.7, 47.6, 46.6, 40.4,
J
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Article
31.5, 28.4. HRMS (ESI+) calcd for C18H25N2O9S [M + H]+:
445.1281. Found: 445.1281.
4.47−4.23 (m, 1H), 4.00−3.71 (m, 4H), 3.67 (s, 3H), 3.63−3.43 (m,
3H), 2.80 (dd, J = 14.5, 8.2 Hz, 2H), 2.48 (dd, J = 14.5, 6.9 Hz, 2H),
2.05−1.80 (m, 2H), 1.69 (s, 1H), 1.59−1.45 (m, 1H), 1.42−1.15 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 171.1, 148.2, 134.3, 131.9, 130.9,
128.4, 124.4, 77.3, 73.4, 73.2, 70.0, 69.5, 52.0, 35.9, 28.4, 23.1. HRMS
(ESI) calcd for C18H24N2NaO9S [M + Na]+: 467.1100. Found:
467.1107.
Methyl 2-((2S,5S,6S)-6-(hydroxymethyl)-5-(2-nitro-N-((R)-ox-
iran-2-ylmethyl)phenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 19c. Following the above protocol, 18c (10.0 g, 14.6
mmol, 1.0 equiv) was treated with HF·pyridine (70 wt %, 5.5 mL, 43.9
mmol, 3.0 equiv) in THF (146 mL). The reaction provided, after
22
purification, 5.7 g (88%) of 19c as a foamy solid. [α]D +77.1 (c 1.0,
Methyl 2-((3S,6aS,8S,10aS)-3-hydroxy-1-((2-nitrophenyl)-
sulfonyl)decahydropyrano[2,3-c][1,5]oxazocin-8-yl)acetate
6d. Following the above protocol, 19d (4.2 g, 9.5 mmol, 1.0 equiv)
was treated with BF3-Et2O (0.24 mL, 1.9 mmol, 0.2 equiv) in CH2Cl2
(189 mL). The reaction provided, after purification, 2.35 g (56%) of
6d as a 9:1 mixture with 20d as a white powder: [α]D22 +146.0 (c 1.0,
CHCl3). IR νmax (cm−1, film) 3432, 2950, 1732, 1542, 1439, 1371,
CHCl3). IR νmax (cm−1, film) 3537, 2951, 1732, 1543, 1372, 1165. 1H
NMR (300 MHz, CDCl3): δ 8.11 (dd, J = 7.3, 1.7 Hz, 1H), 7.80−7.57
(m, 3H), 4.40 (s, 1H), 4.16 (d, J = 16.0 Hz, 1H), 4.03−3.91 (m, 1H),
3.89−3.70 (m, 2H), 3.67 (s, 3H), 3.24−3.06 (m, 1H), 3.00−2.72 (m,
3H), 2.71−2.41 (m, 3H), 2.08−1.80 (m, 2H), 1.76−1.55 (m, 2H),
1.53−1.35 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 171.6, 148.0,
134.2, 132.0, 131.8, 124.5, 72.0, 69.0, 62.3, 54.3, 51.9, 51.8, 48.0, 46.1,
35.9, 28.3, 21.8. HRMS (ESI) calcd for C18H24N2NaO9S [M + Na]+:
467.1100. Found: 467.1108.
1
1348, 1161. H NMR (300 MHz, CDCl3): δ 8.16−7.98 (m, 1H),
7.80−7.65 (m, 2H), 7.64−7.52 (m, 1H), 4.36 (dd, J = 13.7, 6.8 Hz,
1H), 4.17−3.98 (m, 1H), 3.97−3.70 (m, 4H), 3.66 (s, 3H), 3.63−3.39
(m, 3H), 3.03 (s, 1H), 2.83 (dd, J = 14.5, 8.4 Hz, 1H), 2.57−2.28 (m,
2H), 1.97−1.82 (m, 1H), 1.80−1.43 (m, 2H), 1.42−1.24 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ 171.3, 148.0, 134.1, 134.0, 131.9, 130.8,
124.2, 74.4, 72.8, 70.0, 69.9, 59.1, 52.0, 35.9, 28.2, 23.6. HRMS (ESI)
calcd for C18H25N2O9S [M + H]+: 445.1281. Found: 445.1293.
Methyl 2-((2S,5S,6S)-6-(hydroxymethyl)-5-(2-nitro-N-((S)-ox-
iran-2-ylmethyl)phenylsulfonamido)tetrahydro-2H-pyran-2-
yl)acetate 19d. Following the above protocol, 18d (19.3 g, 28.3
mmol, 1.0 equiv) was treated with HF·pyridine (70 wt %, 10.5 mL,
85.0 mmol, 3.0 equiv) in THF (283 mL). The reaction provided, after
purification, 9.9 g (79%) of 19d as a foamy solid. [α]D22 −57.8 (c 1.0,
CHCl3). IR νmax (cm−1, film) 3500, 2951, 1731, 1541, 1439, 1348,
1163. 1H NMR (300 MHz, CDCl3): δ 8.18−8.05 (m, 1H), 7.77−7.60
(m, 3H), 4.36 (s, 1H), 4.16 (d, J = 16.2 Hz, 1H), 3.92−3.75 (m, 1H),
3.62 (s, 4H), 3.47−3.31 (m, 1H), 3.25−3.07 (m, 2H), 3.03−2.78 (m,
3H), 2.72−2.61 (m, 1H), 2.54 (dd, J = 15.0, 5.7 Hz, 1H), 2.39−2.16
(m, 1H), 2.08−1.88 (m, 3H), 1.80−1.62 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 171.6, 147.8, 134.1, 133.1, 132.0, 131.9, 124.5, 70.8,
69.2, 61.8, 53.9, 52.2, 51.9, 48.1, 46.6, 35.9, 28.4, 24.3. HRMS (ESI)
calcd for C18H24N2NaO9S [M + Na]+: 467.1100. Found: 467.1089.
Methyl 2-((3R,6aS,8R,10aS)-3-hydroxy-1-((2-nitrophenyl)-
sulfonyl)decahydropyrano[2,3-c][1,5]oxazocin-8-yl)acetate 6a.
To 19a (5.0 g, 11.3 mmol) in CH2Cl2 (112 mL) was added BF3-Et2O
(1.6 mL, 12.4 mmol, 1.1 equiv) at rt. After 2 h, the reaction was
concentrated under reduced pressure to afford a light brown residue,
which was purified by chromatography on silica gel (gradient: 40−90%
EtOAc in hexanes) to provide 3.2 g (64%) of 6a as a white powder.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds and X-ray
crystallographic information (CIF) for 3c, 14b, and 6a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
■
Present Address
†H3 Biomedicine, 300 Technology Square, Cambridge,
Massachusetts 02139, United States.
Notes
22
[α]D +69.5 (c 1.0, CHCl3). IR νmax (cm−1, film): 3516, 2951, 2874,
1
The authors declare no competing financial interest.
1735, 1532, 1439, 1346, 1160, 1058. H NMR (300 MHz, CDCl3): δ
8.07 (d, J = 8.3 Hz, 1H), 7.83−7.47 (m, 3H), 3.99−3.68 (m, 6H), 3.63
(s, 3H), 3.58−3.47 (m, 3H), 3.41−3.21 (m, 2H), 2.41 (ddd, J = 20.9,
15.5, 6.5 Hz, 2H), 1.68 (d, J = 16.3 Hz, 2H), 1.52−1.21 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ 171.3, 148.2, 134.4, 132.0, 131.1, 128.5,
124.4, 81.2, 77.4, 75.2, 73.4, 69.6, 58.8, 51.9, 51.8, 40.6, 31.4, 27.1.
HRMS (ESI+) calcd for C18H25N2O9S [M + H]+: 445.1281. Found:
445.1276.
ACKNOWLEDGMENTS
■
This work was funded in part by the NIGMS-sponsored Center
of Excellence in Chemical Methodology and Library Develop-
ment (Broad Institute CMLD; P50 GM069721), as well as the
NIH Genomics Based Drug Discovery U54 Grants Discovery
Pipeline RL1CA133834 (administratively linked to NIH grants
RL1HG004671, RL1GM084437, and UL1DE019585). High-
resolution mass spectra were obtained at the Boston University
Chemical Instrumentation Center. X-ray crystallographic
analysis was performed by Dr. Peter Muller at the MIT X-ray
crystallographic laboratory.
Methyl 2-((3S,6aS,8R,10aS)-3-hydroxy-1-((2-nitrophenyl)-
sulfonyl)decahydropyrano[2,3-c][1,5]oxazocin-8-yl)acetate
6b. Following the above protocol, 19b (6.0 g, 13.5 mmol, 1.0 equiv)
was treated with BF3-Et2O (0.34 mL, 2.7 mmol, 0.2 equiv) in CH2Cl2
(270 mL). The reaction provided, after purification, 2.6 g (43%) of 6b
22
as a 9:1 mixture with 20b. 6b (white powder): [α]D + 122.5 (c 1.0,
CHCl3). IR νmax (cm−1, film): 3436, 2951, 2871, 1734, 1536, 1439,
1
1372, 1351, 1185, 1065. H NMR (300 MHz, CDCl3): δ 8.04 (d, J =
REFERENCES
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