Synthesis of Simplified Azasordarin Analogs as Potential Antifungal Agents

Article abstract of DOI:10.1021/acs.joc.9b00296

A new series of simplified azasordarin analogs was synthesized using as key steps a Diels-Alder reaction to generate a highly substituted bicyclo[2.2.1]heptane core, followed by a subsequent nitrile alkylation. Several additional strategies were investigated for the generation of the key tertiary nitrile or aldehyde thought to be required for inhibition at the fungal protein eukaryotic elongation factor 2. This new series also features a morpholino glycone previously reported in semisynthetic sordarin derivatives with broad spectrum antifungal activity. Despite a lack of activity against Candida albicans for these early de novo analogs, the synthetic route reported here permits more comprehensive modifications of the bicyclic core and structure-activity relationship studies that were not heretofore possible.

Full text of DOI:10.1021/acs.joc.9b00296

Subscriber access provided by OCCIDENTAL COLL
Article
Synthesis of Simplified Azasordarin Analogs as Potential Antifungal Agents
Yibiao Wu, and Chris Dockendorff
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00296 • Publication Date (Web): 28 Mar 2019
Downloaded from http://pubs.acs.org on March 28, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Simplified Azasordarin Analogs as Potential
Antifungal Agents
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yibiao Wu and Chris Dockendorff*
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI, 53201-1881, USA
ABSTRACT: A new series of simplified azasordarin analogs was synthesized using as key steps a Diels-Alder reaction to generate
a highly substituted bicyclo[2.2.1]heptane core, followed by a subsequent nitrile alkylation. Several additional strategies were
investigated for the generation of the key tertiary nitrile or aldehyde thought to be required for activity at the fungal protein
eukaryotic elongation factor 2. This new series also features a morpholino glycone previously reported in semisynthetic sordarin
derivatives with broad spectrum antifungal activity. Despite a lack of activity against C. albicans for these early de novo analogs,
the synthetic route reported here permits more comprehensive modifications of the bicyclic core, and SAR studies that were not
heretofore
possible.
INTRODUCTION
thus far to synthesize novel analogs possessing a simplified
bicyclic [2.2.1] scaffold more amenable to systematic
modifications, which could lead to sordarin analogs with
improved properties for clinical use. The strategy of
identifying natural product pharmacophores and preparing
structurally simpler compounds has been conceptualized by
Wender (Function-Oriented Synthesis),12 but has a long and
successful history in medicinal chemistry. Important examples
include the discovery of morphine-inspired opioids such as
fentanyl,13 synthetic statins such as atorvastatin inspired by the
natural HMG-CoA reductase inhibitors compactin and
lovastatin,14,15 and the anticancer drug eribulin identified from
simplification of the sponge metabolite halichondrin B.16 We
believe that this underutilized approach could be fruitfully
applied to sordarin.
The development of resistance to the relatively small
number of antifungal agents in clinical use for invasive fungal
infections is now of great concern. It is estimated that more
than 2 million people die annually of invasive fungal
infections, which can have mortality rates of >50%.1
Additionally, fungi are estimated to destroy approximately
20% of crops worldwide. With increasing resistance observed
for both clinical and agricultural antifungals, the identification
of new classes of antifungals is an urgent matter.2-4 In 1965,
Sigg and Stoll from Sandoz AG submitted a patent application
first describing the natural product sordarin as an antibacterial
and antifungal agent.5 First isolated from the fungus Sordaria
araneosa,6 sordarin has a unique tetracyclic diterpene scaffold,
with a [2.2.1]heptene at its core with adjacent aldehyde and
acid groups (1, Figure 1). Attached to the core is an unusual
carbohydrate glycone, which can be replaced with a multitude
of substituents via semisynthesis, leading to derivatives such
as 2 (GW 471558)7 and 3.8
Cl
OH
HO
O
OMe
N
O
N
O
H
H
H
O
O
O
H
O
H
H
Importantly, the antifungal target of sordarin was later
deduced by groups at Merck and Glaxo to be the ribosomal
protein eukaryotic elongation factor 2 (eEF2),9,10 a necessary
component of protein synthesis which is a target presently
unaddressed by current clinical antifungals. The high potency
against e.g. fluconazole-resistant fungal strains and selectivity
for sordarin derivatives over human eEF2 provided additional
impetus for numerous pharmaceutical companies to pursue
sordarin derivatives as antifungal agents. The complexity of
sordarin as a synthetic target necessitated the near-exclusive
pursuit of semisynthetic derivatives, since sordarin can be
produced on large scales via fermentation,11 and the natural
glycone easily hydrolyzed and replaced with alternatives that
imbue the derivatives with improved properties. Despite these
efforts, to our knowledge no fungal eEF2 inhibitors have
reached clinical stages. This manuscript describes our efforts
CO2H
CO2H
CO2H
O
O
GW 471558
H
H
H
sordarin 1
highly potent azasordarin 2
broad spectrum azasordarin 3
(this work)
OH
Cl
diverse glycone
OMe
HO
replacements are
tolerated
H
N
O
O
Scaffold
simplification
4
2
known
metabolic
sites
6
O
O
H
CO2H
H
isopropyl group may
not be required
R1
O
1
CO2H
CN
4
can optionally be
replaced with a
nitrile
acid is necessary
R1= aryl or alkyl
Figure 1. Sordarin and two representative azasordarin derivatives
(top); known sordarin SAR and our plan for simplified analogs
via scaffold simplification (bottom).
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
Design of Analogs
1
Semisynthetic replacement of the glycone of sordarin has
led to several highly potent and orally active azasordarin
analogs against C. albicans such as 2 (Figure 1),7 as well as a
few analogs with a broader spectrum of antifungal activity
(e.g. 3).8 One liability that has been identified with certain
sordarin derivatives is their unsatisfactory metabolic
stabilities. Sordarin and its aglycone sordaricin are
hydroxylated on the cyclopentane (Figure 1, bottom left) by
rat and mouse hepatic fractions.17 We hypothesize that analogs
with alternative scaffolds, particularly those with substituents
at the "western" side that are resistant to cytochrome P-450-
mediated oxidation, could maintain the pharmacophore for
antifungal activity (Figure 1, bottom right) and possess
improved pharmacokinetic (PK) profiles. Previous SAR
studies have suggested that the key part of the sordarin
pharmacophore is the vicinal aldehyde-carboxylic acid, held
within the rigid bicyclic framework in a perpendicular
orientation which precludes hemiacetal formation.18 X-ray
crystal structures of eEF2 complexed with sordarin have
clarified the importance of the aldehyde and acid moieties,
which form 4 hydrogen bonds with bound waters and two
backbone amides of eEF2 (Figure 2).19,20 It should be noted
that several potent analogs have been reported where the
aldehyde has been replaced with a nitrile.18 We reasoned that a
modified bicyclo[2.2.1]heptane core could maintain a similar
dihedral angle between these moieties, and permit the
identification of novel analogs with comparable potencies to
the natural product and its semisynthetic derivatives, but with
the potential for improved PK properties. A simplified
monocyclic cyclopentane with vicinal aldehyde and acid
moieties was previously reported by Cuevas to possess only
marginal antifungal activity.17
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Proposed strategies for constructing the desired
bicyclo[2.2.1]heptane core with quaternary center at C-2. PG =
protecting group, LG = leaving group.
As described in our previous report,21 we successfully
established a synthetic route to simplified [2.2.1] bicyclic
analogs of sordarin (Scheme 1). This route relied on
chromatographic separation of endo/exo Diels-Alder adduct
rac-15 to give endo-15. Subsequent protecting group
manipulation followed by Wittig reaction and Jones oxidation
furnished simplified alkyl sordarin analog 17. However, 17
failed to show antifungal activity against several strains of C.
albicans at concentrations up to 8 ꢀg/mL. We reasoned that
this may be attributed to the lack of a complex glycone, and/or
the lack of a quaternary center at C-2. Therefore, we chose to
append to our scaffold a morpholine glycone previously
reported in sordarin derivatives showing broad and potent
antifungal activity (3, Figure 1).8
Reasoning that the isopropyl group may not be required for
activity, and its introduction would complicate the current
synthetic routes under consideration, we initially pursued
Scheme 1. Synthesis of our first-generation sordarin
analogs21
analogs without
a substituent at C-6 of the bicycle.
Alternatively, the crystal structure suggests that a small group
at C-5 could be tolerated, which complements our current
synthetic approach. Therefore, primarily for synthetic
expediency, we have initially prepared the scaffold present in
4 (Figure 1) possessing an exo-methylene at C-5.
DHP = 3,4-dihydro-2H-pyran
To construct the tertiary chiral center at C-2, we have thus
far explored five strategies for preparation of key
intermediates 5 that are suitable for elaboration to the desired
analogs 4 (Figure 3). A Diels-Alder approach using 1,1-
disubstituted alkenes could be the most convergent approach
to 5. Reactions using silyloxy diene 6 could avert undesired
1,5-hydride or alkyl shifts that are well known for
cyclopentadienes,22 but are slowed down by electron-rich
diene substituents.23 The silyloxy group is also a versatile
handle for subsequent transformations, and provides the
desired regioselectivity for cycloadditions, with the
aldehyde/nitrile and carboxylic acid precursors on vicinal
carbons in the cycloadducts. The endo/exo diastereoselectivity
Figure 2. X-ray structure of eEF2-sordarin19
2
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
could also be modified by using suitable Lewis acids. The
second approach uses as the key step an asymmetric
1
2
3
4
5
6
7
8
9
organocatalytic Diels-Alder reaction reported by Jørgensen,24
which could also provide highly enantiomerically-enriched
products via the catalytic enamine intermediate 7. This
approach would also have the advantage of avoiding the need
to preactivate the diene component via silylenol ether
formation. The third approach also involves a formal [4+2]
cycloaddition reaction, but one which could proceed via a
double Michael addition mechanism. In this proposed
reaction, enolate 8 could add to the dienophile to generate a
second enolate, which could subsequently cyclize by adding
back to the resulting enone. The fourth strategy, which
depends on a prior cycloaddition reaction, is to install the
nitrile on the endo face of the bicycle by addition of cyanide to
an intermediate carbocation 9. The fifth strategy leverages our
prior cycloaddition reactions with acrylonitrile,21 but uses a
subsequent SNAr or SN2 substitution reaction to introduce the
aryl or alkyl substituent via the exo face of the bicycle.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To potentially circumvent the lack of Diels-Alder reactivity
of acrylates, we turned our attention to the α,β-unsaturated
ester 22 with a more highly activating trifluoromethyl methyl
group to decrease the LUMO level of the dienophile. The
trifluoromethyl group is also a desirable substituent for our
medicinal chemistry studies due to its lipophilic but
metabolically stable profile. After extensive screening of
different solvents and Lewis acids, we learned that diene 14
was indeed not compatible with most Lewis or Brønsted acids
(e.g. trifluoroethanol, Table 1, entry 15), as reported by
Gleason for a related OTBS-substituted cyclopentadiene.23
Lewis acids that were compatible with 14 (Mg(OTf)2,
Mg(ClO4)2, and Eu(hfc)3; entries 4, 18 and 19) didn’t give any
endo selectivity. The diastereomers were tentatively assigned
based on a report by Ishihara characterizing endo/exo isomers
with the same dienophile.27 The diastereoselectivity can be
tilted slightly by using different solvents; the highest exo
selectivity was achieved in DCM (Table 1, entries 8, 9), and
the most endo selective reaction was in hexanes (Table 1,
entry 11). Due to the low tolerance of 14 to Lewis acids, we
didn’t pursue alternative dienophile/Lewis acid combinations
to increase the proportion of the desired endo cycloadducts,
though we anticipate that bulkier substituents than CF3 may
favor the desired endo cycloadducts.
RESULTS AND DISCUSSION
1. Diels-Alder with silyloxy diene
Our initial target compounds possess a fluorinated aryl
group as R1 (4, Figure 1), which we hypothesize should fit into
the lipophilic portion of the eEF2 binding pocket occupied by
the cyclopentane ring of sordarin. The installation of such aryl
substituents has proven to be challenging thus far. Our initial
attempt used the 2-aryl-acrylaldehyde 18, but instead of the
desired adduct 19, the unexpected dihydropyran 20 was
obtained (Scheme 2). This product could be generated from
either a retro-Claisen rearrangement of 19 or an inverse
electron demand, hetero Diels–Alder reaction. Davies reported
that Lewis acid-catalyzed reactions of cyclopentadiene and 2-
arylacroleins generated mixtures of bicyclo[2.2.1]heptenes and
dihydropyrans analogous to 19 and 20, with the heptenes able
to convert to the dihydropyrans.25 One notable difference in
our case is that the dihydropyran was the only product
observed. The aldehyde-containing Diels-Alder adduct and its
rearranged product are expected to be in equilibrium, with the
ratio determined in part by the ring strain and extent of
conjugation of the α-substituent (in this case, a fluorinated
arene).26 Silyl ketal 20 is an unstable species that decomposed
to racemic aldehyde 21 upon treatment with formic acid in
Table 1. Solvent and Lewis acid screening for Diels-Alder
using 22
º
methanol, or after storage in the freezer (–20 C) for a month
dissolved in DCM under neutral conditions. The most
straightforward way to circumvent the undesired hetero Diels-
Alder reaction could be to use the nitrile or ester counterparts
of 18, but unfortunately these dienophiles failed to give any
cycloadducts with 14.
Lewis
acide
endo
/exob
entry
solvent
temp. (ºC)
yieldc
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
InCl3
ZnBr2
N/A decomp.
N/A decomp.
N/A decomp.
Scheme 2. Diels-Alder/Retro-Claisen or hetero-Diels-Alder
reaction of enal 18
Yb(OTf)3
Mg(OTf)2
Zn(OTf)2
Eu(OTf)3
K-10
0.75
68%
N/A decomp.
N/A decomp.
N/A decomp.
–
0.67
83%
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
9
DCM
rt
–
0.71d
40%d
1
2
3
4
5
6
7
8
3. Double Michael addition
10
11
12
13
14
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
–
0.82
1.04
0.85
0.8
85%
96%
91%
63%
86%
Inspired by Yamada's reports of stereoselective sequential
Michael reactions using enolates generated from 3-alkoxy-
cyclopentenones to generate [2.2.1] bicyclic adducts (Scheme
3),28 we explored an analogous reaction starting from our
enone 24c and model enone 24b. These were treated with
LDA to give their corresponding lithium enolates, followed by
the addition of an initial Michael acceptor. However, all
enolates were unreactive in the presence of several Michael
acceptors under a number of different conditions (Table 3).
Despite the fact that the cyclopentanone can be smoothly
deprotonated, as demonstrated by D2O quench (entry 8), use of
Michael acceptors with different reactivities ranging from
methyl 2-(4-fluorophenyl)acrylate to acrylonitrile didn’t
change the result. The addition of HMPA (entries 2, 15, 11,
13) or heating (entries 10–13) were not able to initiate the
desired reaction as well. Upon work up, the cyclopentenones
24b–c were recovered. This inactivity could be explained by
the lack of an electron-donating alkoxy group at C3 of 24b–c.
In the case of 24b, the methyl group at C-4 proximal to the
approaching Michael acceptor likely prevented its reaction due
to steric hindrance (entries 9–11).
hexanes
MeCN
acetone
MeOH
–
–
–
–
0.93
15 F3CCH2OH
–
N/A decomp.
9
16
17
18
19
PhCF3
EtOAc
MeCN
CDCl3
–
–
0.83
0.78
0.87
0.62
100%
74%
98%
trace
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mg(ClO4)2
Eu(hfc)3
aDiene was washed with phosphate buffer (pH 7) before using;
b
all experiments were run for 24 h. Diastereomers were assigned
based on a previously reported analog,27 and the ratio was
determined with 19F NMR. NMR yield using pentachloroethane
c
as internal standard, unless otherwise specified. dIsolated yield. e1
eq. except for entry 18 (0.9 eq.) and entry 19 (0.2 eq.). decomp. =
diene decomposed to 13. K-10 = Montmorillonite K-10. Eu(hfc)3
=
europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-
camphorate]. rt = room temperature (22–23 ºC).
Scheme 3. Sequential Michael reaction reported by
Yamada28
2. Asymmetric organocatalytic Diels-Alder
In order to achieve an endo-selective Diels-Alder reaction
and avoid the acid sensitivity of diene 14, we examined the
organocatalytic asymmetric Diels-Alder reaction reported by
Jørgensen24 The quinidine-derived amine catalyst 25 worked
smoothly with cyclopentenone (Table 2, entry 1), as was
reported. However, we weren’t able to extend the scope to
include 4-substituted cyclopentenones (entries 2, 3). When the
C-4 position of the cyclopentenone is disubstituted, the
reaction didn’t proceed (entry 2), likely because the transition
state is disrupted by the steric repulsion between the
dienamine intermediate and the dienophile. When the C-4
position is monosubstituted (24c), the enone was consumed,
but no cycloaddition products were observed (entry 3).
Table 3. Attempted double Michael addition
Table
cyclopentenones 24
2.
Organocatalytic
Diels-Alder
using
Entry enone Michael acceptorb conditionsa additive resultc
R1= 4-FPh, R2=
1
2
3
4
5
24c
24c
24c
24c
24c
A
A
A
A
A
None
N.R.
N.R.
N.R.
N.R.
N.R.
CO2Me
R1= 4-FPh, R2=
CO2Me
HMPA
(1 eq.)
R1= 4-FPh, R2=
CO2Me
None
None
R1= CF3, R2=
CO2Me
R1= CF3, R2=
CO2Me
HMPA
(1 eq.)
R1= CF3, R2=
CO2Me
Entry
1
Enone
T/t
Result
6
7
24c
24c
24c
A
A
A
A
B
None
None
None
None
None
N.R.
N.R.
deut.d
N.R.
N.R.
24a
60 ºC, 3 d
100% conversion to 26aa
acrolein
none, quenched with
D2O
60 ºC, 3 d;
100 ºC, 24 h
N.R.a
8
2
24b
9
24c R1= H, R2= CO2Et
3
60 ºC, 2 d
Decomposed 24cb
24c
R1= 4-FPh, R2=
10
24c
aDetermined by GC-MS, bDetermined by 1H NMR.
CO2Me
4
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
R1= 4-FPh, R2=
CO2Me
HMPA
(1 eq.)
11
12
13
24c
24c
24c
B
B
B
N.R.
N.R.
N.R.
1
2
3
4
5
6
7
8
9
R1= CF3, R2=
CO2Me
None
R1= CF3, R2=
CO2Me
14 24b R1= H, R2= CO2Et
HMPA
(1 eq.)
A
A
None
None
N.R.
N.R.
15 24b
16 24b
acrylonitrile
R1= 4-FPh, R2=
A
None
N.R.
CO2Me
5. SNAr and SN2 substitutions
aCondition A: Enones were deprotonated at –78 ºC, followed by
the addition of the Michael acceptor. All experiments except for
entry 8 were kept at –78 ºC for 2 h, then warmed up to rt and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An endo-selective SNAr reaction with 2-cyano-5-norbornene
and aryl fluoride reported by Caron33 suggested a promising
path to desirable α-arylated nitriles (Scheme 5). In this
approach, nitriles can be deprotonated with KHMDS and
reacted with both electron-rich and electron-poor aryl
fluorides, with 39 reported as a single (endo), presumably
thermodynamic, diastereomer. We chose nitrile 40 to examine
this approach for our application (Table 4). Under Caron’s
optimal conditions, 40 did not undergo the SNAr substitution
with 1,2-difluorobenzene (entry 1). When forcing conditions
were applied (1,2-difluorobenzene as solvent, 115 ºC), only a
trace amount of 41a was observed via LC-MS, and most of 40
was decomposed, as followed by TLC (entry 2). We
hypothesize that the substituted bridgehead next to the reaction
center obstructed the approach of the arene electrophile.
However, alkylation reactions were successful using
iodomethane and benzyl bromide as electrophiles with
quantitative conversion (entries 4, 5). Single diastereomeric
products were also characterized, which we presume are the
endo products generated from attack at the less hindered face
of the nitrile anion, in accordance with Caron’s report.33
stirred for 22 h. Entry 8 was quenched at –78 °C after LDA
deprotonation; Condition B: Enones were deprotonated at –78 °C,
followed by the addition of the Michael acceptor, then warmed up
b
to rt and refluxed for 3h. 2 eq. of Michael acceptor were used in
entries 1–13, each, and 1.2 eq. in entries 14–16. cN.R. = no
reaction; ddeut. = deuteration of α-carbon confirmed by 1H NMR.
4. Hydrocyanation
We reasoned that the use of a bicyclic[2.2.1]ketone
substrate could be advantageous, because it could permit the
ready generation of varied aryl-containing analogs (e.g. 32)
via arylmetal 1,2-addition reactions, followed by the
conversion of the resulting alcohols to nitriles via intermediate
carbocations (9, Figure 3). However, one disadvantage of the
tertiary alcohol to nitrile conversion is that it may only be high
yielding for electron-rich arenes able to facilitate the SN1-type
transformation. Cyanation of a p-methoxylphenyl-stabilized
tertiary cation has been reported with monocyclic substrates,29-
Scheme 5. SNAr reported by Caron30 using 2-cyano-5-
norbornene
31
and there are also examples of trapping tertiary 2-norbornyl
cations with nucleophiles,32 without the extensive Wagner-
Meerwein
rearrangements
of
these
non-classical
carbocations.28-30 We reasoned that an aryl substituent at the 2-
position of the norbornane could inhibit rearrangements and
permit trapping of the carbocation intermediate by a cyanide
nucleophile at the 2-position. We examined this strategy using
model systems formed by treating camphor with 4-
methoxyphenyl magnesium bromide to generate alcohol 32,
followed by acidic dehydration to generate 33. These were
separately reacted with two different acids and TMSCN
(Scheme 4). Upon treatment with BF3-OEt2 and TMSCN, 32
quickly dehydrated and rearranged to give an inseparable
mixture of dehydration product 33 and three other inseparable
alkene products with GC-MS and NMR analysis consistent
with Wagner–Meerwein and Nametkin rearrangements. The
desired cyanation product 37 was not observed. Trapping of 2-
norbornyl cation generated from 33 using TfOH and
TMSCN30 was also unsuccessful at a higher temperature (20
°C).
Table 4. Arylation/alkylation of secondary nitrile 40
Entrya Electrophile
Solvent Conditions
difluorobenzene THF 75 ºC, 12 h
Results
N.R.b
1,2-
1
2
(4 eq.)
1,2-
difluorobenzene neat
(excess)
Scheme 4. Attempted cyanation of camphor-derived
alcohol 32 and alkene 33
90–115 ºC,
24 h
trace 41ab
18-crown-6 (1
eq.), 100 ºC
12 h
1,2-
3
4
difluorobenzene toluene
(50 eq.)
N.R.b
MeI (45 eq.)
toluene 55 ºC, 12 h
quant. 41bc
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
structure may be needed with related azasordarin analogs in
the future to confirm this assignment. Since we generated
racemic intermediates via this synthetic route, the final
compounds 49 and 50a–c represent an approximate 1:1
mixture of racemic diastereomers, as observed by NMR.
5
BnBr (5.5 eq.)
toluene 55 ºC, 12 h
quant. 41cc
1
2
3
4
aTo a solution of 40 (2 mg, 0.01 M) was added the indicated
amount of electrophile followed by KHMDS. Observed by
LC-MS. Estimated NMR yield using pentachloroethane as
internal standard. N.R. = no reaction.
b
c
5
6
7
Scheme 6. Synthesis of azasordarin analogs
Synthesis of azasordarin analogs
We thus commenced our second-generation synthesis from
the key intermediate 1521 we reported previously (Scheme 6).
First, the bridgehead primary alcohol of 15 was oxidized to the
carboxylic acid and protected using PMBCl to provide ester
42. In previous studies, deprotonation of the carbon alpha to
the ketone in a compound similar to 42 caused ring opening
through a retro-Michael pathway. In part to avoid this
complication, 42 was subjected to a Wittig reaction to give
olefin 43. Normal Wittig conditions resulted in a very sluggish
reaction, presumably due to steric hindrance from the TBDPS
ether, however generation and reaction of the required ylide at
high temperature (90 °C) yielded alkene 43 in nearly
quantitative yield. The nitrile α-carbon of 43 was deprotonated
by KHMDS and alkylated with three different alkyl halides to
give exclusively the desired endo nitrile products, thus
eliminating a significant weakness of our first-generation
synthesis which had to rely on chromatographic separation of
endo/exo diastereomers. The resulting compounds 44a–c were
treated with TBAF to give primary alcohols 45a–c.
Stereochemistry was confirmed at this stage, with nOe
observed between R1 and its two neighboring protons as
shown in Scheme 6. Protons were first assigned using a COSY
experiment, then nOe signals were measured between H-10
and H-7 of 45a–c, as depicted in the Supporting Info. In the
case of 45a, nOe between the exo-methyl protons and 5-
Hexo was also observed.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In vitro antifungal testing
The isomeric mixtures 49 and 50a–c were subjected to
antifungal microdilution assays using Clinical and Laboratory
Standards Institute methods M27-A3 and M38-A2 at the
Fungus Testing Laboratory at the University of Texas Health
Science Center at San Antonio. No inhibition of fungal growth
was observed at up to 8 μg/mL, or 4 μg/mL (50c), against C.
albicans (isolate# CA1, CA2, CA3), A. fumigatus (isolate#
AF1, AF2, AF3), C. parapsilosis (CLSI QC), and P. variotii
(CLSI QC). Minimum inhibitory concentrations (MICs) were
determined after 24 h or 48 h (A. fumigatus), using fluconazole
and voriconazole as positive controls. For comparison,
sordarin itself has a reported MIC of 16 μg/mL vs wild type C.
albicans (strain A28235),39 and the azasordarin 3 was <0.008
μg/mL.8
45a–c were then activated with PhNTf2 to give triflates
46a–c. The glycones 47 and 48 were prepared using
modifications of a reported protocol;34 though 48 has not
previously been used in sordarin analogs, its ease of synthesis
and similarity to other N-PMB morpholine-based glycones7
inspired us to try it. Glycosidation35 of triflates 46 with
glycones 47 and 48 proceeded smoothly, and to our surprise,
the PMB ester was also cleaved during these transformations
to give the desired bridgehead carboxylic acids 49 and 50a–c.
These reactions proceeded in DMF but did not work in THF.
50a–c were obtained exclusively with what we assume to be
the aglycones in the equatorial positions at the anomeric
carbon. This is also consistent with the increased
nucleophilicity of the β-anomer of 1-O-lithiated pyranoses in
their reactions with alkyl triflates, leading to highly selective
CONCLUSION
After examining numerous strategies to stereoselectively
furnish the key tertiary nitrile on the bicyclo[2.2.1]heptane
core, we have established a second-generation synthesis that
enables the incorporation of substituents at the C-2 position.
The key step was the highly endo-selective alkylation of
bicyclic nitrile 43, which was generated via a Diels-Alder
reaction, as described in our previous report.21 Additionally,
our synthetic route facilitates the late stage incorporation of
diverse glycones. Although the synthesized analogs 49 and
50a–c failed to show activity as isomeric mixtures against
several fungal species (at concentrations up to 8 휇g/mL), this
new synthetic route to azasordarin analogs will permit
additional SAR studies not previously feasible.
1
formation of β-glycosides.36,37 The H NMR splitting of the
anomeric proton of 47 in dry CDCl3 (4.94 (ddd, J = 9.0, 3.9,
2.2 Hz) is consistent with the hydroxyl group in the axial
position due to the anomeric effect (the 9.0 Hz coupling is due
to splitting by OH). However, the diastereomeric anomeric
protons in 50a (see expansion in NMR spectrum in Supporting
Information) have larger coupling constants of 4.9 and 5.5 Hz
(versus 3.9 Hz of 47), which is more consistent with an
equatorial disposition of the aglycone. Fuller and coworkers
determined x-ray structures of triterpene natural product
derivatives containing a morpholine-based glycone with
equatorial substitution at the anomeric position, with reported
coupling constants of 4.1 to 6.8 Hz.38 Ultimately, an x-ray
EXPERIMENTAL SECTION
6
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
General Information. Unless otherwise noted, all reagents
acetate (20). To a solution of enal 18 (49.7 mg, 0.296 mmol)
in DCM (2.7 mL) was added cyclopentadiene 14 (94.6 mg,
176 µmol) in DCM (3 mL), and the mixture was stirred at rt
for 24 h. TLC (10% EtOAc/hexanes) indicated complete
consumption of the starting material, so the mixture was
concentrated and purified on a 10g SiO2 column (30%
1
and solvents, including anhydrous solvents, were purchased
from commercial vendors and used as received. Reactions
were performed in ventilated fume hoods with magnetic
stirring and heated in oil baths, unless otherwise noted.
Reactions were performed in air, unless otherwise noted.
Chilled reactions (below –10 °C) were performed in an
acetone bath in a vacuum dewar, using a Neslab CC 100
immersion cooler. Unless otherwise specified, reactions were
not run under N2 atmosphere. Deionized water was purified by
charcoal filtration and used for reaction workups and in
reactions with water. NMR spectra were recorded on Varian
300 MHz or 400 MHz spectrometers as indicated. Proton and
carbon chemical shifts are reported in parts per million (ppm;
δ) relative to tetramethylsilane (1H δ 0), or CDCl3 (13C δ
77.16), (CD3)2CO (1H δ 2.05, 13C δ 29.84), d6-DMSO (1H δ
2.50, 13C δ 39.5), or CD3OD (1H δ 3.31, 13C δ 49.00). NMR
data are reported as follows: chemical shifts, multiplicity (obs
= obscured, app = apparent, br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, comp =
complex overlapping signals); coupling constant(s) in Hz;
integration. Unless otherwise indicated, NMR data were
collected at 25 °C. Filtration was performed by vacuum using
VWR Grade 413 filter paper, unless otherwise noted.
Analytical thin layer chromatography (TLC) was performed
on Agela Technologies glass plates with 0.20 mm silica gel
with F254 indicator. Visualization was accomplished with UV
light (254 nm) and KMnO4 stain, unless otherwise noted.
Flash chromatography was performed using Biotage SNAP
cartridges filled with 40-60 µm silica gel on Biotage Isolera
automated chromatography systems with photodiode array UV
detectors. Unless otherwise mentioned, columns were loaded
with crude compounds as DCM solutions. Tandem liquid
chromatography/mass spectrometry (LC-MS) was performed
on a Shimadzu LCMS-2020 with autosampler, photodiode
array detector, and single-quadrupole MS with ESI and APCI
dual ionization, using a Peak Scientific nitrogen generator.
Unless otherwise noted, a standard LC-MS method was used
to analyze reactions and reaction products: Phenomenex
Gemini C18 column (100 x 4.6 mm, 3 µm particle size, 110 A
pore size); column temperature 40 °C; 5 µL of sample in
MeOH or CH3CN at a nominal concentration of 1 mg/mL was
injected, and peaks were eluted with a gradient of 25−95%
CH3CN/H2O (both with 0.1% formic acid) over 5 min., then
95% CH3CN/H2O for 2 min. Purity was measured by UV
absorbance at 210 or 254 nm. Preparative liquid
chromatography was performed on a Shimadzu LC-20AP
preparative HPLC with autosampler, dual wavelength
detector, and fraction collector. Samples purified by
preparative HPLC were loaded as DMSO solutions. Chemical
names were generated and select chemical properties were
calculated using either ChemAxon Marvin suite or ChemDraw
Professional 15.1. NMR data were processed using either
MestreNova or ACD/NMR Processor Academic Edition
software. High-resolution mass spectra (HRMS) were
obtained at the University of Cincinnati Environmental
Analysis Service Center (EASC) with an Agilent 6540
Accurate-Mass with Q-TOF. Catalyst 25 was prepared
according to a published protocol.40
2
3
4
5
6
7
8
9
1
DCM/hexanes) to give 20 (64.2 mg, 52%) as a yellow oil. H
NMR (300 MHz, acetone-d6) δ 7.76 – 7.60 (m, 4H), 7.52 –
7.33 (m, 6H), 7.26 (td, J = 9.0, 6.6 Hz, 1H), 7.06 – 6.90 (m,
2H), 6.78 (d, J = 1.7 Hz, 1H), 5.93 (d, J = 1.8 Hz, 1H), 4.77
(qt, J = 14.7, 1.4 Hz, 2H), 3.89 (dd, J = 10.7, 4.4 Hz, 1H), 3.80
(dd, J = 10.7, 4.7 Hz, 1H), 2.83 (s, 1H), 2.74 – 2.61 (comp,
3H), 2.03 (s, 3H), 1.05 (s, 9H), 0.91 (s, 9H), 0.22 (s, 3H), 0.16
(s, 3H). 13C{1H} NMR (75 MHz, acetone-d6) δ 170.7, 144.8,
144.0, 143.9, 136.5, 136.4, 134.2 (d, J = 9.8 Hz), 132.0, 130.9,
130.9, 130.8, 130.7, 128.9, 128.8, 124.55 (t, J = 19.8 Hz),
112.16 (dd, J = 20.9, 3.6 Hz), 107.7, 105.06 (d, J = 25.9 Hz),
104.9, 64.1, 62.4, 50.3, 46.9, 27.4, 26.2, 23.6, 20.8, 20.0, 18.5,
–2.8. Decomposed to give 21 under LC-MS conditions (formic
acid/MeOH).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5-(((Tert-butyldiphenylsilyl)oxy)methyl)-4-(2-(2,4-
difluorophenyl)-3-oxopropyl)-3-oxocyclopent-1-en-1-
yl)methyl acetate (21). To a solution of 20 (9.9 mg, 14 µmol)
in MeOH (1 mL) in a 4 mL vial was added formic acid (50 µL,
1.2 mmol). After 5 min., TLC (10% EtOAc/hexanes) indicated
complete consumption of 21, so the reaction mixture was
concentrated and purified by chromatography on a silica gel
packed pipette (10–20% EtOAc/hexanes) to give aldehyde 21
(1:1 diastereomeric mixture, 6.0 mg, 73%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 1.4 Hz, 1H), 9.58 (t,
J = 1.0 Hz, 1H), 7.66 – 7.49 (comp, 8H), 7.48 – 7.33 (comp,
12H), 7.25 – 7.15 (m, 1H), 7.02 (td, J = 8.5, 6.2 Hz, 1H), 6.89
– 6.74 (comp, 4H), 6.11 (q, J = 1.7 Hz, 1H), 6.06 (q, J = 1.7
Hz, 1H), 5.01 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 17.4 Hz, 1H),
4.83 – 4.73 (m, 2H), 4.27 (dd, J = 9.4, 5.3 Hz, 1H), 3.95 (dd, J
= 8.2, 5.6 Hz, 1H), 3.77 (dd, J = 10.4, 4.0 Hz, 1H), 3.64 (dd, J
= 10.5, 6.2 Hz, 1H), 3.59 (d, J = 5.0 Hz, 3H), 2.73 – 2.58 (m,
3H), 2.38 (ddd, J = 13.9, 9.9, 5.3 Hz, 1H), 2.21 – 2.14 (m, 2H),
2.13 (s, 3H), 2.11 (s, 3H), 2.05 – 1.94 (m, 1H), 1.84 (ddd, J =
14.5, 9.4, 5.6 Hz, 1H), 1.01 (s, 9H), 0.97 (d, J = 2.6 Hz, 9H).
13C{1H} NMR (75 MHz, CDCl3) δ 208.8, 208.5, 199.0, 198.5,
174.5, 172.0 (dd, J = 263.0, 2.6 Hz), 135.7, 135.7, 135.6,
135.6, 132.9, 132.6, 132.6 (dd, J = 18.6, 6.2 Hz), 131.2, 131.1,
130.2, 130.2, 130.2, 129.2 (d, J = 10.6 Hz), 128.0, 112.3 (dd, J
= 21.3, 3.5 Hz), 112.1 (dd, J = 20.9, 4.0 Hz), 111.9, 104.64 (t,
J = 25.7 Hz), 64.0, 63.5, 62.8, 62.5, 51.2, 51.0, 50.2, 49.3,
46.2, 45.5, 30.4, 30.0, 29.9, 26.9, 26.8, 20.8, 20.8, 19.3, 19.3.
HRMS (ESI+): calcd for C34H36F2NaO5Si [M+Na]+ 613.2198;
found 613.2207.
Methyl 1-(acetoxymethyl)-5-((tert-butyldimethylsilyl)oxy)-
7-(((tert-butyldiphenylsilyl)oxy)methyl)-2-
(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate
(23). To a solution of cyclopentadiene 14 (10 mg, 18.7 µmol)
in
DCM
(0.4
mL)
was
added
methyl
2-
(trifluoromethyl)acrylate (22) (4.6 µL, 37.4 µmol) in 1 mL
DCM, and the mixture was stirred at rt for 24 h. TLC indicated
complete consumption of the starting material (20%
EtOAc/hexanes), so the mixture was concentrated and purified
by chromatography on a Pasteur pipette packed with silica gel
(4% EtOAc/hexanes) to give cycloadduct 23 (1:1.4
diastereomeric mixture, 5.2 mg, 40%) as a yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.67 – 7.55 (comp, 6H), 7.46 –
(7a-((Tert-butyldimethylsilyl)oxy)-5-(((tert-
butyldiphenylsilyl)oxy)methyl)-3-(2,4-difluorophenyl)-
4,4a,5,7a-tetrahydrocyclopenta[b]pyran-6-yl)methyl
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
7.32 (comp, 8H), 4.56 – 4.02 (comp, 5H), 3.76 (s, 3H), 3.71 (s, CDCl3) δ 7.73 – 7.58 (comp, 7H), 7.49 – 7.31 (comp, 10H),
1
2
3
4
5
6
7
8
2H), 3.63 (dd, J = 10.2, 5.0 Hz, 1H), 3.51 (dd, J = 10.1, 5.0 Hz,
1H), 2.92 – 2.76 (m, 3H), 2.59 (d, J = 13.0 Hz, 1H), 2.50 (ddd,
J = 21.3, 9.2, 5.0 Hz, 2H), 2.19 (dd, J = 12.9, 3.5 Hz, 1H),
1.91 (d, J = 12.5 Hz, 1H), 1.77 (d, J = 2.0 Hz, 6H), 1.03 (d, J =
4.3 Hz, 18H), 0.93 (d, J = 3.1 Hz, 18H), 0.16 (d, J = 7.6 Hz,
5H), 0.12 (d, J = 13.8 Hz, 4H). 19F NMR (376 MHz, CDCl3) δ
–61.52, –64.24. 13C{1H} NMR (75 MHz, CDCl3) δ 170.7,
170.3, 169.8, 169.0, 162.6, 162.3, 135.7, 135.6, 133.9, 133.8,
133.8, 133.7, 129.7, 127.8, 99.6, 97.4, 62.9, 62.6, 61.8, 61.1,
60.5, 60.0, 59.5, 58.4, 52.9, 52.9, 47.4, 46.4, 34.6, 34.5, 27.0,
25.7, 20.6, 19.4, 18.1, 0.2, –4.5, –4.6. HRMS (ESI+): calcd for
C36H50F3O6Si2 [M+H] 691.3098; found 691.3111.
4.98 (t, J = 2.5 Hz, 1H), 4.93 – 4.87 (m, 1H), 4.80 (s, 1H),
4.71 (s, 1H), 4.65 – 4.57 (m, 1H), 4.57 – 4.49 (m, 2H), 3.90 (d,
J = 10.1 Hz, 1H), 3.73 (d, J = 10.1 Hz, 1H), 3.70 – 3.61 (m,
1H), 3.59 – 3.43 (comp, 4H), 3.35 (s, 2H), 3.24 (s, 3H), 3.09
(ddd, J = 12.0, 5.0, 2.5 Hz, 1H), 2.85 (d, J = 4.3 Hz, 1H), 2.75
(q, J = 5.8, 5.2 Hz, 1H), 2.47 (dd, J = 17.1, 2.1 Hz, 1H), 2.28
(dd, J = 12.3, 4.3 Hz, 1H), 2.23 – 1.96 (comp, 5H), 1.89 (dd, J
= 12.6, 9.4 Hz, 1H), 1.69 (dd, J = 12.5, 5.0 Hz, 1H), 1.05 (s,
6H), 1.03 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ 150.3,
149.5, 135.7, 135.7, 135.7, 135.6, 133.6, 133.5, 133.4, 133.2,
129.9, 129.8, 127.9, 127.8, 127.8, 127.8, 121.5, 121.1, 107.1,
106.6, 96.9, 96.6, 69.4, 66.3, 61.1, 61.1, 55.5, 55.4, 53.1, 52.9,
52.8, 47.6, 38.0, 35.4, 34.9, 34.5, 33.7, 32.4, 26.9, 19.3, 19.3.
HRMS (ESI+): calcd for C29H37NNaO3Si [M+Na]+ 498.2440;
found 498.2452.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,2S,4R)-2-(4-Methoxyphenyl)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ol (32)41 and (1S,4R)-2-
(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]hept-2-
ene (33).42 To a solution of (R)-camphor (219 mg, 1.44
mmol) in THF (7 mL) was added anhydrous cerium(III)
chloride (355 mg, 1.44 mmol). The mixture was sealed under
4-Methoxybenzyl-7-(((tert-
butyldiphenylsilyl)oxy)methyl)-2-cyano-5-
oxobicyclo[2.2.1]heptane-1-carboxylate (42). CrO3 (525
mg, 5.25 mmol) was dissolved in H2O (2 mL). To the solution
was added concentrated H2SO4 (0.45 mL), to give Jones
reagent (2.5 mL). To a solution of alcohol 15 (767 mg, 1.769
mmol) in acetone (20 mL) in a 50 mL round bottom flask at 0
ºC was added Jones reagent (1.77 mL, 4.42 mmol), and the
mixture was stirred for 30 min. at rt. TLC (40%
EtOAc/hexanes) showed complete consumption of the starting
material, so the mixture was quenched with MeOH (5 mL).
Na2SO4 was added and the mixture was filtered through Celite,
and the mother liquor was condensed to a green residue. The
crude was dissolved in DCM (10 mL) and passed through a 10
g silica gel pad, eluting with 80% EtOAc/hexanes. The
resulting eluent was concentrated to give a crude yellow oil,
which was dissolved in acetone (20 mL) in a 50 mL flask. To
this solution was added PMBCl (360 µL, 2.65 mmol), K2CO3
(1.222 g, 8.84 mmol) and TBAI (13.1 mg, 0.0354 mmol). The
mixture was stirred for 24h at rt, after which time LC-MS
indicated incomplete consumption of the starting material.
Additional PMBCl (0.200 mL, 1.47 mmol) was added, and the
mixture was stirred for another 24 h, after which time LC-MS
showed complete conversion to the desired product. The
mixture was filtered through Celite, concentrated, and purified
N2 and stirred for 0.5 h, then 0.5
M
(4-
methoxyphenyl)magnesium bromide in THF (3.2 mL, 1.58
mmol) was added. The resulting yellow solution was stirred
for 0.5 h at rt, then quenched with NH4Cl (5 mL). GC-MS
indicated the organic layer contained a mixture of 32, 33 and
unreacted starting material. The organic layer was separated
and the aqueous layer was extracted with EtOAc (3 x 5 mL).
The combined organics were dried over Na2SO4, filtered,
concentrated, and purified by flash chromatography (25 g SiO2
column, 0–7% EtOAc/hexanes) to give 32 (131 mg, 35%) as a
colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 8.9
Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 2.28 (d, J =
13.8 Hz, 1H), 2.18 (ddd, J = 13.9, 4.2, 3.0 Hz, 1H), 1.89 (t, J =
4.3 Hz, 1H), 1.78 (s, 1H), 1.77 – 1.64 (m, 1H), 1.26 (s, 3H),
1.24 – 1.11 (m, 2H), 0.92 – 0.90 (m, 3H), 0.90 (s, 3H), 0.89 –
0.78 (m, 1H). 33 was also obtained (41 mg, 12%) as a yellow
solid. 1H NMR (CDCl3) δ 7.19 (d, J = 8.9 Hz, 2H), 6.85 (d, J =
8.9 Hz, 2H), 5.90 (d, J = 3.3 Hz, 1H), 3.80 (s, 3H), 2.36 (t, J =
3.5 Hz, 1H), 1.93 (ddt, J = 11.6, 8.7, 3.7 Hz, 1H), 1.70 – 1.61
(m, 1H), 1.33 – 1.22 (m, 1H), 1.13 – 1.05 (comp, 4H), 0.88 (s,
3H), 0.81 (s, 3H).
7-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-
((methoxymethoxy)methyl)-5-
by chromatography on
a 10 g SiO2 column (0–40%
EtOAc/hexanes) to give ester 42 (388 mg, 39% over 3 steps)
as a colorless oil (1:1 diastereomeric mixture). 1H NMR (300
MHz, CDCl3) δ 7.67 – 7.51 (comp, 8H), 7.48 – 7.31 (comp,
12H), 7.19 (dd, J = 14.1, 8.7 Hz, 4H), 6.81 (dd, J = 8.7, 1.8
Hz, 4H), 5.18 – 4.92 (comp, 4H), 3.89 (dd, J = 11.3, 4.5 Hz,
1H), 3.78 (s, 6H), 3.60 (t, J = 6.2 Hz, 2H), 3.55 – 3.46 (m,
1H), 3.04 – 2.83 (comp, 4H), 2.82 – 2.75 (m, 2H), 2.69 – 2.59
(m, 2H), 2.46 (ddd, J = 13.7, 11.8, 4.9 Hz, 1H), 2.40 – 2.33
(m, 1H), 2.28 (dt, J = 13.8, 4.8 Hz, 1H), 2.16 – 2.06 (m, 2H),
1.79 (dd, J = 13.6, 5.4 Hz, 1H), 1.00 (d, J = 4.6 Hz, 18H).
13C{1H} NMR (75 MHz, CDCl3) δ 209.8, 209.7, 169.6, 169.4,
159.9, 135.7, 135.6, 132.6, 132.5, 130.5, 130.2, 130.1, 130.0,
128.8, 128.0, 127.9, 127.0, 127.0, 119.9, 119.2, 114.2, 114.1,
67.7, 60.7, 60.5, 55.6, 55.4, 54.5, 52.4, 51.7, 51.3, 43.8, 39.7,
35.2, 33.9, 29.7, 29.0, 26.8, 19.2. HRMS (ESI+): calcd for
C34H37 NNaO5Si [M+Na]+ 590.2339; found 590.2352.
methylenebicyclo[2.2.1]heptane-2-carbonitrile (40). To a
solution of 15 (110 mg, 0.254 mmol) in CHCl3 (5 mL) was
added dimethoxymethane (224 µL, 2.54 mmol) and P2O5 (500
mg, 1.76 mmol).43 The mixture was sealed under N2 and
stirred for 10 min. TLC (20% EtOAc/hexanes) indicated
complete consumption of the starting material, the mixture
was filtered through Celite and concentrated, and the
intermediate MOM ether was used directly in the next step. To
a solution of methyltriphenylphosphonium bromide (272 mg,
0.762 mmol) in toluene (5 mL) sealed under N2 was added
KHMDS (0.5 M in toluene, 1.52 mL, 0.762 mmol). The
mixture was heated to 90 ºC for 30 min., then the intermediate
MOM ether was added (in toluene, 5 mL). The mixture was
º
stirred at 90 C for 10 min., after which time TLC (40%
EtOAc/hexanes) indicated complete consumption of the
starting material. The mixture was filtered through Celite,
concentrated, and loaded as a toluene solution onto a 10 g
SiO2 column, and purified by chromatography (5–10%
EtOAc/hexanes) to give alkene 40 (1:0.7 diastereomeric
4-Methoxybenzyl-7-(((tert-
butyldiphenylsilyl)oxy)methyl)-2-cyano-5-
methylenebicyclo[2.2.1]heptane-1-carboxylate (43). To a
solution of methyltriphenylphosphonium bromide (18.9 mg,
1
mixture, 75 mg, 62%) as a colorless oil. H NMR (300 MHz,
8
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
0.0528 mmol) in dry toluene (1 mL) sealed under N2
NMR (101 MHz, CDCl3) δ 172.5, 159.9, 147.1, 134.9, 130.5,
1
2
3
4
5
6
7
8
atmosphere was added KHMDS (0.5 M in toluene, 106 µL,
0.0528 mmol), and the mixture was heated at 90 ºC for 30 min.
To the reaction was added 42 (5.0 mg, 8.8 µmol) in toluene
(0.5 mL), and the mixture was stirred for 10 min. at the same
temperature. TLC (20% EtOAc/hexanes) indicated complete
consumption of the starting material, so the mixture was
filtered through Celite and concentrated, then purified by
chromatography on a silica gel packed pipette (5–10%
EtOAc/hexanes) to give alkene 43 (4.7 mg, 94%) as a
colorless oil (1:1 diastereomeric mixture). 1H NMR (300
MHz, CDCl3) δ 7.68 – 7.53 (comp, 8H), 7.48 – 7.30 (comp,
12H), 7.17 (dd, J = 11.9, 8.7 Hz, 4H), 6.87 – 6.74 (comp, 4H),
5.14 – 4.90 (m, 6H), 4.82 (s, 1H), 4.78 (s, 1H), 3.99 (dd, J =
10.2, 4.6 Hz, 1H), 3.79 (d, J = 1.1 Hz, 6H), 3.66 (dd, J = 10.6,
6.2 Hz, 1H), 3.56 – 3.35 (m, 3H), 3.06 (d, J = 4.2 Hz, 1H),
2.87 (d, J = 4.1 Hz, 1H), 2.83 (dd, J = 9.3, 5.1 Hz, 1H), 2.73
(s, 2H), 2.59 (dd, J = 10.3, 4.6 Hz, 1H), 2.47 (d, J = 17.1 Hz,
1H), 2.35 (dd, J = 12.3, 4.2 Hz, 1H), 2.30 – 2.11 (m, 3H), 1.97
(dd, J = 12.6, 9.3 Hz, 1H), 1.69 (dd, J = 12.5, 5.0 Hz, 1H),
1.03 (s, 18H). 13C{1H} NMR (75 MHz, CDCl3) δ 171.1, 171.0,
159.9, 148.3, 147.9, 135.8, 135.7, 133.6, 133.4, 130.4, 130.2,
130.0, 129.9, 129.8, 127.9, 127.9, 127.8, 127.5, 127.5, 121.1,
120.6, 114.2, 114.1, 107.8, 67.3, 61.1, 60.9, 56.9, 56.5, 56.5,
55.5, 53.0, 48.4, 47.5, 38.3, 36.0, 35.5, 34.8, 34.5, 33.5, 29.9,
27.0, 19.5, 19.4. HRMS (ESI+): calcd for C35H39NNaO4Si
[M+Na]+ 588.2546; found 588.2564.
130.4, 129.7, 128.7, 127.8, 127.2, 123.4, 114.1, 114.1, 114.1,
114.0, 107.9, 67.4, 60.3, 60.2, 55.4, 50.8, 47.5, 45.0, 41.5,
36.2, 24.5. HRMS (ESI+): calcd for C20H23NNaO4 [M+Na]+
364.1525; found 364.1530.
4-Methoxybenzyl-2-cyano-2-ethyl-7-(hydroxymethyl)-
5-methylenebicyclo[2.2.1]heptane-1-carboxylate (45b).
43 (20.0 mg, 33.7 µmol) was treated following the procedure
of 45a using EtI instead of MeI. 45b was obtained in 4.6 mg,
1
38% yield. H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 8.8
9
Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.22 (d, J = 11.9 Hz, 1H),
5.13 (d, J = 11.9 Hz, 1H), 5.02 (t, J = 2.6 Hz, 1H), 4.86 (t, J =
2.2 Hz, 1H), 3.81 (d, J = 0.5 Hz, 3H), 3.70 (dd, J = 11.7, 7.4
Hz, 1H), 3.60 – 3.43 (m, 1H), 3.12 – 2.94 (m, 2H), 2.70 – 2.52
(m, 2H), 2.31 (t, J = 6.4 Hz, 1H), 1.97 – 1.81 (m, 2H), 1.50 –
1.34 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ 172.7, 159.9, 147.2, 130.4, 127.2, 122.2,
114.1, 107.9, 67.3, 60.7, 60.3, 55.4, 51.3, 47.8, 47.7, 41.8,
36.6, 29.3, 8.9. HRMS (ESI+): calcd for C21H25NNaO4
[M+Na]+ 378.1681; found 378.1687.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methoxybenzyl-2-benzyl-2-cyano-7-(hydroxymethyl)-
5-methylenebicyclo[2.2.1]heptane-1-carboxylate (45c).
43 (20.0 mg, 33.7 µmol) was treated following the procedure
of 45a using BnBr instead of MeI. 45c was obtained in 12 mg,
85% yield. 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.27 (comp,
5H), 7.23 – 7.13 (m, 2H), 6.96 – 6.82 (m, 2H), 5.28 (d, J =
11.8 Hz, 1H), 5.11 (d, J = 11.8 Hz, 1H), 4.97 (t, J = 2.6 Hz,
1H), 4.84 (t, J = 2.1 Hz, 1H), 3.77 (d, J = 0.9 Hz, 4H), 3.63 –
3.49 (m, 1H), 3.18 (s, 1H), 3.09 (d, J = 17.7 Hz, 1H), 2.75 –
2.55 (comp, 4H), 2.46 (t, J = 6.4 Hz, 1H), 2.07 (dd, J = 13.1,
4.3 Hz, 1H), 1.56 (d, J = 13.1 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3) δ 172.5, 160.0, 147.0, 134.2, 130.6, 130.5,
128.6, 127.7, 127.2, 122.7, 114.2, 107.9, 67.4, 61.0, 60.3,
55.4, 51.4, 47.7, 47.1, 41.2, 41.0, 36.5. HRMS (ESI+): calcd
for C26H27NNaO4 [M+Na]+ 440.1838; found 440.1841.
4-Methoxybenzyl-2-cyano-7-(hydroxymethyl)-2-
methyl-5-methylenebicyclo[2.2.1]heptane-1-carboxylate
(45a). To a solution of 43 (57.3 mg, 101 µmol) in toluene (1
mL), sealed under N2, was added iodomethane (63.0 µL, 1.01
mmol), followed by KHMDS (0.5 M in toluene, 0.61 mL, 0.30
mmol). The mixture was stirred at rt for 3 h, after which time
TLC (10% EtOAc/hexanes) indicated complete consumption
of the starting material. The mixture was quenched with
saturated aqueous NH4Cl (1 mL), the organic phase was
separated, and the aqueous phase was extracted with EtOAc (3
x 1 mL). The combined organics were dried over Na2SO4,
filtered, concentrated, and used directly in the next step. To a
solution of this intermediate (44a) (49.0 mg, 84.5 µmol) in
THF (1 mL) was added a solution of TBAF (1.00 M in THF,
127 µL, 0.127 mmol) at 0 ºC, and the mixture was removed
from the ice bath and stirred at rt for 2 h. LC-MS indicated
that some of the desired PMB ester product had been
hydrolyzed to the carboxylic acid. The mixture was
concentrated, then 1 N aqueous HCl (2 mL) was added, and
the solution was extracted with EtOAc (3 x 2 mL). The
combined organics were dried over Na2SO4, concentrated, and
re-dissolved in acetone (3 mL). To the solution was added
PMBCl (9.2 µL, 0.0676 mmol), K2CO3 (14.0 mg, 0.101
mmol), and 5 to 10 crystals of TBAI, and the mixture was
stirred for 24 h at rt. TLC (100% EtOAc) indicated that the
carboxylic acid was consumed. The mixture was filtered
6-(2-Chloroallyl)-9-oxa-6-azaspiro[4.5]decan-8-ol (47).
44
To a solution of (1-aminocyclopentyl)methanol (3.10 g, 26.9
mmol)
in EtOH
(100
mL)
was
added
2,2-
dimethoxyacetaldehyde (60% in water, 4.47 mL, 29.6 mmol).
The mixture was stirred at rt for 18 h, after which time crude
NMR indicated complete conversion to the intermediate
imine. The mixture was quenched with 50 mL 1 N aq. NaOH
followed by 50 mL H2O, then extracted with DCM (3 x 100
mL). The combined organics were dried over Na2SO4, filtered,
concentrated, and redissolved in Et2O (100 mL) in a flask
sealed under N2. LiAlH4 (1.02 g, 26.9 mmol) was added, and
the mixture was stirred at rt for 30 min. The reaction was
quenched by adding EtOAc (50 mL) and saturated aqueous
Rochelle's salt (100 mL). The organic phase was separated and
the aqueous phase was extracted with EtOAc (3 x 100 mL).
The combined organics were washed with brine (100 mL),
dried over Na2SO4, filtered, and concentrated to give a
colorless oil. The intermediate amine was dissolved in EtOH
(60 mL) and 2,3-dichloroprop-1-ene (1.05 mL, 11.4 mol),
NaHCO3 (2.00 g, 23.8 mol) and NaI (114 mg, 0.763 mmol)
through
Celite
and
concentrated,
then
purified
by chromatography on a silica gel-packed Pasteur pipette,
(30–40% EtOAc/hexanes), to give 45a (15.9 mg, 55%) as a
1
colorless oil. H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 8.8
were added. The mixture was heated to 80 °C under N2
Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.26 (d, J = 11.9 Hz, 1H),
5.11 (d, J = 11.9 Hz, 1H), 5.01 (t, J = 2.6 Hz, 1H), 4.87 (t, J =
2.2 Hz, 1H), 3.81 (s, 3H), 3.76 – 3.63 (m, 1H), 3.60 – 3.44 (m,
1H), 3.10 (d, J = 8.4 Hz, 1H), 2.98 (dq, J = 17.5, 2.0 Hz, 1H),
2.68 – 2.54 (m, 2H), 2.32 (t, J = 6.4 Hz, 1H), 2.12 – 1.97 (m,
1H), 1.84 (dd, J = 12.4, 3.6 Hz, 1H), 1.25 (s, 3H). 13C{1H}
atmosphere for 18 h, after which time crude NMR indicated
about 10% conversion to the desired product. Additional NaI
(1.14 g, 7.63 mmol), NaHCO3 (2.00 g, 23.8 mol), 5 to 10
crystals of TBAI and 2,3-dichloroprop-1-ene (0.1 mL, 1.09
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
7-(((-6-(2-Chloroallyl)-9-oxa-6-azaspiro[4.5]decan-8-
yl)oxy)methyl)-2-cyano-2-methyl-5-
methylenebicyclo[2.2.1]heptane-1-carboxylic acid (50a).
To a solution of 45a (18.0 mg, 52.7 µmol) and PhNTf2 (20.7
mg, 58.0 µmol) in Et2O (1 mL), sealed under N2 and at –50
mmol) were added. The mixture was refluxed at 87 °C under
N2 atmosphere for 24 h, after which time crude NMR
indicated about 80% conversion. The mixture was heated to
1
2
3
4
5
6
7
8
100 °C for another 2 h, then filtered through Celite and
concentrated to a yellow oil, which was dissolved in conc. HCl
(60 mL). The mixture was then refluxed at 105 °C under N2
°C, was added KHMDS (0.5 M in toluene, 211 µL, 105 µmol),
and the mixture was stirred at the same temperature for 10
min. TLC indicated complete consumption of the starting
material (40% EtOAc/hexane). The mixture was quenched
with aq. NH4Cl (1 mL) at the same temperature, then extracted
with EtOAc (3 x 1 mL). The combined organics were dried
over Na2SO4, filtered, and concentrated to give the crude
triflate, which was used directly in the next step. To a
solution of 47 (6.1 mg, 26 µmol) in DMF (0.2 mL) was added
atmosphere for 2 h, the solvent was evaporated, and 6 N
NaOH (30 mL) was added. The mixture was extracted
with EtOAc (3 x 30 mL), and the combined organics were
washed with brine and dried over Na2SO4, filtered,
concentrated, and purified by chromatography (10–40%
EtOAc/hexanes) to give 47 (390 mg, 22% overall yield) as a
colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.40 (app q, J
= 1.2 Hz, 1H), 5.30 (app q, J = 1.0 Hz, 1H), 4.94 (ddd, J = 9.0,
3.9, 2.2 Hz, 1H), 3.82 (d, J = 9.1 Hz, 1H), 3.69 (dd, J = 11.4,
1.2 Hz, 1H), 3.25 (dd, J = 11.4, 0.7 Hz, 1H), 3.16 (dt, J = 15.0,
1.3 Hz, 1H), 2.96 (d, J = 14.8 Hz, 1H), 2.69 (dd, J = 11.6, 2.2
Hz, 1H), 2.46 (dd, J = 11.6, 3.9 Hz, 1H), 1.86 – 1.30 (comp,
8H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.2, 114.2, 91.5,
69.4, 66.0, 56.4, 52.8, 31.7, 28.4, 25.9, 25.8. HRMS (ESI+):
calcd for C11H19ClNO2 [M+H] 232.1104; found 232.1106.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NaH (60% in mineral oil, 3.4 mg, 88 µmol) at 0 °C. The
mixture was stirred at rt for 15 min., then a solution of the
crude triflate in DMF (0.1 mL) was added. The mixture was
stirred at rt for 1 h, after which time LC-MS indicated
complete consumption of the starting material. The reaction
was quenched with saturated aqueous NH4Cl (3 mL)
and extracted with EtOAc (3 x 3 mL). The combined organics
were washed with brine, dried over Na2SO4, filtered,
concentrated, and purified by preparative HPLC to give 50a
(3.3 mg, 43%) as a colorless oil (1.0 : 1.1 diastereomeric
mixture). 1H NMR (300 MHz, CDCl3) δ 5.61 – 5.50 (m, 2H),
5.31 (d, J = 1.2 Hz, 2H), 5.11 – 5.02 (m, 2H), 4.94 (s, 2H),
4.59 (dd, J = 4.9, 2.7 Hz, 1H), 4.54 (dd, J = 5.5, 2.7 Hz, 1H),
4.08 (dd, J = 9.7, 5.7 Hz, 1H), 3.68 (d, J = 7.8 Hz, 2H), 3.59
(dd, J = 11.1, 3.8 Hz, 2H), 3.38 – 3.17 (m, 3H), 3.04 (d, J =
5.5 Hz, 5H), 2.97 (s, 1H), 2.84 (d, J = 3.9 Hz, 1H), 2.79 (d, J =
4.0 Hz, 1H), 2.72 – 2.64 (comp, 3H), 2.60 (d, J = 2.7 Hz, 1H),
2.44 (ddd, J = 11.7, 9.3, 5.1 Hz, 2H), 2.16 – 2.30 (comp, 12H,
presumably obs w/ H2O), 2.13 (dd, J = 12.6, 2.3 Hz, 2H), 1.89
(dt, J = 12.7, 3.8 Hz, 2H), 1.59 (d, J = 10.5 Hz, 6H), 1.51 (d, J
= 1.0 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.4,
172.4, 147.2, 147.1, 140.1, 140.0, 123.4, 123.3, 113.3, 113.1,
108.6, 108.5, 98.7, 98.2, 70.8, 70.3, 68.1, 65.6, 65.5, 65.5,
65.3, 59.5, 59.5, 57.0, 56.9, 52.1, 52.0, 48.2, 48.1, 47.7, 47.6,
44.9, 44.9, 41.9, 41.8, 41.0, 36.2, 36.2, 29.9, 29.8, 25.8, 25.7,
25.0, 25.0, 22.9, 14.3. HRMS (ESI+): calcd for C23H32ClN2O4
[M+H] 435.2051; found 435.2060; HPLC (Phenomenex
2-Hydroxy-4-(4-methoxybenzyl)morpholin-3-one
(48).34 A solution of 50 wt% aqueous glyoxylic acid (9.14 g,
99.3 mmol) in THF (20 mL) was heated to reflux, then 2-(4-
45
methoxybenzylamino)ethanol
(6.00 g, 33.1 mmol) was
added over 30 min, and the reaction was refluxed for another 2
h. THF was distilled off under atmospheric pressure while
maintaining a constant volume by simultaneous addition of
water (20 mL). The mixture was cooled to rt, then placed in an
ice bath for 30 min., where the product crystallized. The solids
were filtered with a Buchner funnel, washed with water, and
º
then dried under vacuum at 60 C for 24 h to give 48 (3.6 g,
46%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.20
(d, J = 7.0 Hz, 2H), 6.86 (d, J = 7.0 Hz, 2H), 5.34 (s, 1H), 4.91
(s, 1H), 4.65 (d, J = 14.4 Hz, 1H), 4.44 (d, J = 14.4 Hz, 1H),
4.30 – 4.18 (m, 1H), 3.80 (s, 3H), 3.78 – 3.74 (m, 1H), 3.42
(td, J = 11.2, 10.6, 3.9 Hz, 1H), 3.11 (d, J = 12.4 Hz, 1H).
2-Cyano-7-(((-4-(4-methoxybenzyl)-3-oxomorpholin-2-
yl)oxy)methyl)-2-methyl-5-
methylenebicyclo[2.2.1]heptane-1-carboxylic acid (49).
45a (6.0 mg, 17.6 µmol) was treated following the same
procedure of 50a using 48 instead of 47, 49 was obtained in
1.5 mg, 19% yield, as a diastereomeric mixture. 1H NMR (400
MHz, CD3OD) δ 7.18 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1
Hz, 2H), 5.10 – 4.95 (m, 1H), 4.94 – 4.80 (m, 1H), 4.63 (t, J =
15.7 Hz, 1H), 4.37 (t, J = 16.0 Hz, 1H), 4.24 – 3.89 (m, 2H),
3.72 – 3.60 (m, 1H), 3.42 (td, J = 12.4, 11.7, 4.8 Hz, 1H), 3.09
(d, J = 12.6 Hz, 1H), 2.93 – 2.75 (m, 2H), 2.44 (d, J = 17.8 Hz,
1H), 2.31 (d, J = 9.9 Hz, 1H), 2.03 – 1.82 (m, 2H), 1.58 (s,
0H), 1.45 (s, 3H), 1.36 – 1.13 (comp, 5H). 13C{1H} NMR (151
MHz, CD3OD) δ 174.1, 174.0, 166.3, 166.2, 160.9, 160.9,
150.0, 150.0, 130.7, 130.6, 129.2, 124.8, 124.8, 115.2, 115.1,
108.4, 108.2, 97.9, 97.0, 91.7, 67.8, 67.6, 67.0, 60.8, 57.9,
57.9, 50.0, 49.7, 46.6, 46.4, 46.1, 45.9, 42.6, 37.3, 33.1, 30.6,
30.5, 30.3, 30.2, 28.1, 26.9, 25.1, 25.0, 23.8. HRMS (ESI+):
calcd for C24H28N2NaO6 [M+Na]+ 463.1845; found 463.1855,
HPLC (Phenomenex Gemini C18) (25% (0-1.5 min.) - 95%
(3.5-10 min), MeCN/H2O; flow rate, 1.0 mL/min). RT= 8.10
min.
Gemini C18) (25% (0-1.5 min.)
- 95% (3.5-10 min),
MeCN/H2O; flow rate, 1.0 mL/min). RT= 7.30 min.
7-(((-6-(2-Chloroallyl)-9-oxa-6-azaspiro[4.5]decan-8-
yl)oxy)methyl)-2-cyano-2-ethyl-5-
methylenebicyclo[2.2.1]heptane-1-carboxylic acid (50b).
Following the same procedure of 50a using 45b (5.6 mg, 16
µmol) instead of 45a, 50b was obtained (1.5 mg, 20%) as a
diastereomeric mixture (1.0 : 1.1). 1H NMR (400 MHz,
CDCl3) δ 5.60 – 5.52 (m, 2H), 5.30 (s, 2H), 5.10 – 5.05 (m,
2H), 4.94 (s, 2H), 4.61 – 4.56 (m, 1H), 4.54 (dd, J = 5.5, 2.7
Hz, 1H), 4.08 (dd, J = 9.7, 5.5 Hz, 1H), 3.81 (d, J = 1.0 Hz,
1H), 3.68 (d, J = 7.0 Hz, 2H), 3.58 (dd, J = 11.0, 4.5 Hz, 2H),
3.32 (t, J = 9.2 Hz, 1H), 3.23 (dd, J = 16.4, 11.1 Hz, 2H), 3.13
– 2.96 (comp, 6H), 2.86 (s, 1H), 2.80 (s, 1H), 2.71 – 2.56 (m,
2H), 2.49 – 2.35 (comp, 4H), 2.07 – 1.97 (m, 1H), 1.95 (t, J =
3.1 Hz, 5H), 1.92 – 1.78 (m, 2H), 1.69 – 1.45 (comp, 16H,
presumably obs w/ H2O), 1.28 (s, 1H), 1.15 – 1.04 (m, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 173.0, 147.2, 147.2,
140.1, 140.1, 133.8, 114.1, 113.3, 113.1, 108.6, 108.5, 98.8,
98.1, 76.9, 70.8, 70.2, 65.7, 65.5, 65.5, 65.3, 57.0, 56.9, 52.1,
10
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
º
52.0, 48.6, 48.0, 47.8, 47.8, 41.7, 41.6, 40.9, 37.1, 36.7, 36.7,
78 C was added TMSCN (10.6 µL, 84.9 µmol), followed by
1
2
3
4
5
6
7
8
36.1, 32.1, 29.9, 29.8, 29.5, 29.5, 27.4, 25.8, 25.8, 25.8, 25.7,
22.9, 14.3. HRMS (ESI+): calcd for C24H34ClN2O4 [M+H]
449.2207; found 449.2225; HPLC (Phenomenex Gemini C18)
(25% (0-1.5 min.) - 95% (3.5-10 min), MeCN/H2O; flow rate,
1.0 mL/min). RT= 7.06 min.
the addition of boron trifluoride etherate (8.8 µL, 72 µmol),
which caused the colorless solution to turn yellow. The
mixture was stirred at –78 C for 15 min., then warmed to rt.
º
The reaction was stirred for another 15 min., then it was
quenched with sat. aq. NaHCO3 (1 mL). The organic phase
was separated and the aqueous phase was extracted with DCM
(3 x 1 mL). The combined organics were dried over Na2SO4,
2-Benzyl-7-(((-6-(2-chloroallyl)-9-oxa-6-
azaspiro[4.5]decan-8-yl)oxy)methyl)-2-cyano-5-
methylenebicyclo[2.2.1]heptane-1-carboxylic acid (50c).
Following the same procedure of 50a using 45c (7.8 mg, 19
µmol) instead of 45a, 50c was obtained (1.9 mg, 21%) as a
1
filtered, and concentrated prior to to GC-MS and H NMR
analysis.
9
Alternatively, PhCF3 (0.5 mL) was sealed under N2, cooled
to –20 ºC, and TfOH (18.8 µL, 0.21 mmol) and TMSCN (25.8
µL, 0.21 mmol) were added. After 5 min., 33 (10 mg, 0.04
mmol) in PhCF3 (0.5 mL) was added dropwise at the same
temperature. The mixture was allowed to warm to rt and
stirred for 0.5 h. The reaction was quenched with aqueous
NaOH (1 M, 1 mL), extracted with ethyl acetate (3 x 1 mL),
dried over Na2SO4, filtered, and concentrated prior to GC-MS
and 1H NMR analysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
diastereomeric mixture (1 : 1.0). H NMR (400 MHz, CDCl3)
δ 7.38 – 7.27 (comp, 10H), 5.57 (s, 1H), 5.53 (s, 1H), 5.30 (s,
2H), 5.01 (d, J = 7.5 Hz, 2H), 4.89 (s, 2H), 4.64 – 4.58 (m,
1H), 4.57 – 4.50 (m, 1H), 4.25 – 4.08 (m, 1H), 3.70 (dd, J =
20.1, 11.3 Hz, 2H), 3.59 (t, J = 10.7 Hz, 2H), 3.32 (t, J = 9.0
Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 3.20 (dd, J = 12.3, 6.3 Hz,
2H), 3.14 – 2.96 (comp, 6H), 2.84 (s, 1H), 2.77 (s, 1H), 2.72
(d, J = 12.0 Hz, 1H), 2.69 – 2.63 (m, 2H), 2.62 (d, J = 0.7 Hz,
1H), 2.45 (ddd, J = 16.5, 12.8, 7.4 Hz, 5H), 2.14 – 2.02 (m,
2H), 1.57 (comp, 20H, presumably obs w/ H2O). HRMS
(ESI+): calcd for C29H35ClN2O4 [M+H] 511.2364; found
511.2370; HPLC (Phenomenex Gemini C18) (25% (0-1.5 min.)
- 95% (3.5-10 min), MeCN/H2O; flow rate, 1.0 mL/min). RT=
8.27 min.
General procedure for aryl/alkylation of secondary
nitrile 40 (Table 4). To a solution of 40 (2.5 mg, 5.3 µmol) in
the indicated solvent (0.5 mL) sealed under N2 was added the
indicated amount of electrophile. KHMDS (0.5 M in toluene,
52.6 µL, 0.026 mmol) was then added. The mixture was
heated at the indicated temperature for the indicated time. The
reaction was worked up by washing with 1 N HCl (0.5 mL)
and extracting with EtOAc (3 x 0.5 mL). The combined
organics were dried over Na2SO4, filtered, and concentrated to
give a crude product which was dissolved in CDCl3 containing
pentachloroethane (5.26 µmol), prior to 1H NMR analysis.
General procedure for Diels-Alder reaction using 22
(Table 1). A solution of the indicated amount of Lewis acid
and methyl 2-(trifluoromethyl)acrylate (2.3 µL, 18.7 µmol) in
the indicated solvent (0.5 mL) was sealed under N2 and cooled
º
to –78 C. 14 (5.0 mg, 9.4 µmol) in the indicated solvent (0.2
ASSOCIATED CONTENT
mL) was then added by syringe, and the mixture was stirred
º
1H, 13C, COSY, and NOESY NMR spectra and LC-MS traces of
select compounds. The Supporting Information is available free of
charge on the ACS Publications website.
and gradually warmed up to –30 C over 1 h. In an aluminum
foil wrapped Dewar flask, the mixture was stirred for 24 h at rt.
The mixture was filtered through a PTFE syringe filter,
concentrated, and dissolved in 0.6 mL CDCl3 containing
pentachloroethane (1.1 µL, 9.4 umol). 1H and 19F NMR
analysis was then conducted.
AUTHOR INFORMATION
Corresponding Author
Representative procedure for organocatalytic Diels-
*Email: christopher.dockendorff@mu.edu
Tel.: +1-414-288-1617
ORCID: Chris Dockendorff: 0000-0002-4092-5636
Alder reaction using cyclopentanones (Table 2). To a
40
solution of 25 in toluene (0.2 M, 0.36 mL) and propionic
acid (5.4 µL, 0.07 mmol), was added cyclopent-2-en-1-one (20
µL, 0.24 mmol). (E)-4-phenylbut-3-en-2-one (17.5 mg, 0.12
mmol) was added, and the mixture was sealed under N2 and
Author Contributions
º
Conceived the project: C.D. Designed compounds and
synthetic routes: C.D., Y.W. Tested reactions, synthesized
compounds, characterized products: Y.W. Wrote and edited
the manuscript: Y.W., C.D. Prepared the Supporting Info:
Y.W.
heated to 60 C The experiments were monitored by GC-MS
after 24 h.
General procedure for double Michael addition (Table
3). 24a or 24b (14.0 µmol) was sealed under N2, dissolved in
º
THF (0.5 mL), and cooled to 0 C. LDA (1.37 M in heptane,
10.2 µL, 14.0 µmol) was added, and HMPA (2.4 µL, 14 µmol)
Funding Sources
º
was optionally added. The mixture was cooled to –78 C and
We thank Marquette University for startup funding. This
work utilized NIAID’s suite of preclinical services for in
vitro assessment (Contract No. HHSN272201100018I).
the indicated amount of Michael acceptor in THF (0.5 mL)
was added by syringe. The mixture was stirred for 2 h, then
warmed up to rt and stirred for another 22 h. The reaction was
quenched with saturated NH4Cl solution (1 mL) and extracted
with EtOAc (3 x 1 mL). The combined organics were dried
Notes
1
A patent application including this work has been
submitted. A preliminary version of this manuscript was
submitted to the preprint server ChemRxiv.46
over Na2SO4, filtered, and concentrated prior to H NMR and
LC-MS analyses.
Attempted cyanation of camphor-derived alcohol 32
and alkene 33 (Scheme 4). To a solution of 32 (17.4 mg,
66.8 µmol) in DCM (0.7 mL) sealed under N2 and cooled to –
ACKNOWLEDGMENT
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
(16) Towle, M. J.; Salvato, K. A.; Budrow, J.; Wels, B. F.;
We thank Dr. Michael Serrano-Wu (3 Point Bio) for helpful
advice; Dr. Sheng Cai (Marquette University) for assistance with
LC-MS and NMR experiments; Prof. K. A. Jørgensen for advice
regarding organocatalytic Diels-Alder reactions; and ACD Labs
and ChemAxon Inc. for providing NMR processing and
prediction software. We also thank Dr. Nathan Wiederhold
(Fungus Testing Laboratory, University of Texas Health Science
Center at San Antonio) for antifungal assays.
Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Zheng, W.; Seletsky, B. M.;
Palme, M. H.; Habgood, G. J.; Singer, L. A.; Dipietro, L. V.; Wang,
Y.; Chen, J. J.; Quincy, D. A.; Davis, A.; Yoshimatsu, K.; Kishi, Y.;
Yu, M. J.; Littlefield, B. A. In Vitro and in Vivo Anticancer Activities
of Synthetic Macrocyclic Ketone Analogues of Halichondrin B.
Cancer Res. 2001, 61, 1013–1021.
(17) Cuevas, J. C.; Lavandera, J. L.; Martos, J. L. Design and
Synthesis of Simplified Sordaricin Derivatives as Inhibitors of Fungal
Protein Synthesis. Bioorg. Med. Chem. Lett. 1999, 9, 103–108.
(18) Tse, B.; Balkovec, J. M.; Blazey, C. M.; Hsu, M. J.; Nielsen,
J.; Schmatz, D. Alkyl Side-Chain Derivatives of Sordaricin as Potent
Antifungal Agents Against Yeast. Bioorg. Med. Chem. Lett. 1998, 8,
2269–2272.
(19) Jørgensen, R.; Ortiz, P. A.; Carr-Schmid, A.; Nissen, P.;
Kinzy, T. G.; Andersen, G. R. Two Crystal Structures Demonstrate
Large Conformational Changes in the Eukaryotic Ribosomal
Translocase. Nat. Struct. Biol. 2003, 10, 379–385.
(20) Søe, R.; Mosley, R. T.; Justice, M.; Nielsen-Kahn, J.; Shastry,
M.; Merrill, A. R.; Andersen, G. R. Sordarin Derivatives Induce a
Novel Conformation of the Yeast Ribosome Translocation Factor
eEF2. J. Biol. Chem. 2007, 282, 657–666.
1
2
3
4
5
6
7
8
REFERENCES
9
(1) Hahn-Ast, C.; Glasmacher, A.; Mückter, S.; Schmitz, A.;
Kraemer, A.; Marklein, G.; Brossart, P.; Lilienfeld-Toal, von, M.
Overall Survival and Fungal Infection-Related Mortality in Patients
with Invasive Fungal Infection and Neutropenia After
Myelosuppressive Chemotherapy in a Tertiary Care Centre From
1995 to 2006. Journal of Antimicrobial Chemotherapy 2010, 65, 761–
768.
(2) Brown, G. D.; Denning, D. W.; Gow, N. A. R.; Levitz, S. M.;
Netea, M. G.; White, T. C. Hidden Killers: Human Fungal Infections.
Sci. Transl. Med. 2012, 4, 165rv13.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Wiederhold, N. P. Antifungal Resistance: Current Trends and
Future Strategies to Combat. Infect. Drug Resist. 2017, 10, 249–259.
(4) Perfect, J. R. The Antifungal Pipeline: a Reality Check. Nat.
Rev. Drug Discovery 2017, 16, 603–616.
(5) Sigg, H. P.; Stoll, C. Antibiotic SL 2266. U.S. 3,432,598;
Mar. 11, 1969.
(6) Hauser, D.; Sigg, H. P. Isolierung Und Abbau Von Sordarin.
1. Mitteilung Über Sordarin. Helv. Chim. Acta 1971, 54, 1178–1190.
(7) Herreros, E.; Almela, M. J.; Lozano, S.; Gomez De Las
Heras, F.; Gargallo-Viola, D. Antifungal Activities and Cytotoxicity
Studies of Six New Azasordarins. Antimicrob. Agents Chemother.
2001, 45, 3132–3139.
(8) Serrano-Wu, M. H.; Laurent, D. R. S.; Carroll, T. M.; Dodier,
M.; Gao, Q.; Gill, P.; Quesnelle, C.; Marinier, A.; Mazzucco, C. E.;
Regueiro-Ren, A.; Stickle, T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng,
M.; Zoeckler, M. E.; Vyas, D. M.; Balasubramanian, B. N.
Identification of a Broad-Spectrum Azasordarin with Improved
Pharmacokinetic Properties. Bioorg. Med. Chem. Lett. 2003, 13,
1419–1423.
(9) Justice, M. C.; Hsu, M. J.; Tse, B.; Ku, T.; Balkovec, J.;
Schmatz, D.; Nielsen, J. Elongation Factor 2 as a Novel Target for
Selective Inhibition of Fungal Protein Synthesis. J. Biol. Chem. 1998,
273, 3148–3151.
(10) Dominguez, J. M.; Martín, J. J. Identification of Elongation
Factor 2 as the Essential Protein Targeted by Sordarins in Candida
Albicans. Antimicrob. Agents and Chemother. 1998, 42, 2279–2283.
(11) Tully, T. P.; Bergum, J. S.; Schwarz, S. R.; Durand, S. C.;
Howell, J. M.; Patel, R. N.; Cino, P. M. Improvement of Sordarin
Production Through Process Optimization: Combining Traditional
Approaches with DOE. J. Ind. Microbiol. Biotechnol. 2007, 34, 193–
202.
(12) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H.
Function-Oriented Synthesis, Step Economy, and Drug Design. Acc.
Chem. Res. 2008, 41, 40–49.
(13) Janssen, P. A. J.; Gardocki, J. F. Method for Producing
Analgesia. U.S. 3,141,823; Jul. 21, 1964.
(21) Wu, Y.; Dockendorff, C. Synthesis of a Novel Bicyclic
Scaffold Inspired by the Antifungal Natural Product Sordarin.
Tetrahedron Lett. 2018, 59, 3373–3376.
(22) McLean, S.; Haynes, P. The Rearrangement of Substituted
Cyclopentadienes. Tetrahedron Lett. 1964, 5, 2385–2390.
(23) Hudon, J.; Cernak, T. A.; Ashenhurst, J. A.; Gleason, J. L.
Stable 5-Substituted Cyclopentadienes for the Diels-Alder
Cycloaddition and Their Application to the Synthesis of Palau'amine.
Angew. Chem. Int. Ed. 2008, 47, 8885–8888.
(24) Mose, R.; Jensen, M. E.; Preegel, G.; Jørgensen, K. A. Direct
Access to Multifunctionalized Norcamphor Scaffolds by Asymmetric
Organocatalytic Diels-Alder Reactions. Angew. Chem. Int. Ed. 2015,
54, 13630–13634.
(25) Davies, H. M. L.; Dai, X. Lewis Acid-Catalyzed Tandem
Diels−Alder Reaction/Retro-Claisen Rearrangement as an Equivalent
of the Inverse Electron Demand Hetero Diels−Alder Reaction. J. Org.
Chem. 2005, 70, 6680–6684.
(26) Boeckman, R. K.; Flann, C. J.; Poss, K. M. Synthetic and
Mechanistic Studies of the Retro-Claisen Rearrangement: an Example
of Cation Acceleration of a [3,3]-Sigmatropic Rearrangement. J. Am.
Chem. Soc. 1985, 107, 4359–4362.
(27) Hatano, M.; Goto, Y.; Izumiseki, A.; Akakura, M.; Ishihara,
K. Boron Tribromide-Assisted Chiral Phosphoric Acid Catalyst for a
Highly
Enantioselective
Diels–Alder
Reaction
of
1,2-
Dihydropyridines. J. Am. Chem. Soc. 2015, 137, 13472–13475.
(28) Miyaoka, H.; Baba, T.; Mitome, H.; Yamada, Y. Total
Synthesis of Marine Diterpenoid Stolonidiol. Tetrahedron Lett. 2001,
42, 9233–9236.
(29) Chen, G.; Wang, Z.; Wu, J.; Ding, K. Facile Preparation of
Α-Aryl Nitriles by Direct Cyanation of Alcohols with TMSCN Under
the Catalysis of InX3. Org. Lett. 2008, 10, 4573–4576.
(30) Yanagisawa, A.; Nezu, T.; Mohri, S.-I. Brønsted Acid-
Promoted Hydrocyanation of Arylalkenes. Org. Lett. 2009, 11, 5286–
5289.
(31) Yanagisawa, A.; Nishimura, K.; Ando, K.; Nezu, T.; Maki,
A.; Kato, S.; Tamaki, W.; Imai, E.; Mohri, S.-I. A Practical Synthesis
of the PDE4 Inhibitor, KW-4490. Org. Process Res. Dev. 2010, 14,
1182–1187.
(32) Lattanzi, A.; Iannece, P.; Vicinanza, A.; Scettri, A.
Renewable Camphor-Derived Hydroperoxide: Synthesis and Use in
the Asymmetric Epoxidation of Allylic alcohols. Chem. Commun.
2003, 1440–1441.
(14) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E.
J.; Deana, A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, J.
D.; Smith, R. L. 3-Hydroxy-3-Methylglutaryl-Coenzyme a Reductase
Inhibitors. 1. Structural Modification of 5-Substituted 3,5-
Dihydroxypentanoic Acids and Their Lactone Derivatives. J. Med.
Chem. 1985, 28, 347–358.
(15) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson,
E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.;
Sliskovic, D. R.; Stratton, C. D. Inhibitors of Cholesterol
Biosynthesis. 3. Tetrahydro-4-Hydroxy-6-[2-(1H-Pyrrol-1-Yl)Ethyl]-
2H-Pyran-2-One Inhibitors of HMG-CoA Reductase. 2. Effects of
Introducing Substituents at Positions Three and Four of the Pyrrole
Nucleus. J. Med. Chem. 1991, 34, 357–366.
(33) Caron, S.; Vazquez, E.; Wojcik, J. M. Preparation of Tertiary
Benzylic Nitriles From Aryl Fluorides. J. Am. Chem. Soc. 2000, 122,
712–713.
(34) Zhang, F.; Liu, C.; Qiu, P.; Chai, J.; Cai, Q. 4-Substituent-2-
Hydroxylmorholine-3-One and Preparation Method Thereof. U.S.
9,676,736; Jun. 13, 2017.
12
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
(35) Coterón, J. M.; Chiara, J. L.; Fernández-Mayoralas, A.;
(41) Paramahamsan, H.; Pearson, A. J.; Pinkerton, A. A.; Zhurova,
E. A. Toward an Understanding of 1,5-Asymmetric Induction During
Nucleophilic Addition to (Arene)Chromium Tricarbonyl Complexes:
Conformational Preference of the Chromium Tricarbonyl Tripod for
Transmission of Chirality. Organometallics 2008, 27, 900–907.
(42) Deno, N. C.; Groves, P. T.; Jaruzelski, J. J.; Lugasch, M. N.
Carbonium Ions. IX. Monoarylalkyl Cations 1,2. J. Am. Chem. Soc.
1960, 82, 4719–4723.
(43) Fuji, K.; Nakano, S.; Fujita, E. An Improved Method for
Methoxymethylation of Alcohols Under Mild Acidic Conditions.
Synthesis 1975, 276–277.
(44) Strum, J. C.; Bisi, J. E.; Roberts, P. J.; Roberts; Gaston, R. D.;
Gadwood, R. C. Tricyclic Lactams for Use in HSPC-Sparing
Treatments for RB-Positive Abnormal Cellular Proliferation. U.S.
9,717,735; Aug. 1, 2017.
(45) James, T.; MacLellan, P.; Burslem, G. M.; Simpson, I.;
Grant, J. A.; Warriner, S.; Sridharan, V.; Nelson, A. A Modular Lead-
Oriented Synthesis of Diverse Piperazine, 1,4-Diazepane and 1,5-
Diazocane Scaffolds. Org. Biomol. Chem. 2014, 12, 2584–2591.
(46) Wu, Y.; Dockendorff, C. Synthesis of Simplified Azasordarin
Analogs as Potential Antifungal Agents. ChemRxiv (preprint) 2019,
https://doi.org/10.26434/chemrxiv.7634849.v1
Fiandor, J. M.; Valle, N. Stereocontrolled Glycosylation of Sordaricin
in the Presence of Ammonium Salts. Tetrahedron Lett. 2000, 41,
4373–4377.
(36) Schmidt, R. R.; Reichrath, M.; Moering, U. 1- O-Alkylation
of D-Glucopyranose. J. Carbohydr. Chem. 1984, 3, 67–84.
(37) Schmidt, R. R. New Methods for the Synthesis of Glycosides
and Oligosaccharides? Are There Alternatives to the Koenigs-Knorr
Method? Angew. Chem. Int. Ed. 1986, 25, 212–235.
(38) Fuller, N. O.; Hubbs, J. L.; Austin, W. F.; Shen, R.; Ives, J.;
Osswald, G.; Bronk, B. S. Optimization of a Kilogram-Scale
Synthesis of a Potent Cycloartenol Triterpenoid-Derived Γ-Secretase
Modulator. Org. Process Res. Dev. 2014, 18, 683–692.
(39) Regueiro-Ren, A.; Carroll, T. M.; Chen, Y.; Matson, J. A.;
Huang, S.; Mazzucco, C. E.; Stickle, T. M.; Vyas, D. M.;
Balasubramanian, B. N. Core-Modified Sordaricin Derivatives:
Synthesis and Antifungal Activity. Bioorg. Med. Chem. Lett. 2002,
12, 3403–3405.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(40) Liu, Y.; Kang, T.-R.; Liu, Q.-Z.; Chen, L.-M.; Wang, Y.-C.;
Liu, J.; Xie, Y.-M.; Yang, J.-L.; He, L. Enantioselective [4 + 2]
Cycloaddition of Cyclic N-Sulfimines and Acyclic Enones or Ynones:
a Concise Route to Sulfamidate-Fused 2,6-Disubstituted Piperidin-4-
Ones. Org. Lett. 2013, 15, 6090–6093.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14
ACS Paragon Plus Environment