Multicomponent, Enantioselective Michael-Michael-Aldol-β-Lactonizations Delivering Complex β-Lactones

Article abstract of DOI:10.1021/acs.joc.7b02543

Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides to deliver chiral, α,β-unsaturated acylammonium salts. These intermediates participate in a catalytic, enantioselective, three-component process delivering bi- and tricyclic β-lactones through a Michael-Michael-aldol-β-lactonization. In a single operation, the described multicomponent, organocascade process forms complex bi- and tricyclic β-lactones by generating four new bonds, two rings, and up to four contiguous stereocenters. In the racemic series, yields of 22-75% were achieved using 4-pyrrolidinopyridine as Lewis base. In the enantioselective series employing isothiourea catalysts, a kinetic resolution of the initially formed racemic Michael adduct appears operative, providing yields of 46% to quantitative (based on 50% max) with up to 94:6 er. Some evidence for a dynamic kinetic asymmetric transformation for tricyclic-β-lactone 1d was obtained following optimization (yields up to 61%, 94:6 er) through a presumed reversible Michael.

Full text of DOI:10.1021/acs.joc.7b02543

Subscriber access provided by University of Florida | Smathers Libraries
Article
Multicomponent, Enantioselective Michael-Michael-
Aldol-#-Lactonizations Delivering Complex #-Lactones
Khoi N. Van, and Daniel Romo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02543 • Publication Date (Web): 08 Dec 2017
Downloaded from http://pubs.acs.org on December 9, 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.

Multicomponent, Enantioselective MichaelꢀMichaelꢀAldolꢀβ
Lactonizations Delivering Complex βꢀLactones
ꢀ
Page 1 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Khoi N. Van† and Daniel Romo*§
† Department of Chemistry, Texas A&M University, College Station, TX.
§ Department of Chemistry & Biochemistry, Baylor University, Waco, TX
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
O
R1O
R2
O
O
Li
3o amine
catalyst
O
R1
• multicomponent reaction
• kinetic resolution (up to 94:6 er)
• 4 new bonds (3 CꢀC, 1 CꢀO)
• 2 new rings
OR4
CO2R4
*
base
*
R1
*
*
R2
R2
(±)
O
R3
+
R4O2C
CO2R4
CH2
CO2R4
R4O2C
• 4 stereocenters introduced
R3
Cl
ABSTRACT: Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides
to deliver chiral, α,βꢀunsaturated acylammonium salts. These intermediates participate in a
catalytic, enantioselective, threeꢀcomponent process delivering biꢀ and tricyclic βꢀlactones
through a MichaelꢀMichaelꢀaldolꢀβꢀlactonization. In a single operation, the described multiꢀ
component, organocascade process forms complex biꢀ and triꢀcyclic βꢀlactones by generating
four new bonds, two rings and up to four contiguous stereocenters. In the racemic series,
yields of 22ꢀ75% were achieved using 4ꢀpyrrolidinopyridine as Lewis base. In the enantioseꢀ
lective series employing isothiourea catalysts, a kinetic resolution of the initially formed raceꢀ
mic, Michael adduct appears operative providing yields of 46% to quantitative (based on 50%
max) with up to 93.5:6.5 er. Some evidence for a dynamic kinetic asymmetric transformation
for tricyclicꢀβꢀlactone 1d was obtained following optimization (yields up to 61%, 94:6 er)
through a presumed reversible Michael.
Introduction
Multicomponent reactions (MCRs) are transformations in which three or more subꢀ
strates are combined to form a product in one pot without isolation of intermediates.1 Comꢀ
pared to traditional sequential synthetic methods, MCRs can quickly deliver complex scaffolds
through multiple bond forming events in a single operation while significantly reducing the time
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 31
of preparation and purification in addition to labor and cost. These factors contribute to the
great utility of MCRs for chemists in a time when sustainable synthesis is sought.2 The develꢀ
opment of new MCRs increases the numbers of accessible targets with a common core strucꢀ
ture through simple variation of each component making these processes popular for mediciꢀ
nal chemistry and drug discovery.3 Despite these advantages, relatively few new multicompoꢀ
nent processes have emerged since their initial development nearly 100 years ago, and enanꢀ
tioselective MCRs are even more limited.1,4 The field of organocatalysis has recently increased
dramatically,5 with new applications emerging constantly stemming from discovery of new reꢀ
activity and activation modes.6 Not surprisingly, the joining of organocatalysis and MCRs is
highly desirable.7
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
Ketones and aldehydes are ubiquitous components of MCRs mainly as a result of iminꢀ
ium/enamine catalysis, which is one of the most common activation modes employed for orꢀ
ganocatalytic MCRs.1,3ꢀ4,7 Seminal work in this area employing secondary amines includes the
groups of Barbas,8 MacMillan,9 Jørgensen,10 and Enders.11 However, MCRs utilizing tertiary
amine catalysis are rare.1
Results and Discussion
We previously described a method for the synthesis of biꢀ and tricyclicꢀβꢀlactones (e.g.
βꢀlactone 1) employing the intramolecular nucleophile (Lewis base)ꢀcatalyzed aldol βꢀ
lactonization (NCAL) process that relies on the intermediacy of chiral ammonium enolates
(Figure 1a).12 The groups of Smith,13 Lupton,14 Matsubara,15 and Birman16 and our group have
described several organocascade processes that utilize chiral Lewis bases (nucleophilic cataꢀ
lysts) to generate chiral unsaturated acylammonium salts.17 We utilized unsaturated acid chloꢀ
rides as key intermediates for Michaelꢀproton transferꢀlactamizations,18 nucleophile(Lewis
base)ꢀcatalyzed, Michaelꢀaldolꢀβꢀlactonizations (NCMAL),19 Michaelꢀenol lactonizations,18,20
DielsꢀAlderꢀlactonizations21 and DielsꢀAlderꢀlactamizations.22 Despite the efficiency of generatꢀ
ing three bonds in one operation using commodity acid chlorides, the NCMAL methodology
requires the preparation of a malonate substrate bearing a pendant ketone or aldehyde. A poꢀ
tential solution we envisioned was the in situ generation of the required malonate substrate via
a Michael addition between ketone 4 and an alkylidene malonate 5 that would also directly deꢀ
liver the required malonate enolate (e.g. 6) as a racemate. A subsequent enantioselective Miꢀ
chaelꢀaldolꢀβꢀlactonization cascade involving a potential kinetic resolution of the derived raceꢀ
mic enolate (±)ꢀ6 would deliver optically active biꢀ or tricyclicꢀβꢀlactones 1. Herein, we detail
complexityꢀgenerating, MCR organocascades that deliver biꢀ and tricyclic βꢀlactones 1 through
2
ACS Paragon Plus Environment

Page 3 of 31
The Journal of Organic Chemistry
formation of 3 CꢀC bonds, 1 CꢀO bond, 2 rings, and up to 4 stereocenters from commercially
available or readily available unsaturated acid chlorides 3, ketones 4, and alkylidene maloꢀ
nates 5.
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
Figure 1. a) Previously described intramolecular nucleophile (Lewis base)ꢀcatalyzed aldolꢀβꢀ
lactonization (NCAL) process toward bicyclicꢀβꢀlactones. b) This work: a multiꢀcomponent apꢀ
proach toward bicyclicꢀβꢀlactones via a MichaelꢀMichaelꢀaldolꢀβꢀlactonization involving a poꢀ
tential kinetic resolution.
The [4.2.0] bicyclic βꢀlactone motif is found in several bioactive natural products and is
also a useful intermediate to access other structures.23 Papyriogenin G,24 isolated from a plant
species used in traditional medicine to treat bacterial infections, inflammation and cancer,
rubesanolides A/B,25 and the unnamed, naturally occuring βꢀlactone 9 which exhibits thrombin
inhibitory activity all bear the bicyclic βꢀlactone motif (Figure 2). In addition, the alkoxy acids 10
could potentially be obtained through hydrolysis and esterification of an appropriately substiꢀ
tuted [4.2.0] bicyclic βꢀlactone.26
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 31
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
Figure 2. Natural products and bioactive molecules containing or potentially derived from
[4.2.0] bicyclicꢀβꢀlactones (highlighted in red).
We began our studies by exploring various Michael donors and acid chlorides employing the
achiral Lewis base, 4ꢀpyrrolidinopyridine (4ꢀPPY) for a MMAL delivering racemic product buildꢀ
ing on our single example reported previously.19 Both cyclic and acyclic βꢀketoesters along
with diketones were studied in addition to simple ketones as Michael donors. The initial proceꢀ
dure involved deprotonation of the Michael donor 4 with LiHMDS, addition of alkylidene maloꢀ
nate 5, 4ꢀpyrrolidinopyridine (4ꢀPPY), and Hünig’s base, and finally slow addition of acid chloꢀ
ride 3 in a binary solvent, 1:4 THF/CH2Cl2. In our initial studies, we used acyclic Michael donor
4a, methylene malonate 5a, and acryloyl chloride (3a) which indeed gave the adduct 1a in low
yield. A brief optimization of a few reaction parameters revealed that 1:1 THF/CH2Cl2 gave the
best yields providing the bicyclic βꢀlactone 1a in 54% yield but as a 1:1 mixture of diastereꢀ
omers (Table 1, entry 1). These conditions were then applied to other Michael donors and acid
chlorides. Acyclic βꢀketoester, αꢀbenzyl βꢀketoester 4b, also gave the bicyclic βꢀlactone 1b in
75% yield as a ~1:1 mixture of diastereomers. In contrast to the acyclic βꢀketoesters, cyclic βꢀ
1
ketoester 4c gave adduct 1c as a single diastereomer (>19:1, crude H NMR) employing croꢀ
tonoyl chloride albeit in <10% yield, however use of racemic HBTM led to some improvement
in conversion (22%, Table 1, entry 3). Use of the more reactive Michael acceptor, ethyl fumaꢀ
royl chloride (3c), led to an improved yield of adduct 1d (32%, Table 1, entry 4). Employing
highly reactive acryloyl chloride led to further improvement delivering tricyclic βꢀlactone 1e in
58% yield with useful diastereoselectivity (9:1) (Table 1, entry 5). Other Michael donors (e.g.
cyclohexanone, 2,4ꢀpentanedione, 2ꢀmethylꢀ1,3ꢀcyclohexanedione, 3,4ꢀdihydronaphthalenꢀ
2(1H)ꢀone, 3,3,5,5ꢀtetramethylcyclohexanꢀ1ꢀone), Michael acceptors (bisꢀsulfonyl, bisꢀcyano,
and βꢀphenyl and β,βꢀdimethyl alkylidene malonates), and acid chlorides (βꢀiꢀpropyl, βꢀphenyl,
4
ACS Paragon Plus Environment

Page 5 of 31
The Journal of Organic Chemistry
α,βꢀdimethyl and βꢀpropenyl acryloyl chloride) were investigated, however only trace amounts
of βꢀlactones were detected by IR analysis of crude reaction mixtures (βꢀlactone C=O stretch:
~1820 cmꢀ1; see SI for further details).
1
2
3
4
5
6
7
8
9
Table 1. Screening Michael donors 4 in the MMAL organocascade delivering racemic βꢀ
lactone 1
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
aYields refer to isolated yields. bRacemic HBTM ((±)ꢀ
14, 20 mol %) was used as Lewis base and the reꢀ
action was performed at ꢀ20 °C.
We next optimized the enantioselective variant of this organocascade employing the
cyclic βꢀketoester 4c and crotonoyl chloride (3b) since racemic HBTM ((±)ꢀ14) had previously
delivered βꢀlactone 1c in low yield (Table 1, entry 3). The UV active dibenzyl methylenemaloꢀ
nate 5b was employed to facilitate optical purity determination by chiral HPLC. It is important
to note that without equilibration of the initial Michael reaction, if a kinetic resolution is operaꢀ
tive, the maximum yield would be 50%. However, if equilibration is possible, a dynamic kinetic
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 31
asymmetric transformation (DYKAT) is possible. Given the typically high enantioselectivity obꢀ
served with isothiourea catalysts, we anticipated a matched/mismatched pairing between the
enantiomeric malonate anions 6 and the chiral unsaturated acylammonium salt would lead to a
kinetic resolution. Several chiral Lewis bases were screened including the commercially availꢀ
able isothiourea Lewis bases benzotetramisole (BTM, 11) and tetramisole (12). These gave
the desired adduct 1c in moderate enantiomeric ratios (Table 2, entries 1ꢀ3). The silylated cinꢀ
chona alkaloid, TMSQN (13), led to an improved enantioselectivity (93:7 er) albeit in only 18%
yield (Table 2, entry 4). Improvements in both yields and enantioselectivity were observed
when the isothiourea catalysts HBTM (14) and HBTM 2.1 (15) were employed (Table 2, entries
5ꢀ9). In particular, use of HBTM 2.1 (15), a readily prepared derivative of Birman’s HBTM Lewꢀ
is base developed by Smith,27 delivered tricyclic βꢀlactone 1c in 43% yield and 93.5:6.5 er (Taꢀ
ble 2, entry 7). Neither increasing the amount of acid chloride 3b (Table 2, entry 8) nor reversꢀ
ing the stoichiometry of the reagents (Table 2, entry 9) led to any further improvement in yields
or enantioselectivity of the desired βꢀlactone 1c. The maximum yield obtained (<50%) provides
indirect evidence that a kinetic resolution of the initially formed Michael adduct (±)ꢀ6 is indeed
in operation.
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
Table 2. Optimization of the enantioselective MMAL with cyclopentyl Michael donor 4c and
crotonoyl chloride (3b)
aPerformed with 2.0 equiv of 3b. bPerformed with 2.0
equiv of 4c, 2.1 equiv of 5b and 1.0 equiv of 3b.
6
ACS Paragon Plus Environment

Page 7 of 31
The Journal of Organic Chemistry
We next sought to expand the scope of the enantioselective MMAL by studying various elecꢀ
tron withdrawing groups on both cyclopentyl and cyclohexyl Michael donors 4 and the use of
various acid chlorides 3 (Table 3). Ethyl fumaroyl chloride (3c, R2 = CO2Et) and Michael donor
4c with BTM (11) gave a 61% yield of the tricylic adduct 1d with a 94:6 enantiomeric ratio. This
yield suggests that a DYKAT is in operation to some extent and may reflect the greater stability
of the highly conjugated unsaturated acylammonium salt derived from 3c. When acryloyl chloꢀ
ride (3a) was used with both the ethyl (5a) and benzyl (5b) alkylidene malonates, the enantioꢀ
meric ratio dropped dramatically to 66.5:33.5 and 72:28 for er adducts 1e and 1f, respectively.
Reduced enantioselectivity was also observed when an αꢀcyanocyclopentanone (4d) was emꢀ
ployed as Michael donor leading to adducts 1g and 1h, respectively. We propose that the inaꢀ
bility to form a bidentate chelate with the Li cation in the intermediate βꢀcyano enolates of theꢀ
se Michael donors may lead to less ordered transition states and therefore reduced enantioꢀ
meric ratios. The importance of Li+ as a counter ion, versus Na+ for example, enabling chelaꢀ
tion with the Michael donor (enolate) and Michael acceptor (carbonyl of unsaturated acyl amꢀ
monium salt) (cf. Li chelate, Fig. 4, inset) was also observed in our previously described Miꢀ
chaelꢀproton transferꢀenolꢀlactamization and lactonization.18 αꢀCarboethoxy cyclohexanone
Michael donor 4f with αꢀmethylacryloyl chloride (3b) and ethyl fumaroyl chloride (3c) also deꢀ
livered the anticipated adducts 1i and 1j, respectively, albeit in reduced yields. αꢀ
Phenylsulfonyl Michael donor 4e was also a suitable substrate in this reaction producing 1k
and 1l in moderate yield and enantioselectivity. Generally, BTM (19) was the superior catalyst
for ethyl fumaroyl chloride (3c) while HBTM 2.1 was better suited for the less reactive croꢀ
tonoyl chloride (3b). As previously reported, the relative and absolute stereochemistry of βꢀ
lactone 1d was confirmed by Xꢀray crystallography of a derived amide.19 The relative and abꢀ
solute stereochemistry of other tricylic βꢀlactones was assigned by analogy to 1d along with
coupling constant analysis (see SI for details). As expected, the enantiomeric series of cyꢀ
cloadducts was obtained when (2S, 3R)ꢀHBTM 2.1 (15) was utilized as Lewis base versus (S)ꢀ
BTM (11) and this was confirmed by comparative chiral HPLC.
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
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 31
Table 3. Substrate scope of the enantioselective MMAL organocascade
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
b
aPerformed with 20 mol% 15 at 0 ºC, 0.1 M conc. Performed
c
with 20 mol % 11 at ꢀ20 ºC, 0.1 M. Performed with 20 mol %
(S)ꢀ11 at 0 → 23 ºC, 0.1 M. Performed with 20 mol% 15 at 0
d
→ 23 ºC, 0.05 M.
While the reaction yields of most of these multicomponent organocascade processes reꢀ
mained below 50% as expected for a kinetic resolution, due to a presumed slower mismatched
catalyst/substrate enantiomeric pair, a few substrates under varying conditions did provide
>50% yield with enantiomeric ratios indicative of a potential dynamic kinetic asymmetric transꢀ
formation (DYKAT) (e.g. adduct 1d).28 The potential for a DYKAT was investigated further by
screening several reaction parameters (catalysts and catalyst loadings, reaction times, temꢀ
peratures) to determine if conditions could be identified to increase yields through a retroꢀ
Michael addition enabling racemization of the initial Michael adduct (±)ꢀ6. Selected optimizaꢀ
tion reactions are provided in Table 4. Initial reaction conditions involved deprotonation of keꢀ
toester 4c at ꢀ78 °C then addition of Brønsted and Lewis bases at the same temperarute folꢀ
lowed by warming to 0 °C and syringe pump addition of acid chloride 3c at that temperature.
Increased reaction times did not improve the yield, however increased catalyst loading to 40
mol% and warming to ambient temperature led to the first yields above 50% (entry 3). Use of
8
ACS Paragon Plus Environment

Page 9 of 31
The Journal of Organic Chemistry
thermodynamic base conditions (Hunig’s base/LiCl) with a 72 h reaction time did provide the
desired product but in lower yields (45%) and lower er (entry 4). Lowering the reaction temꢀ
perature for the 2nd stage of the process did lead to an increase in yield (53%) with a shorter
reaction time being optimal (20 vs 72 h, entry 6). Increasing the equivalents of the highly reacꢀ
tive Michael acceptor 5b did not improve conversion (entries 7,8). Running the entire seꢀ
1
2
3
4
5
6
7
8
o
9
quence at ꢀ20 C and a shorter initial deprotonation (30 min) led to the best conversion (61%,
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
entry 9) with good enantioselectivity (94:6 er) and comparable results were obtained with the
enantiomeric benzotetramisole catalyst (entry 10). Addition of LiHMDS to the mixture of keꢀ
toester 4c and malonate 5b did not alter the results (entry 11). Other isothiourea catalysts inꢀ
cluding HBTM (14) and HBTM 2.1(15) did not lead to further improvements (entries 12,13). In
summary, the maximum yield achieved for this presumed DYKAT was ~60% and likely reflects
the high reactivity of the alkylidene malonate 5b regenerated upon a retroꢀMichael reaction.
Table 4. Optimization studies of a potential DYKAT involving the MMAL organocascade leadꢀ
ing to tricyclicꢀβꢀlactone (+)ꢀ1d
O
O
ii)
EtO2C
Cl
O
i) LiHMDS, THF,
temp., 1 h
O
3c
O
CO2Et
EtO2C
Lewis base, iꢀPr2NEt
CO2Et
4c
BnO2C
CO2Bn
CO2Et
THF:CH2Cl2 (1:1)
temp., 20 h
(5 h syringe pump
addition of 3c)
OBn
Li
BnO2C CO2Bn
BnO2C
(±)ꢀ6
CH2
5b
(+)ꢀ1d
O
>19:1 dr
Entry
Lewis base (mol %)
% Yield, er
Conditions
1
2
(S)ꢀ(–)ꢀ11 (20)
ꢀ78→0→23 ºC, 5.5 h
ꢀ78 → 0 → 23 ºC, 20 h
43, 94.5:5.5
47, 94.5:5.5
“
“ (40)
“
56, 97.5:2.5
45, 90:10
3
4
5
“ (20)a
“ (20)
23 ºC, 72 h
ꢀ78 → ꢀ30 ºC, 72 h
ꢀ78 → ꢀ20 ºC, 20 h
ꢀ78 → ꢀ20 ºC, 20 h
30, 91.5:8.5
53, 96.5:3.5
6
“
“ (20)b
“ (20)c
“ (20)d
7
8
46, 96:4
47, 95.5:4.5
“
9
61, 94:6
ꢀ20 ºC, 20 h
(R)ꢀ(+)ꢀ11 (20)d
57, 90:10f
10
11
“
(S)ꢀ(–)ꢀ11 (20)e
(2S,3R)ꢀ15 (20)d
(S)ꢀ14 (20 mol%)
ꢀ20 ºC, 20 h
0 ºC, 20 h
53, 90:10
28, 82:18f
39, 82:18
12
13
ꢀ78 → 0 → 23 ºC, 20 h
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 31
All the reactions were performed with 1.0 equiv of 4c, 1.2 equiv of 5b
and 1.5 equiv of 3c unless indicated otherwise: a Thermodynamic base
conditions, iꢀPr2NEt (3 equiv) and LiCl (1 equiv), rather than LiHMDS
were used to generate the malonate anion. b 2 equiv of compound 5b
was used. c 4.0 equiv of 5b was used. d 30 min reaction time for step 1.
e4c and 5b were combined prior to addition of LiHMDS. fEnantiomeric
adduct (–)ꢀ1d was obtained.
1
2
3
4
5
6
7
8
9
We recognized the potential to introduce an additional stereocenter via a TsujiꢀTrost Pd(0)ꢀ
mediated deallylative decarboxylation with an appropriate malonate bearing a single alꢀ
lylester.29 Tricyclic βꢀlactone (–)ꢀ1m was prepared from the allyl, benzyl methylenemalonate 5c
and acid chloride 3c in 52% yield (Scheme 1). The βꢀlactone was determined to not be comꢀ
patible with temperatures required for the deallylative decarboxylation, thus it was opened with
benzylamine to deliver amide 16. Subjecting this amide to standard deallylative decarboxylaꢀ
tion conditions gave benzyl ester (+)ꢀ17 in 94% yield (12:1 dr). Under these decarboxylation
conditions, the αꢀethyl ester epimerized to the antiꢀ1,2ꢀdiester in high diastereomeric purity.
The enantiomeric purity of the major diastereomer was determined at this point and found to
be 97:3 er (12:1 dr).
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 1. Synthesis of bicyclic amide (+)ꢀ17 bearing five stereogenic centers
The relative and absolute stereochemistry of amide 17 was determined through NMR experiꢀ
ments including DEPT 135, 1Hꢀ13C HSQC, 1Hꢀ1H COSY, 1Hꢀ13C HMBC which were used to asꢀ
sign the H1, H2, and H3 protons. A NOESY experiment showed key correlations between H1
and H2, and H2 and H3. Coupling constants (JH1ꢀH2 = 3.9 Hz, JH2ꢀH3 = 5.4 Hz) were then used
to assign the relative stereochemistry of 17 (Figure 3). The absolute stereochemistry of 17 was
assigned by analogy to βꢀlactone 1d (secured through Xꢀray analysis of a derived amide19)
employing the same Lewis base promoter, (–)ꢀBTM (11).
10
ACS Paragon Plus Environment

Page 11 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Figure 3. Key coupling assignments and NOESY correlations enabling assignment of the relaꢀ
tive stereochemistry of amide (+)ꢀ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 proposed catalytic cycle for the MMAL process is shown in Figure 4. During the
MMAL organocascade, an in situ generated, racemic Michael adduct (±)ꢀ6 from βꢀketoester 4c
and alkylidene malonate 5b is formed initially. Based on a previously described DFTꢀ
calculated model of the unsaturated acylammonium salt 18 derived from BTM (11),21b this inꢀ
termediate adopts an extended sꢀcis conformation of the unsaturated amide and alleviates
nonꢀbonded interactions enforced by a proposed no → σ*CꢀS interaction.21b,13a,13c,30 The chiral
α,βꢀunsaturated acylammonium salt 18 then undergoes a stereochemicalꢀsetting Michael reꢀ
action with one enantiomer of enolate (±)ꢀ6 leading to a kinetic resolution and proceeding from
the least hindered face, opposite the phenyl group of the catalyst via a possible Liꢀchelate as
depicted (inset, Figure 4). The intermediate ammonium enolate 19, bearing a pendant ketone,
can adopt a chairꢀlike transition state arrangement enforced by a presumed Liꢀbidentate cheꢀ
late enabling the aldol βꢀlactonization to form βꢀlactone 1d via aldolate 20. We previously reꢀ
ported that the diastereoselectivity of the initial aldol reaction is substrateꢀcontrolled due to
A1,3ꢀstrain12b and the ring strain associated with formation of an alternative transꢀfused bicyclic
system further enforces this diastereoselectivity in the aldol step followed by a rapid βꢀ
lactonization to give βꢀlactone 1d. Again, yields that only reach 61% provide some evidence
for a DYKAT but the described MMAL is primarily a simple kinetic resolution.
Figure 4. Proposed catalytic cycle for the MMAL reaction and DFTꢀderived conformational
model of the HBTMꢀderived acylammonium salt (inset)
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 31
CO2Et
O
BnO2C
BnO2C
O
+ LiCl
1
2
3
4
5
6
EtO2C
Cl
S
O
3c
2nd Michael
addition
N
BnO
CO2Et
N
EtO2C
1d
(±)ꢀ6
O
Ph
O
Nꢀacylation
(S)ꢀBTM (11)
O
siꢀface
OBn
addition
βꢀlactonization
Li
nO → σ*CꢀS
2.8 Å
S
7
8
9
S
O
O
O
EtO2C
BnO2C
BnO2C
EtO2C
N
N
O
N
N
Cl
Cl
18
Ph
18
Ph
EtO2C
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
Li
20
kinetic resolution
of (±)ꢀ6
O
CO2Et
BnO2C
CO2Bn
LiHMDS
Li
H
+
CO2Et
Aldol
reaction
OBn
O
O
BnO2C
EtO2C
BnO2C
CH2
5b
S
CO2Et
1st Michael
addition
2nd Michael
addition
BnO2C
(±)ꢀ6
O
4c
N
N
Li
Ph
Cl
Reversible? → DYKAT
19
aThe energyꢀminimized conformation of unsaturated acylammonium 18 was computed using
SMD(DCM)ꢀM06ꢀ2X/6ꢀ31G(d) (see refs. 18,21b) Inset shows the second, stereochemicalꢀ
setting Michael addition and the proposed Li+ chelate between the acylammonium and the
Michael donor.
In conclusion, chiral α,βꢀunsaturated acylammonium salts are useful intermediates for a
catalytic, enantioselective, threeꢀcomponent organocascade providing access to tricyclic βꢀ
lactones through a MichaelꢀMichaelꢀaldolꢀβꢀlactonization. In a single operation, this orꢀ
ganocascade forms four bonds, two rings and up to four contiguous stereocenters with serꢀ
viceable enantioꢀ and diastereoselectivity. While some evidence for a DYKAT process was
found for this organocascade proceeding through a presumed MichaelꢀretroꢀMichael process,
maximum yields were 53ꢀ61% (94:6 → 97.5:2.5 er). By exploiting this multicomponent proꢀ
cess, complex, stereochemically rich biꢀ and tricyclic structural motifs can be accessed in a
single step that also importantly bear a βꢀlactone, useful for further functionalizations17a,31 and
as tools for activityꢀbased proteomics.32
EXPERIMENTAL SECTION
General information
All nonꢀaqueous reactions were performed under a nitrogen or argon atmosphere in
ovenꢀdried glassware. Dichloromethane (CH2Cl2), tetrahydrofuran (THF) were dried by passꢀ
ing through activated molecular sieves or alumina (solvent purification system). Diisoproꢀ
pylethylamine (iꢀPr2NEt) was distilled from potassium hydroxide prior to use. Other solvents
and reagents were used as received from commercially available sources. Deuterated solꢀ
vents were purchased from either Aldrich or Cambridge Isotopes and used as received. 1H
12
ACS Paragon Plus Environment

Page 13 of 31
The Journal of Organic Chemistry
NMR spectra were measured at 600, 500, 400 and 300 MHz and referenced relative to residꢀ
ual chloroform (7.26 ppm) and was reported in parts per million. Coupling constants (J) were
reported in Hertz (Hz), with multiplicity reported following usual convention: s, singlet; d, douꢀ
blet; t, triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, douꢀ
1
2
3
4
5
6
7
8
13
blet of triplets; dq, doublet of quartets; m, multiplet; bs, broad singlet; app, apparent. C NMR
9
spectra were measured at 150, 125, 100, and 75 MHz and referenced relative to residual chloꢀ
roform (77.2 ppm) and was reported in parts per million (ppm). Flash column chromatography
was performed with 60Å Silica Gel (230ꢀ400 mesh) as stationary phase using a gradient solꢀ
vent system or on an automated flash chromatography system (EtOAc/hexanes as eluent unꢀ
less indicated otherwise). High resolution mass spectra (ESI) were obtained through Texas
A&M University Laboratory for Biological Mass Spectrometry and Baylor University Mass
Spectrometry Center. Thin Layer Chromatography (TLC) was performed using glassꢀbacked
silica gel F254 (Silicycle, 250 ꢁm thickness). Visualization of developed plates was performed
by fluorescence quenching unless indicated otherwise. Fourier Transform Infrared (FTIR)
spectra were recorded as thin films on NaCl plates. Optical rotations were recorded on a polarꢀ
imeter at 589 nm employing a 25 mm cell. High Performance Liquid Chromatography (HPLC)
was performed on a chromatographic system using various chiral columns (25 cm) as noted.
Xꢀray analysis was performed in the Xꢀray Diffraction Laboratory at Texas A&M University.
OꢀTMS quinine33 (TMSQN) was synthesized according to literature procedures. Benzoꢀ
tetramisole, (+)ꢀBTM and (–)ꢀBTM were purchased from TCI chemicals. Acid chlorides 3aꢀc
were purchased from SigmaꢀAldrich and used as received.
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
Safety/Hazards
PhSeBr is highly toxic and careful handling should be exercised. Specifically, besides standard
personal protection equipment (lab coat, goggles, and gloves), minimum inhalation exposure
was ensured by handling of this reaction in a wellꢀventilated hood or in closed vial when being
weighed. The residual amount of PhSeBr, left in vials or syringes, was quenched with sat. soꢀ
lution of Na2S2O3 followed by appropriate disposal of the solution and containing vessels.
Diethyl 2ꢀmethylenemalonate (5a). The alkylidene malonate was prepared by a modified litꢀ
erature procedure.34 Into an ovenꢀdried, 500ꢀmL roundꢀbottomed flask equipped with a stir bar
was placed NaH (60% suspension in mineral oil, 1.50 g, 37.5 mmol, 1.5 equiv) and THF (90
mL) under N2. The slurry was cooled to 0 °C and diethyl 2ꢀmethylmalonate (purchased from
SigmaꢀAldrich and used as received) (4.27 mL, 25.0 mmol, 1.0 equiv) was added dropwise via
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 31
a syringe over 5 min. After gas evolution had ceased, a solution of PhSeBr (7.08 g, 30.0 mmol,
1.2 equiv) in THF (30 mL) was quickly added at 0 °C, resulting in a bright yellow solution. After
30 min, the reaction mixture was diluted with Et2O (20 mL) and quenched with saturated Naꢀ
HCO3 (50 mL). The organic layer was separated and washed with 10% NaHSO3 (2 ✕ 50 mL),
1
2
3
4
5
6
7
8
H2O (3 ✕ 50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated by rotary
9
evaporation, and purified by an automated flash chromatography system (0 → 50%
EtOAc/hexanes) to afford diethyl 2ꢀmethylꢀ2ꢀ(phenylselenyl)malonate which was carried on
directly to the next step.
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 ovenꢀdried, 250ꢀmL roundꢀbottomed flask was charged with a solution of diethyl 2ꢀ
methylꢀ2ꢀ(phenylselenyl)malonate in anhydrous CCl4 (34 mL), followed by addition of H2O2
(35% in H2O, 21.4 mL, 250 mmol, 10.0 equiv). The reaction temperature was maintained at
ambient temperature (23 °C) using a water bath. After 2 h, H2O (10 mL) was added to dissolve
the white precipitate. The organic layer was then separated and the aqueous phase was exꢀ
tracted with anhydrous CCl4 (3 ✕ 10 mL), and the combined organics were dried over anhyꢀ
drous Na2SO4. The filtrate was concentrated by rotary evaporation (without heating) to afford
diethyl 2ꢀmethylenemalonate 5a (4.1 g, 94% yield, light yellow liquid) of sufficient purity to be
used directly in the next step (Note: purification of this unstable compound led to extensive
loss of material on silica gel). The reactive malonate alkylidene 5a was stored as a solution in
anhydrous benzene (1.0 M) at –20 °C to prevent decomposition likely through polymerization.
TLC (EtOAc:hexanes, 1:9 v/v): Rf = 0.50; 1H NMR (300 MHz, CDCl3): δ 6.46 (s, 2H), 4.24 (q, J
= 7.2 Hz, 4H), 1.28 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 164.0, 135.2, 134.0, 61.5,
14.1. Other spectral data matched that previously reported.35
Dibenzyl 2ꢀmethylenemalonate (5b). Dibenzyl 2ꢀmethylmalonate A1 was prepared by a
modified literature procedure.36 In an ovenꢀdried, 250ꢀmL roundꢀbottomed flask, dibenzyl maꢀ
lonate (14.2 g, 50.0 mmol, 1.0 equiv) and anhydrous K2CO3 (8.3 g, 60.0 mmol, 1.2 equiv) were
dissolved in anhydrous acetone (50 mL) and stirred at ambient temperature (23 °C) for 5 min,
then iodomethane (3.73 mL, 60.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture
was refluxed (60ꢀ65 °C) for 20 h. Upon completion (as judged by TLC with complete consumpꢀ
tion of dibenzyl malonate), the reaction mixture was diluted with Et2O (50 mL) and filtered
through a pad of celite (Et2O wash). The filtrate was concentrated by rotary evaporation, and
purified by an automated flash chromatography system (0 → 10% EtOAc/hexanes) to obtain
dibenzyl 2ꢀmethylmalonate A1 (12.6 g, 85% yield) as a clear liquid. Spectral data matched that
previously reported.37
14
ACS Paragon Plus Environment

Page 15 of 31
1
2
3
4
5
6
7
The Journal of Organic Chemistry
Dibenzyl 2ꢀmethylenemalonate 5b was prepared by a modified literature procedure.34
Into an ovenꢀdried, 250ꢀmL roundꢀbottomed flask equipped with a stir bar was added NaH
(60% suspension in mineral oil, 1.40 g, 35.0 mmol, 1.5 equiv) and then THF (80 mL) and the
slurry was cooled to 0 °C under N2. To the slurry was slowly added a solution of dibenzyl 2ꢀ
methylmalonate A1 (6.90 g, 23.3 mmol, 1.0 equiv) in THF (10 mL) via a syringe over 30 min
using a syringe pump. After gas evolution had ceased (~ 5 min after complete addition of A1
solution), a solution of PhSeBr (6.61 g, 28.0 mmol, 1.2 equiv) in THF (20 mL) was quickly
added at 0 °C using a syringe over 2 min, resulting in a bright yellow solution. After 30 min, the
reaction mixture was diluted with Et2O (20 mL) and quenched with saturated NaHCO3 (50 mL).
The organic layer was separated and washed with 10% NaHSO3 (2 ✕ 50 mL), H2O (3 ✕ 50
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
mL) and dried over anhydrous Na2SO4. The filtrate was concentrated by rotary evaporation,
and purified by an automated flash chromatography system (0 → 10% EtOAc/hexanes) to afꢀ
ford dibenzyl 2ꢀmethylꢀ2ꢀ(phenylselanyl)malonate and carried directly to the next step.
An 100ꢀmL roundꢀbottomed flask was charged with a solution of dibenzyl 2ꢀmethylꢀ2ꢀ
(phenylselanyl)malonate in anhydrous CCl4 (30 mL), followed by addition of H2O2 (35% in
H2O, 20.0 mL, 233 mmol, 10.0 equiv). The reaction temperature was maintained at ambient
temperature (23 °C) using a water bath. After 2 h, H2O (10 mL) was added to dissolve the
white precipitate. The organic layer was then separated and the aqueous phase was extracted
with anhydrous CCl4 (3 ✕ 10 mL), and the combined organics were dried over anhydrous
Na2SO4. The filtrate was concentrated by rotary evaporation to afford pure dibenzyl 2ꢀ
methylenemalonate 5b (5.67 g, 83% yield, light yellow liquid) of sufficient purity to be used diꢀ
rectly in the next step (Note: purification of this compound led to extensive loss of material on
silica). The compound 5b was stored as a solution in anhydrous benzene (1.0 M) at –20 °C to
1
prevent decomposition. TLC (EtOAc:hexanes, 2:8 v/v): Rf = 0.80; H NMR (400 MHz, CDCl3):
δ 7.42ꢀ7.35 (m, 10H), 6.65 (s, 2H), 5.31 (s, 4H); 13C NMR (100 MHz, CDCl3): δ 163.7 (2),
135.6 (2), 135.4, 134.5, 128.6 (4), 128.4 (2), 128.3 (4), 67.3 (2); IR (thin film): 3066, 3034,
2956, 1735, 1498, 1456 cmꢀ1; HRMS (ESI+) m/z calcd for C18H16O4Na [M+Na]+: 319.0941;
found 319.0929.
Representative procedure for MichaelꢀMichaelꢀaldolꢀβꢀlactonization delivering racemic βꢀ
lactone as described for bicyclic βꢀlactone 1a:
Triethyl (1S,6S)ꢀ5,6ꢀdimethylꢀ8ꢀoxoꢀ7ꢀoxabicyclo[4.2.0]octaneꢀ3,3,5ꢀtricarboxylate ((±)ꢀ
1a). An ovenꢀdried, 10ꢀmL roundꢀbottomed flask was charged with a solution of LHMDS (0.33
mL of 1.0 M solution in THF, 0.33 mmol, 1.1 equiv) and diluted with THF (0.5 mL) at ꢀ78 °C,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 31
followed by slow, dropwise addition of a solution of βꢀketoester 4a (43 mg, 0.30 mmol, 1.0
equiv) in THF (0.5 mL) by syringe over ~ 2 min. The resulting mixture was warmed to 0 °C and
stirred for 30 min, then a solution of diester 5a (0.33 mL of 1.0 M solution in benzene, 0.33
mmol, 1.1 equiv), diluted to 1.0 mL with THF, was added dropwise via a syringe over ~ 3 min.
After 30 min at 0 °C, a solution of 4ꢀPPY (9 mg, 0.06 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL,
0.30 mmol, 1.0 equiv), weighed out in a vial and diluted with CH2Cl2 (1.0 mL), was added via a
syringe. A solution of acid chloride 3a (41 mg, 1.5 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL) was
then added at 0 °C over 30 min by a syringe pump. The reaction temperature was maintained
at 0 °C throughout the addition of 3a and then the reaction was stirred at ambient temperature
(23 °C) for an additional 15 h. The reaction was then concentrated by rotary evaporation and
the product was purified by an automated flash chromatography system (gradient of 0 to 40%
EtOAc/hexanes) to afford two separable 2 diastereomers of bicyclicꢀβꢀlactone 1a (diastereꢀ
omer A: 30 mg, 27% yield; diastereomer B: 30 mg, 27% yield;) as a yellow, viscous liquid. Diꢀ
astereomer A: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.38. 1H NMR (500 MHz,
benzeneꢀd6): δ 4.00 – 3.81 (m, 6H), 3.52 (d, J = 16.0 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H), 2.70
(dd, J = 6.3, 2.6 Hz, 1H), 2.61 (dd, J = 16.6, 2.6 Hz, 1H), 2.52 (dd, J = 16.6, 6.3 Hz, 1H), 1.37
(s, 3H), 1.13 (s, 3H), 0.91 (t, J = 7.1 Hz, 3H), 0.85 (app q, J = 7.1 Hz, 6H); 13C NMR (125 MHz,
benzeneꢀd6) δ 172.6, 172.2, 171.2, 168.9, 78.7, 62.4, 62.0, 61.5, 54.3, 51.3, 47.9, 31.6, 23.5,
21.3, 20.2, 14.0, 13.9, 13.8. IR (thin film): 2983, 2940, 1828, 1731, 1449 cmꢀ1; HRMS (ESI+)
m/z calcd for C18H26O8Na [M+Na]+: 393.1520, found: 393.1506. Diastereomer B: TLC
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
1
(EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.32. H NMR (500 MHz, benzeneꢀd6): δ
4.00 – 3.81 (m, 6H), 3.52 (d, J = 16.0 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H), 2.70 (dd, J = 6.3, 2.6
Hz, 1H), 2.61 (dd, J = 16.6, 2.6 Hz, 1H), 2.52 (dd, J = 16.6, 6.3 Hz, 1H), 1.37 (s, 3H), 1.13 (s,
3H), 0.91 (t, J = 7.1 Hz, 3H), 0.85 (app q, J = 7.1 Hz, 6H); 13C NMR (125 MHz, benzeneꢀd6): δ
172.6, 172.2, 171.2, 168.9, 78.7, 62.4, 62.0, 61.5, 54.3, 51.3, 47.9, 31.6, 23.5, 21.3, 20.2,
14.0, 13.8, 13.8; IR (thin film): 2983, 2940, 1828, 1731, 1449 cmꢀ1; HRMS (ESI+) m/z calcd for
C18H26O8Na [M+Na]+: 393.1520, found: 393.1506.
Triethyl (1S,6S)ꢀ5ꢀbenzylꢀ6ꢀmethylꢀ8ꢀoxoꢀ7ꢀoxabicyclo[4.2.0]octaneꢀ3,3,5ꢀtricarboxylate
((±)ꢀ1b): Prepared according to the procedure described for compound 1a using LHMDS (0.33
mL of 1.0 M solution in THF, 0.33 mmol, 1.1 equiv) in THF (0.5 mL), ethyl 2ꢀ
benzylacetoacetate 4b (66 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL), a solution of diester 5a
(0.33 mL of 1.0 M solution in benzene, 0.33 mmol, 1.1 equiv) in THF (0.5 mL), a solution of 4ꢀ
PPY (9 mg, 0.06 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (1.0
mL), and a solution of acid chloride 3a (41 mg, 1.5 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL). After
16
ACS Paragon Plus Environment

Page 17 of 31
The Journal of Organic Chemistry
20 h, the crude product was purified by an automated flash chromatography system (gradient
of 0 to 40% EtOAc/hexanes) to afford a 1:1 diastereomeric mixture of bicyclicꢀβꢀlactone 1b
(117 mg, 75% yield) as a yellow, viscous liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s
stain): Rf = 0.37. 1H NMR (500 MHz, benzeneꢀd6): δ 7.10 – 6.94 (m, 5H), 4.00 – 3.76 (m, 6H),
3.22 (d, J = 15.9 Hz, 1H), 3.09 (d, J = 13.5 Hz, 1H), 2.93 (d, J = 13.5 Hz, 1H), 2.81 – 2.73 (m,
1H), 2.70 – 2.63 (m, 2H), 2.61 – 2.51 (m, 1H), 1.48 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H), 0.82 (t, J =
7.2 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, benzeneꢀd6): δ 172.5, 172.2, 171.8,
171.17, 171.16, 170.9, 169.0, 168.6, 136.71, 136.69, 131.0, 130.0, 128.5, 128.35, 127.09,
126.94, 79.53, 79.43, 62.54, 62.46, 61.86, 61.76, 61.46, 61.08, 54.6, 52.69, 52.19, 52.09,
51.2, 40.3, 38.7, 31.8, 26.2, 24.3, 23.7, 22.6, 21.9, 13.91, 13.87, 13.80, 13.66, 13.54; IR (thin
film): 2980, 2918, 2849, 1829, 1733, 1455 cmꢀ1; HRMS (ESI+) m/z calcd for C24H30O8Na
[M+Na]+: 469.1833, found: 469.1818.
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
4,4ꢀdibenzyl
5aꢀethyl
(2aS,3S,5aR,8aS)ꢀ3ꢀmethylꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀ
b]oxeteꢀ4,4,5a(5H,6H)ꢀtricarboxylate ((±)ꢀ1c): Prepared according to the procedure for comꢀ
pound 1a using LHMDS (0.33 mL of 1.0 M solution in THF, 0.33 mmol, 1.1 equiv) in THF (0.5
mL), ethyl 2ꢀoxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL), a
solution of diester 5b (0.33 mL of 1.0 M solution in benzene, 0.33 mmol, 1.1 equiv) in THF (0.5
mL), a solution of (±)ꢀHBTM 14 (16 mg, 0.06 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol,
1.0 equiv) in CH2Cl2 (1.0 mL), and a solution of acid chloride 3b (47 mg, 1.5 mmol, 1.5 equiv)
in CH2Cl2 (1.0 mL). After 20 h, the crude product was purified by an automated flash chromaꢀ
tography system (gradient of 0 to 30% EtOAc/hexanes) to afford a single diasteremer (as
1
judged by crude H NMR) of tricyclicꢀβꢀlactone 1c (34.3 mg, 22% yield) as a yellow, viscous
liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.50. 1H NMR (500 MHz, CDCl3):
δ 7.43 – 7.22 (m, 10H), 5.21 (s, 2H), 5.13 (d, J = 4.3 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.26 (d,
J = 11.6 Hz, 1H), 2.98 (d, J = 15.2 Hz, 1H), 2.82 (dq, J = 13.3, 6.7 Hz, 1H), 2.60 (dt, J = 12.8,
6.6 Hz, 1H), 2.31 – 2.16 (m, 2H), 2.10 – 1.84 (m, 2H), 1.74 – 1.55 (m, 2H), 1.25 (t, J = 7.1 Hz,
3H), 1.21 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 173.1, 171.0, 170.8, 170.2, 135.3,
134.7, 128.83, 128.78 (4), 128.6 (2), 128.5, 128.4 (2), 87.3, 67.7, 67.6, 61.8, 57.5, 57.0, 52.5,
39.7, 39.0, 38.7, 33.7, 23.7, 16.8, 14.1; IR (thin film): 3065, 3034, 2963, 1828, 1729, 1498,
1455 cmꢀ1; HRMS (ESI+) m/z calcd for C30H33O8 [M+H]+: 521.2175, found: 521.2159.
4,4ꢀdibenzyl 3,5aꢀdiethyl (2aS,3S,5aR,8aS)ꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ
3,4,4,5a(5H,6H)ꢀtetracarboxylate ((±)ꢀ1d): Prepared according to the procedure for comꢀ
pound 1a using LHMDS (0.33 mL of 1.0 M solution in THF, 0.33 mmol, 1.1 equiv) in THF (0.5
mL), ethyl 2ꢀoxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL), a
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 31
solution of diester 5b (0.33 mL of 1.0 M solution in benzene, 0.33 mmol, 1.1 equiv) in THF (0.5
mL), a solution of 4ꢀPPY (9 mg, 0.06 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0
equiv) in CH2Cl2 (1.0 mL), and a solution of acid chloride 3c (73 mg, 1.5 mmol, 1.5 equiv) in
CH2Cl2 (1.0 mL). After 20 h, the crude product was purified by an automated flash chromatogꢀ
raphy system (gradient of 0 to 30% EtOAc/hexanes) to afford a single diasteremer (as judged
1
2
3
4
5
6
7
8
1
9
by crude H NMR) of tricyclicꢀβꢀlactone 1d (56.3 mg, 32% yield) as a yellow, viscous liquid:
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
TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.42; H NMR (500 MHz, CDCl3): δ
7.36ꢀ7.28 (m, 10H), 5.19 (app s, 2H), 5.16, 5.12 (ABq, JAB = 11.9 Hz, 2H), 4.15ꢀ4.04 (m, 4H),
4.02, 3.81 (ABq, JAB = 9.6 Hz, 2H), 3.06 (d, J = 15.1 Hz, 1H), 2.67ꢀ2.62 (m, 1H), 2.41 (d, J =
15.1 Hz, 1H), 2.18ꢀ2.14 (m, 1H), 1.80ꢀ1.70 (m, 1H), 1.67ꢀ1.54 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H),
1.17 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 172.5, 170.3, 170.2, 169.3, 168.1,
135.0, 134.3, 129.1 (2), 128.9, 128.7 (2), 128.6 (2), 128.4, 128.2 (2), 85.7, 68.3, 68.1, 61.91,
61.90, 55.9, 52.7, 52.2, 43.3, 39.7, 39.3, 39.2, 23.3, 13.9, 13.8; IR (thin film): 2978, 1836,
1737, 1453, 1370 cmꢀ1; HRMS (ESI+) m/z calcd for C32H35O10 [M+H]+: 579.2230, found:
579.2251.
Triethyl
(2aS,5aR,8aS)ꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ4,4,5a(5H,6H)ꢀ
tricarboxylate ((±)ꢀ1e): Prepared according to the procedure for compound 1a using LHMDS
(0.33 mL of 1.0 M solution in THF, 0.33 mmol, 1.1 equiv) in THF (0.5 mL), ethyl 2ꢀ
oxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL), a solution of
diester 5a (0.33 mL of 1.0 M solution in benzene, 0.33 mmol, 1.1 equiv) in THF (0.5 mL), a soꢀ
lution of 4ꢀPPY (9 mg, 0.06 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in
CH2Cl2 (1.0 mL), and a solution of acid chloride 3a (41 mg, 1.5 mmol, 1.5 equiv) in CH2Cl2 (1.0
mL). After 20 h, the crude product was purified by an automated flash chromatography system
1
(gradient of 0 to 45% EtOAc/hexanes) to afford a single diasteremer (as judged by crude H
NMR) of tricyclicꢀβꢀlactone 1e (66.4 mg, 58% yield) as a yellow, viscous liquid: TLC
1
(EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.47. H NMR (500 MHz, benzeneꢀd6): δ
3.99 – 3.90 (m, 4H), 3.82 (q, J = 7.1 Hz, 2H), 3.32 (dd, J = 10.2, 9.3 Hz, 1H), 3.04 (d, J = 15.2
Hz, 1H), 2.76 (dd, J = 14.2, 10.2 Hz, 1H), 2.63 – 2.47 (m, 2H), 2.25 (dd, J = 15.2, 1.3 Hz, 1H),
2.07 – 1.94 (m, 1H), 1.77 – 1.63 (m, 2H), 1.58 – 1.36 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H), 0.89 (t,
13
J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H); C NMR (125 MHz, benzeneꢀd6): δ 172.9, 171.6,
170.7, 169.4, 85.3, 61.8, 61.8, 61.7, 52.7, 52.5, 51.2, 39.4, 39.0, 37.1, 27.0, 23.3, 13.9, 13.9,
13.9; IR (thin film): 2979, 2873, 1834, 1733, 1465, 1367 cmꢀ1; HRMS (ESI+) m/z calcd for
C19H26O8Na [M+Na]+: 405.1520, found: 405.1508.
18
ACS Paragon Plus Environment

Page 19 of 31
The Journal of Organic Chemistry
Representative procedure for the enantioselective MichaelꢀMichaelꢀaldolꢀβꢀlactonization as
described for 1c and 1d:
1
2
3
4,4ꢀDibenzyl
5aꢀethyl
(2aS,3S,5aR,8aS)ꢀ3ꢀmethylꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀ
4
5
6
7
8
b]oxeteꢀ4,4,5a(5H,6H)ꢀtricarboxylate ((+)ꢀ1c). Into an ovenꢀdried, 10ꢀmL roundꢀbottomed
flask containing a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv)
in THF (0.5 mL) at 0 °C, was added dropwise a solution of ethyl 2ꢀoxocyclopentanecarboxylate
4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL) over ~ 2 min. The resulting mixture was
stirred for 15 min at 0 °C, followed by a dropwise addition of a solution of diester 5b (0.36 mL
of 1.0 M solution in benzene, 0.36 mmol, 1.2 equiv) in THF (0.5 mL) via syringe over ~ 2 min.
After 15 min at 0 °C, a solution of (2S,3R)ꢀHBTM 2.1 (19 mg, 0.060 mmol, 20 mol%) and i-
Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was added via syringe. A solution of
acid chloride 3b (38 mg, 0.36 mmol, 1.2 equiv) in CH2Cl2 (1.0 mL) was then added at 0 °C
over 5 h using a syringe pump. The reaction temperature was maintained at 0 °C throughout
the addition of 3b and then the reaction was stirred at this temperature for an additional 15 h.
The reaction was then concentrated by rotary evaporation and the product was purified by an
automated flash chromatography system (0 to 30% gradient of EtOAc/hexanes) to afford a
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
13
single diastereomer (>19:1 as judged by H and C NMR) of tricyclicꢀβꢀlactone 1c (67 mg,
43% yield) as a yellow, viscous liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf =
23.3
0.50.
+1.60 (c = 1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in
[α]
D
comparison with authentic racemic material using a Chiracel ADꢀH column: hexanes:iPrOH =
95:5, flow rate 1.0 mL/min, λ = 210 nm: tminor = 16.6 min, tmajor = 18.4 min; 93.5:6.5 er. Absolute
stereochemistry was tentatively assigned by analogy to βꢀlactone 1d via the use of “enantioꢀ
1
meric” HBTM 2.1 catalyst. H NMR (500 MHz, CDCl3): δ 7.43 – 7.22 (m, 10H), 5.21 (s, 2H),
5.13 (d, J = 4.3 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.26 (d, J = 11.6 Hz, 1H), 2.98 (d, J = 15.2
Hz, 1H), 2.82 (dq, J = 13.3, 6.7 Hz, 1H), 2.60 (dt, J = 12.8, 6.6 Hz, 1H), 2.31 – 2.16 (m, 2H),
2.10 – 1.84 (m, 2H), 1.74 – 1.55 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 173.1, 171.0, 170.8, 170.2, 135.3, 134.7, 128.83, 128.78 (4), 128.6
(2), 128.5, 128.4 (2), 87.3, 67.7, 67.6, 61.8, 57.5, 57.0, 52.5, 39.7, 39.0, 38.7, 33.7, 23.7, 16.8,
14.1; IR (thin film): 3065, 3034, 2963, 1828, 1729, 1498, 1455 cmꢀ1; HRMS (ESI+) m/z calcd
for C30H33O8 [M+H]+: 521.2175, found: 521.2159.
(2aR,3R,5aS,8aR)ꢀ4,4ꢀDibenzyl 3,5aꢀdiethyl 2ꢀoxohexahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ
3,4,4,5a(5H)ꢀtetracarboxylate ((+)ꢀ1d). Following the representation procedure, into an ovenꢀ
dried, 10ꢀmL roundꢀbottomed flask containing a solution of LHMDS (0.36 mL of 1.0 M solution
in THF, 0.36 mmol, 1.2 equiv) in THF (0.5 mL) at ꢀ20 °C, was added dropwise a solution of
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 31
ethyl 2ꢀoxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL) over ~
2 min. The resulting mixture was stirred for 15 min at ꢀ20 °C, followed by dropwise addition of
a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2 equiv) in THF
(0.5 mL) via syringe over ~ 2 min. After 15 min at ꢀ20 °C, a solution of (S)ꢀBTM (15 mg, 0.060
mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was prepared
in a vial and added via syringe. A solution of acid chloride 3c (59 mg, 0.36 mmol, 1.2 equiv) in
CH2Cl2 (1.0 mL) was then added at ꢀ20 °C over 5 h using a syringe pump. The reaction temꢀ
perature was maintained at ꢀ20 °C throughout the addition of 3c and then the reaction was
stirred at this temperature for an additional 15 h. The reaction was then concentrated by rotary
evaporation and the product was purified by an automated flash chromatography system (0 to
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
1
30% gradient of EtOAc/hexanes) to afford a single diastereomer (>19:1 as judged by H and
13C NMR) of tricyclicꢀβꢀlactone 1d (107 mg, 61% yield) as a yellow, viscous liquid: TLC
17
[ ] D
(EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.42;
+3.49 (c = 1.0, CHCl3). Enantiꢀ
α
omeric ratio was determined by HPLC analysis in comparison with authentic racemic material
using a Chiracel ASꢀH column: hexanes:iPrOH = 90:10, flow rate 1.0 mL/min, λ = 210 nm: tmaꢀ
jor = 11.7 min, tminor = 18.0 min; 94:6 er. Absolute and relative stereochemistry were determined
1
by amidation of βꢀlactone 1d as indicated below. H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.28 (m,
10H), 5.19 (app s, 2H), 5.16, 5.12 (ABq, JAB = 11.9 Hz, 2H), 4.15ꢀ4.04 (m, 4H), 4.02, 3.81
(ABq, JAB = 9.6 Hz, 2H), 3.06 (d, J = 15.1 Hz, 1H), 2.67ꢀ2.62 (m, 1H), 2.41 (d, J = 15.1 Hz,
1H), 2.18ꢀ2.14 (m, 1H), 1.80ꢀ1.70 (m, 1H), 1.67ꢀ1.54 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.17 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 172.5, 170.3, 170.2, 169.3, 168.1, 135.0, 134.3,
129.1 (2), 128.9, 128.7 (2), 128.6 (2), 128.4, 128.2 (2), 85.7, 68.3, 68.1, 61.91, 61.90, 55.9,
52.7, 52.2, 43.3, 39.7, 39.3, 39.2, 23.3, 13.9, 13.8; IR (thin film): 2978, 1836, 1737, 1453, 1370
cmꢀ1; HRMS (ESI+) m/z calcd for C32H35O10 [M+H]+: 579.2230, found: 579.2251. Absolute steꢀ
reochemistry was assigned by derivatization as described below.
Triethyl
(2aR,5aS,8aR)ꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ4,4,5a(5H,6H)ꢀ
tricarboxylate ((–)ꢀ1e). Prepared according to the procedure for compound 1d using a soluꢀ
tion of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv) in THF (0.5 mL), a
solution of ethyl 2ꢀoxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5
mL), a solution of diester 5a (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2 equiv) in
THF (0.5 mL), (S)ꢀBTM (15 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0
equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3a (41 mg, 0.45 mmol, 1.5 equiv) in
CH2Cl2 (1.0 mL). The reaction was warmed to 23 °C and stirred for an additional 15 h and then
20
ACS Paragon Plus Environment

Page 21 of 31
The Journal of Organic Chemistry
concentrated by rotary evaporation and the product was purified by an automated flash chroꢀ
matography system (0 to 30% gradient of EtOAc/hexanes) to afford a single diastereomer
(>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1e (44 mg, 39% yield) as a yellow,
1
2
3
4
5
6
7
22.5
viscous liquid: Spectral data match with previously synthesized lactone 1e.
= ꢀ12.13 (c =
[α]
D
1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authenꢀ
tic racemic material using a Chiracel ADꢀH column: hexanes:iPrOH = 99:1, flow rate 1.0
mL/min, λ = 230 nm: tminor = 42.0 min, tmajor = 46.7 min; 66.5:33.5 er. Absolute stereochemistry
was tentatively assigned by analogy to βꢀlactone 1d via the use of the same (–)ꢀBTM catalyst.
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
4,4ꢀDibenzyl
5aꢀethyl
(2aR,5aS,8aR)ꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ
4,4,5a(5H,6H)ꢀtricarboxylate ((–)ꢀ1f). Prepared according to the procedure for compound 1d
using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv) in THF
(0.5 mL), a solution of ethyl 2ꢀoxocyclopentanecarboxylate 4c (47 mg, 0.30 mmol, 1.0 equiv) in
THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2
equiv) in THF (0.5 mL), (S)ꢀBTM (15 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3a (41 mg, 0.45 mmol, 1.5
equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at 0 °C for an additional 15 h. The reaction
was then concentrated by rotary evaporation and the product was purified by an automated
flash chromatography system (0 to 30% gradient of EtOAc/hexanes) to afford a single diaꢀ
stereomer (>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1f (29 mg, 19% yield) as
24.0
a yellow, viscous liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): R = 0.47.
= ꢀ
[α]
D
f
52.00 (c = 1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison
with authentic racemic material using a Chiracel ASꢀH column: hexanes:iPrOH = 90:10, flow
rate 1.0 mL/min, λ = 210 nm: tminor = 21.7 min, tmajor = 27.5 min; 72:28 er. Absolute stereochemꢀ
istry was tentatively assigned by analogy to βꢀlactone 1d via the use of the same (–)ꢀBTM catꢀ
alyst. 1H NMR (500 MHz, CDCl3): δ 7.36 – 7.23 (m, 10H), 5.17 – 5.03 (m, 4H), 4.13 (q, J = 7.2
Hz, 2H), 3.52 (dd, J = 10.2, 9.4 Hz, 1H), 2.88 (d, J = 15.4 Hz, 1H), 2.65 – 2.43 (m, 3H), 2.27 –
2.15 (m, 2H), 1.94 – 1.77 (m, 2H), 1.68 – 1.57 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 173.0, 171.2, 170.5, 170.0, 135.2, 134.8, 128.9, 128.8 (2), 128.70 (2), 128.67
(2), 128.6, 128.3 (2), 85.7, 68.0, 67.8, 61.8, 52.4, 52.3, 50.6, 39.3, 38.8, 36.6, 26.7, 23.1, 14.1.
IR (thin film): 3064, 3034, 2927, 2871, 1832, 1732, 1498 cmꢀ1; HRMS (ESI+) m/z calcd for
C29H30O8Na [M+Na]+: 529.1833, found: 529.1819.
Dibenzyl (2aS,3S,5aS,8aS)ꢀ5aꢀcyanoꢀ3ꢀmethylꢀ2ꢀoxohexahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ
4,4(5H)ꢀdicarboxylate ((+)ꢀ1g): Prepared according to the procedure for compound 1c using
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 31
a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv) in THF (0.5
mL), a solution of cyclopentanoneꢀ2ꢀcarbonitrile 4d (33 mg, 0.30 mmol, 1.0 equiv) in THF (0.5
mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2 equiv) in
THF (0.5 mL), (2S,3R)ꢀHBTM 2.1 (19 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3b (38 mg, 0.36 mmol, 1.2
equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at 0 °C for an additional 15 h. The reaction
was then concentrated by rotary evaporation and the product was purified by an automated
flash chromatography system (gradient of EtOAc/hexanes) to afford a single diastereomer
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
(>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1g (35 mg, 25% yield) as a yellow,
24.6
viscous liquid: TLC (EtOAc:hexanes, 4:6 v/v, Hanessian’s stain): R = 0.53.
+13.33 (c =
[α]
D
f
0.68, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with auꢀ
thentic racemic material using a Chiracel ASꢀH column: hexanes:iPrOH = 80:20, flow rate 1.0
mL/min, λ = 210 nm: tmajor = 17.8 min, tminor = 26.7min; 60.5:39.5 er. Absolute stereochemistry
was tentatively assigned by analogy to βꢀlactone 1d via the use of “enantiomeric” HBTM 2.1
catalyst. 1H NMR (500 MHz, CDCl3): δ 7.42 – 7.18 (m, 10H), 5.23 (d, J = 12.1 Hz, 1H), 5.20 (d,
J = 12.1 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 3.31 (d, J = 8.3 Hz, 1H),
3.18 (dq, J = 8.4, 6.9 Hz, 1H), 2.80 (d, J = 15.3 Hz, 1H), 2.57 – 2.48 (m, 1H), 2.39 – 2.28 (m,
1H), 2.22 – 2.10 (m, 2H), 2.05 – 1.88 (m, 2H), 1.86 – 1.75 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ 169.8, 169.6, 167.9, 134.9, 134.4, 128.92, 128.82 (2), 128.78
(2), 128.67 (2), 128.63, 128.60 (2), 119.8, 84.3, 68.3, 68.07, 58.1, 56.3, 41.9, 39.8, 37.1, 36.8,
32.1, 22.8, 17.4. IR (thin film): 3034, 2968, 1838, 1735, 1455, 1217 cmꢀ1; HRMS (ESI+) m/z
calcd for C28H27NO6Na [M+Na]+: 496.1736, found: 496.1753.
4,4ꢀDibenzyl
3ꢀethyl
(2aR,3R,5aR,8aR)ꢀ5aꢀcyanoꢀ2ꢀoxohexahydroꢀ2Hꢀindeno[3a,4ꢀ
b]oxeteꢀ3,4,4(5H)ꢀtricarboxylate ((–)ꢀ1h): Prepared according to the procedure for comꢀ
pound 1d using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv)
in THF (0.5 mL), a solution of cyclopentanoneꢀ2ꢀcarbonitrile 4d (33 mg, 0.30 mmol, 1.0 equiv)
in THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2
equiv) in THF (0.5 mL), (S)ꢀBTM (15 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3c (59 mg, 0.36 mmol, 1.2
equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at ꢀ20 °C for an additional 15 h. The reacꢀ
tion was then concentrated by rotary evaporation and the product was purified by an automatꢀ
ed flash chromatography system (gradient of EtOAc/hexanes) to afford a single diastereomer
(>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1h (41 mg, 26% yield) as a yellow,
22
ACS Paragon Plus Environment

Page 23 of 31
The Journal of Organic Chemistry
25.2
viscous liquid: TLC (EtOAc:hexanes, 4:6 v/v, Hanessian’s stain): R = 0.43.
= ꢀ13.87 (c =
[α]
D
f
1
2
3
4
5
6
7
8
9
1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authenꢀ
tic racemic material using a Chiracel ADꢀH column: hexanes:iPrOH = 80:20, flow rate 1.0
mL/min, λ = 210 nm: tminor = 14.98 min, tmajor = 18.88 min; 79:21 er. Absolute stereochemistry
was tentatively assigned by analogy to βꢀlactone 1d via the use of the same (–)ꢀBTM catalyst.
1H NMR (500 MHz, CDCl3): δ 7.41 – 7.16 (m, 10H), 5.29 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.1
Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 5.02 (d, J = 12.2 Hz, 1H), 4.09 – 3.91 (m, 4H), 2.92 (dd, J =
15.2, 1.2 Hz, 1H), 2.66 – 2.56 (m, 1H), 2.46 – 2.34 (m, 1H), 2.29 (d, J = 15.2 Hz, 1H), 2.25 –
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
2.17 (m, 1H), 2.02 – 1.91 (m, 2H), 1.90 – 1.81 (m, 1H), 1.21 (dt, J = 46.0, 7.2 Hz, 3H); C
NMR (125 MHz, CDCl3): δ 171.3, 168.3, 168.0, 166.0, 134.57, 134.34, 128.98, 128.78 (2),
128.75 (2), 128.63 (2), 128.59, 128.41 (2), 119.8, 82.1, 68.80, 68.26, 62.5, 54.83, 54.25,
42.74, 42.59, 42.39, 39.0, 35.5, 23.0, 14.0. IR (thin film): 2964, 1844, 1737, 1454, 1372 cmꢀ1;
HRMS (ESI+) m/z calcd for C30H30NO8 [M+H]+: 532.1971, found: 532.1992.
4,4ꢀDibenzyl 5aꢀethyl (2aS,3S,5aR,9aS)ꢀ3ꢀmethylꢀ2ꢀoxohexahydronaphtho[8a,1ꢀb]oxeteꢀ
4,4,5a(2H,5H)ꢀtricarboxylate ((+)ꢀ1i): Prepared according to the procedure for compound 1c
using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv) in THF
(0.5 mL), a solution of ethyl 2ꢀoxocyclohexaneꢀ1ꢀcarboxylate 4f (51 mg, 0.30 mmol, 1.0 equiv)
in THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2
equiv) in THF (0.5 mL), (2S,3R)ꢀHBTM 2.1 (19 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78
ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3b (38 mg, 0.36
mmol, 1.2 equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at 0 °C for an additional 15 h.
The reaction was then concentrated by rotary evaporation and the product was purified by an
automated flash chromatography system (gradient of EtOAc/hexanes) to afford a single diaꢀ
stereomer (>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1i (44 mg, 27% yield) as
25.0
a yellow, viscous liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): Rf = 0.35.
[α]
D
+8.13 (c = 1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison
with authentic racemic material using a Chiracel ADꢀH column: hexanes:iPrOH = 95:5, flow
rate 1.0 mL/min, λ = 210 nm: tminor = 18.0 min, tmajor = 22.8 min; 82:18 er. Absolute stereochemꢀ
istry was tentatively assigned by analogy to βꢀlactone 1d via the use of “enantiomeric” HBTM
2.1 catalyst. 1H NMR (500 MHz, CDCl3): δ 7.37 – 7.17 (m, 10H), 5.16 (d, J = 1.5 Hz, 2H), 5.15
– 5.03 (m, 2H), 4.21 (dq, J = 10.8, 7.1 Hz, 1H), 3.99 (dq, J = 10.8, 7.1 Hz, 1H), 2.86 (d, J =
12.2 Hz, 1H), 2.76 – 2.68 (m, 2H), 2.59 (d, J = 15.4 Hz, 1H), 2.26 (ddd, J = 15.1, 13.5, 4.3 Hz,
1H), 2.08 – 2.00 (m, 1H), 1.89 (m, 1H), 1.75 – 1.62 (m, 3H), 1.60 – 1.35 (m, 2H), 1.21 (t, J =
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 31
13
7.1 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl3): δ 174.3, 171.6, 170.86,
170.13, 135.4, 134.7, 128.77, 128.62 (2), 128.59 (2), 128.54 (2), 128.51, 128.45 (2), 77.4,
67.76, 67.62, 61.7, 60.0, 57.2, 46.6, 36.4, 34.0, 32.9, 30.9, 21.2, 20.4, 17.6, 14.0. IR (thin film):
3034, 2939, 2866, 1823, 1727, 1455 cmꢀ1; HRMS (ESI+) m/z calcd for C31H34O8Na [M+Na]+:
557.2151, found: 557.2176.
1
2
3
4
5
6
7
8
9
4,4ꢀDibenzyl
3,5aꢀdiethyl
(2aR,3R,5aS,9aR)ꢀ2ꢀoxohexahydronaphtho[8a,1ꢀb]oxeteꢀ
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
3,4,4,5a(2H,5H)ꢀtetracarboxylate ((–)ꢀ1j): Prepared according to the procedure for compound
1d using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2 equiv) in THF
(0.5 mL), a solution of ethyl 2ꢀoxocyclohexaneꢀ1ꢀcarboxylate 4f (51 mg, 0.30 mmol, 1.0 equiv)
in THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benzene, 0.36 mmol, 1.2
equiv) in THF (0.5 mL), (S)ꢀBTM (15 mg, 0.060 mmol, 20 mol%) and i-Pr2NEt (78 ꢂL, 0.30
mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid chloride 3c (59 mg, 0.36 mmol, 1.2
equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at ꢀ20 °C for an additional 15 h. The reacꢀ
tion was then concentrated by rotary evaporation and the product was purified by an automatꢀ
ed flash chromatography system (gradient of EtOAc/hexanes) to afford a single diastereomer
(>19:1 as judged by 1H and 13C NMR) of tricyclicꢀβꢀlactone 1j (40 mg, 23% yield) as a yellow,
25.0
viscous liquid: TLC (EtOAc:hexanes, 2:8 v/v, Hanessian’s stain): R = 0.38.
= ꢀ41.47 (c =
[α]
D
f
1.0, CHCl3). Enantiomeric ratio was determined by HPLC analysis in comparison with authenꢀ
tic racemic material using a Chiracel ADꢀH column: hexanes:iPrOH = 95:5, flow rate 1.0
mL/min, λ = 210 nm: tminor = 47.7 min, tmajor = 52.6 min; 94:6 er. Absolute stereochemistry was
1
tentatively assigned by analogy to βꢀlactone 1d via the use of the same (–)ꢀBTM catalyst. H
NMR (500 MHz, CDCl3): δ 7.35 – 7.24 (m, 10H), 5.19 – 5.05 (m, 4H), 4.18 – 4.09 (m, 1H),
4.08 – 3.92 (m, 4H), 3.59 (d, J = 9.1 Hz, 1H), 2.76 (d, J = 15.7 Hz, 1H), 2.60 (d, J = 15.6 Hz,
1H), 2.00 (ddd, J = 14.3, 9.8, 3.7 Hz, 2H), 1.89 – 1.80 (m, 1H), 1.67 (ddd, J = 14.6, 10.5, 4.3
Hz, 1H), 1.61 – 1.48 (m, 2H), 1.47 – 1.20 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 173.6, 170.98, 170.48, 170.32, 168.2, 135.0, 134.7,
128.88, 128.78 (2), 128.71 (2), 128.67 (2), 128.60, 128.52 (2), 77.2, 68.39, 68.37, 61.88,
61.76, 55.9, 55.1, 46.6, 42.0, 35.1, 34.4, 31.7, 21.5, 20.6, 14.03, 14.00. IR (thin film): 3065,
3034, 2939, 2867, 1834, 1731, 1498 cmꢀ1; HRMS (ESI+) m/z calcd for C33H36O10Na [M+Na]+:
615.2201, found: 615.2181.
Dibenzyl
(2aS,3S,5aR,8aS)ꢀ3ꢀmethylꢀ2ꢀoxoꢀ5aꢀ(phenylsulfonyl)hexahydroꢀ2Hꢀ
indeno[3a,4ꢀb]oxeteꢀ4,4(5H)ꢀdicarboxylate ((+)ꢀ1k): Prepared according to the procedure for
compound 1c using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol, 1.2
equiv) in THF (0.5 mL), a solution of 2ꢀ(phenylsulfonyl)cyclopentanꢀ1ꢀone38 4e (67 mg, 0.30
24
ACS Paragon Plus Environment

Page 25 of 31
The Journal of Organic Chemistry
mmol, 1.0 equiv) in THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in benꢀ
zene, 0.36 mmol, 1.2 equiv) in THF (0.5 mL), (2S,3R)ꢀHBTM 2.1 (19 mg, 0.060 mmol, 20
mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid
chloride 3b (47 mg, 0.45 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL). The reaction was warmed to 23
°C and stirred for an additional 15 h. The reaction was then concentrated by rotary evaporation
and the product was purified by an automated flash chromatography system (gradient of
EtOAc/hexanes) to afford a single diastereomer (>19:1 as judged by 1H and 13C NMR) of tricyꢀ
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
clicꢀβꢀlactone 1k (54 mg, 32% yield) as a light yellow solid: m.p. 74 – 75 °C. TLC
22.6
(Et O:hexanes, 8:2 v/v, Hanessian’s stain): R = 0.59;
= +15.60 (c = 1.0, CHCl3). Enanꢀ
[α]
D
2
f
tiomeric ratio was determined by HPLC analysis in comparison with authentic racemic material
using a Chiracel ADꢀH column: hexanes:iPrOH = 95:5, flow rate 1.0 mL/min, λ = 210 nm: tminor
= 71.8 min, tmajor = 75.5 min; 85.5:14.5 er. Absolute stereochemistry was tentatively assigned
1
by analogy to βꢀlactone 1d via the use of “enantiomeric” HBTM 2.1 catalyst. H NMR (600
MHz, CDCl3): δ 8.00 – 7.94 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.39 –
7.15 (m, 10H), 5.20 – 5.02 (m, 4H), 3.40 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 15.3 Hz, 1H), 2.80
(dt, J = 14.4, 7.2 Hz, 1H), 2.49 (d, J = 15.4 Hz, 1H), 2.41 – 2.26 (m, 2H), 1.80 (dt, J = 13.7, 6.9
Hz, 1H), 1.68 (dt, J = 14.4, 6.9 Hz, 1H), 1.58 (dp, J = 14.1, 7.1 Hz, 1H), 1.35 – 1.24 (m, 1H),
1.18 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 169.68, 169.39, 168.7, 136.7, 134.66,
134.24, 134.17, 131.6 (2), 129.12 (2), 128.99, 128.80, 128.78 (2), 128.77 (2), 128.75 (2),
128.58 (2), 83.9, 70.5, 68.08, 67.86, 60.0, 56.5, 40.2, 39.1, 38.6, 35.1, 21.7, 16.0. IR (thin
film): 3065, 3034, 2966, 2885, 1833, 1730, 1650, 1498 cmꢀ1; HRMS (ESI+) m/z calcd for
C33H32O8SNa [M+Na]+: 611.1710, found: 611.1705.
4,4ꢀDibenzyl
3ꢀethyl
(2aS,3S,5aR,8aS)ꢀ2ꢀoxoꢀ5aꢀ(phenylsulfonyl)hexahydroꢀ2Hꢀ
indeno[3a,4ꢀb]oxeteꢀ3,4,4(5H)ꢀtricarboxylate ((+)ꢀ1l): Prepared according to the procedure
for compound 1c using a solution of LHMDS (0.36 mL of 1.0 M solution in THF, 0.36 mmol,
1.2 equiv) in THF (0.5 mL), a solution of 2ꢀ(phenylsulfonyl)cyclopentanꢀ1ꢀone38 4e (67 mg,
0.30 mmol, 1.0 equiv) in THF (0.5 mL), a solution of diester 5b (0.36 mL of 1.0 M solution in
benzene, 0.36 mmol, 1.2 equiv) in THF (0.5 mL), (2S,3R)ꢀHBTM 2.1 (19 mg, 0.060 mmol, 20
mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid
chloride 3c (73 mg, 0.45 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL). The reaction was warmed to 23
°C and stirred for an additional 15 h. The reaction was then concentrated by rotary evaporation
and the product was purified by an automated flash chromatography system (gradient of
EtOAc/hexanes) to afford a single diastereomer (>19:1 as judged by 1H and 13C NMR) of tricyꢀ
clicꢀβꢀlactone 1l (101 mg, 52% yield) as a light yellow solid: m.p. = 81 – 82 °C. TLC
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 31
25.0
(EtOAc:hexanes, 4:6 v/v, Hanessian’s stain): Rf = 0.47.
= +33.87 (c = 1.0, CHCl3). Enꢀ
[α]
D
1
2
3
4
5
antiomeric ratio was determined by HPLC analysis in comparison with authentic racemic mateꢀ
rial using a Chiracel ADꢀH column: hexanes:iPrOH = 60:40, flow rate 1.0 mL/min, λ = 210 nm:
tmajor = 11.5 min, tminor = 13.98 min; 89:11 er. Absolute stereochemistry was tentatively asꢀ
6
7
8
1
signed by analogy to βꢀlactone 1d via the use of “enantiomeric” HBTM 2.1 catalyst. H NMR
9
(600 MHz, CDCl3): δ 7.93 – 7.90 (m, 2H), 7.59 (td, J = 7.4, 1.3 Hz, 1H), 7.43 – 7.27 (m, 12H),
5.26 – 5.06 (m, 4H), 4.05 – 4.02 (m, 2H), 3.56 (d, J = 10.1 Hz, 1H), 3.24 – 3.15 (m, 1H), 2.79
(dt, J = 13.7, 6.8 Hz, 1H), 2.66 – 2.56 (m, 1H), 2.24 (dd, J = 13.9, 6.6 Hz, 1H), 1.85 (dt, J =
13.5, 6.6 Hz, 1H), 1.65 – 1.58 (m, 3H), 1.40 – 1.24 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3): δ 169.54, 169.30, 168.5, 166.7, 136.8, 134.8, 134.23, 134.03, 131.6 (2),
129.34 (2), 129.14, 128.84, 128.82 (2), 128.79 (2), 128.74 (2), 128.53 (2), 83.5, 70.3, 68.72,
68.52, 62.2, 56.2, 54.8, 43.3, 40.3, 39.5, 37.9, 21.9, 14.0. IR (thin film): 2977, 1842, 1737,
1447 cmꢀ1; HRMS (ESI+) m/z calcd for C35H34O10SLi [M+Li]+: 653.2033, found: 653.2025.
Allyl benzyl malonate (A2). In an oven dried, 100ꢀmL roundꢀbottomed flash, monobenzyl
malonate (6.0 g, 31 mmol, 1.0 equiv) was dissolved in CH2Cl2 (30 mL) and cooled to 0 °C. Oxꢀ
alyl chloride (10.5 mL, 124 mmol, 4.0 equiv) was added dropwise followed by one drop of
DMF. After 1 h, the ice bath was removed and the reaction mixture was stirred for 15 h. Exꢀ
cess oxalyl chloride was removed by azeotroping with benzene (3 x 10 mL). The crude prodꢀ
uct was concentrated by rotary evaporation and carried on directly to the next step.
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 an oven dried, 250ꢀmL roundꢀbottomed flask, the crude product in the previous step (30.9
mmol, 1.0 equiv) and allyl alcohol (2.52 mL, 37.1 mmol, 1.2 equiv) were dissolved in CH2Cl2
(100 mL) and cooled to 0 °C. Et3N (6.5 mL, 46 mmol, 1.5 equiv) was added dropwise over 30
min. The ice bath was removed and solution was stirred for 1 h. The reaction was quenched
with water (30 mL). The organic layer was isolated and washed with saturated NaHCO3 (3 x
45 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated by rotary evaporation
to afford 4.6 g (>99% yield) of A2 which was of sufficient purity to be carried on to the next
1
step without purification. H NMR (500 MHz, CDCl3): δ 7.40 – 7.34 (m, 5H), 6.00 – 5.84 (m,
1H), 5.34 (dd, J = 17.2, 1.5 Hz, 1H), 5.25 (dd, J = 10.4, 1.3 Hz, 1H), 5.20 (s, 2H), 4.65 (dt, J =
13
5.7, 1.4 Hz, 2H), 3.47 (s, 2H); C NMR (125 MHz; CDCl3): δ 166.24, 166.03, 135.23, 131.45,
128.56 (2), 128.40 (2), 128.29, 118.74, 67.19, 66.04, 41.46.
1ꢀAllyl 3ꢀbenzyl 2ꢀmethylmalonate (A3): An ovenꢀdried roundꢀbottomed flask was charged
with allyl benzyl malonate (2.24 g, 9.59 mmol, 1.0 equiv), anhydrous K2CO3 (2.65 g, 19.2
mmol, 2.0 equiv), and anhydrous acetone (56 mL). The reaction mixture was stirred at ambient
temperature (23 °C) for 10 min before iodomethane was added dropwise to the reaction mixꢀ
26
ACS Paragon Plus Environment

Page 27 of 31
The Journal of Organic Chemistry
ture. The reaction was refluxed for 40 h. Upon completion (as judged by TLC, disappeareance
1
2
3
4
of A2), the reaction was filtered and concentrated to give A3 (2.1 g, 89% yield) which was of
1
sufficient purity to be carried on to the next step without purification. H NMR (500 MHz,
5
6
7
8
CDCl3): δ 7.38 – 7.29 (m, 5H), 5.92 – 5.80 (m, 1H), 5.35 – 5.27 (m, 1H), 5.22 (dd, J = 10.4, 1.3
Hz, 1H), 5.18 (dd, J = 16.4, 2.1 Hz, 3H), 4.62 (m, 1H), 3.56 (m, 1H), 1.48 (dd, J = 7.3, 1.8 Hz,
3H); 13C NMR (125 MHz; CDCl3): δ 169.77, 169.58, 135.4, 131.6, 128.53 (2), 128.29 (2),
128.10, 118.5, 67.1, 65.9, 46.1, 13.6.
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
1ꢀAllyl 3ꢀbenzyl 2ꢀmethylenemalonate (5c): Prepared according to the procedure for prepaꢀ
ration of compound 5b using NaH (0.48 g, 12 mmol, 1.5 equiv), a solution of A3 (2.0 g, 8.1
mmol, 1.0 equiv) in THF (5 mL), a solution of PhSeBr (2.3 g, 9.7 mmol, 1.2 equiv) in THF (10
mL). The reaction was concentrated and the crude mixture was purified by automated flash
chromatography (0 to 5% EtOAc:hexane) to deliver 1ꢀallyl 3ꢀbenzyl 2ꢀmethylꢀ2ꢀ
(phenylselanyl)malonate which was carried on directly to the next step.
An ovenꢀdried, 100ꢀmL roundꢀbottomed flask was charged with a solution of 1ꢀallyl 3ꢀbenzyl 2ꢀ
methylꢀ2ꢀ(phenylselanyl)malonate in anhydrous benzene (8 mL), followed by addition of H2O2
(35% in H2O, 14.0 mL, 162 mmol, 20.0 equiv). The reaction temperature was maintained at
ambient temperature (23 °C) using a water bath. After 2 h, H2O (10 mL) was added to dissolve
the white precipitate. The organic layer was then separated, washed with H2O, and dried over
anhydrous Na2SO4. The filtrate was concentrated by rotary evaporation to afford pure 5c (1.4
g, 70% yield over 2 steps, light yellow liquid) of sufficient purity to be used directly in the next
step (Note: purification of this compound led to extensive loss of material on silica likely due to
facile polymerization). The compound 5c was stored as a solution in anhydrous benzene (1.0
1
M) at –20 °C to slow decomposition. H NMR (300 MHz, CDCl3): δ 7.42 – 7.28 (m, 5H), 6.58
13
(s, 2H), 5.93 (m, 1H), 5.42 – 5.14 (m, 4H), 4.71 (dt, J = 5.7, 1.5 Hz, 2H); C NMR (75 MHz,
CDCl3): δ 163.51, 163.32, 135.32, 135.19, 134.4, 131.5, 128.50 (2), 128.29 (2), 128.10, 118.6,
67.1, 65.9.
4ꢀAllyl 4ꢀbenzyl 3,5aꢀdiethyl (2aR,3R,5aS,8aR)ꢀ2ꢀoxotetrahydroꢀ2Hꢀindeno[3a,4ꢀb]oxeteꢀ
3,4,4,5a(5H,6H)ꢀtetracarboxylate ((–)ꢀ1m). Prepared according to the representative proceꢀ
dure described for compound 1d using a solution of LHMDS (0.36 mL of 1.0 M solution in
THF, 0.36 mmol, 1.2 equiv) in THF (0.5 mL), a solution of ethyl 2ꢀoxocyclopentanecarboxylate
4c (47 mg, 0.30 mmol, 1.0 equiv) in THF (0.5 mL), a solution of diester 5c (0.36 mL of 1.0 M
solution in benzene, 0.36 mmol, 1.2 equiv) in THF (0.5 mL), (S)ꢀBTM (15 mg, 0.060 mmol, 20
mol%) and i-Pr2NEt (78 ꢂL, 0.30 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL), and a solution of acid
chloride 3c (73 mg, 0.45 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL). The reaction was stirred at ꢀ20
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 31
°C for an additional 15 h. The reaction was concentrated by rotary evaporation and the product
was purified by an automated flash chromatography system (gradient of EtOAc/hexanes) to
1
2
3
4
5
6
7
afford a 1:1 mixture of inseparable diastereomers of tricyclicꢀβꢀlactone 1m (83 mg, 52% yield)
24.7
as a yellow, viscous liquid: TLC (EtOAc:hexanes, 3:7 v/v, Hanessian’s stain): R = 0.44.
[α]
D
f
1
ꢀ40.40 (c = 1.0, CHCl3). NMR data is reported for the mixture of diastereomers (1:1): H NMR
(500 MHz, CDCl3): δ 7.40 – 7.26 (m, 10H), 5.92 – 5.75 (m, 2H), 5.35 – 5.07 (m, 8H), 4.64 (d, J
= 5.8 Hz, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.22 – 3.96 (m, 10H), 3.79 (dd, J = 9.5, 0.6 Hz, 1H),
3.76 (dd, J = 9.6, 0.6 Hz, 1H), 3.07 (d, J = 15.1 Hz, 1H), 3.04 (d, J = 15.1 Hz, 1H), 2.74 – 2.58
(m, 2H), 2.40 (d, J = 15.0 Hz, 1H), 2.39 (d, J = 15.1 Hz, 1H), 2.37 – 2.09 (m, 2H), 1.95 – 1.79
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
(m, 2H), 1.80 – 1.49 (m, 6H), 1.30 – 1.16 (m, 12H); C NMR (125 MHz, CDCl3): δ 172.64,
172.62, 170.41, 170.39, 170.30 (2), 169.38, 169.31, 168.18, 168.16, 135.1, 134.5, 131.4,
130.9, 129.22, 129.16, 128.97, 128.78, 128.66, 128.64, 128.60, 128.53, 128.35, 128.30,
120.1, 118.9, 85.81, 85.79, 68.4, 68.2, 67.09, 66.99, 62.02, 61.99, 55.94, 55.86, 53.0, 52.8,
52.36, 52.32, 43.35 (2), 39.83 (2), 39.69, 39.47 (2), 39.43, 39.34, 39.1, 23.46, 23.41, 14.05,
14.01 (2), 13.96. IR (thin film): 2981, 1836, 1738, 1453 cmꢀ1; HRMS (ESI+) m/z calcd for
C28H32O10Na [M+Na]+: 551.1888, found: 551.1843. Absolute stereochemistry was tentatively
assigned by analogy to βꢀlactone 1d via the use of the same (–)ꢀBTM catalyst.
5ꢀAllyl
5ꢀbenzyl
3a,6ꢀdiethyl
(3aS,6R,7R,7aR)ꢀ7ꢀ((4ꢀbromobenzyl)carbamoyl)ꢀ7aꢀ
hydroxyhexahydroꢀ5Hꢀindeneꢀ3a,5,5,6(4H)ꢀtetracarboxylate (16). Into an ovenꢀdried, 1ꢀ
dram vial containing a solution of βꢀlactone (–)ꢀ1m (30 mg, 0.057 mmol, 1.0 equiv) in THF (1
mL), was added dropwise 4ꢀbromobenzylamine (29 ꢂL, 0.23 mmol, 4.0 equiv). The reaction
was allowed to stir at ambient temperature (23 °C) for 20 h. Upon completion (as judged by
TLC, disappearance of βꢀlactone 1m), the reaction was concentrated by rotary evaporation
and purified by an automated flash chromatography system (gradient of Et2O/hexanes) to afꢀ
ford a 1:1 diastereomeric mixture of bicyclic amide 16 (26 mg, 62% yield) as a white solid: TLC
(Et2O:hexanes, 6:4 v/v, Hanessian’s stain): Rf = 0.38; NMR data is reported as a 1:1 diastereꢀ
omeric mixture of bicyclic amide 16: 1H NMR (400 MHz, CDCl3): δ 7.47 – 7.43 (m, 4H), 7.35 –
7.28 (m, 10H), 7.20 (t, J = 8.2 Hz, 4H), 6.57 (t, J = 5.9 Hz, 1H), 6.43 (t, J = 5.8 Hz, 1H), 5.81
(m, 2H), 5.29 (m, 2H), 5.26 – 5.08 (m, 8H), 4.63 – 4.52 (m, 4H), 4.48 (app dt, J = 14.9, 5.7 Hz,
2H), 4.34 (app ddd, J = 15.4, 10.3, 5.5 Hz, 2H), 4.23 – 4.06 (m, 4H), 4.03 – 3.89 (m, 4H), 3.89
– 3.81 (m, 2H), 2.99 (d, J = 14.9 Hz, 1H), 2.93 (d, J = 14.8 Hz, 1H), 2.62 (d, J = 11.9 Hz, 1H),
2.55 (d, J = 12.0 Hz, 1H), 2.44 (d, J = 11.5 Hz, 1H), 2.42 (d, J = 11.6 Hz, 1H), 2.14 – 1.29 (m,
12H), 1.26 (t, J = 7.1 Hz, 6H), 1.11 (app dt, J = 20.1, 7.1 Hz, 6H); 13C NMR (150 MHz; CDCl3):
δ 175.7, 175.4, 173.1, 172.9, 172.2, 171.97, 170.60, 170.54, 170.26, 170.16, 137.15, 137.09,
28
ACS Paragon Plus Environment

Page 29 of 31
The Journal of Organic Chemistry
135.2, 134.8, 131.81 (2), 131.80 (2), 131.5, 131.1, 129.8, 129.73, 129.71 (2), 128.82 (2),
128.72, 128.67, 128.64 (2), 128.62, 128.49, 128.35 (2), 121.46, 121.41, 119.3, 118.9, 80.38,
80.24, 67.95, 67.93, 67.88, 67.83, 66.85, 66.76, 61.48, 61.43, 56.81, 56.75, 54.38, 54.29,
48.85, 48.34, 44.79, 44.55, 43.33, 43.23, 35.89, 35.58, 33.22, 33.04, 32.70, 31.68, 29.8 (2),
20.0, 19.8, 14.2, 13.9; IR (ATR): 3364, 3068, 2981, 2931, 2856, 1725, 1647, 1543 cmꢀ1;
HRMS (ESI+) m/z calcd for C35H41BrNO10 [M+H]+: 714.1910; found 714.1908.
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
5ꢀBenzyl
3a,6ꢀdiethyl
(3aS,5S,6S,7R,7aR)ꢀ7ꢀ((4ꢀbromobenzyl)carbamoyl)ꢀ7aꢀ
hydroxyoctahydroꢀ3aHꢀindeneꢀ3a,5,6ꢀtricarboxylate ((+)ꢀ17). An ovenꢀdried, 10ꢀmL microꢀ
wave vial containing a solution of amide 16 (21.4 mg, 0.0300 mmol, 1.0 equiv),
Pd2(dba)3—CHCl3 (3.0 mg, 0.0030 mmol, 10 mol%), PPh3 (0.4 mg, 0.0015 mmol, 5.0 mol %),
and HCO2NH4 (7.6 mg, 0.12 mmol, 4.0 equiv) in CH3CN (0.6 mL) was degassed with Ar (3
times) and then heated in a microwave reactor at 100 °C for 2 h. Upon completion (as judged
by TLC by disappearance of 16), the reaction was concentrated by rotary evaporation and puꢀ
rified by flash chromatography (gradient of Et2O/hexanes) to afford a 12:1 diastereomeric mixꢀ
ture of bicyclic amide (+)ꢀ17 (17.8 mg, 94% yield) as a clear yellow liquid: TLC (Et2O:hexanes,
22.5
8:2 v/v, Hanessian’s stain): Rf = 0.44;
+4.27 (c = 0.5, CHCl3). Enantiomeric ratio was
[α]
D
determined by HPLC analysis in comparison with authentic racemic material using a Chiracel
ADꢀH column: hexanes:iPrOH = 95:5, flow rate 1.0 mL/min, λ = 210 nm: tminor = 60.8 min, tmajor
= 66.7 min; 97:3 er. 1H NMR (400 MHz, CDCl3): δ 7.37 – 7.24 (m, 9H), 6.21 (t, J = 5.6 Hz, 1H),
5.57 (s, 1H), 5.18 (d, J = 12.3 Hz, 1H), 5.05 (d, J = 12.3 Hz, 1H), 4.55 (dd, J = 14.7, 6.3 Hz,
0H), 4.48 (dd, J = 14.6, 5.8 Hz, 1H), 4.35 (dd, J = 14.6, 5.3 Hz, 1H), 4.21 (qd, J = 7.1, 1.8 Hz,
2H), 4.01 (q, J = 7.1 Hz, 2H), 3.65 (ddd, J = 11.8, 5.6, 3.8 Hz, 1H), 3.47 (ddd, J = 5.4, 3.9, 1.1
Hz, 1H), 3.08 (d, J = 3.9 Hz, 1H), 2.70 (ddd, J = 14.7, 3.9, 1.3 Hz, 1H), 2.28 – 2.16 (m, 1H),
2.02 – 1.57 (m, 6H), 1.28 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz;
CDCl3): δ 177.1, 173.5, 173.1, 172.6, 138.0, 136.1, 128.81 (2), 128.55 (2), 128.34 (2), 128.22,
128.06 (2), 127.6, 81.9, 66.4, 61.63, 61.26, 53.3, 49.8, 44.0, 43.2, 37.9, 37.6, 37.2, 29.3, 19.7,
14.12, 14.10; IR (ATR): 3362, 3064, 3032, 2977, 2928, 1724, 1649, 1539, 1454 cmꢀ1; HRMS
(ESI+) m/z calcd for C31H37BrNO8 [M+H]+: 630.1697; found 630.1655.
ASSOCIATED CONTENT
Supporting Information
1
Analytical data including chiral HPLC traces and copies of H and 13C spectra for all new comꢀ
pounds.
AUTHOR INFORMATION
Corresponding Author
29
ACS Paragon Plus Environment