Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic N-Heterocycle-Fused β-Lactones

Article abstract of DOI:10.1021/acs.joc.7b02235

The utility of the nucleophile-catalyzed (Lewis base) aldol lactonization (NCAL) process for the diastereo- and enantioselective synthesis of N-heterocycle-fused-β-lactones from N-linked ketoacids is described. A series of bi- and tricyclic, N-heterocycle

Full text of DOI:10.1021/acs.joc.7b02235

Subscriber access provided by READING UNIV
Article
Diastereo- and Enantioselective Synthesis of Bi-
and Tricyclic N-Heterocycle-Fused #-Lactones
Weixu Kong, and Daniel Romo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02235 • Publication Date (Web): 10 Nov 2017
Downloaded from http://pubs.acs.org on November 10, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 35
The Journal of Organic Chemistry
1
2
3
4
5
6
Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic N-Heterocycle-
Fused β-Lactones
7
8
9
Weixu Kong‡ and Daniel Romo*,†,‡
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
‡Department of Chemistry & Biochemistry, Baylor University, Waco, TX 76710. †Department of
Chemistry, Texas A&M University, College Station, TX 77840.
Email: daniel_romo@baylor.edu
Abstract
The utility of the nucleophileꢀcatalyzed (Lewis base) aldol lactonization (NCAL) process
for the diastereoꢀ and enantioselective synthesis of Nꢀheterocycleꢀfusedꢀβꢀlactones from Nꢀlinked
ketoacids is described. A series of biꢀ and tricyclic, Nꢀheterocycleꢀfused, βꢀlactones were first
synthesized in racemic fashion via the NCAL process with excellent diastereoselectivity (>19:1)
utilizing 4ꢀpyrrolidinopyridine as an effective achiral Lewis base. A catalytic, enantioselective
version of this NCAL process using isothiourea catalysts provided access to bicyclic βꢀlactoneꢀ
fused, Nꢀheterocycles in moderate to good yields (up to 80%) with high enantiocontrol (up to
>99:1 er). An unusual diastereodivergent NCAL process was discovered that leads to two
different products; a tricyclic Nꢀheterocycleꢀfused βꢀlactone and a bicyclic enamine derived from
in situ decarboxylation of the diastereomeric tricyclic βꢀlactone. The reactivity of these adducts
was briefly explored.
Introduction
As a class of unique oxygenꢀcontaining, strained heterocycles, βꢀlactones are not only
versatile intermediates in synthetic chemistry1,2 but are gaining increased use as tools for probing
cellular function of enzymes and proteins with nucleophilic residues.3ꢀ5 Our group first reported
the catalytic, asymmetric intramolecular, nucleophile (Lewis base) catalyzed aldol lactonization
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 35
1
2
(NCAL) process of aldehyde acids in 20016 building on the elegant work of Wynberg7 which
makes use of in situ generated ammonium enolate intermediates2,8 to deliver carbocycleꢀfused,
bicyclic βꢀlactones. The NCAL process was subsequently extended to keto acids leading to a
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
variety of biꢀ and tricyclic carbocycleꢀfused βꢀlactones9 and was applied to the synthesis of
several natural products by our group10,11 and others.12,13 In addition, we also applied the NCAL
reaction to the synthesis of oxygen heterocycleꢀfused βꢀlactones.14 We returned to the original
inspiration for development of the NCAL process, namely the structure of the proteasome
inhibitors omuralide and salinosporamide, and considered application of the NCAL process to Nꢀ
heterocycleꢀfused βꢀlactones. Following application of the NCAL process to a racemic synthesis
of a γꢀlactamꢀfused βꢀtoward (±)ꢀsalinosporamide A, we described a diastereoselective synthesis
of this same γꢀlactamꢀfusedꢀβꢀlactone employing substrate control from a chiral ketoacid
precursor leading to a bioinspired, 9ꢀstep enantioselective, synthesis of (+)ꢀsalinosporamide A
from Rꢀ(–)ꢀOꢀBn serine.15 The Dikshit group described application of the NCAL to Nꢀlinked
aldehyde acids for the enantioselective synthesis of pyrrolidineꢀ and piperidineꢀfusedꢀβꢀlactones
employing cinchona alkaloid Lewis bases.16 Herein, we describe application of the NCAL
process to Nꢀlinked keto acids for the diastereoꢀ and enantioselective synthesis of biꢀ and tricyclic
Nꢀheterocycleꢀfused βꢀlactones 8 including several that are substructures or potential precursors
to substructures of natural products (Figure 1).
OH
OH CH3
CH3
H3C
OH
H
N
O
OH
CH3
H
N
O
toussaintine C (1)
pumiliotoxin B (2)
Me
H
H
O
CO2Me
H
R2
O
HO
N
H
OH
O
Me
OH
N
H3C
Ts
N
CH3
R1
Ph
tussilagine (3)
crepidine (4)
ACS Paragon Plus Environment

Page 3 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
Figure 1. General structure of biꢀ and tricyclic Nꢀheterocycleꢀfused βꢀlactones (inset) available through the described
nucleophile (Lewis base)ꢀcatalyzed, aldolꢀlactonization (NCAL) process described herein and potentially useful for
accessing various substructures (red) of natural products.
7
8
Mechanistically, the aldolꢀβꢀlactonization of Nꢀlinked keto acids towards Nꢀheterocycleꢀ
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
fusedꢀβꢀlactones would be derived through carboxylic acid activation and use of a chiral Lewis
base in the presence of a Brønsted base (Scheme 1). Activation of the carboxylic acid by use of
various activating agents, such as pꢀtoluenesulfonyl chloride9,17,18 and modified Mukaiyama’s
reagent,16,19 enables engagement by a chiral Lewis base through an initial n→π* mode of
interaction20, 8 to ultimately form an acylammonium salt intermediate 6. Deprotonation by the
Brønsted base leads to ammonium enolate 7 which then undergoes a thermodynamically
controlled synꢀaldol reaction, since the antiꢀaldol cannot lactonize, followed by βꢀlactonization to
afford βꢀlactone 8. Although ketene formation is possible under these reaction conditions via
elimination of acylammonium salt 6 enabling a possible racemic, [2+2] cycloaddition pathway to
the βꢀlactone, the nucleophilicity of the Lewis base, slow elimination to ketene, and thus low
concentration of ketene at ambient temperature presumably allows the NCAL process to be the
prevalent pathway.21
O
O
R2
R2
OH
R1
i) activating agent
ii) Lewis base catalyst,
Bronsted base
O
O
Ts
N
Ts
N
R1
5
8
acid activation/
aldolꢀ
βꢀlactonization
Lewis base engagement
(n → π*)
O
X
O
R2
R2
ammonium
enolate
formation
NR3
NR3
O
O
Ts
N
Ts
N
R1
R1
6
7
Scheme 1. The catalytic, enantioselective, nucleophile (Lewis base)ꢀcatalyzed aldolꢀlactonization (NCAL) process
to nitrogenꢀheterocycleꢀfused βꢀlactones 8 from Nꢀlinked keto acids 5.
Results and Discussion
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 35
1
2
3
4
5
6
7
8
9
A series of Nꢀlinked keto acid substrates to be studied in the NCAL process were
prepared through various synthetic routes (Scheme 2). A sequential ozonolysis/Pinnick oxidation
of known terminal alkenes 9a-c22 and 9d23 led to keto acids 5a-d in good yield (45ꢀ67%, 2 steps,
Scheme 2a). Keto acid 5e was prepared via a Mitsunobu reaction/hydrogenolysis sequence from
known NꢀTs aminoester 9e24 and 1ꢀhydroxyꢀ4ꢀpentanone in 52% yield (2 steps, Scheme 2b). An
azaꢀMichael reaction of NꢀTs allylic amine 9f25 and benzyl methacrylate followed by ozonolysis
and hydrogenolysis generated keto acid (±)ꢀ5f (Scheme 2c). The synthesis of cyclic keto acid
substrates 5g-i to access tricyclic βꢀlactones began with amino cyclohexanone 9g26 and amino
alcohol 9h27 (Schemes 2d, 2e). Keto acid 5g was obtained from amino ketone 9g in a 2ꢀstep
sequence involving Nꢀalkylation and hydrogenolysis while a 4ꢀstep sequence delivered keto acids
5h and 5i from βꢀamino alcohol 9h.
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
ACS Paragon Plus Environment

Page 5 of 35
The Journal of Organic Chemistry
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
Scheme 2 Synthesis of ketoacids 5a-i as substrates for the NCAL process leading to biꢀ and tricyclic, Nꢀheterocycle
fused βꢀlactones
With scalable access to Nꢀlinked keto acids 5a-i, we first explored the NCAL process
towards racemic Nꢀheterocycleꢀfusedꢀβꢀlactones synthesis employing 4ꢀpyrrolidinopyridine (4ꢀ
PPY) as Lewis base (Table 1). Under typical NCAL conditions employed previously for
carbocycleꢀfused βꢀlactones, with inexpensive pꢀtoluenesulfonyl chloride as a carboxylic acid
activating agent,18 keto acids 5a-i delivered the corresponding Nꢀheterocycleꢀfused, βꢀlactones 8.
Pyrrolidineꢀfused βꢀlactones (8a, 8d, 8g, 8h) were obtained in yields ranging from 72ꢀ82%. The
sterically congested bisꢀquaternary center containing pyrrolidine 8f could also be obtained but in
only ~24% yield. Generally, piperidineꢀfused βꢀlactones (8b, 8e, 8i) were formed in lower yields
(45ꢀ69%) compared to pyrrolidineꢀfused systems as previously observed in the carbocyclic series
likely reflecting the kinetic differences in 5 vs 6ꢀmembered ring formation and lower stability of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 35
1
2
3
4
5
6
7
8
9
6ꢀmembered ringꢀfused βꢀlactones.19 The Nꢀtosyl protecting group was found to be optimal for
these reactions after a brief screen since other protecting groups (e.g. carbamates) led to mostly
recovered starting material. In addition, use of a tosyl group facilitated synthesis of substrates for
example through azaꢀMichael additions (cf. Scheme 2c). An attempt was made to prepare the
azepaneꢀfused βꢀlactone 8c however this did not provide detectable amounts of βꢀlactone. The
tricyclic βꢀlactones 8g, h were obtained in high diastereoselectivity (>19:1) and the relative
stereochemistry shown for these adducts is supported by 2D NMR studies of pyrrolidineꢀfused,
tricyclic βꢀlactone 8h (see SI for details).
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
Table 1. Synthesis of Racemic N-Heterocycle-Fused β-
Lactones 8 via the NCAL Process with 4-PPY as Lewis
Base
O
4ꢀPPY (1.5 equiv)
pꢀTsCl (1.5 equiv)
iꢀPr2NEt (2.5 equiv)
O
R2
R2
OH
O
O
Ts
N
Ts
N
CH2Cl2 (0.05 M)
23 oC, 12 h
R1
R1
5
8
H
H
H
O
O
O
TsN
O
TsN
O
O
TsN
Me
(±)ꢀ8a (72%)
Ts
Me
(±)ꢀ8b (45%)
Ts
Me
(±)ꢀ8c (0%)
H
Me
O
H
O
O
N
N
TsN
O
O
O
Me
(±)ꢀ8f (~24%)
Me
Me
(±)ꢀ8e (48%)
(±)ꢀ8d (78%)
O
O
O
O
O
O
Ts
N
H
N
N
H
H
Ts
Ts
(±)ꢀ8i
(69%, dr > 19:1)
(±)ꢀ8g
(79%, dr > 19:1)
(±)ꢀ8h
(82%, dr > 19:1)
We next studied the enantioselective NCAL for the synthesis of Nꢀheterocycleꢀfused βꢀ
lactones (NCAL) and keto acid 5a was utilized for initial screening of catalysts and conditions.
The chiral isothiourea catalysts benzotetramisole (BTM, 10) and homobenzotetramisole (HBTM,
11) developed by Birman28,29 and HBTM 2.1 (12) developed by Smith30 have served as excellent
Lewis bases for the in situ preparation of chiral ammonium enolates9,10,31ꢀ34 and more recently
ACS Paragon Plus Environment

Page 7 of 35
The Journal of Organic Chemistry
1
2
unsaturated acylammonium enolates.35 We therefore studied these Lewis bases initially and
found that (S)ꢀHBTM provided the best enantiomeric ratios among these catalysts (Table 2,
entries 1ꢀ3) providing a 98:2 er albeit in low yield (34%). We studied the use of K2CO3 as
stoichiometric insoluble base with the use of Hünig's base as a shuttle base36ꢀ39 (Table 2, entry 4),
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
1
however this did not improve the yield dramatically. Crude H NMR analysis of these initial
reactions and considering mass recovery before and after chromatographic purification suggested
that some loss of βꢀlactone product was likely occurring on silica gel through possible acylation.
We considered that excess Hünig's base present in the crude reaction mixture could promote βꢀ
lactone acylation of silica gel, so excess amounts were removed from the crude reaction mixture
1
(confirmed by crude H NMR) by aqueous extraction prior to purification by automated flash
chromatography. This led to an improvement in yield from 36 to 44% of βꢀlactone 8a (Table 2,
entry 5). Furthermore, use of normal flash chromatography instead of automated flash
chromatography led to a further improvement to 52% likely due to the smaller particle size and
increased surface area of the prepacked columns (Table 2, entry 5). We determined that use of the
shuttle base was not responsible for major yield improvements but rather the method of
purification was key and thus subsequent reactions only employed Hünig's base and normal flash
chromatography. The use of LiCl as additive was investigated next, given the utility in related
reactions,9,40 which led to a major improvement in yield to 78% with 99:1 er.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 35
1
2
3
4
5
6
7
8
9
Table 2. Optimization of the Enantioselective NCAL
Leading to Pyrrolidine-Fused β-Lactone 8aa
cat* (20 mol%)
pꢀTsCl (1.2 equiv)
H
O
O
Ts
iꢀPr2NEt (4.0 equiv)
N
OH
TsN
O
CH2Cl2 (0.1 M)
23 oC, 12 h
O
Me
8a
5a
cat.
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
erc
% yieldb
additive
entry
1
10
ꢀ
ꢀ
12d
34d
85:15
2
3
11
12
98:2
ND
traced
36,d 44,e 52f
78e
K2CO3
LiCl
4
5
11
11
99:1
99:1
iPr
Ph
N
Ph
Ph
N
N
S
N
S
N
N
S
(R)ꢀBTM (10)
HBTMꢀ2.1 (12)
(S)ꢀHBTM (11)
aThe keto acid 5a was added by syringe pump to the reaction
mixture over 6 h. bYields refer to isolated and purified pyrrolidine 8a.
Determined by chiral HPLC analysis. dPurification involved
c
concentration of the crude reaction mixture and direct loading on an
automated flash chromatograph silica column. eAn aqueous workup
was performed to remove excess Hünig's base prior to purification
by normal flash chromatography. fAn aqueous workup was
performed to remove excess Hünig's base prior to loading on an
automated flash chromatography silica column. (er = enantiomeric
ratio; ND = not determined)
With optimized conditions in hand, a brief survey of the scope of this NCAL process was
explored with various Nꢀlinked keto acids (Table 3). For most bicyclic βꢀlactones (8a, 8b, 8d,
8e), the yields were comparable to the corresponding racemic NCAL and the enantiomeric ratios
were excellent (97:3 to 99:1). However, attempts to prepare βꢀlactone 8f were unsuccessful likely
due to the increased sterics of the Lewis base in forming vicinal quaternary centers. Absolute
stereochemistry was assigned by comparison of the optical rotation of 8d with literature values,23
and was consistent with our previous transition state models of the NCAL toward bicyclic
carbocycle fused βꢀlactones.41
ACS Paragon Plus Environment

Page 9 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 3 Catalytic, Asymmetric Synthesis of N-
Heterocycle-Fused Bicyclic β-Lactones 8 via the
NCAL Process
(S)ꢀHBTM (20 mol%, 11)
7
8
9
O
pꢀTsCl (1.2 equiv)
LiCl (1.0 equiv)
iꢀPr2NEt (4.0 equiv)
O
R2
R2
OH
O
O
Ts
N
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
CH2Cl2 (0.1 M)
23 oC, 12ꢀ36 h
Ts N
R1
R1
O
O
TsN
O
TsN
O
Me
(−)ꢀ8a
(78%, 99:1 er)
Me
(−)ꢀ8b
(45%, 99:1 er)
Ts
Ts
O
O
N
N
O
O
Me
(−)ꢀ8d
(80%, 97:3 er)
Me
(+)ꢀ8e
(51%, 99:1 er)
The keto acid 5g that could deliver a tricyclicꢀβꢀlactone was also explored as a substrate
for the enantioselective NCAL (Scheme 3). This process could lead to high enantiopurity of
tricyclicꢀβꢀlactone through a kinetic resolution since the substrate is racemic. Under the
optimized conditions, tricyclic βꢀlactone 8g was obtained in 65% yield however with only a
70:30 er. Enamine (–)ꢀ17, derived from presumed in situ decarboxylation of the βꢀlactone adduct,
was also isolated in 10% yield, but surprisingly in high enantiopurity (95:5 er).
We propose that the observed enantioenriched enamine (–)ꢀ17 is a result of a
diastereodivergent process,42,43 wherein one enantiomeric starting material proceeds through a
NCAL pathway ((S)ꢀ6g) while the other ((R)ꢀ6g) proceeds through
a
[2+2]
cycloaddition/decarboxylation pathway (Scheme 3). The NCAL pathway would be expected to
lead to high diastereoselectivity and enantioselectivity in the matched case, transition state
arrangement A, via acylammonium salt (S)ꢀ6g, as observed in the bicyclic series herein and also
previously in the carbocyclic series,9 however an intervening [2+2] cycloaddition pathway with
the presumed mismatched case (i.e. acylammonium salt (R)ꢀ6g) leads to a nonꢀdiastereoselective
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 35
1
2
3
4
5
6
[2+2] cycloaddition pathway providing both diastereomeric βꢀlactones (+)ꢀ8g and 8g’. The
presence of the enantiomeric (+)ꢀ8g serves to lower the enantiopurity of the isolated tricyclic βꢀ
7
8
9
lactone (–)ꢀ8g (70:30 er). On the other hand, the strain associated with the diastereomeric βꢀ
lactone 8g’, which could not be isolated likely due to its instability due to strain, leads to in situ
decarboxylation under the reaction conditions providing enamine (–)ꢀ17 with high enantiopurity
since it is derived primarily from ketene (R)ꢀ18. Calculation of the total energy difference
between diastereomeric βꢀlactones 8g and 8g’ support the hypothesis that βꢀlactone 8g’ may
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
undergo decarboxylation at ambient temperature (ꢀE8g/8g’ ~2.4ꢀ2.6 kcal/mol, from Chem3D and
Avogrado using MMFF94 force fields). Heating in the presence of silica gel was required to
induce decarboxylation of (+)ꢀ8g/(–)ꢀ8g and confirmed our prediction that the major product was
the enantiomeric enamine (+)ꢀ17 obtained in 79% yield (70:30 er). Overall, while a kinetic
resolution is operative in this process, an intervening [2+2] cycloaddition pathway leads to lower
ACS Paragon Plus Environment

Page 11 of 35
The Journal of Organic Chemistry
1
2
3
4
enantiopurity of the tricyclic βꢀlactone (–)ꢀ8g.
5
6
7
8
9
Scheme 3. Enantioselective NCAL leading to tricyclic βꢀlactone 8g proceding through transition
state arrangement A with alkene (−)ꢀ17 as byꢀproduct and proposed mechanistic rationale for the
high optical purity of alkene (−)ꢀ17.
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
A few transformations of the derived Nꢀheterocycleꢀfused βꢀlactones were explored.
Methanolysis of βꢀlactone (±)ꢀ8g under basic conditions afforded hydroxy ester (±)ꢀ19 in 81%
yield (Scheme 4). As expected, treatment of βꢀlactone (±)ꢀ8g with Mgo in MeOH under
sonication conditions led to cleavage of the tosyl group with concomitant opening of the βꢀ
lactone to provide amino ester (±)ꢀ20. Conditions were not found that enabled tosyl deprotection
without βꢀlactone cleavage.
O
(S)ꢀHBTM (20 mol%)
pꢀTsCl (1.2 equiv)
iꢀPr2NEt (4.0 equiv)
O
O
(R)
(S)
OH
NTs
+
N
Ts
H
N
Ts
(S)
O
H
CH2Cl2 (0.1 M)
23 oC, 12ꢀ36 h
(±)ꢀ5g
(−)ꢀ8g
(65%, 70:30 er)
(−)ꢀ17
(10%, 95:5 er)
Ts
N
O
O
O
Li
NR3
silica gel
NCAL
(fast)
NTs
N
N
S
Ts
PhCF3
O
60oC, 12 h
OTs
H
N
(S)
(S)ꢀ6g
(+)ꢀ17
(79%, 69:31 er)
A (matched case)
enantiomers
O
O
O
NR3
NCAL
Ts
N
Ts
N
H
(slow)
O
OTs
(+)ꢀ8g
(R)ꢀ6g
ꢀHNR3 OTs
O
O
ꢀCO2
O
[2+2]
NTs
H
•
(+)ꢀ8g
N
+
Ts
O
Ts
N
8g’
(thermodynamically unstable)
(−)ꢀ17
(10%, 95:5 er)
(R)ꢀ18
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 35
1
2
3
4
5
6
O
K2CO3
MeOH
Mg(0), MeOH
sonication
CO2Me
Ts
HO
O
HO
CO2Me
NH
23 oC, 3 h
23 oC, 30 min
Ts
N
N
H
H
H
(81%)
(67%)
7
(±)ꢀ8g
(±)ꢀ19
(±)ꢀ20
8
9
Scheme 4. Transformations of Nꢀheterocycle fused tricyclic βꢀlactone (±)ꢀ8g
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
Attempted dyotropic rearrangement of βꢀlactone (±)ꢀ8i with stoichiometric amounts of
MgBr2•OEt2,9,10,44,45 led to alternative conditions for decarboxylation (37%) providing alkene (±)ꢀ
21 albeit in low yield (Scheme 5).
Scheme 5. Decarboxylation of fused tricyclic βꢀlactone 8i leading to alkene 21
In summary, the intramolecular NCAL process has been extended to Nꢀlinked keto acid
substrates leading to the synthesis of pyrrolidine and piperidineꢀfused βꢀlactones. Stoichiometric
4ꢀPPY was identified as an optimal Lewis base for the racemic synthesis of several biꢀ and
tricyclic Nꢀheterocycle fused βꢀlactones in moderate to good yields (40ꢀ82%) with high
diastereoselectivity in all cases (>19:1). Lower yields were obtained when synthesis of a
pyrrolidine fusedꢀβꢀlactone bearing adjacent quaternary carbons was attempted (24%).
A
catalytic, asymmetric version of these NCAL reactions was optimized and led to moderate to
good yields (45ꢀ80%) of optically active bicyclic βꢀlactones (97:3ꢀ99:1 er) however lower
enantioselectivity was obtained with a tricyclicꢀβꢀlactone 8g (70:30 er). A unique type of
diastereodivergent process42 is proposed to account for an alkene byꢀproduct obtained in high
enantiomeric purity (95:5 er) through a [2+2] cycloaddition/decarboxylation pathway from
racemic starting material. This unique kinetic resolution which delivers two different products
ACS Paragon Plus Environment

Page 13 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
from racemic starting materials is under continued investigation. The described NCAL
organocascade allows simultaneous assembly of a nitrogen heterocycle and a fused βꢀlactone
readied for further transformations.
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
Experimentals
General Information
All nonꢀaqueous reactions were performed under a nitrogen atmosphere in ovenꢀdried
glassware. Dichloromethane (CH2Cl2) and Tetrahydrofuran (THF) were dried by passing through
activated molecular sieves or alumina (solvent purification system). Diisopropylethylamine
(DIPEA) was distilled from potassium hydroxide prior to use. Other solvents and reagents were
used as received from commercially available sources. Deuterated solvents were purchased from
1
either Aldrich or Cambridge Isotopes and used as received. H NMR spectra were measured at
600 MHz and 400 MHz and referenced relative to residual chloroform (7.26 ppm) and are
reported in parts per million. Coupling constants (J) are reported in Hertz (Hz), with multiplicity
reported following usual conventions: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; ddd, doublet of doublet of doublets; dddd, doublet of doublet of doublet of doublets; dt,
doublet of triplets; dq, doublet of quartets; ddq, doublet of doublet of quartets; m, multiplet; bs,
broad singlet. 13C NMR spectra were measured at 150 MHz and 101 MHz and referenced relative
to residual chloroform (77.23 ppm) and are reported in parts per million (ppm). Flash column
chromatography was performed with 60Å Silica Gel (230ꢀ400 mesh) as stationary phase using a
gradient solvent system or on an automated flash chromatography system (EtOAc/hexanes as
eluent unless indicated otherwise). Highꢀresolution mass spectra (ESI) were obtained in the Mass
Spectrometry Laboratory (Baylor University) using an ion trap mass analyzer. Thin Layer
Chromatography (TLC) was performed using glassꢀbacked silica gel F254 (Silicycle, 250 µm
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 35
1
2
3
4
5
6
7
8
9
thickness). Visualization of developed plates was performed by fluorescence quenching. Fourier
Transform Infrared (FTIR) spectra were recorded as thin films on NaCl plates. Optical rotations
were recorded on a polarimeter at 589 nm employing a 25 mm cell. HighꢀPerformance Liquid
Chromatography (HPLC) was performed on a chromatographic system using various chiral
columns (25 cm) as noted.
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
(S)ꢀHomobenzotetramisole (HBTM, 10)29 and HBTMꢀ2.1 (11)33 was synthesized according to
literature procedures. (R)ꢀBenzotetramisole (BTM, 12) was purchased from TCI chemicals.
Alkenes 9a-c,22 9d,23 9g27 and 9h26 were prepared according to literature procedures.
Representative Procedure for Synthesis of Keto Acid Substrates via Sequential Ozonolysis
and Pinnick Oxidation as Described for Keto acid 5a: (3-((4-Methyl-N-(2-
oxopropyl)phenyl)sulfonamido)propanoic acid, 5a): A solution of alkene 9a (2.70 g, 9.70
mmol, 1.0 equiv) in CH2Cl2 was treated with ozone under ꢀ78 ºC via gas dispersion tube. After
the solution turned pale blue, nitrogen gas was introduced until the blue color faded away. Then,
dimethylsulfide (DMS) (14.5 mL, 193.7 mmol, 20.0 equiv) was added at ꢀ78 ºC. The reaction
mixture was warmed up to 23 ºC and stirred for 18 h. The solution was concentrated in vacuo,
and the mixture was used directly in the next step without further purification.
The crude aldehyde was dissolved in a mixture of tBuOH (60 mL) and water H2O (20 mL)
at 23 ºC. Then, sodium phosphate mono basic (NaH2PO4) (10.40 g, 87.3 mmol, 9.0 equiv) and 2ꢀ
methylꢀ2ꢀbutene (10.50 mL, 97.0 mmol, 10.0 equiv) was added and the reaction mixture was
kept stirring until the inorganic salt was completely dissolved. Sodium chlorite (2.67 g, 12.7
mmol, 2.0 equiv), was then added in one portion. Upon completion (as judged by TLC), 1N HCl
was added to adjust pH to 2ꢀ3. Additional water (100 mL) was added and the aqueous phase was
ACS Paragon Plus Environment

Page 15 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine
(100 mL) and dried over sodium sulfate. The organic solvent was removed in vacuo. The crude
product was purified by automated flash chromatography (0 → 100%, EtOAc/hexanes) to afford
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
acid 5a as a white solid (1.95 g, 67%, over 2 steps). TLC (EtOAc, 100%): Rf = 0.35; H NMR
(400 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 4.12 (s, 2H), 3.42 (t, J =
13
6.7 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H), 2.14 (s, 3H); C NMR (101 MHz, CDCl3) δ
203.8, 177.2, 144.1, 136.0, 129.9 (2), 127.6 (2), 58.4, 45.0, 34.4, 27.0, 21.7. IR (thin film): 3200ꢀ
3600 (br), 1731, 1714 cmꢀ1; HRMS (ESI+) m/z calcd for C13H17NNaO5S [M+Na]+: 322.0725,
found: 322.0725.
4-((4-Methyl-N-(2-oxopropyl)phenyl)sulfonamido)butanoic acid (5b): Prepared according to
the representative procedure for the sequential ozonolysis/Pinnick oxidation employing alkene 9b
(882 mg, 3.0 mmol, 1.0 equiv) and DMS (4.5 mL, 60.0 mmol, 20.0 equiv) for the ozonolysis and
NaClO2 (541 mg, 6.0 mmol, 2.0 equiv), NaH2PO4 (3.21 g, 9.0 equiv, 27.0 mmol), 2ꢀmethylꢀ1ꢀ
butene (3.24 mL, 30.0 mmol, 10.0 equiv), tBuOH (24 mL), H2O (8 mL) for the Pinnick oxidation.
The crude product was purified by automated flash chromatography (0 → 100%,
EtOAc/hexanes) to afford keto acid 5b as a while solid (423 mg, 45% yield over two steps). TLC
(EtOAc, 100%): Rf = 0.45; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.3 Hz, 2H), 7.33 (d, J =
8.3 Hz, 2H), 4.00 (s, 2H), 3.24 (t, J = 7.1 Hz, 2H), 2.50ꢀ2.34 (m, 5H), 2.20 (s, 3H), 4.13 (app p, J
13
= 7.1 Hz, 2H); C NMR (101 MHz, CDCl3) δ 203.9, 178.0, 144.0, 136.2, 129.9 (2), 127.6 (2),
57.0, 48.4, 30.7, 27.2, 23.1, 21.8; IR (thin film): 2800ꢀ3600 (br), 1730, 1650 cmꢀ1; HRMS (ESI+)
m/z calcd for C14H19NO5SNa [M+Na]+: 336.0882, found: 336.0878.
5-((4-Methyl-N-(2-oxopropyl)phenyl)sulfonamido)pen-tanoic acid (5c): Prepared according to
the representative procedure for the sequential ozonolysis/Pinnick oxidation employing alkene.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 35
1
2
3
4
9c (982 mg, 3.2 mmol, 1.0 equiv), DMS (4.8 mL, 20.0 equiv, 64.0 mmol) were used for
5
6
ozonolysis. NaClO2 (865 mg, 9.6 mmol, 3.0 equiv), NaH2PO4 (3.45 g, 29.0 mmol, 9.0 equiv), 2ꢀ
7
8
9
t
methylꢀ1ꢀbutene (3.45 mL, 32.0 mmol, 10.0 equiv), BuOH (24 mL), H2O (8 mL) were used for
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
Pinnick oxidation. Upon completion (as judged by TLC), the crude product was purified by
automated flash chromatography (0 → 100%, EtOAc/hexanes) to afford keto acid 5c as a
colorless oil (579 mg, 56% yield over two steps). TLC (EtOAc, 100%): Rf = 0.50; 1H NMR (400
MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 3.93 (s, 2H), 3.15 (t, J = 7.0
13
Hz, 2H), 2.42 (s, 3H), 2.34 (t, J = 6.9 Hz, 2H), 2.19 (s, 3H), 1.74 – 1.33 (m, 4H); C NMR (101
MHz, CDCl3): δ 204.4, 178.9, 143.9, 136.1, 129.9 (2), 127.6 (2), 57.0, 48.9, 33.4, 27.5, 27.2,
21.8, 21.7; IR (thin film): 1732 cmꢀ1; HRMS (ESI+) m/z calcd for C15H21NO5SNa [M+Na]+:
350.1038, found: 350.1028.
N-(3-oxobutyl)-N-tosylglycine (5d): Prepared according to the representative procedure for the
sequential ozonolysis/Pinnick oxidation employing alkene 9d23 (1.20 g, 4.27 mmol, 1.0 equiv),
DMS (3.2 mL, 42.7 mmol, 10.0 equiv) were used for ozonolysis. NaClO2 (1.15 g, 12.7 mmol, 3.0
equiv), NaH2PO4 (4.60 g, 38.6 mmol, 9.0 equiv), 2ꢀmethylꢀ1ꢀbutene (4.60 mL, 42.7 mmol, 10.0
t
equiv), BuOH (30 mL), H2O (10 mL) were used for Pinnick oxidation. Upon completion (as
judged by TLC), the crude product was purified by automated flash chromatography (0 → 100%,
EtOAc/hexanes) to afford keto acid 5d as a white solid (817 mg, 64% yield over two steps). TLC
1
(EtOAc, 100%): Rf = 0.42; H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.31 (d, J =
8.3 Hz, 2H), 4.10 (s, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 2.15 (s,
13
3H). C NMR (101 MHz, CDCl3) δ 207.8, 174.2, 144.1, 136.1, 130.0 (2), 127.5 (2), 50.5, 44.3,
43.9, 30.3, 21.8.; IR (thin film): 3000ꢀ3700, 1639; HRMS (ESI+) m/z calcd for C13H17NNaO5S
[M+Na]+: 322.0725, found: 322.0724.
ACS Paragon Plus Environment

Page 17 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-(3-oxobutyl)-N-tosylglycine (5e): To a solution of amino ester 9e (1.13g, 3.6 mmol, 1.2
equiv), 5ꢀhydroxyꢀ2ꢀpentanone (306 mg, 3.0 mmol, 1.0 equiv) and triphenylphosphine (786 mg,
3.0 mmol, 1.0 equiv) in THF (30 mL) was added diethyl azodicarboxylate in toluene (1.56 mL,
3.6 mmol, 1.2 equiv) at 0 ºC dropwise over 5 min. Upon completion (as judged by TLC), the
solvent was removed by rotary evaporation. The crude product was purified by automated flash
chromatography (0 → 50%, EtOAc/hexanes) to afford keto ester 5e inseparable from hydrazine
derived from diethyl azodicarboxylate. The crude mixture (1.05 g) was taken directly into the
next step without further purification.
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 a solution of the crude keto ester in methanol was added Pd/C (105 mg). The suspension
was charged with H2 and stirred under H2 atmosphere at 23 ºC. Upon completion (as judged by
TLC), the suspension was filtered through a pad of Celite and the solvent was removed by rotary
evaporation. The crude product was then purified by automated flash chromatography (0 →
100%, EtOAc/hexanes) to afford keto acid 5e as a white solid (508 mg, 52% yield). TLC
(EtOAc): Rf = 0.45; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz,
2H), 5.69 (br, 1H), 3.98 (s, 2H), 3.20 (t, J = 6.7 Hz, 2H), 2.57 (t, J = 6.7 Hz, 2H), 2.41 (s, 3H),
2.14 (s, 3H), 1.76 (app p, J = 6.7, 2H). 13C NMR (101 MHz, CDCl3) δ 209.0, 173.5, 143.9, 136.3,
129.9(2), 127.5(2), 48.5, 48.3, 39.9, 30.3, 21.7, 21.6; IR (thin film): 2800ꢀ3600 (br), 1715 cmꢀ1;
HRMS (ESI+) m/z calcd for C14H19NO5SNa [M+Na]+: 336.0882, found: 336.0873.
Benzyl 2-methyl-3-((4-methyl-N-(2-oxopropyl)phenyl)sulf-onami-do)propanoate (S1): To a
solution of allylic amine 9f (1.00 g, 1.0 equiv, 4.4 mmol) and K2CO3 (1.84 g, 3.0 equiv, 13.2
mmol) in acetonitrile at 23 ºC was added benzyl methacrylate (1.56 g, 2.0 equiv, 8.9 mmol). The
reaction mixture was stirred at 23 ºC for 12 h. Upon completion (as judged by TLC), the solid
was removed by filtration and the organic solvent was removed by rotary evaporation. The crude
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 35
1
2
3
4
5
6
7
8
9
product was then purified by automated flash chromatography (0 → 50%, EtOAc/hexanes) to
afford ester S1 as a colorless oil (1.28 g, 72% yield). TLC (EtOAc/Hexanes, 1:1 v/v): Rf = 0.55;
1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.44 – 7.29 (m, 5H), 7.27 (d, J = 8.2
Hz, 2H), 5.09 (d, J = 19.5 Hz, 1H), 5.07 (d, J = 19.5 Hz, 1H), 4.85 (d, J = 17.7 Hz, 1H), 3.67 (d,
J = 24.2 Hz, 1H), 3.64 (d, J = 24.2 Hz, 1H), 3.33 (dd, J = 14.4, 7.1 Hz, 1H), 3.33 (dd, J = 56.0,
14.4, 7.1 Hz, 1H), 3.19 (dd, J = 56.0, 14.4, 7.1 Hz, 1H), 2.89 (td, 7.1, 7.1 Hz, 1H), 2.41 (s, 3H),
1.65 (s, 3H), 1.17 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 174.9, 143.5, 140.8, 136.6,
136.0, 129.8 (2), 128.7 (2), 128.4, 128.3 (2), 127.5 (2), 115.0, 66.6, 56.2, 51.3, 39.5, 21.7, 20.1,
15.6; IR (thin film): 1733, 1160 cmꢀ1; HRMS (ESI+) m/z calcd for C22H27NO4SNa [M+Na]+:
424.1558 found: 424.1578.
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
2-Methyl-3-((4-methyl-N-(2-oxopropyl)phenyl)sulfonamido) propanoic acid (5f): A solution
of alkene ester S1 (1.20 g, 1.0 equiv, 3.0 mmol) in CH2Cl2 (60 mL) under ꢀ78 ºC was treated with
ozone. After the solution turned pale blue, nitrogen gas was introduced until the blue color faded
away. Then, DMS (2.3 mL, 30 mmol, 10.0 equiv) was added at ꢀ78 ºC. The reaction mixture was
warmed up to 23 ºC and stirred overnight. The solvent was removed by rotary evaporation and
the crude keto ester was directly used for the next step without further purifications.
To a solution of the crude keto ester in methanol (60 mL) was added Pd/C (122 mg, 10% wt).
The suspension was charged with H2 and stirred under H2 atmosphere at 23 ºC. Upon completion
(as judged by TLC), the suspension was filtered through a pad of Celite and the solvent was
removed by rotary evaporation. The crude product was then purified by automated flash
chromatography (0 → 100%, EtOAc/hexanes) to afford keto acid 5f as a white solid (695 mg,
74% yield over two steps). TLC (EtOAc): Rf = 0.38; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J =
8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 4.10 (d, J = 2.1Hz , 2H), 3.31 (d, J = 7.1 Hz, 2H), 2.87 (td,
ACS Paragon Plus Environment

Page 19 of 35
The Journal of Organic Chemistry
1
2
13
3
J = 7.1, 7.1 Hz, 1H), 2.42 (s, 3H), 2.12 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H); C NMR (101 MHz,
CDCl3): δ 203.8, 180.7, 144.0, 136.0, 129.9 (2), 127.7 (2), 58.6, 52.0, 40.1, 27.0, 21.8, 15.5; IR
(thin film): 1732 cmꢀ1; HRMS (ESI+) m/z calcd for C14H19NO5SNa [M+Na]+: 336.0882, found:
336.0897.
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
N-((2-oxocyclohexyl)methyl)-N-tosylglycine (5g): To a solution of amino ketone 9g27 (1.50 g,
5.0 mmol, 1.0 equiv) and K2CO3 (2.10 g, 15 mmol, 3.0 equiv) in DMF (25 mL) was added
benzyl 2ꢀbromoacetate (2.3 mL, 10.0 mmol, 2.0 equiv). The reaction was stirred for 3 h at
ambient temperature (23 ºC). Upon completion (as judged by TLC), the inorganic salts were
removed through filtration. Diethyl ether (100 mL) was added, and the organic phase was washed
with water (100 mL x 2) and brine (100 mL). The organic phase was dried over MgSO4. The
solvent was removed by rotary evaporation. The crude mixture was filtered through a short pad
of silica gel (100% hexane, then 100% EtOAc) to remove the excess benzyl 2ꢀbromoacetate. The
crude mixture was directly used in the next step without further purification.
To a solution of the crude keto ester (1.25 g) in methanol was added Pd/C (125 mg, 10 wt%).
The suspension was charged with H2 and stirred under H2 atmosphere at 23 ºC for 4 h. Upon
completion (as judge by TLC), the suspension was filtered through a pad of Celite and the
solvent was removed by rotary evaporation. The crude product was then purified by automated
flash chromatography (0 → 100%, EtOAc/hexanes) to afford keto acid 5g as a white solid (864
1
mg, 51% yield). (EtOAc, 100%): Rf = 0.60; H NMR (600 MHz, CDCl3): δ 7.67 (d, J = 8.3 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 4.23 (d, J = 18.5 Hz, 1H), 4.04 (d, J = 18.5 Hz, 1H), 3.40 (d, J =
15.0 Hz, 1H), 3.23 (d, J = 15.0 Hz, 1H), 2.82 (td, J = 12.5, 6.0 Hz, 1H), 2.43 (s, 3H), 2.37 (dddd,
J = 13.4, 4.6, 3.1, 1.5 Hz, 1H), 2.31 (dt, J = 13.1, 6.1 Hz, 1H), 2.25 (ddd, J = 13.2, 5.7, 2.9 Hz,
1H), 2.09 (ddt, J = 12.5, 6.1, 2.9 Hz, 1H), 1.92 – 1.85 (m, 1H), 1.77 – 1.54 (m, 2H), 1.37 (dq, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 35
1
2
13
3
12.8, 3.7 Hz, 1H); C NMR (150 MHz, CDCl3): δ 213.1, 174.4, 144.0, 136.2, 129.9 (2), 127.5
(2), 51.7, 50.5, 49.4, 42.3, 32.6, 28.2, 25.2, 21.7; IR (thin film): 1704 cmꢀ1; HRMS (ESI+) m/z
calcd for C16H21NNaO5S [M+Na]+: 362.1038, found: 362.1034.
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
Representative Procedure for the Sequential N-alkylation and 2-iodoxybenzoic acid (IBX)
Oxidation
as
Described
for
S2.
N-(but-3-en-1-yl)-4-methyl-N-(2-
oxocyclohexyl)benzenesulfon-amide (S2): To a solution of amino alcohol 9h26 (3.23 g, 10.0
mmol 1.0 equiv) and K2CO3 (5.2 g, 30.0 mmol, 3.0 equiv) in acetone (50 mL) was added 4ꢀ
bromoꢀ1ꢀbutene (2.8 mL, 20.0 mmol, 2.0 equiv) at 23 ºC. The reaction mixture was heated up to
65 ºC for 24 h. Upon completion (as judged by TLC), the inorganic salts were removed by
filtration and the solvent was removed by rotary evaporation. The remaining 4ꢀbromoꢀ1ꢀbutene
was removed under high vacuum. The crude product was directly used in the next step without
further purification.
To a solution of crude secondary alcohol in ethyl acetate (50 mL) was added IBX. The reaction
mixture was heated up to 80 ºC for 12 h. Upon completion (as judged by TLC), the solid was
removed by filtration and the solvent was removed by rotary evaporation. The crude product was
purified by automated flash chromatography (0 → 50%, EtOAc/hexanes) to afford keto alkene
S2 (1.48 g, 46% yield over two steps). TLC (EtOAc:Hexanes, 1:3, v/v): Rf = 0.43; 1H NMR (400
MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.70 (ddt, J = 17.1, 10.3, 6.8
Hz, 1H), 5.09 – 4.85 (m, 2H), 4.57 (dd, J = 12.2, 5.7 Hz, 1H), 3.39 (ddd, J = 15.5, 11.0, 5.0 Hz,
1H), 2.92 (ddd, J = 15.5, 11.0, 5.5 Hz, 1H), 2.66 – 2.51 (m, 1H), 2.43 – 2.35 (m, 4H), 2.34 – 2.17
(m, 3H), 2.14 – 1.94 (m, 2H), 1.90 – 1.68 (m, 2H), 1.63 – 1.48 (m, 1H); 13C NMR (101 MHz,
CDCl3): δ 206.0, 143.3, 137.4, 135.2, 129.6 (2), 127.5 (2), 116.8, 66.2, 46.3, 42.0, 36.2, 34.3,
ACS Paragon Plus Environment

Page 21 of 35
The Journal of Organic Chemistry
1
2
26.8, 25.3, 21.8; IR (thin film): 1720 cmꢀ1; HRMS (ESI+) m/z calcd for C17H23NO3SNa [M+Na]+:
3
4
5
6
344.1296, found: 344.1291.
7
8
9
4-Methyl-N-(2-oxocyclohexyl)-N-(pent-4-en-1-yl)benzenesulfonamide
(S3):
Prepared
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
according to the representative procedure for sequential Nꢀalkylation and IBX oxidation. Amino
alcohol 9h (5.38 g, 20.0 mmol, 1.0 equiv), K2CO3 (10.3 g, 60.0 mmol), acetone (100 mL), and 5ꢀ
bromoꢀ1ꢀpentene (6.0 mL, 40.0 mmol, 2.0 equiv) were used for Nꢀalkylation. 2ꢀiodoxybenzoic
acid (IBX) (10.2 g, 40 mmol, 2.0 equiv) and ethyl acetate (100 mL) were used for IBX oxidation.
Upon completion (as judged by TLC), the crude product was purified by automated flash
chromatography (0 → 50%, EtOAc/hexanes) to afford keto alkene S3 (3.87 g, 57% yield over
1
two steps). TLC (EtOAc:Hexanes, 1:3, v/v): Rf = 0.45; H NMR (400 MHz, CDCl3): δ 7.66 (d, J
= 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 5.75 (ddt, J = 16.8, 10.2, 6.4 Hz, 1H), 5.19 – 4.87 (m,
2H), 4.56 (dd, J = 12.2, 5.7 Hz, 1H), 3.32 (ddd, J = 15.4, 11.3, 4.4 Hz, 1H), 2.86 (ddd, J = 15.7,
10.8, 5.3 Hz, 1H), 2.49 – 2.34 (m, 4H), 2.34ꢀ2.18 (m, 2H) 2.09 – 1.88 (m, 5H), 1.86 – 1.67 (m,
2H), 1.67 – 1.46 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 206.0, 143.3, 137.8, 137.5, 129.6 (2),
127.5 (2), 115.4, 66.1, 46.4, 42.0, 34.3, 31.3, 30.9, 26.8, 25.4, 21.8; IR (thin film): cmꢀ1; HRMS
(ESI+) m/z calcd for C18H25NO3SNa [M+Na]+: 358.1453, found: 358.1450.
N-(3-oxobutyl)-N-tosylglycine (5h): Prepared according to the representative procedure for the
sequential ozonolysis/Pinnick oxidation. Keto alkene S2 (605 mg, 1.0 equiv, 1.8 mmol) and DMS
(1.4 mL, 10.0 equiv, 18.0 mmol) was used for ozonolysis. NaClO2 (0.38 g, 2.0 equiv, 3.6 mmol),
NaH2PO4 (1.10 g, 5.0 equiv, 38.6 mmol), 2ꢀmethylꢀ2ꢀbutene (2.0 mL, 10.0 equiv, 18.0 mmol), tꢀ
BuOH (14 mL), H2O (4.5 mL) were used for Pinnick oxidation. Upon completion (as judged by
TLC), the crude product was purified by automated flash chromatography (0 → 100%,
EtOAc/hexanes) to afford keto acid 5h as a white solid (817 mg, 46% yield over two steps). TLC
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 35
1
2
(EtOAc, 100%): Rf = 0.62; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.28 (d, J =
8.3 Hz, 2H), 4.59 (dd, J = 12.4, 5.7 Hz, 1H), 3.54 (ddd, J = 15.5, 10.0, 5.5 1H), 3.26 (ddd, J =
15.5, 10.0, 5.5 Hz, 1H), 3.04 (ddd, J = 17.0, 9.9, 5.5 Hz, 1H), 2.70 (ddd, J = 17.0, 10.0, 5.5 Hz,
1H), 2.41 (m, 4H), 2.31 – 2.16 (m, 2H), 2.11 – 1.94 (m, 1H), 1.92 – 1.69 (m, 2H), 1.56 (qt, J =
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
13
12.9, 3.8 Hz, 1H), 1.23 (dt, J = 20.1, 7.1 Hz, 1H); C NMR (101 MHz, CDCl3): δ 206.0, 176.6,
143.7, 136.8, 129.8 (2), 127.5 (2), 66.5, 41.9, 41.6, 36.2, 33.6, 26.7, 25.2, 21.8; IR (thin
film):1720 cmꢀ1; HRMS (ESI+) m/z calcd for C16H21NNaO5S [M+Na]+: 362.1038, found:
362.1034.
N-(3-oxobutyl)-N-tosylglycine (5i): Prepared according to the representative procedure for the
sequential ozonolysis/Pinnick oxidation. S3 (1.20 g, 1.0 equiv, 3.60 mmol), DMS (2.7 mL, 10
equiv, 36.0 mmol) were used for ozonolysis. NaClO2 (975 mg, 3.0 equiv, 10.8 mmol), NaH2PO4
(2.20 g, 5.0 equiv, 18.0 mmol), 2ꢀmethylꢀ2ꢀbutene (4.0 mL, 10.0 equiv, 36.0 mmol), tꢀBuOH (25
mL), H2O (8 mL) were used for Pinnick oxidation. Upon completion (as judged by TLC), the
crude product was purified by automated flash chromatography (0 → 100%, EtOAc/hexanes) to
afford ketoacid 5i as a white solid (726 mg, 65% yield over two steps). TLC (EtOAc, 100%): Rf =
0.65; 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 4.55 (dd,
J = 12.7, 5.7 Hz, 1H), 3.34 (ddd, J = 15.5, 10.2, 5.4 Hz, 1H), 2.98 (ddd, J = 15.5, 10.2, 5.4 Hz,
1H), 2.45 – 2.33 (m, 6H), 2.31 – 2.18 (m, 2H), 2.14 – 1.95 (m, 3H), 1.95 – 1.68 (m, 3H), 1.55
13
(dddd, J = 17.7, 13.9, 8.9, 4.2 Hz, 1H); C NMR (101 MHz, CDCl3): δ 206.1, 178.8, 143.5,
137.1, 129.6 (2), 127.5 (2), 66.1, 45.8, 42.0, 34.0, 31.1, 26.8, 26.4, 25.3, 21.8; IR (thin film):1722
cmꢀ1; HRMS (ESI+) m/z calcd for C17H23NNaO5S [M+Na]+: 376.1195, found: 376.1189.
ACS Paragon Plus Environment

Page 23 of 35
The Journal of Organic Chemistry
1
2
3
4
Representative Procedure for the Racemic Nucleophile-Catalyzed Aldol Lactonization
5
6
7
(NCAL) Cascade as Described for β-Lactone (±)-8a.
5-Methyl-3-tosyl-6-oxa-3-
8
9
azabicyclo[3.2.0]heptan-7-one ((±)-8a): To an ovenꢀdried, roundꢀbottom flask equipped with a
magnetic stir bar was added pꢀtoluenesulfonyl chloride (28 mg, 0.15 mmol, 1.5 equiv), 4ꢀPPY
(22 mg, 0.15 mmol, 1.5 equiv), CH2Cl2 (1.5 mL) and N,Nꢀdiisopropylethylamine (37.5 ꢁL, 0.25
mmol, 2.5 equiv) under nitrogen atmosphere at 23°C. The keto acid 5a (30 mg, 0.10 mmol, 1.0
equiv) in CH2Cl2 (0.5 mL) was added dropwise through syringe pump over 3 h. After the
addition was complete, the reaction was allowed to stir for an additional 9 h. Upon completion
(as judged by TLC), the solvent was concentrated by rotary evaporation and the crude mixture
was purified by flash chromatography (0 → 40%, EtOAc/hexanes) to afford the βꢀlactone (±)ꢀ8a
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
as a white solid (21 mg, 72% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.34. H NMR (400
MHz; CDCl3): δ 7.71 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.94 (d, J = 10.7 Hz, 1H),
3.88 (d, J = 11.9 Hz, 1H), 3.59 (d, J = 6.2 Hz, 1H), 2.97 (dd, J = 10.7, 6.4 Hz, 1H), 2.75 (d, J =
13
11.9 Hz, 1H), 2.45 (s, 3H), 1.66 (s, 3H); C NMR (101 MHz; CDCl3): δ 167.2, 144.7, 132.6,
130.1 (2), 128.1 (2), 83.7, 58.8, 55.4, 48.1, 21.81, 19.4; IR (thin film): 1826 cmꢀ1; HRMS (ESI+)
m/z calcd for C13H15NO4SNa [M+Na]+: 304.0619, found: 304.0622.
1-Methyl-3-tosyl-8-oxa-3-azabicyclo[4.2.0]octan-7-one ((±)ꢀ8b): Prepared according to
representative procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (pꢀTsCl, 28 mg,
0.15 mmol, 1.5 equiv), 4ꢀpyrrolidinopyridine (4ꢀPPY, 22 mg, 0.15 mmol, 1.5 equiv), CH2Cl2 (1.5
mL), N,Nꢀdiisopropylethylamine (37.5 ꢁL, 0.25 mmol, 2.5 equiv) and keto acid 5b (31 mg, 0.10
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL). The crude mixture was purified by flash chromatography
(0 → 40%, EtOAc/hexanes) to afford βꢀlactone (±)ꢀ8b as a white solid (12 mg, 42% yield). TLC
1
(EtOAc:hexanes, 3:7 v/v): Rf = 0.40. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 35
1
2
3
4
5
6
7
8
9
7.33 (d, J = 8.3 Hz, 2H), 3.85 (d, J = 14.4 Hz, 1H), 3.43 – 3.34 (m, 1H), 3.27 (d, J = 14.4), 3.22
(td, J = 11.8, 6.0 Hz, 1H), 2.43 (s, 3H), 2.18 – 2.07 (m, 1H), 1.93 (ddt, J = 14.9, 10.6, 6.4 Hz,
1H), 1.59 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 168.9, 144.2, 134.4, 130.0 (2), 127.7 (2), 76.5,
51.8, 49.8, 40.8, 23.2, 21.8, 19.7; IR (thin film): 1812 cmꢀ1; HRMS (ESI+) m/z calcd for
C14H17NO4SNa [M+H]+: 318.0776, found: 318.0784.
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-methyl-2-tosyl-6-oxa-2-azabicyclo[3.2.0]heptan-7-one ((±)-8d): Prepared according to
representative procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (28 mg, 0.15
mmol, 1.5 equiv), 4ꢀPPY (22 mg, 0.15 mmol, 1.5 equiv), CH2Cl2 (1.5 mL) and N,Nꢀ
diisopropylethylamine (37.5 ꢁL, 0.25 mmol, 2.5 equiv) under nitrogen atmosphere at 23°C and
keto acid 5d (30 mg, 0.10 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL). The crude mixture was purified
by flash chromatography (0→40%, EtOAc/hexanes) to afford βꢀlactone (±)ꢀ8d as a white solid
1
(22 mg, 78% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.37. H NMR (400 MHz, CDCl3): δ
7.78 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 5.07 (s, 1H), 3.99 (dd, J = 11.2, 8.2 Hz, 1H),
3.14 (td, J = 11.4, 5.8 Hz, 1H), 2.43 (s, 3H), 2.21 (dd, J = 14.3, 5.8 Hz, 1H), 1.80 (ddd, J = 14.3,
13
11.6, 8.2 Hz, 1H), 1.67 (s, 3H); C NMR (101 MHz; CDCl3): δ 164.7, 144.7, 135.0, 130.0 (2),
128.1 (2), 87.5, 73.7, 46.9, 35.4, 21.8, 20.9; IR (thin film): 1829 cmꢀ1; HRMS (ESI+) m/z calcd
for C13H15NO4SNa [M+Na]+: 304.0619, found: 304.0633.
6-methyl-2-tosyl-7-oxa-2-azabicyclo[4.2.0]octan-8-one ((±)-8e): Prepared according to
representative procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (28 mg, 0.15
mmol, 1.5 equiv), 4ꢀPPY (22 mg, 0.15 mmol, 1.5 equiv), CH2Cl2 (1.5 mL), N,Nꢀ
diisopropylethylamine (37.5 ꢁL, 0.25 mmol, 2.5 equiv) and keto acid 5e (31 mg, 0.10 mmol, 1.0
equiv) in CH2Cl2 (0.5 mL). The crude mixture was purified by flash chromatography (0→40%,
EtOAc/hexanes) to afford βꢀlactone (±)ꢀ8e as a white solid (14 mg, 48% yield). TLC
ACS Paragon Plus Environment

Page 25 of 35
The Journal of Organic Chemistry
1
2
1
3
4
(EtOAc:hexanes, 3:7 v/v): Rf = 0.45. H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.3 Hz, 2H),
5
6
7
8
7.34 (d, J = 8.3 Hz, 2H), 5.20 (s, 1H), 3.49 (dt, J = 11.1, 8.9 Hz, 1H), 3.28 – 3.07 (m, 1H), 2.43
(s, 3H), 2.19 – 2.09 (m, 1H), 1.78 (m, 3H), 1.63 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 168.5,
144.4, 135.2, 130.0 (2), 127.8 (2), 80.9, 65.1, 42.0, 31.1, 24.5, 21.8, 16.8; IR (thin film): 1828
cmꢀ1; HRMS (ESI+) m/z calcd for C14H17NO4SNa [M+Na]+: 318.0776, found: 318.0784.
1,5-Dimethyl-3-tosyl-6-oxa-3-azabicyclo[3.2.0]heptan-7-one ((±)-8f): Prepared according to
representative procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (56 mg, 0.30
mmol, 1.5 equiv), 4ꢀPPY (44 mg, 0.30 mmol, 1.5 equiv), CH2Cl2 (3.0 mL), N,Nꢀ
diisopropylethylamine (73.0 ꢁL, 0.50 mmol, 2.5 equiv) and keto acid 5f (62 mg, 0.20 mmol, 1.0
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
equiv) in CH2Cl2 (1.0 mL). The crude mixture was purified by flash chromatography (0→40%,
EtOAc/hexanes) to afford βꢀlactone (±)ꢀ8f as a white solid (14 mg, 24% yield). TLC
1
(EtOAc:hexanes, 3:7 v/v): Rf = 0.46; H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 2H),
7.34 (d, J = 8.3 Hz, 2H), 3.95 (d, J = 10.6 Hz, 1H), 3.91 (d, J = 11.9 Hz, 1H), 2.78 (d, J = 11.9,
1H), 2.65 (d, J = 10.6, 1H), 2.45 (s, 3H), 1.50 (s, 3H), 1.25 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ 170.9, 144.6, 132.9, 130.1 (2), 128.1 (2), 86.1, 62.8, 55.7, 54.2, 21.8, 16.4, 11.4; IR (thin film):
1826 cmꢀ1; HRMS (ESI+) m/z calcd for C14H17NO4SNa [M+Na]+: 318.0776, found: 318.0771.
3-tosyloctahydro-2H-oxeto[3,2-c]isoindol-2-one ((±)-8g): Prepared according to the
representative procedure for the racemic NCAL as described for (±)ꢀ8a using pꢀtoluenesulfonyl
chloride (85 mg, 0.45 mmol, 1.5 equiv), 4ꢀPPY (66 mg, 0.45 mmol, 1.5 equiv), CH2Cl2 (5.5 mL),
N,Nꢀdiisopropylethylamine (0.12 mL, 0.75 mmol, 2.5 equiv) and keto acid 5g (101 mg, 0.30
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL). The crude mixture was purified by flash chromatography
(0→40%, EtOAc/hexanes) to afford βꢀlactone (±)-8g as a white solid (76 mg, 79% yield). TLC
1
(EtOAc:hexanes, 3:7 v/v): Rf = 0.52; H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.3 Hz, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 35
1
2
3
4
5
6
7.31 (d, J = 8.3 Hz, 2H), 5.02 (s, 1H), 3.57 (d, J = 10.1 Hz, 1H), 3.24 (dd, J = 10.1, 5.0 Hz, 1H),
2.42 (s, 3H), 2.25 (ddd, J = 11.9, 6.4, 4.9 Hz, 1H), 2.21 – 2.14 (m, 1H), 2.02 – 1.84 (m, 3H), 1.72
7
8
9
13
(ddd, J = 17.4, 10.2, 6.6 Hz, 1H), 1.39 (app dq, J = 13.6, 3.7 Hz, 1H), 1.32 – 1.15 (m, 2H); C
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
NMR (101 MHz, CDCl3): δ 164.2, 144.3, 135.5, 129.8 (2), 128.0 (2), 89.0, 71.4, 52.0, 41.0, 30.3,
28.6, 23.7, 23.5, 21.8; IR (thin film): 1829 cmꢀ1; HRMS (ESI+) m/z calcd for C16H19NO4SNa
[M+Na]+: 344.0932, found: 344.0938.
4-tosyloctahydro-2H-oxeto[3,2-c]indol-2-one ((±)-8h): Prepared according to the representative
procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (85 mg, 0.45 mmol, 1.5
equiv), 4ꢀPPY (66 mg, 0.45 mmol, 1.5 equiv), CH2Cl2 (5.5 mL), N,Nꢀdiisopropylethylamine
(0.12 mL, 0.75 mmol, 2.5 equiv) and keto acid 5h (101 mg, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5
mL). The crude mixture was purified by flash chromatography (0→40%, EtOAc/hexanes) to
afford βꢀlactone (±)-8h as a white solid (79 mg, 82% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf =
0.50; 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 4.07 (dd,
J = 10.8, 7.0 Hz, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.58 (dd, J = 12.0, 6.5 Hz, 1H), 3.50 (d, J = 6.5
Hz, 1H), 2.42 (s, 3H), 2.32 (app qt, J = 7.1, 2.4 Hz, 1H), 2.28 – 2.14 (m, 1H), 1.97 (td, J = 13.7,
4.8 Hz, 1H), 1.88 (ddt, J = 13.5, 4.9, 2.6 Hz, 1H), 1.76 (dt, J = 8.9, 2.7 Hz, 1H), 1.33 – 1.24 (m,
13
2H), 1.24 – 1.10 (m, 1H); C NMR (101 MHz; CDCl3): δ 167.8, 144.1, 136.7, 129.9 (2), 127.4
(2), 86.3, 61.5, 57.6, 45.7, 31.1, 29.3, 23.6, 22.8, 21.8; IR (thin film): 1834 cmꢀ1; HRMS (ESI+)
m/z calcd for C16H19NO4SNa [M+Na]+: 344.0932, found: 344.0929.
5-tosyloctahydrooxeto[3,2-d]quinolin-2(2aH)-one ((±)-8i): Prepared according to the
representative procedure for the racemic NCAL using pꢀtoluenesulfonyl chloride (85 mg, 0.45
mmol, 1.5 equiv), 4ꢀPPY (66 mg, 0.45 mmol, 1.5 equiv), CH2Cl2 (5.5 mL), N,Nꢀ
diisopropylethylamine (0.12 mL, 0.75 mmol, 2.5 equiv)and keto acid 5i (106 mg, 0.30 mmol, 1.0
ACS Paragon Plus Environment

Page 27 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
equiv) in CH2Cl2 (0.5 mL) . The crude mixture was purified by flash chromatography (0→40%,
EtOAc/hexanes) to afford βꢀlactone (±)-8i as a white solid (69 mg, 69% yield). TLC
7
8
9
1
(EtOAc:hexanes, 3:7 v/v): Rf = 0.54; H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H),
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
7.29 (d, J = 8.2 Hz, 2H), 4.02 (dd, J = 12.1, 5.4 Hz, 1H), 3.70 (ddd, J = 11.5, 6.1, 2.1 Hz, 1H),
3.28 (dd, J = 4.7, 2.8 Hz, 1H), 3.06 (td, J = 12.1, 5.9 Hz, 1H), 2.41 (s, 3H), 2.34 (ddd, J = 12.8,
5.3, 2.4 Hz, 1H), 2.27 – 2.16 (m, 1H), 2.16 – 2.06 (m, 1H), 1.97 (dd, J = 12.4, 3.1 Hz, 1H), 1.92 –
1.81 (m, 2H), 1.77 (dt, J = 13.1, 2.9 Hz, 1H), 1.49 (ddd, J = 12.7, 12.2, 3.3 Hz, 1H), 1.45 – 1.30
13
(m, 1H), 1.23 – 1.05 (m, 1H); C NMR (101 MHz, CDCl3): δ 168.8, 143.8, 135.1, 129.7 (2),
127.6 (2), 78.9, 56.3, 50.5, 38.9, 36.8, 35.3, 24.4, 23.9, 21.8, 19.5; IR (thin film): 1823 cmꢀ1;
HRMS (ESI+) m/z calcd for C17H21NO4SNa [M+Na]+: 358.1089, found: 358.1084.
Representative Procedure for the Enantioselective NCAL as Described for β-Lactone (–)-
8a. (1S,5S)-5-Methyl-3-tosyl-6-oxa-3-azabicyclo[3.2.0]heptan-7-one ((–)-8a): To an ovenꢀ
dried, 10 mL roundꢀbottomed flask equipped with a magnetic stir bar was added pꢀ
toluenesulfonyl chloride (58 mg, 0.30 mmol, 1.2 equiv), lithium chloride (11 mg, 0.25 mmol, 1.0
equiv), (S)ꢀHBTM (13 mg, 0.05 mmol, 0.2 equiv), CH2Cl2 (2.5 mL) and N,Nꢀ
diisopropylethylamine (0.18 mL, 1.0 mmol, 4.0 equiv). To this mixture was added keto acid 5a
(80.5 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) through syringe pump over 6 h. After the
addition was complete, the reaction was allowed to stir for an additional 6 h. Upon completion
(as judged by TLC), the reaction mixture was diluted with ether (20 mL), and the organic phase
was then washed with water (2×20 mL) to remove H nig’s base and then brine (20 mL). The
organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude mixture
was purified by normal flash chromatography (0 → 40%, EtOAc/hexanes) to afford the βꢀlactone
20
D
[α]
(–)ꢀ8a as a white solid (55 mg, 78% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.34;
ꢀ6.00
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 35
1
2
3
4
5
6
7
8
9
(c = 1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with
authentic racemic material using a Chiralcel IA column: hexanes:iPrOH = 85:15, flow rate 1.0
mL/min, λ = 230 nm: tmajor = 19.6 min, tminor = 24.9 min; 99:1 er. Absolute stereochemistry was
assigned by analogy to βꢀlactone (–)ꢀ8d given that (S)ꢀHBTM was employed as Lewis base.
(1S,6S)-1-Methyl-3-tosyl-8-oxa-3-azabicyclo[4.2.0]octan-7-one ((–)-8b): Prepared according
to representative procedure for the enantioselective NCAL using pꢀtoluenesulfonyl chloride (58
mg, 0.30 mmol, 1.2 equiv), lithium chloride (11 mg, 0.25 mmol, 1.0 equiv), (S)ꢀHBTM (13 mg,
0.05 mmol, 0.2 equiv), CH2Cl2 (2.5 mL), N,Nꢀdiisopropylethylamine (0.18 mL, 1.2 mmol, 4.0
equiv) and keto acid 5b (79 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2 (0.5 ml). The crude mixture
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
was purified by flash chromatography (0→40%, EtOAc/hexanes) to afford βꢀlactone (–)ꢀ8b as a
20
D
white solid (33 mg, 45% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.40;
[α
]
–78.40 (c = 0.5,
CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authentic
racemic material using a Chiralcel IA column: hexanes:iPrOH = 85:15, flow rate 1.0 mL/min, λ =
230 nm: tminor = 17.5min, tmajor = 21.0 min; 99:1 er. Absolute stereochemistry was assigned by
analogy to βꢀlactone (–)ꢀ8d given that (S)ꢀHBTM was employed as Lewis base.
(1S,5R)-5-Methyl-2-tosyl-6-oxa-2-azabicyclo[3.2.0]heptan-7-one ((–)-8d): Prepared according
to representative procedure for the enantioselective NCALusing pꢀtoluenesulfonyl chloride (58
mg, 0.30 mmol, 1.2 equiv), lithium chloride (11 mg, 0.3 mmol, 1.0 equiv), (S)ꢀHBTM (13 mg,
0.05 mmol, 0.2 equiv), CH2Cl2 (2.5 mL), N,Nꢀdiisopropylethylamine (0.18 mL, 1.2 mmol, 4.0
equiv) and keto acid 5d (75 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL). The crude mixture
was purified by flash chromatography (0→40%, EtOAc/hexanes) to afford βꢀlactone (–)ꢀ8d as a
white solid (56 mg, 80% yield). TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.37;
[
α
2D0 = ꢀ119.20 (c =
]
1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authentic
ACS Paragon Plus Environment

Page 29 of 35
The Journal of Organic Chemistry
1
2
3
4
racemic material using a Chiralcel IA column: hexanes:iPrOH = 85:15, flow rate 1.0 mL/min, λ =
5
6
230 nm: tmajor = 16.1 min, tminor = 20.6 min; 97:3 er. Absolute stereochemistry was assigned by
7
8
9
25
D
comparison of the optical rotation to a literature value:
[α
]
ꢀ127 (c = 1.08, CHCl3).23
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,6R)-6-methyl-2-tosyl-7-oxa-2-azabicyclo[4.2.0]octan-8-one ((+)-8e): Prepared according to
representative procedure for the enantioselective NCAL using pꢀtoluenesulfonyl chloride (58 mg,
0.30 mmol, 1.2 equiv), lithium chloride (11 mg, 0.3 mmol, 1.0 equiv), (S)ꢀHBTM (13 mg, 0.05
mmol, 0.2 equiv), CH2Cl2 (2.5 mL), N,Nꢀdiisopropylethylamine (0.18 mL, 1.2 mmol, 4.0 equiv)
and keto acid 5e (79 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2. The crude mixture was purified by
flash chromatography (0→40%, EtOAc/hexanes) to afford βꢀlactone (+)ꢀ8e as a white solid (38
20
[ ] D
mg, 48% yield). TLC (EtOAc:hexanes, 1:1 v/v): Rf = 0.45;
+45.60 (c = 1.0, CHCl3).
α
Enantiomeric ratio was determined by HPLC analysis in comparison with authentic racemic
material using a Chiralcel IA column: hexanes:iPrOH = 85:15, flow rate 1.0 mL/min, λ = 230
nm: tminor = 11.0 min, tmajor = 13.3 min; 99:1 er. Absolute stereochemistry was assigned by
analogy to βꢀlactone (–)ꢀ8d given that (S)ꢀHBTM was employed as Lewis base.
(2aS,4aS,8aR)-3-tosyloctahydro-2H-oxeto[3,2-c]isoindol-2-one ((–)-8g): Prepared according to
representative procedure for the enantioselective NCAL using pꢀtoluenesulfonyl chloride (58 mg,
0.30 mmol, 1.2 equiv), lithium chloride (11 mg, 0.3 mmol, 1.0 equiv), (S)ꢀHBTM (13 mg, 0.05
mmol, 0.2 equiv), CH2Cl2 (2.5 mL), N,Nꢀdiisopropylethylamine (0.18 mL, 1.2 mmol, 4.0 equiv)
and keto acid 5g (85 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL). The crude mixture was
purified by flash chromatography (0→40%, EtOAc/hexanes) to afford βꢀlactone (–)ꢀ8g (55 mg,
20
[ ] D
65% yield) as a white solid. TLC (EtOAc:hexanes, 3:7 v/v): Rf = 0.52;
α
ꢀ51.20 (c = 1.0,
CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authentic
racemic material using a Chiralcel IA column: hexanes:iPrOH = 90:10, flow rate 1.0 mL/min, λ =
ACS Paragon Plus Environment