Studies on the Synthesis of Phlegmarine-Type Lycopodium Alkaloids: Enantioselective Synthesis of (-)-Cermizine B, (+)-Serratezomine E, and (+)-Luciduline

Article abstract of DOI:10.1021/acs.joc.8b00983

The synthesis of the Lycopodium alkaloids, (-)-cermizine B, (+)-serratezomine E, and (+)-luciduline using phenylglycinol-derived tricyclic lactams as chiral scaffolds, is reported. The requisite lactams are prepared by a cyclocondensation reaction between (R)- or (S)-phenylglycinol and the substituted δ-keto ester 11, easily accessible from (R)-pulegone. The factors governing the stereoselectivity of these cyclocondensation reactions are discussed. Key steps of the synthesis from the stereochemical standpoint are the stereoselective elaboration of the allyl substituent to the (S)-2-(piperidyl)methyl moiety and the stereoselective removal of the chiral inductor to give a cis-decahydroquinoline.

Full text of DOI:10.1021/acs.joc.8b00983

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Studies on the Synthesis of Phlegmarine-type
Lycopodium Alkaloids. Enantioselective Synthesis of (–)-
Cermizine B, (+)-Serratezomine E, and (+)-Luciduline
Alexandre Pinto, Miriam Picciche, Rosa Griera, Elies Molins, Joan Bosch, and Mercedes Amat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00983 • Publication Date (Web): 27 Jun 2018
Downloaded from http://pubs.acs.org on June 27, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Studies on the Synthesis of Phlegmarine-type Lycopodium Alkaloids.
Enantioselective Synthesis of (–)-Cermizine B, (+)-Serratezomine E,
and (+)-Luciduline
Alexandre Pinto, † Miriam Piccichè, † Rosa Griera, † Elies Molins, ‡ Joan Bosch,† and Mercedes Amat*†
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
†Laboratory of Organic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of
Biomedicine (IBUB), University of Barcelona, 08028-Barcelona, Spain
‡Institut de Ciència de Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu
Abstract
The synthesis of the Lycopodium alkaloids (–)-cermizine B, (+)-serratezomine E, and (+)-luciduline
using phenylglycinol-derived tricyclic lactams as chiral scaffolds, is reported. The requisite lactams are
prepared by a cyclocondensation reaction between (R)- or (S)-phenylglycinol and the substituted δ-keto
ester 11, easily accessible from (R)-pulegone. The factors governing the stereoselectivity of these
cyclocondensation reactions are discussed. Key steps of the synthesis from the stereochemical standpoint
are the stereoselective elaboration of the allyl substituent to an (S)-2-(piperidyl)methyl moiety and the
stereoselective removal of the chiral inductor to give a cis-decahydroquinoline.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
Introduction
5
6
7
8
The decahydroquinoline (DHQ) ring system is a common structural feature present in a large number
of biologically active natural products. Unlike most alkaloid types, DHQ-containing alkaloids occur not
only in plant species (e.g., phlegmarine in Lycopodium and myrioxazine A in Myrioneuron)1 but also in
other terrestrial (e.g., pumiliotoxin C and gephyrotoxin 287C in amphibians and arthropods)2 and
marine (e.g., cylindricines, lepadiformines, and lepadins in tunicates and flatworms)3 organisms (Figure
1).
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
H
H
H
N
O
H
HO
N
N
H
H
N
H
H
H
(+)-Myrioxazine A
( )-Phlegmarine
OH
( )-Lepadiformine A
H
H
N
H
H
H
H
N
N
HO
H
H
H
(
)-Lepadin B
(
)-Gephyrotoxin 287C
( )-Pumiliotoxin C
Figure 1. Representative plant, amphibian and marine decahydroquinoline alkaloids.
In particular, Lycopodium alkaloids can be grouped in four main structural classes, namely,
lycopodine, lycodine, fawcettimine, and phlegmarine (also called the miscellaneous class), each one
named after their most representative member. The phlegmarine-type alkaloids are characterized by a
cis- or trans-decahydroquinoline ring system with a 7(R)-methyl substituent and a (2-piperidyl)methyl-
derived appendage at C-5 with both possible relative stereochemistries (Figure 2). In some members,
the piperidine ring is oxidized to a nitrone or a pyridine, and in a few cases the DHQ 3- and 5-positions
are connected by an oxidized two-carbon unit. Phlegmarine is believed to be the key intermediate in the
biosynthesis of all Lycopodium alkaloids.
2
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ac
N
Me
H
H
H
H
H
H
N
N
Me
N
H
H
N
N
H
H
(-)-Serralongamine A
Me
(-)-Cermizine B
(+)-Serratezomine E
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
Me
H
N
H
H
H
H
N
N
O
N
H
H
H
N
O
(+)-Nankakurine A
(+)-Lycoposerramine Z
(+)-Luciduline
Figure 2. Representative phlegmarine-type Lycopodium alkaloids.
As a consequence of their widespread distribution and different biogenetic origins, DHQ-containing
alkaloids are structurally diverse in their substitution pattern and stereochemistry, which has stimulated
the development of general methodologies and unified synthetic strategies for the stereoselective
synthesis of substituted DHQ derivatives.4 In this context, in previous work we have used tricyclic
aminoalcohol-derived oxazoloquinolone lactams as multipurpose enantiopure scaffolds for
diastereoselective transformations into a variety of diversely substituted cis-decahydroquinolines,
including the DHQ alkaloids (–)-pumiliotoxin, C,5 (–)-lepadins A-C,6 (+)-lepadin D,6b (+)-myrioxacin
A,7 and (+)-gephyrotoxin 287C8 (Scheme 1).
Scheme 1. Access to Decahydroquinoline Alkaloids from Chiral Aminoalcohol-Derived Tricyclic
Lactams
From the stereochemical standpoint, crucial steps in our syntheses of pumiliotoxin C and lepadins
were a stereoselective cyclocondensation reaction of (R)-phenylglycinol with a cyclohexenone-derived
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
9
δ-keto ester and the subsequent stereoselective hydrogenation of the resulting rigid cis-fused tricyclic
lactams 16,9 (Scheme 2). The configuration of the bridgehead carbons in 1 results from the irreversible
lactamization of the intermediate oxazolidine A (in equilibrium with other three diastereoisomeric
oxazolidines via the corresponding dienamine), through a chair-like transition state in which the ester
chain avoids repulsive interactions with the R (A1,2 strain) and C6H5 substituents. Trans-fused lactams
cannot be formed due to steric constraints. In turn, the hydrogenation of the C–C double bond of
unsaturated lactams 1 takes place stereoselectively from the most accessible face to give lactams 2, with
a 4a-H/5-H trans relative configuration (when R ≠ H; DHQ numbering).
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. Stereoselective Access to Phenylglycinol-Derived Oxazoloquinolone Tricyclic Lactams
Results and Discussion
We report herein our studies on the enantioselective synthesis of phlegmarine-type Lycopodium
alkaloids using phenylglycinol-derived tricyclic lactams as chiral scaffolds. Only a limited number of
enantioselective synthesis of these alkaloids have been reported to date.10-12 In a first approach, we
envisaged unsaturated lactam 1a as a suitable starting material, because its allylic oxidation should
afford an enone, from which the substituents at the DHQ C-5 and C-7 positions could be incorporated in
13
a stereocontrolled manner. In the event, treatment of 1a with SeO2 afforded allylic alcohol 3 as a
single stereoisomer,14 which was further oxidized under Dess–Martin conditions to give enone 4 in high
4
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
overall yield. To test the feasibility of conjugate addition reactions for the introduction of the DHQ C-5
substituent and easily analyze their stereochemical outcome, in a model experiment enone 4 was
allowed to react with n-BuLi in the presence of CuI. When the reaction was carried out in the usual THF
or Et2O solvents, a nearly equimolecular mixture (determined by NMR) of 5 and its C-5 epimer was
obtained (70-75% yield).15 However, surprisingly, the conjugate addition proceeded smoothly in
CH2Cl2 to afford ketone 5 in 83% yield as a single diastereoisomer with a 4a-H/5-H trans relationship
(Scheme 3). The configuration of 5 was unambiguously established after reduction of the ketone
carbonyl. The resulting tricyclic lactam 2c was identical to that previously obtained9 by catalytic
hydrogenation of unsaturated lactam 1c. The observed diastereoselectivity in the above conjugate
addition reaction, involving a nucleophilic attack from the most hindered face of the enone, can be
rationalized by considering that, in the absence of ethereal solvents, the oxazolidine oxygen coordinates
with the nucleophilic species, thus directing the delivery of the nucleophile syn with respect to this
oxygen.
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 3. The Decahydroquinoline C-5 Stereocenter. Model Studies
These results prompted us to investigate an alternative way of generating the DHQ C-5 stereocenter,
by conjugate reduction of enone 6. However, SeO2-promoted allylic oxidation of unsaturated lactam 1c
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
took place at the exocyclic methylene carbon instead of the endocyclic DHQ C-7 position to give ketone
7c in excellent yield (Scheme 4). A similar oxidation from 1b gave aldehyde 7b in nearly quantitative
yield. Steric factors probably account for the regioselectivity of the oxidation. Aldehyde 7b was
efficiently converted in two steps to the silyl derivative 8, the TIPS analog of the intermediate 1d in our
synthesis of lepadins.6
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 4. Regioselective Exocyclic Allylic Oxidation
The desired regioselective endocyclic allylic oxidation of unsaturated lactam 1c was accomplished,
although in moderate yield, by manganese(III) acetate-catalyzed oxidation using TBHP as the
cooxidant.16 A subsequent methylcopper(I)-catalyzed conjugate reduction of the resulting enone 6 by
DIBALH in the presence of HMPA17 afforded in good yield and complete facial selectivity the same
tricyclic ketone 5 previously obtained by conjugate addition of a butyl residue. This result makes
evident that the conjugate additions of hydride and butyl occur with opposite facial selectivity, both
leading to the same trans 4a-H/5-H (DHQ numbering) relative stereochemistry, which had also been
obtained by hydrogenation of the unsaturated lactams 1 resulting from the cyclocondensation reaction
(Scheme 2).
Although the above approach would allow the stepwise preparation of tricyclic lactams bearing
substituents at the DHQ C-5 and C-7 positions, en route to phlegmarine-type alkaloids, at this point we
turned our attention to an alternative, more efficient approach based on the direct generation of such
disubstituted lactams using appropriately substituted cyclohexanone-derived δ-keto esters in the
reaction with (R)- or (S)-phenylglycinol. These keto esters would be accessible by a conjugate addition
to enone 9, which already incorporates the methyl substituent with the (R) absolute stereochemistry
characteristic of the target alkaloids (Scheme 5).
6
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 5. Preparation of the Starting Enantiomeric Scaffold for the Synthesis of (–)-Cermizine B
6
7
8
O
MeO2C
see text
(R)
O
MeO2C
O
ref 18
(R)
(R)
9
70%
(R)-Pulegone
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
10
9
O
H3C
(CH2)2CO2Me
SiMe3
H
9
Nu
InCl3, TMSCl
99%
C6H5
O
(R)
H
C6H5
(R)
H
N
C6H5
O
CO2Me
O
OH
N
MeO2C
O
H2N
(R)
(R)
H
82%
H
H
12a
11
B
Me
Enone 9 was prepared in four steps on a multigram scale (~70% overall yield) following literature
procedures18 from (R)-pulegone, a commercially available compound of the chiral pool.19 Unfortunately,
attempts to directly introduce a (2-pyridyl)methyl substituent by conjugate addition of a metalated 2-
picoline to enone 9 under a variety of experimental conditions20 were unsuccessful and the desired
adduct 10 was not detected. To circumvent this problem, we decided to perform the conjugate addition
of an allyl group, which would be subsequently elaborated to the (2-piperidyl)methyl moiety present in
most phlegmarine-type alkaloids. The 1,4-addition was satisfactorily accomplished in nearly
quantitative yield by an InCl3-catalyzed Sakurai reaction21 of enone 9 with allyltrimethylsilane in the
presence of TMSCl. The reaction was completely stereoselective due to the stereoelectronic control,22
affording 3,5-trans cyclohexanone 11 as an inconsequential 1:1 mixture of C-2 epimers. The
subsequent acid-catalyzed cyclocondensation of 11 with (R)-phenylglycinol also took place with
complete stereoselectivity, via oxazolidine B, leading to the anticipated tricyclic lactam 12a14 in 82%
yield, in a process that involves the epimerization of the configurationally labile stereocenter to the
ketone group.23 The DHQ 4a-, 5-, and 7-carbons in lactam 12a had the required configuration for the
synthesis of (–)-cermizine B, an alkaloid isolated from the club moss of Lycopodium cernuum.24 To
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
complete the synthesis, it was only necessary to stereoselectively install the (S)-(2-piperidyl)methyl
moiety by manipulating the allyl substituent and generate the cis fusion for the DHQ system by
stereoselective cleavage of the oxazolidine ring.
9
The S stereogenic center α to the amino group of the DHQ C-5 substituent was installed by reaction of
N-sulfinyl imine 13 with allylmagnesium bromide,25 which led to sulfinamide 14 as a single
stereoisomer in 96% yield. Compound 13 was prepared from lactam 12a by RuCl3/NaIO4-promoted26
oxidative cleavage of the allyl group, followed by Ti(O-i-Pr)4-mediated condensation of the resulting
aldehyde with (R)-(+)-tert-butanesulfinamide27 (Scheme 6).
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 6. Enantioselective Synthesis of (–)-Cermizine B
The six-membered heterocyclic ring of the DHQ C-5 side chain was assembled from sulfinamide 14 in
the three steps: cleavage of the sulfinyl group by acidic methanolysis, acylation of the resulting primary
homoallylic amine with acryloyl chloride to give diene 15 (67% overall yield), and a final ring-closing
metathesis reaction (83% yield). After catalytic hydrogenation of the C–C double bond of
dihydropyridone 16 and methylation of the resulting piperidone, treatment with LiAlH4-AlCl3 caused
both the reduction of the piperidone and perhydroquinolone lactam carbonyls and the stereoselective
reductive cleavage of the oxazolidine C–O bond to give cis-DHQ 17 in 57% overall yield. A final
8
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
debenzylation by catalytic hydrogenation afforded (–)-cermizine B, whose NMR spectroscopic data
matched those reported for the natural product.24,28
6
7
8
9
The above successful result prompted us to develop a similar sequence for the synthesis of (+)-
serratezomine E, a cis-DHQ alkaloid isolated from the club moss Lycopodium serratum var. serratum29
bearing the same C-5 and C-7 absolute configuration as (–)-cermizine B, but with the opposite
configuration at the ring fusion carbons. It was expected that using (S)-phenylglycinol instead of the R
enantiomer in the reaction with δ-keto ester 11 would afford tricyclic lactam 18b, with the required
stereochemistry. As observed in related cyclocondensations,5-9 lactamization would preferentially take
place from an oxazolidine (D; R1=H, R2=C6H5) in which the ester group approaches the nitrogen atom
avoiding the repulsive interactions of the methoxy group with the phenyl substituent. Such interactions
would occur in the tetrahedral intermediate generated in the alternative cyclization from oxazolidine C
(R1=H, R2=C6H5). However, unexpectedly, in sharp contrast with the result of the cyclocondensation
with (R)-phenylglycinol (Scheme 5 and Table 1, entry 1), the reaction of 11 with (S)-phenylglycinol was
not stereoselective, affording (78% yield) a nearly equimolecular mixture of the expected lactam 18b
and its diastereoisomer 18a (entry 2).30 To gain insight into the factors governing the stereoselectivity of
the above cyclocondensation reactions, we studied the reaction of 11 with 2-aminoethanol, which lacks
the phenyl substituent of the amino alcohol moiety, as well as other cyclocondensations using δ-keto
esters 19 and 20 (mixtures of C-2 diastereoisomers), related to 11 but lacking one of the substituents at
the cyclohexanone ring. The results are summarized in Table 1.23
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
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
Table 1. Cyclocondensation Reactions
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
entry
1
amino alcohol
R1
R2
H
δ-keto ester R3
R4
products a/b ratio
yield (%)
82
(R)-Phenylglycinol
C6H5
CH3 CH2CH=CH2
CH3 CH2CH=CH2
CH3 CH2CH=CH2
1:0
11
11
12
18
C6H
5
2
(S)-Phenylglycinol
H
55:45
78
3
4
2-Aminoethanol
H
H
H
85:15
1:0
81
76
11
19
19
21
22
(R)-Phenylglycinol
C6H5
CH3
CH3
H
H
C6H
5
5
6
7
(S)-Phenylglycinol
(R)-Phenylglycinol
(S)-Phenylglycinol
H
C6H5
H
H
23
24
25
85:15
1:1
83
68
76
H
CH3
CH3
20
20
C6H
5
H
0:1
The reaction of 11 with 2-aminoethanol afforded an 85:15 mixture of lactams 21a and 21b (entry 3).
Taking into account that lactamization of both possible oxazolidine precursors C and D (R1 = R2 = H)
involves a chair-like transition state with one axial substituent (R4 or R3) on the cyclohexane ring, the
preferential lactamization from oxazolidine C (R1 = R2 = H) in the absence of the phenyl substituent can
be rationalized by considering that D suffers from additional repulsive gauche interactions between the
equatorial allyl group and the propionate chain. Similar gauche interactions would explain the
stereochemical outcome of the above cyclocondensation leading to lactams 18a and 18b.
In the same way, the stereochemical outcome of the cyclocondensations of keto esters 19 and 20 with
(R)- and (S)-phenylglycinol (table 1, entries 4-7) can be accounted for by analyzing in each case the
10
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
repulsive interactions during the irreversible lactamization of the intermediate equilibrating
oxazolidines C and D: i) 1,3-diaxial interactions between the phenyl ring and the methoxy group; ii)
axial substituents on the cyclohexane ring; and iii) gauche interactions between the equatorial R4
substituent and the propionate chain. The existence or not of these interactions determines the
stereoconvergent generation of tricyclic lactams 22a and 25b in the reactions of keto ester 19 with (R)-
phenylglycinol (entry 4) and keto ester 20 with (S)-phenylglycinol (entry 7), respectively; it also
explains why the alternative cyclizations of 19 with (S)-phenylglycinol and 20 with (R)-phenylglycinol,
leading to lactams 23 and 24, respectively, were less (a/b ratio 85:15; entry 5) or even not
stereoselective (1:1 ratio; entry 6).
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
Following our synthetic plan, lactam 18b was converted to (+)-serratezomine E as outlined in Scheme
7. The synthetic sequence parallels the one previously developed for the synthesis of (–)-cermizine B,
and proceeds via aldehyde 26, N-sulfinyl imine 27, sulfinamide 28, diene 29, dihydropyridone 30, and
cis-DHQ 31. The piperidine nitrogen was protected as an N-Boc derivative to allow the selective
acetylation of the DHQ nitrogen after the reductive removal of the phenylethanol moiety by
hydrogenolysis. A final deprotection with TFA gave (+)-serratezomine E. The NMR data of our
synthetic (+)-serratezomine E were coincident with those reported in the literature,10f while the specific
rotation {[α]D = +6.1 (c 0.62, CHCl3)} was in good agreement with the value reported {[α]D = + 9.0 (c
1, CHCl3)}10f for this natural product in its basic form.31
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
Scheme 7. Enantioselective Synthesis of (+)-Serratezomine E
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
Taking into account that luciduline32 and nankakurines A and B33 (Figure 2) possess the same
configuration at the C-4a, C-5, C-7, and C-8a DHQ stereocenters as serratezomine E, tricyclic lactam
18b was also envisaged as a synthetic precursor of these more complex Lycopodium alkaloids. The
additional bridged six-membered ring would be assembled taking advantage of the allyl substituent,
which would be converted to an acetate chain, able to undergo a base-catalyzed cyclization with the
position of the lactam carbonyl. The stereoselective removal of the chiral inductor, with simultaneous
N-Boc protection, was accomplished from aldehyde 26 by the usual alane reduction / hydrogenolysis
procedure to give the cis-DHQ-5-ethanol derivative 32 in 91% yield. A subsequent treatment with
ruthenium tetroxide brought about both the reoxidation of the N-Boc-DHQ to the corresponding N-acyl
lactam34 and the oxidation of the alcohol functionality to an acid, which was then converted to ester 33
as shown in Scheme 8. The synthesis of (+)-luciduline was completed by cyclization of lactam ester 33
with lithium isopropylcyclohexylamide, followed by LiAlH4 reduction of the resulting luciduline lactam
3435 to give dihydroluciduline and a final Jones oxidation.11a Our synthetic luciduline showed NMR data
and a specific rotation coincident with those reported11 for the natural product. Given that luciduline had
previously been converted into nankakurines in the racemic series,36 the above synthesis also constitutes
a formal total synthesis of (+)-nankakurines A and B.
12
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
Scheme 8. Enantioselective Synthesis of (+)-Luciduline
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
Conclusion
Phenylglycinol-derived tricyclic oxazoloquinolone lactams have proven to be multipurpose scaffolds
for the enantioselective synthesis of structurally diverse DHQ-containing alkaloids. The results reported
in this paper demonstrate that these lactams can be successfully used to assemble phlegmarine-type
Lycopodium alkaloids, such as (–)-cermizine B, (+)-serratezomine E, and (+)-luciduline. Key
stereoselective steps of the synthesis are the elaboration of the (S)-(2-piperidyl)methyl moiety from the
allyl substituent and the generation of the cis-DHQ ring fusion by reductive opening of the oxazolidine
ring.
The chiral lactam scaffolds bearing the required DHQ C-5 and C-7 substituents and stereochemistry
are more efficiently prepared by a straightforward cyclocondensation reaction between (R)- or (S)-
phenylglycinol and an appropriately substituted δ-keto ester 11, easily accessible from the chiral pool,
than by a stepwise stereoselective introduction of the DHQ substituents on unsubstituted unsaturated
tricyclic lactams. The factors governing the stereoselectivity of these and related cyclocondensation
reactions have been rationalized, which will allow the design of related stereocontrolled
cyclocondensations leading to enantiopure cis-DHQs with different substitution and stereochemical
patterns.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
Experimental Section
(3R,7aS,10R,11aS)-10-Hydroxy-5-oxo-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]
9
quinoline (3): SeO2 (1.08 g, 9.76 mmol) was added to a stirring solution of lactam 1a (610 mg, 2.27
mmol) in anhydrous dioxane (76 mL) at room temperature. The resulting suspension was heated at
reflux for 24 h. The solvent was evaporated, and the residue was taken up in EtOAc. The organic
solution was washed with water, dried, and concentrated. Flash chromatography (2:8 hexane–EtOAc)
afforded alcohol 3 (505 mg, 78 %) as a white solid: [α]23D ‒ 26.8 (c 1.2, CHCl3); 1H-NMR (CDCl3, 400
MHz, COSY, g-HSQC) δ (ppm): 1.58-1.68 (m, 2H, H-7, OH), 1.99 (dd, J = 4.8, 14.8 Hz, 1H, H-11),
2.02-2.06 (m, 1H, H-7), 2.26 (dd, J = 1.6, 14.8 Hz, 1H, H-11), 2.33-2.36 (m, 1H, H-7a), 2.46-2.53 (m,
1H, H-6), 2.68 (dd, J = 4.0, 6.0 Hz, 1H, H-6), 4.07-4.12 (m, 2H, H-2, H-10), 4.56 (t, J = 8.8 Hz, 1H, H-
2), 5.54 (t, J = 8.4 Hz, 1H, H-3), 5.83 (dd, J = 4.8, 9.6 Hz, 1H, H-9), 5.97 (dd, J = 4.8, 10 Hz, 1H, H-8),
7.19 (d, J = 8.0 Hz, 2H, H-Ar), 7.24-7.28 (m, 1H, H-Ar), 7.32-7.36 (m, 2H, H-Ar); 13C-NMR (75.4
MHz, CDCl3) δ (ppm): 24.7 (C-7), 31.1 (C-6), 34.2 (C-11), 40.5 (C-7a), 58.5 (C-3), 64.9 (C-10), 69.3
(C-2), 94.2 (C-11a), 125.3 (2CH-Ar), 127.3 (CH-Ar), 128.3 (C-9) 128.6 (2CH-Ar), 129.1 (C-8), 139.8
(C-Ar), 169.3 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19NO3H 286.1438; Found
286.1438.
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
(3R,7aS,11aS)-5,10-Dioxo-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinoline (4): Dess-
Martin periodinane (1.97 g, 4.65 mmol) was added to a stirring solution of alcohol 3 (500 mg) in
anhydrous CH2Cl2 (186 mL). The resulting suspension was stirred overnight at room temperature.
Saturated aqueous NaHCO3 (60 mL) and saturated aqueous Na2S2O3 (60 mL) were added, and the
mixture was stirred for 45 minutes. The layers were separated, and the aqueous solution was extracted
with CH2Cl2. The combined organic extracts were dried and concentrated. Flash chromatography (3:7
hexane–EtOAc) afforded enone 4 (343 mg, 85%) as a white-yellow residue: [α]23D ‒ 119 (c 1.0, CHCl3);
1H-NMR (400 MHz, CDCl3, COSY, g-HSQC) δ (ppm): 1.82-1.97 (m, 1H, H-7), 2.18-2.27 (m, 1H, H-
7), 2.52-2.66 (m, 2H, H-7a, H-11), 2.72-2.89 (m, 3H, H-6, H-11), 3.98 (t, J = 8.2 Hz, 1H, H-2), 4.53 (t,
J = 8.2 Hz, 1H, H-2), 5.46 (t, J = 8.2 Hz, 1H, H-3), 6.09 (d, J = 10.2 Hz, 1H, H-9), 6.95 (dd, J = 5.6,
10.2Hz, 1H, H-8), 7.16 (d, J = 7.4 Hz, 2H, H-Ar), 7.26 (t, J = 7.4 Hz, 1H, H-Ar), 7.34 (t, J = 7.4 Hz,
2H, H-Ar); 13C-NMR (75.4 MHz, CDCl3) δ (ppm): 23.7 (C-7), 31.0 (C-6), 41.6 (C-7a), 43.9 (C-11),
58.9 (C-3), 69.6 (C-2), 94.9 (C-11a), 125.3 (2CH-Ar), 127.6 (CH-Ar), 128.3 (C-9) 128.8 (2CH-Ar),
139.1 (Cq-Ar), 148.0 (C-8), 168.6 (NCO), 194.8 (C=O); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H17NO3H 284.1281; Found 284.1291.
14
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(3R,7aS,8R,11aS)-8-Butyl-5,10-dioxo-3-phenylperhydrooxazolo[2,3-j]quinoline (5): Method A. n-
BuLi (560 µL, 2.5 M in hexane, 1.41 mmol) was added dropwise under argon to a suspension of CuI
(135 mg, 0.71 mmol) in anhydrous Et2O (3.0 mL) at ‒20 ºC. After 30 minutes, the solvent was
evaporated under a stream of argon. The resulting residue was dissolved in anhydrous CH2Cl2 (5 mL),
and the mixture was stirred for 10 min at ‒20 ºC. Enone 4 (40 mg, 0.14 mmol) in anhydrous CH2Cl2
(1.0 mL) was added dropwise at –78 ºC. The mixture was stirred at ‒78 ºC for 30 minutes and at ‒30 ºC
for 3 h. Saturated aqueous NH4Cl was added, the phases were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic extracts were dried and concentrated. Flash
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
chromatography (3:7 hexane−EtOAc) afforded compound 5 (40 mg, 83%) as a yellowish oil: [α]23
‒
D
1
80.1 (c 0.19, CHCl3); H-NMR (400 MHz, CDCl3, COSY, g-HSQC) δ: 0.91 (t, J = 6.8 Hz, 3H, CH3),
1.25-1.37 (m, 4H, H-2’, H-3’), 1.39-1.49 (m, 1H, H-1’), 1.57-1.66 (m, 1H, H-1’), 1.77-1.83 (m, 1H, H-
8), 1.85-1.92 (m, 1H, H-7a), 1.93-2.01 (m, 1H, H-7), 2.03-2.11 (m, 1H, H-7), 2.42 (dd, J = 4.8, 16.0,
Hz, 2H, H-9), 2.54 (ddd, J = 4.0, 10.8, 18.0 Hz, 1H, H-6), 2.64 (brs, 2H, H-11), 2.73 (dd, J = 4.0, 5.6
Hz, 1H, H-6), 3.94 (dd, J = 7.6, 8.8 Hz, 1H, H-2), 4.52 (t, J = 8.8 Hz, 1H, H-2), 5.41 (t, J = 8.2 Hz, 1H,
H-3), 7.12 (d, J = 7.4 Hz, 2H, H-Ar), 7.24 (t, J = 7.4 Hz, 1H, H-Ar), 7.32 (t, J = 7.4 Hz, 2H, H-Ar); 13C-
NMR (100.6 MHz, CDCl3) δ: 14.0 (CH3), 22.6 (C-3’), 25.3 (C-7), 29.4 (C-2’), 31.3 (C-6), 34.8 (C-1’),
38.2 (C-8), 41.8 (C-9), 43.7 (C-7a), 45.3 (C-11), 58.0 (C-3), 69.5 (C-2), 96.2 (C-11a), 125.3 (2CH-Ar),
127.4 (CH-Ar), 128.7 (2CH-Ar), 139.4 (Cq-Ar), 169.4 (C-5), 207.1 (C-10); HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C21H27NO3H 342.2064; Found 342.2063.
Method B. MeLi (74 µL, 1.6 M in Et2O, 0.12 mmol) was added to a suspension of CuI (23 mg, 0.12
mmol) in anhydrous THF (300 µL) at 0 ºC. The resulting yellow/brown suspension was cooled to ‒50
ºC, and HMPA (60 µL, 20 % v/v) and DIBALH (240 µL, 1 M in hexane, 0.24 mmol) were sequentially
added. After 30 minutes, the mixture was cooled to ‒65 ºC, and compound 6 (see below; 20 mg, 0.06
mmol) in anhydrous THF (300 µL) was added dropwise. The mixture was allowed to warm to ‒50 ºC,
and stirring was continued for 2 h. 1 M aqueous HCl was added, the phases were separated, and the
aqueous phase was extracted with CH2Cl2. The combined organic extracts were filtered over Celite®,
and the solvent was evaporated. Flash chromatography (4:6 hexane−EtOAc) afforded compound 5 (15
mg, 75%) as a yellowish oil.
(3R,7aS,8R,11aS)-8-Butyl-5-oxo-3-phenylperhydrooxazolo[2,3-j]quinoline (2c): 1st step. BF3·Et2O
(5 µL, 0.04 mmol) was added to a solution of ketone 5 (44 mg, 0.13 mmol) and 1,3-propanedithiol (20
µL, 0.194 mmol) in anhydrous CH2Cl2 (2.0 mL), and the mixture was stirred at room temperature for 16
h. 2 M aqueous NaOH was added, the phases were separated, and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried, and concentrated to afford crude
dithiane.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
7
8
9
2nd step. Ni-Raney (200 mg) was added to a solution of the above crude in absolute EtOH (2.3 mL), and
the slurry suspension was heated to reflux for 23 h. After cooling to room temperature, 5% aqueous HCl
was added, and the resulting suspension was filtered over Celite®. The solvent was evaporated, and the
residue was re-dissolved in 10% aqueous NaOH and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated. Flash chromatography (6:4, hexane–EtOAc) afforded lactam 2c
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
(24 mg, 55% overall yield) as a white residue: [α]23 − 77.1 (c 1.1, MeOH); H-NMR (400 MHz,
D
CDCl3, COSY, g-HSQC) δ (ppm): 0.91 (t, J = 6.8 Hz, 3H, H-4’), 1.24-1.84 (m, 15H), 2.11-2.23 (m,
1H), 2.47 (ddd, J = 18.5, 11.0, 7.2 Hz, 1H, H-6), 2.64 (dd, J = 18.5, 7.2 Hz, 1H, H-6), 3.83 (t, J = 8.4
Hz, 1H, H-2), 4.51 (t, J = 8.4 Hz, 1H, H-2), 5.30 (t, J = 8.4 Hz, 1H, H-3), 7.15-7.33 (m, 5H, H-Ar); 13C-
NMR (100.6 MHz, CDCl3) δ (ppm): 14.2 (CH3), 18.0 (C-10), 22.8 (C-7), 24.2 (C-11), 24.8 (C-7), 30.5
(C-9), 30.6 (CH2), 31.3 (C-6), 32.9 (CH2), 39.9 (C-8), 43.7 (C-7a), 58.0 (C-3), 69.6 (C-2), 95.5 (C-11a),
125.4 (2CH-Ar), 127.0 (CH-Ar), 128.5 (2CH-Ar), 140.3 (C-i), 169.5 (NCO).
(3R,7aS,11aS)-8-Butyl-5,10-dioxo-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinolone
(6): Mn(OAc)3 (8.3 mg, 0.03 mmol) was added under argon to a stirring solution of lactam 1c (50 mg,
0.15 mmol) and TBHP (140 µL, 5.5 M in decane, 0.77 mmol) in EtOAc (9 mL) containing 3Ǻ
molecular sieves (180 mg). The mixture was stirred at 50 ºC for 40 h and filtered over Celite®. After
washing with EtOAc, the solvent was evaporated. Flash chromatography (6:4 hexane–EtOAc) afforded
enone 6 (21 mg, 40%) as a colorless oil: [α]23D ‒ 97.1 (c 1.05, CHCl3); H-NMR (400 MHz, CDCl3,
1
COSY, g-HSQC) δ: 0.95 (t, J = 7.4 Hz, 3H, CH3), 1.34-1.43 (m, 2H, H-3’), 1.45-1.66 (m, 2H, H-2’),
1.79-1.95 (m, 1H, H-1’), 2.21-2.40 (m, 3H, H-7, H-1’), 2.45 (dd, J = 3.6, 13.2 Hz, 1H, H-7a), 2.56-2.65
(m, 1H, H-6), 2.72-2.86 (m, 3H, H-6, H-11), 3.94 (t, J = 8.4 Hz, 1H, H-2), 4.50 (t, J = 8.4 Hz, 1H, H-2),
5.41 (t, J = 8.4 Hz, 1H, H-3), 5.95 (s, 1H, H-9), 7.18 (d, J = 7.4 Hz, 2H, H-Ar), 7.26 (t, J = 7.4 Hz, 1H,
13
H-Ar), 7.34 (t, J = 7.4 Hz, 2H, H-Ar); C-NMR (100.6 MHz, CDCl3) δ: 13.8 (CH3), 22.3 (C-3’), 23.7
(C-1’), 29.1 (C-2’), 31.1 (C-6), 35.2 (C-7), 43.1 (C-11), 45.4 (C-7a), 59.1 (C-3), 69.7 (C-2), 95.2 (C-
11a), 124.5 (C-9), 125.4 (2CH-Ar), 127.6 (CH-Ar), 128.8 (2CH-Ar), 139.1 (Cq-Ar), 164.3 (C-8), 168.5
(NCO), 194.7 (C=O); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H25NO3H 340.1907; Found
340.1917.
(3R,7aS,11aS)-8-Formyl-5-oxo-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinoline (7b):
Operating as in the preparation of compound 3, from lactam 1b (100 mg, 0.35 mmol) and SeO2 (169
mg, 1.52 mmol) in anhydrous dioxane (12 mL), aldehyde 7b (105 mg, 99%) was obtained as a dark
orange foam after filtration over a short pad of silica: mp: 175-177 ºC; [α]23D ‒ 128.7 (c 0.875, CHCl3);
1H-NMR (400 MHz CDCl3, COSY, g-HSQC) δ (ppm): 1.59-1.62 (m, 1H, H-7), 1.80-1.92 (m, 1H, H-
11), 1.94-2.04 (m, 1H, H-11), 2.25-2.36 (m, 1H, H-7), 2.39-2.47 (m, 2H, H-10), 2.55-2.59 (m, 2H, H-6),
2.69-2.75 (m, 1H, H-7a), 3.93 (t, J = 8.3 Hz, 1H, H-2), 4.56 (t, J = 8.3 Hz, 1H, H-2), 5.51 (t, J = 8.3 Hz,
16
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
1H, H-3), 6.84 (t, J = 3.6 Hz, 1H, H-9), 7.18 (dd, J = 7.2, 3.6 Hz, 2H, H-Ar), 7.26 (t, J = 7.2 Hz, 1H, H-
13
Ar), 7.34 (t, J = 7.4 Hz, 2H, H-Ar), 9.48 (s, 1H, CHO); C-NMR (100.6 MHz, CDCl3) δ (ppm): 24.5
6
7
8
9
(C-10), 25.0 (C-7), 26.4 (C-11), 31.1 (C-6), 37.9 (C-7a), 58.4 (C-3), 69.6 (C-2), 93.2 (C-11a), 125.3
(2CH-Ar.), 127.3 (CH-Ar.), 128.7 (2CH-Ar.), 140.1 (Cq-Ar.), 141.5 (C-8), 149.7 (C-9), 169.5 (C-5),
192.7 (CHO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19NO3H 298.1438; Found 298.1432.
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
(3R,7aS,11aS)-5-Oxo-8-(4-oxobutyl)-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinoline
(7c): Operating as in the preparation of compound 3, from lactam 1c (50 mg, 0.15 mmol) and SeO2 (74
mg, 0.66 mmol) in anhydrous dioxane (5 mL), ketone 7c (47 mg, 89%) was obtained after flash
chromatography (7:4 hexane–EtOAc) as a colorless oil: [α]23D ‒ 181.8 (c 1.1, CHCl3); IR (NaCl): 1663
1
cm-1; H-NMR (400 MHz, CDCl3, COSY, g-HSQC ) δ (ppm): 0.93 (t, J = 7.4 Hz, 3H, CH3), 1.47-1.58
(m, 1H, H-7), 1.59-1.74 (m, 2H, H-3’), 1.75-1.88 (m, 1H, H-11), 1.90-1.99 (m, 1H, H-11), 2.19-2.27
(m, 1H, H-7), 2.34 (brs, 2H, H-10), 2.57-2.69 (m, 4H, H-6, H-2’), 2.83 (d, J = 11.6 Hz, 1H, H-7a), 3.91
(t, J = 8.2 Hz, 1H, H-2), 4.54 (t, J = 8.2 Hz, 1H, H-2), 5.49 (t, J = 8.2 Hz, 1H, H-3), 6.93 (t, J = 3.4 Hz,
1H, H-9), 7.18 (d, J = 7.4 Hz, 2H, H-Ar), 7.25 (d, J = 5.2 Hz, 1H, Ar), 7.33 (t, J = 7.4 Hz, 2H, Ar); 13C-
NMR (100.6 MHz, CDCl3) δ (ppm):13.8 (CH3), 18.0 (C-3’), 24.1 (C-10), 25.7 (C-11), 25.8 (C-7), 31.3
(C-6), 38.8 (C-7a), 39.1 (C-2’), 58.5 (C-3), 69.5 (C-2), 93.7 (C-11a), 125.3 (2CH-Ar), 127.2 (CH-Ar),
128.6 (2CH-Ar), 138.6 (C-9) 139.4 (Cq-Ar), 140.2 (C-8), 169.7 (NCO), 199.7 (C=O); HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C21H25NO3H 340.1907; Found 340.1911.
(3R,7aS,11aS)-8-(Hydroxymethyl)-5-oxo-3-phenyl-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-
j]quinoline: NaBH4 (13 mg, 0.34 mmol) was added in portions to a stirring solution of aldehyde 7b
(100 mg, 0.34 mmol) in absolute EtOH (3 mL) at 0 ºC, and the mixture was stirred at room temperature
for 45 minutes. Then, water was added, the ethanol was removed under reduced pressure, and the
aqueous phase was extracted with EtOAc. The combined organic extracts were dried and concentrated
to afford the title alcohol (90 mg, 90%) as a sticky yellowish solid: [α]23 ‒ 101.2 (c 1.0, CHCl3); IR
D
1
(NaCl): 3041, 1655, 1629 cm-1; H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.61-1.86 (m,
2H, H-11), 1.90 (dd, J = 14.4, 5.8 Hz, 1H, H-7), 2.03-2.23 (m, 2H, H-10), 2.25-2.36 (m, 1H, H-7), 2.37
(brs, 1H, H-7a) 2.52 (ddd, J = 11.4, 7.6, 4.2 Hz, 1H, H-6), 2.68 (dd, J = 18.4, 6.4 Hz, 1H, H-6), 3.91 (t,
J = 8.4 Hz, 1H, H-2), 4.06-4.18 (m, 2H, CH2OH) 4.57 (t, J = 8.4 Hz, 1H, H-2), 5.47 (t, J = 8.4 Hz, 1H,
13
H-3), 5.75 (brs, 1H, H-9), 7.15-7.37 (m, 5H, H-Ar); C-NMR (CDCl3, 100.6 MHz) δ (ppm): 22.9 (C-
10), 25.1 (C-7), 26.1 (C-11), 31.3 (C-6), 40.9 (C-11), 58.5 (C-3), 65.3 (CH2OH), 69.5 (C-2), 94.2 (C-
11a), 123.4 (C-9), 125.3 (2CH-Ar), 127.2 (CH-Ar), 128.6 (2CH-Ar), 137.4 (C-8), 140.2 (Cq-Ar), 169.6
(C-5); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H21NO3H 300.1594; Found 300.1591.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
(3R,7aS,11aS)-5-Oxo-3-phenyl-8-[(triisopropylsilyloxy)methyl]-2,3,5,6,7,7a,10,11-
octahydrooxazolo[2,3-j]quinoline (8): TIPSCl (300 µL, 1.4 mmol) was added to a stirring solution of
the above alcohol (280 mg, 0.94 mmol) and imidazole (96 mg, 1.4 mmol) in anhydrous DMF (2 mL),
and the mixture was stirred at room temperature for 17 h. Brine was added, and the resulting mixture
was stirred for 20 minutes and extracted with CH2Cl2. The combined organic extracts were washed with
brine, dried, and concentrated. Flash chromatography (from hexane to 75:25 hexane–EtOAc) afforded
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
compound 8 (360 mg, 84%) as a sticky white residue: IR (NaCl): 1645 (NCO) cm-1; [α]23 ‒ 37.2 (c
D
1
0.48 CHCl3); H-NMR (CDCl3, 400 MHz) δ (ppm): 1.05-1.15 [m, 21H, Si(iPr)3] 1.65-1.92 (m, 3H),
2.05-2.20 (m, 2H), 2.25-2.37 (m, 2H), 2.45-2.54 (m, 1H), 2.68 (dd, J = 18.4, 6.4 Hz, 1H), 3.90 (t, J =
8.0 Hz, 1H), 4.25 [brs, 2H, CH2OSi(iPr)3], 4.56 (t, J = 8.0 Hz, 1H), 5.46 (t, J = 8.0 Hz, 1H), 5.72 (brs,
1H), 7.18-7.35 (m, 5H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 12.0 (CH); 18.0 (CH3); 22.8
(CH2), 25.4 (CH2), 26.3 (CH2), 31.4 (CH2), 41.2 (CH2), 58.5 (CH), 65.8 [CH2OSi(iPr)3], 69.5 (CH2)
93.3 (Cq), 120.8 (CH), 125.3 (CH-Ar), 125.4 (CH-Ar), 127.1 (CH-Ar), 128.5 (CH-Ar), 128.6 (CH-Ar),
136.9 (Cq), 140.3 (Cq-Ar), 169.7 (Cq); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H41NO3SiH
456.2928; Found 456.2933.
Methyl (2R,4R)-2-allyl-4-methyl-6-oxocyclohexanepropionate (11): A solution of compound 918 (4.0
g, 20.4 mmol) in anhydrous CH2Cl2 (8.0 mL), TMSCl (13 mL, 102 mmol), and AllylTMS (3.57 mL,
22.44 mmol) were added sequentially to a solution of InCl3 (451 mg, 2.04 mmol) in anhydrous CH2Cl2
(68 mL), and the resulting mixture was stirred at room temperature for 4 h. Saturated aqueous NaHCO3
was added, and the aqueous phase was separated and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated. Flash chromatography (96:4 hexane–EtOAc), afforded keto ester
1
11 (4.8 g, 99%; 1:1 mixture of C-2 epimers) as a colorless oil: H-NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ (ppm): 0.93 and 0.96 (d, J = 6.4 Hz, 3H, CH3), 1.38-1.45 (m, 1H), 1.47-1.54 (m, 1H), 1.59-
1.67 (m, 1H), 1.83-1.90 (m, 1H), 1.92-1.98 (m, 1H), 2.00-2.16 (m, 4H), 2.18-2.24 (m, 1H), 2.28 (t, J =
7.6 Hz, 1H), 2.32-2.39 (m, 1H), 2.50-2.54 (m, 1H), 3.63 (s, 3H), 4.93-5.03 (m, 2H), 5.58-5.74 (m, 1H);
13C-NMR (100.6 MHz, CDCl3) δ (ppm): 21.0 and 22.2 (CH3), 21.8 and 24.7 (CH2), 29.3 and 29.5
(CH), 31.7 and 31.9 (CH2), 34.3 (CH2), 36.6 and 39.1 (CH2), 39.1 and 40.4 (CH), 47.2 and 50.2 (CH2),
51.4 and 51.5 (OCH3), 52.7 and 53.6 (CH), 116.4 and 117.0 (CH2), 135.7 and 136.2 (CH), 173.6 and
173.8 (COO), 211.6 and 213.4 (CO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H22O3H 239.1642;
Found 239.1639.
(3S,7aS,8R,10R,11aS)-8-Allyl-10-methyl-5-oxo-3-phenylperhydrooxazolo[2,3-j]quinoline (18a) and
(3S,7aR,8R,10R,11aR)-8-allyl-10-methyl-5-oxo-3-phenylperhydrooxazolo[2,3-j]quinoline
(18b):
(S)-Phenylglycinol (1.7 g, 12.6 mmol) was added to a solution of keto ester 11 (2.0 g, 8.39 mmol) and
AcOH (720 µL, 12.6 mmol) in benzene (67 mL). The mixture was heated at reflux with azeotropic
18
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
elimination of water by a Dean-Stark system. After 24 h, the mixture was cooled to room temperature
and concentrated, and the resulting oil was taken up in EtOAc. The organic solution was washed with
saturated aqueous NaHCO3, 1 M aqueous HCl and brine, dried, and concentrated. Flash
chromatography (from 9:1 to 7:3 hexane–EtOAc) afforded pure lactams 18a (1.15 mg, 43%) and 18b
(971 mg, 35%) as yellowish residues. 18b (higher Rf): [α]23 + 79.0 (c 2.0, CHCl3); IR (NaCl): 1655,
D
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
1398 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.13 (d, J = 7.6 Hz, 3H, CH3), 1.32-
1.41 (m, 1H, H-9), 1.50 (dt, J = 5.2, 13.2 Hz, 1H, H-9), 1.79-1.89 (m, 5H, H-7, H-7a, H-11), 2.11-2.23
(m, 3H,-10, H-1’), 2.30-2.35 (m, 1H, H-8), 2.43-2.53 (m, 1H, H-6), 2.66-2.74 (m, 1H, H-6), 3.92 (t, J =
8.6 Hz, 1H, H-2), 4.35 (t, J = 8.6 Hz, 1H, H-2), 5.07-5.14 (m, 2H, CH=CH2), 5.37 (t, J = 8.6 Hz, 1H, H-
3), 5.78-5.90 (m, 1H, CH=CH2), 7.23 (d, J = 7.4 Hz, 2H, H-Ar), 7.28-7.33 (m, 1H, H-Ar), 7.38 (t, J =
7.4 Hz, 2H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.0 (C-11), 19.4 (CH3), 27.4 (C-10), 30.6
(C-6), 30.7 (C-8), 31.4 (C-9), 34.2 (C-7), 37.7 (C-1’), 43.2 (C-7a), 58.8 (C-3), 69.5 (C-2), 95.9 (C-11a),
116.1 (C=CH2), 125.3 (2CH-Ar), 127.0 (CH-Ar), 128.5 (2CH-Ar), 136.6 (CH=C), 140.1 (Cq-Ar), 169.2
(C-5); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27NO2H 326.2115; Found 326.2122. 18a (lower
Rf): [α] ‒ 44.5 (c 2.0, CHCl3); IR (NaCl): 1656, 1435 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-
23
D
HSQC) δ (ppm): 0.91 (d, J = 6.0 Hz, 3H, CH3), 1.15 (t, J = 13.8 Hz, 1H, H-11), 1.33 (dt, J = 4.8, 8.4
Hz, 1H, H-9), 1.49-1.53 (m, 1H, H-9), 1.71-1.81 (m, 2H, H-7, H-8), 1.87-1.96 (m, 2H, H-10. H-11),
1.97-2.03 (m, 1H, H-7), 2.05-2.12 (m, 1H, H-7a), 2.22-2.30 (m, 1H, H-1’), 2.32-2.40 (m, 2H, H-6, H-
1’), 2.48-2.58 (m, 1H, H-1’), 3.86 (dd, J = 1.8, 7.2 Hz, 1H, H-2), 4.35 (dd, J = 1.8, 7.2 Hz, 1H, H-2),
4.86 (dd, J = 1.8, 7.2 Hz, 1H, H-3), 5.04-5.10 (m, 2H, CH=CH2), 5.80 (dddd, J = 7.2, 10.2, 14.4, 17.2
Hz 1H, CH=CH2), 7.15-7.20 (m, 1H, H-Ar), 7.22-7.30 (m, 4H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ
(ppm): 21.9 (CH3), 24.2 (C-7), 24.6 (C-10), 30.3 (C-1’), 32.8 (C-9), 38.1 (C-11), 38.3 (C-6), 39.4 (C-8),
41.0 (C-7a), 58.6 (C-3), 70.8 (C-2), 95.3 (C-11a), 116.1 (C=CH2), 126.2 (2CH-Ar), 127.2 (CH-Ar),
128.4 (2CH-Ar), 138.2 (CH=C), 142.1 (Cq-Ar), 167.2 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C21H27NO2H 326.2115; Found 326.2119.
(3S,7aR,8S,10R,11aR)-10-Methyl-5-oxo-8-(2-oxoethyl)-3-phenylperhydrooxazolo[2,3-j]quinoline
(26): RuCl3.nH2O in H2O (3.9 mL, 0.14 mmol, 0.035 M stock solution) was added to a solution of
lactam 18b (1.27 g, 3.9 mmol) in MeCN (23 mL) under vigorous stirring. NaIO4 (1.67 g, 7.8 mmol) was
then added in portions over 5 min, and the stirring was continued for 1 h 20 min. Saturated aqueous
Na2S2O3 was added, the resulting mixture was diluted with EtOAc, the phases were separated, and the
aqueous solution was extracted with EtOAc. The combined organic extracts were dried and
concentrated. Flash chromatography (4:6 hexane–EtOAc) afforded aldehyde 26 (970 mg, 76%) as a
1
white foam: [α]23 + 121.1 (c 1.1, CHCl3); IR (NaCl): 2931, 2707 and 1721, 1611 cm-1; H-NMR
D
(CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.11 (d, J = 7.6 Hz, 3H, CH3), 1.28-1.32 (m, 1H, H-9),
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
1.51 (ddd, J = 21.2, 6.8, 5.6 Hz, 1H, H-9), 1.72-1.86 (m, 5H, H-7, H-7a, H-11), 2.03-2.08 (m, 1H, H-
10), 2.34-2.47 (m, 3H, H-6, H-1’), 2.66 (dd, J = 18, 6.4 Hz, 1H, H-6), 2.86-2.94 (m, 1H, H-8), 3.87 (dd,
J = 8.4, 8.8 Hz, 1H, H-2), 4.53 (t, J = 8.8 Hz, 1H, H-2), 5.31 (t, J = 8.2 Hz, 1H, H-3), 7.16-7.18 (m, 2H,
H-Ar), 7.22-7.26 (m, 1H, H-Ar), 7.30-7.34 (m, 2H, H-Ar), 9.76 (s, 1H, CHO); 13C-NMR (CDCl3, 100.6
MHz) δ (ppm): 16.5 (C-7), 19.2 (CH3), 25.9 (C-8), 27.2 (C-10), 30.4 (C-6), 31.3 (C-9), 33.7 (C-11),
43.5 (C-7a), 47.2 (C-1’), 58.8 (C-3), 69.4 (C-2), 95.4 (C-11a), 125.2 (2CH-Ar), 127.0 (CH-Ar), 128.4
(2CH-Ar), 140.0 (Cq-Ar), 168.8 (NCO), 201.2 (CHO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H25NO3H 328.1907; Found 328.1916.
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
(3S,7aR,8S,10R,11aR)-8-[(R,E)-2-(tert-Butylsulfinylimino)ethyl]-10-methyl-5-oxo-3-
phenylperhydrooxazolo[2,3-j]quinoline (27): (R)-(+)-tert-butanesulfinamide (63 mg, 0.55 mmol) was
added to a solution of 26 (131 mg, 0.4 mmol) and Ti(iOPr)4 (270 µL, 0.88 mmol) in anhydrous THF (2
mL) under vigorous stirring. After 7 h at room temperature, brine was added under vigorous stirring,
and the mixture was diluted with EtOAc. The suspension was filtered over Celite® and washed with
EtOAc. The filtrate was dried and concentrated. Flash chromatography (4:6 hexane–EtOAc) afforded
compound 27 (143 mg, 83%) as a white foam: [α]23 ‒ 98.35 (c 0.85, CHCl3); IR (NaCl): 1654, 1622,
D
1082 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC)) δ (ppm): 1.08 (d, J = 7.2 Hz, 3H, CH3), 1.21
[s, 9H, C(CH3)3], 1.36-1.40 (m, 1H, H-9), 1.54 (ddd, J = 21.2, 6.6, 5.4 Hz, 1H, H-9), 1.78-1.89 (m, 5H,
H-7, H-7a, H11), 2.02-2.11 (m, 1H, H-10), 2.34-2.43 (m, 1H, H-6), 2.51-2.55 (m, 2H, H-1’), 2.64-2.70
(m, 1H, H-6), 2.76-2.85 (m, 1H, H-8), 3.86 (dd, J = 8.8, 8.0 Hz, 1H, H-2), 4.51 (t, J = 8.8 Hz, 1H, H-2),
5.30 (t, J = 8.4 Hz, 1H, H-3), 7.16-7.18 (m, 2H, H-Ar), 7.22-7.26 (m, 1H, H-Ar), 7.32 (t, J = 7.4 Hz, 2H,
H-Ar), 8.09 (t, J = 4.8 Hz, 1H, H-2’); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.5 (C-7), 19.5 (CH3),
22.4 [C(CH3)3], 27.4 (C-10), 28.7 (C-8), 30.5 (C-6), 31.4 (C-9), 34.1 (C-11), 39.9 (C-1’), 43.9 (C-7a),
56.6 [C(CH3)3], 58.9 (C-3), 69.6 (C-2), 95.5 (C-11a), 125.4 (2CH-Ar), 127.2 (CH-Ar), 128.6 (2CH-Ar),
140.0 (Cq-Ar), 168.2 (NCO), 168.9 (HC=NSO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H34N2O3SH 431.2363; Found 431.2365.
(3S,7aR,8S,10R,11aR)-8-{(S)-2-[(R)-tert-Butylsulfinylamino]pent-4-enyl}-10-methyl-5-oxo-3-
phenylperhydrooxazolo[2,3-j]quinoline (28): Allylmagnesium bromide (4.64 mL, 1 M in Et2O, 4.64
mmol) was slowly added to a stirring solution of N-sulfinyl imine 27 (1.0 g, 2.32 mmol) in anhydrous
CH2Cl2 (23 mL) at 0 ºC. After 2 h, saturated aqueous NH4Cl was added, and the resulting mixture was
diluted with EtOAc. The phases were separated, and the aqueous solution was extracted with EtOAc.
The combined organic extracts were dried and concentrated. Flash chromatography (from CH2Cl2 to
9.85:0.15 CH2Cl2–MeOH) afforded sulfinamide 28 (965 mg, 88%) as a yellow foam: [α]23 + 46.3 (c
D
1
0.88, CHCl3); IR (NaCl): 3427, 1645, 1056 cm-1; H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ
(ppm): 1.04 (d, J = 7.2 Hz, 3H, CH3), 1.22-1.26 [m, 10H, C(CH3)3, H-9], 1.36-1.53 (m, 3H, H-9, H-1’),
20
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.69-1.84 (m, 5H, H-7, H-7a, H-11), 2.00-2.06 (m, 1H, H-10), 2.35-2.47 (m, 4H, H-6, H-3’, H-8), 2.65
(dd, J =6.2, 18.2 Hz, 1H, H-6), 3.22 (d, J = 7.6 Hz, 1H, NH), 3.29-3.38 (m, 1H, H-2’), 3.83 (dd, J =8.0,
8.8 Hz, 1H, H-2), 4.43 (t, J = 8.6 Hz, 1H, H-2), 5.15-5.19 (m, 2H, H-5’), 5.29 (t, J = 8.2 Hz, 1H, H-3),
5.73-5.84 (m, 1H, H-4’), 7.15-7.17 (m, 2H, H-Ar), 7.21-7.24 (m, 1H, H-Ar), 7.29-7.33 (m, 2H, H-Ar);
13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.2 (C-7), 19.4 (CH3), 22.7 [C(CH3)3], 26.9 (C-8), 27.4 (C-
10), 30.6 (C-6), 32.0 (C-9), 34.2 (C-11), 38.4 (C-1’), 41.0 (C-3’), 42.7 (C-7a), 52.9 (C-2’), 56.0
[C(CH3)3], 58.8 (C-3), 69.4 (C-2), 95.7 (C-11a), 119.4 (C-5’), 125.4 (2CH-Ar), 127.1 (CH-Ar), 128.5
(2CH-Ar), 133.6 (C-4’), 140.0 (Cq-Ar), 169.1 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C27H40N2O3SH 473.2832; Found 473.2841.
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
(3S,7aR,8S,10R,11aR)-8-[(S)-2-(Acryloylamino)pent-4-enyl]-10-methyl-5-oxo-3-
phenylperhydrooxazolo[2,3-j]quinoline (29): 1st step. 1 M HCl in Et2O (4.14 mL, 4.14 mmol) was
slowly added to a stirred solution of sulfinamide 28 (738 mg, 1.66 mmol) in anhydrous MeOH (2 mL).
After 1 h, the solvent was evaporated, and the resulting amine HCl salt was used without further
purification in the next step.
2nd step. Acryloyl chloride (2.0 mL, 26.5 mmol) was slowly added to a biphasic mixture of the above
crude amine hydrochloride in H2O–CH2Cl2 (16.5 mL, 1:1) and Et3N (3.70 mL, 26.5 mmol) at 0 ºC. The
mixture was stirred for 20 h at room temperature. Then, the mixture was diluted with CHCl3, and the
layers were separated. The aqueous solution was extracted with CHCl3. The combined organic extracts
were washed with brine, dried, and concentrated. Flash chromatography (from 4:6 to 3:7 hexane–
EtOAc) afforded acrylamide 29 (445 mg, 64%) as a white foam: [α]23 + 83.55 (c 1.03, CHCl3); IR
D
(NaCl): 2924, 1655, 1403 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.04 (d, J = 7.6
Hz, 3H, CH3), 1.31-1.33 (m, 1H, H-9), 1.42-1.52 (m, 3H, H-9, H-1’), 1.69-1.80 (m, 5H, H-7, H-7a,
H11), 2.00-2.05 (m, 1H, H-10), 2.16-2.44 (m, 4H, H-6, H-8, H-3’), 2.58-2.64 (m, 1H, H-6), 3.82 (dd, J
= 8.0, 8.4 Hz, 1H, H-2), 4.07-4.16 (m, 1H, H-2’), 4.46 (t, J = 8.8 Hz, 1H, H-2), 5.06-5.10 (m, 2H, H-
5’), 5.25-5.29 (m, 1H, H-3), 5.58 (dd, J = 1.6, 10.0 Hz, 1H, CH2=CHCO), 5.71-5.81 (m, 2H, H-4’, NH),
6.06 (dd, J = 10.4, 16.8 Hz, 1H, CH2=CHCO), 6.24 (dd, J = 1.6, 16.8 Hz, 1H, CH2=CHCO), 7.14-7.16
(m, 2H, H-Ar), 7.20-7.23 (m, 1H, H-Ar), 7.28-7.31 (m, 2H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ
(ppm): 16.3 (C-7), 19.4 (CH3), 27.3 (C-10), 27.6 (C-8), 30.7 (C-6), 31.5 (C-9), 34.2 (C-11), 37.5 (C-1’),
38.7 (C-3’), 43.4 (C-7a), 46.3 (C-2’), 58.8 (C-3), 69.4 (C-2), 95.6 (C-11a), 118.2 (C-5’), 125.3 (2CH-
Ar), 126.1 (CH2=CHCO), 127.0 (CH-Ar), 128.5 (2CH-Ar), 131.0 (CH2=CHCO), 134.0 (C-4’), 140.1
(Cq-Ar), 165.0 (NCO), 169.0 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H34N2O3H
423.2642; Found 423.2640.
(3S,7aR,8S,10R,11aR)-10-Methyl-8-{[(S)-6-oxo-2-piperidyl]methyl}-5-oxo-3-phenyl
perhydrooxazolo[2,3-j]quinoline (30): Second generation Grubbs’ catalyst (33 mg, 0.04 mmol) was
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
added to a stirring solution of acrylamide 29 (330 mg, 0.78 mmol) in degassed anhydrous CH2Cl2 (26
mL). The resulting brown solution was stirred at reflux temperature for 4 h. After cooling to room
temperature, the mixture was stirred for an additional hour exposed to air. The solvent was evaporated
under reduced pressure. Flash chromatography (from EtOAc to 95:5 EtOAc–MeOH) afforded
dihydropyridone 30 (267 mg, 86%) as a brown foam: [α]23 + 61.3 (c 0.95, CHCl3); IR (NaCl): 3229,
D
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
1676, 1651 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.08 (d, J = 7.6 Hz, 3H, CH3),
1.26-1.29 (m, 1H, H-9), 1.47-1.63 (m, 3H, H-9, H-1’), 1.72-1.87 (m, 5H, H-7, H-7a, H-11), 2.01-2.21
(m, 3H, H-10, H-7’), 2.31-2.46 (m, 2H, H-6, H-8), 2.67 (dd, J = 6.8, 18.4 Hz, 1H, H-6), 3.63-3.71 (m,
1H, H-2’), 3.85 (t, J = 8.6 Hz, 1H, H-2), 4.51 (t, J = 8.6 Hz, 1H, H-2), 5.30 (t, J = 8.4 Hz, 1H, H-3),
5.92-6.06 (m, 2H, H-5’, NH), 6.59-6.64 (m, 1H, H-6’), 7.16-7.18 (m, 2H, H-Ar), 7.23-7.27 (m, 1H, H-
Ar), 7.31-7.35 (m, 2H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.3 (C-7), 19.4 (CH3), 27.0 (C-
8), 27.1 (C-10), 30.1 (C-7’), 30.5 (C-6), 31.6 (C-9), 34.0 (C-11), 38.7 (C-1’), 43.5 (C-7a), 48.2 (C-2’),
58.9 (C-3), 69.5 (C-2), 95.5 (C-11a), 124.5 (C-5’), 125.3 (2CH-Ar), 127.1 (CH-Ar), 128.5 (2CH-Ar),
140.0 (Cq-Ar), 140.3 (C-6’), 166.3 (NCO), 168.8 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H30N2O3H 395.2329; Found 395.2332.
(3S,7aR,8S,10R,11aR)-10-Methyl-8-{[(S)-6-oxo-2-piperidyl]methyl}-5-oxo-3-phenyl
perhydrooxazolo[2,3-j]quinoline: A solution of dihydropyridone 30 (262 mg, 0.66 mmol) in MeOH
(5.8 mL) containing Pd/C (52 mg, 10% Pd) was stirred under hydrogen at room temperature for 15 h.
The catalyst was removed by filtration, and the solvent was evaporated affording the title piperidone
(252 mg, 96%) as a colorless oil: [α]23 + 87.2 (c 1.11, CHCl3); IR (NaCl): 2930, 1655 cm-1; 1H-NMR
D
(CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.07 (d, J = 7.2 Hz, 3H, CH3), 1.23-1.27 (m, 1H, H-9),
1.34-1.53 (m, 4H, H-9, H-1’, H-6’), 1.65-1.84 (m, 5H, H-7, H-9, H-7’, H-7a, H-11), 1.89-1.97 (m, 3H,
H-10, H-6’, H-7’), 2.03-2.08 (m, 1H, H-10), 2.25-2.46 (m, 4H, H-6, H-8, H-5’), 2.66 (dd, J = 6.2, 18.6
Hz, 1H, H-6), 3.40-3.48 (m, 1H, H-2’), 3.85 (t, J = 8.6 Hz, 1H, H-2), 4.51 (t, J = 8.8 Hz, 1H, H-2), 5.30
(t, J = 8.2 Hz, 1H, H-3), 6.26 (s, 1H, NH), 7.16-7.18 (m, 2H, H-Ar), 7.22-7.26 (m, 1H, H-Ar), 7.29-7.34
(m, 2H, H-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.3 (C-7), 19.4 (CH3), 19.6 (C-7’), 26.8 (C-8),
27.1 (C-10), 28.6 (C-6’), 30.5 (C-6), 31.2 (C-5’), 31.6 (C-9), 34.0 (C-11), 40.2 (C-1’), 43.5 (C-7a), 50.1
(C-2’), 58.8 (C-3), 69.4 (C-2), 95.4 (C-11a), 125.2 (2CH-Ar), 127.0 (CH-Ar), 128.4 (2CH-Ar), 140.0
(Cq-Ar), 168.8 (NCO), 172.2 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H32N2O3H
397.2486; Found 397.2478.
(4aR,5S,7R,8aS)-1-[(S)-2-Hydroxy-1-phenylethyl]-7-methyl-5-{[(S)-2-piperidyl]
methyl}decahydroquinoline: LiAlH4 (3.57 mL, 1 M in THF, 3.57 mmol) was added to a stirring
solution of AlCl3 (147 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0 ºC. After 10 minutes, the
mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. The mixture
22
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
was cooled to ‒78 ºC, and after 10 minutes a solution of the above piperidone (218 mg, 0.55 mmol) in
anhydrous THF (3.0 mL) was added. The stirring was continued at –78 °C for 90 min and at room
temperature for 2 h. Water was slowly added, and the resulting mixture was diluted with EtOAc. The
phases were separated, and the aqueous solution was extracted with EtOAc. The combined organic
extracts were dried and concentrated. Flash chromatography (from CH2Cl2 to 8:2 CH2Cl2–MeOH)
afforded the title cis-DHQ (157 mg, 77%) as a colorless oil: [α]23D ‒ 0.83 (c 0.68 , CHCl3); IR (NaCl):
3331, 2928 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 0.47 (d, J = 7.2 Hz, 3H, CH3),
0.97-1.05 (m, 2H), 1.08-1.14 (m, 1H), 1.18-1.36 (m, 7H), 1.37-1.57 (m, 2H), 1.59-1.71 (m, 4H), 1.75-
1.84 (m, 3H), 1.88-1.96 (m, 1H, H-7), 2.47-2.54 (m, 1H), 2.58-2.67 (m, 2H), 2.87-2.94 (m, 2H), 3.09-
3.12 (m, 1H), 3.21 (brs, 1H, OH), 3.63 (t, J = 4.6, 1H, H-1’), 3.73 (dd, J = 4.2, 10.6 Hz, 1H, H-2’), 3.88
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
(dd, J = 5.2, 10.8 Hz, 1H, H-2’), 7.27-7.38 (m, 5H, CH-Ar); C-NMR (CDCl3, 100.6 MHz) δ (ppm):
17.4 (CH2), 17.8 (CH3), 23.3 (C-3), 24.4 (CH2), 25.6 (CH2), 27.3 (C-7), 29.7 (CH2), 30.4 (C-5), 32.3
(CH2), 33.0 (CH2), 40.1 (CH), 40.2 (CH2), 43.8 (CH2), 46.6 (CH2), 51.8 (CH), 53.7 (CH), 63.1 (C-2’),
67.2 (C-1’), 127.5 (CH-Ar), 128.3 (2CH-Ar), 128.6 (2CH-Ar), 140.1 (Cq-Ar); HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C24H38N2OH 371.3057; Found 371.3045.
(4aR,5S,7R,8aS)-5-{[(S)-1-tert-(Butoxycarbonyl)-2-piperidyl]methyl}-1-[(S)-2-hydroxy-1-
phenylethyl]-7-methyldecahydroquinoline (31): Di-tert-butyl dicarbonate (86 mg, 0.39 mmol) was
added to a stirring solution of the above cis-DHQ (132 mg, 0.36 mmol) in anhydrous CH2Cl2 (6 mL) at
room temperature. After 24 h, the solvent was evaporated under reduced pressure. Flash
chromatography (from CH2Cl2 to 8:2 CH2Cl2–MeOH) of the residue afforded carbamate 31 (140 mg,
1
83%) as a brown oil: [α]23 + 2.16 (c 1.375, CHCl3); IR (NaCl): 3288, 1686 cm-1; H-NMR (CDCl3,
D
400 MHz) δ (ppm): 0.43 (brs, 3H, CH3), 1.21-1.30 (m, 7H), 1.31-1.41 (m, 4H), 1.47 [s, 9H, C(CH3)3],
1.51-1.57 (m, 3H), 1.63-1.78 (m, 1H), 1.80-1.87 (m, 1H), 1.95 (brs, 1H), 2.05-2.43 (m, 5H), 2.66-2.74
(m, 2H), 3.10 (brs, 1H), 3.64-3.94 (m, 3H), 4.19 (brs, 1H), 7.28-7.34 (m, 3H, CH-Ar), 7.42-7.44 (m, 2H,
CH-Ar); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 16.8 (CH2), 17.5 (CH3), 18.9 (CH2), 23.4, 25.6
(CH2), 27.2 (CH), 28.4 (CH2), 28.5 [OC(CH3)3], 29.2, 29.6 (CH2), 30.9 (CH2), 31.0 (CH), 32.5 (CH2),
33.0 (CH2), 38.7(CH2), 44.7 (CH2), 47.8 (CH2), 63.2 (CH2), 67.2 (CH), 79.1, [OC(CH3)3], 128.1 (CH-
Ar), 128.5 (2CH-Ar), 129.0 (2CH-Ar), 154.9 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C29H46N2O3H 471.3581; Found 471.3576.
(4aR,5S,7R,8aS)-1-Acetyl-5-{[(S)-1-tert-(butoxycarbonyl)-2-piperidyl]methyl}-7-
methyldecahydroquinoline: 1st step. A suspension of 31 (120 mg, 0.26 mmol) in MeOH (4.6 mL)
containing Pd(OH)2 (48 mg) was stirred under hydrogen at room temperature for 24 h. The catalyst was
then removed by filtration over Celite® and washed with MeOH, and the solvent was evaporated to give
crude N-unsubstituted DHQ.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
2nd step. TEA (39 µL, 0.28 mmol) and acetyl chloride (18 µL, 0.26 mmol) were added to a stirring
solution of the above residue in CH2Cl2 (0.5 mL) at 0 ⁰C, and the mixture was stirred for 15 h at room
temperature. Then, saturated aqueous NaHCO3 was added, the phases were separated, and the aqueous
solution was extracted with CH2Cl2. The combined organic extracts were dried and concentrated. Flash
chromatography (from CH2Cl2 to 8:2 CH2Cl2–MeOH) afforded the title N-acetyl-DHQ (76 mg, 76%)
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 yellow oil: [α]23 ‒ 6.22 (c 0.58, CHCl3); IR (NaCl): 1686, 1644 cm-1; H-NMR (CDCl3, 400
D
MHz, COSY, g-HSQC) δ (ppm): 1.08 and 1.04 (d, J = 7.6, 7.2 Hz, 3H, CH3), 1.14-1.20 (m, 2H), 1.28-
1.40 (m, 4H), 1.44 and 1.45 [s, 9H, C(CH3)3], 1.47-1.58 (m, 5H), 1.62-1.79 (m, 4H), 1.88-1.94 (m, 1H),
1.95-2.03 (m, 1H), 2.04 and 2.06 (s, 3H, COCH3), 2.08-2.17 (m, 2H), 2.60 (ddd, J = 3.2, 13.2, 14.4 Hz,
0.5H, H-2), 2.74 (t, J = 12.2 Hz, 1H, H-4’), 3.11 (ddd, J = 2.8, 12.6 Hz, 0.5H, H-2), 3.55 (d, J = 14.0
Hz, 0.5H, H-2), 3.87 (ddd, J = 2.6, 7.6, 8.8 Hz, 0.5H, H-8a), 3.97 (brs, 1H), 4.18-4.24 (m, 1H, H-4’),
13
4.47 (dd, J = 2.8, 13.6 Hz, 0.5H, H-2), 4.86 (ddd, J = 4.8, 8.4, 9.2 Hz, 0.5H, H-8a); C-NMR (CDCl3,
100.6 MHz) δ (ppm): 17.5 and 17.7 (C-4), 18.5 and 18.7 (CH3), 18.8 and 19.0 (CH2), 21.2 and 22.1
(COCH3), 25.1 and 26.1 (C-3), 25.6 (CH2), 27.3 and 27.7 (C-7), 28.4 (C-8), 28.5 [C(CH3)3], 29.8 (CH2),
30.7 (C-5), 32.0 and 32.4 (C-6), 32.9 and 33.1 (C-1’), 36.5 and 41.7 (C-2), 38.9 (C-4’), 38.9 and 39.3
(C-4a), 46.3 and 52.1 (C-8a), 47.9 (C-2’), 79.2 [C(CH3)3], 154.9 (NCO), 168.5 and 168.9 (CO); HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C23H40N2O3H 393.3112; Found 393.3100.
(+)-Serratezomine E: TFA (41 µL, 0.535 mmol) was slowly added to a stirring solution of the above
DHQ (21 mg, 0.0535 mmol) in anhydrous CH2Cl2 (535 µL) at room temperature. The mixture was
stirred for 1 h, and the solvent was evaporated. Flash chromatography (KP-NH Biotage® SNAP
cartridges, from CH2Cl2 to 8:2 CH2Cl2–MeOH) afforded (+)-serratezomine E (14.6 mg, 95%) as a
colorless oil: [α]23 + 6.10 (c 0.62, CHCl3) [Lit10f +9 (c 1, CHCl3)]; H-NMR (CDCl3, 400 MHz) δ
1
D
(ppm): δ 1.06 and 1.08 (d, J = 7.2 Hz, 3H, CH3), 1.14- 1.25 (m, 4H), 1.28-1.46 (m, 6H), 1.51 (m, 1H),
1.60-1.80 (m, 6H), 1.89-1.94 (m, 2H), 2.05 and 2.09 (s, 3H, COCH3), 2.11-2.15 (m, 1H), 2.39-2.50 (m,
1H), 2.55 (t, J = 3.2 Hz, 0.5 H), 2.58-2.65 (m, 1H), 3.03-3.09 (m, 0.5H), 3.12 (td, J = 4.0, 13.2 Hz, 1H),
3.55 (m, 0.5H), 3.91 (dt, J = 4.2, 12.4 Hz, 0.5H), 4.46 (dd, J = 4.0, 13.0 Hz, 0.5 H), 4.88 (dt, J = 4.4,
13
13.2 Hz, 0.5H); C-NMR (CDCl3, 100.6 MHz) δ 17.5 and 17.6 (CH2), 18.5 and 18.7 (CH3), 21.3 and
22.1 (COCH3), 24.7 and 24.8 (CH2), 25.0 and 26.0 (CH2), 26.4 and 26.5 (CH2), 27.3 and 27.7 (CH),
28.5 and 30.0 (CH2), 29.5 and 29.8 (CH), 32.5 and 32.8 (CH2), 33.1 and 33.3 (CH2), 36.4 and 41.8
(CH2), 38.5 and 39.5 (CH), 40.6 and 40.7 (CH2), 46.2 and 52.1 (CH), 47.0 and 47.1 (CH2), 53.4 (CH),
168.6 and 169.1 (CO).
(4aR,5S,7R,8aS)-1-(tert-Butoxycarbonyl)-5-(2-hydroxyethyl)-7-methyldecahydroquinoline
(32):
1st step. LiAlH4 (5.88 mL, 1 M in THF, 5.88 mmol) was added to a stirring solution of AlCl3 (2418 mg,
1.84 mmol) in anhydrous THF (18 mL) at 0 ºC. After 30 minutes, the mixture was cooled to ‒78 ºC, and
24
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
after 10 minutes a solution of 26 (296 mg, 0.9 mmol) in anhydrous THF (3 mL) was added. The stirring
was continued at –78 °C for 90 min and at room temperature for 3 h. Water was slowly added, and the
resulting mixture was diluted with EtOAc. The phases were separated, and the aqueous solution was
extracted with EtOAc. The combined organic extracts were dried and concentrated to give crude
dialcohol.
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
2nd step. A solution of the above residue and Boc2O (237 mg, 1.08 mmol) in MeOH (18 mL) containing
Pd(OH)2 (115 mg) was stirred under hydrogen at room temperature for 24 h. The catalyst was removed
by filtration over Celite®, and the filtrate was concentrated. Flash chromatography (85:15 hexane–
EtOAc) afforded cis-decahydroquinoline 32 (246 mg, 91%) as a colorless oil: [α]23 + 15.7 (c 0.97,
D
CHCl3); IR (NaCl): 3355, 1732 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.03 and
1.07 (d, J = 7.2 Hz, 3H, CH3), 1.14-1.24 (m, 2H), 1.28-1.35 (m, 2H), 1.38-1.42 (m, 2H), 1.42-1.47 [m,
10H, C(CH3)3], 1.48-1.57 (m, 1H), 1.60-1.73 (m, 3H), 1.89-1.97 (m, 2H), 2.09-2.10 (m, 1H, H-7), 2.70-
2.84 (m, 1H, H-2), 3.60-3.69 (m, 2H, CH2OH), 3.82-3.86 (m, 0.5H, H-2), 3.90-3.93 (m, 0.5H, H-2),
4.20 (dt, J = 4.2, 13.2 Hz, 0.5H, H-8a), 4.37 (m, J = 4.4, 13.2 Hz, 0.5H, H-8a); 13C-NMR (CDCl3,
100.6 MHz) δ (ppm): 17.3 and 17.4 (CH2), 18.3 and 18.7 (CH3), 25.2 and 25.6 (CH2), 27.5 and 27.7 (C-
7), 28.4 and 28.9 (CH2), 28.4 and 28.5 [OC(CH3)3], 30.3 and 30.4 (CH), 32.3 and 32.5 (CH2), 36.2 and
36.3 (CH2), 38.4 and 39.4 (C-2), 39.0 and 39.2 (CH), 48.2 and 49.4 (CH), 60.7 and 60.9 (CH2OH), 79.0
and 79.1 [OC(CH3)3], 154.7 and 155.1 (NCO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H31NO3H 298.2377; Found 298.2380.
Methyl (4aR,5S,7R,8aS)-1,7-dimethyl-2-oxodecahydroquinolin-5-acetate (33): 1st step. 10%
aqueous solution of NaIO4 (4.1 mL) and RuO2·nH2O (3 mg, 0.02 mmol) were added to a stirred solution
of 32 (246 mg, 0.83 mmol) in EtOAc (1.6 mL). After 17 h, EtOAc (1.5 mL) was added, the organic
layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts
were filtered over Celite®, and the filtrate was dried and concentrated to give a crude lactam acid.
2nd step. TFA (630 µL, 8.3 mmol) was slowly added to a stirring solution of the above acid in
anhydrous CH2Cl2 (8.3 mL) at room temperature. After 1 h of stirring, the solvent was evaporated and
the residue was taken up with anhydrous DMF (8.3 mL). NaH (99 mg, 4.13 mmol) was added to the
solution, and the resulting suspension was stirred at room temperature for 1 h. Then, MeI (256 µL, 4.13
mmol) was added, and the stirring was continued for 48 h. Saturated aqueous NH4Cl was added, the
mixture was diluted with CH2Cl2, the layers were separated, and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried, and concentrated. Flash
chromatography (3:1 hexane–acetone) afforded 33 (121 mg, 58%) as a yellowish oil: [α]23 + 22.2 (c
D
1.42, CHCl3); IR (NaCl): 1736, 1639 cm-1; 1H-NMR (CDCl3, 400 MHz, COSY, g-HSQC) δ (ppm): 1.04
(d, J = 7.2 Hz, 3H, CH3), 1.23-1.28 (m, 1H), 1.41 (ddd, J = 5.0, 6.4, 21.6 Hz, 1H), 1.49-1.58 (m, 2H),
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
1.72-1.83 (m, 2H), 2.02-2.09 (m, 1H), 2.10-2.15 (m, 1H), 2.18-2.32 (m, 3H), 2.34-2.40 (m, 1H), 2.42-
13
2.48 (m, 1H), 2.89 (s, 3H, NCH3), 3.41 (dt, J = 4.6, 12.4 Hz, 1H, H-8a), 3.66 (s, 3H, COCH3); C-
6
7
8
9
NMR (CDCl3, 100.6 MHz) δ (ppm): 15.4 (CH2), 18.4 (CH3), 27.2 (CH), 30.6 (CH), 31.1 (CH2), 31.9
(CH2), 32.0 (CH2), 33.7 (NCH3), 37.4 (CH), 38.1 (CH2), 51.6 (COCH3), 56.8 (C-8a), 169.6 (NCO),
172.8 (CO2Me); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H23NO3H 254.1751; Found 254.1753.
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
(+)-Luciduline lactam (34): A solution of N-isopropylcyclohexylamine (190 µL, 1.15 mmol) in
anhydrous THF (3.8 mL) was treated with n-BuLi (720 µL, 1.6 M in THF, 1.15 mmol) at –78 °C, and
the mixture was stirred for 30 min at this temperature. The resulting solution was added dropwise under
argon at –78 °C over 20 min to a solution of 33 (117 mg, 0.46 mmol) in anhydrous THF (23 mL). After
stirring at this temperature for 2 h, the solution was poured into 1 M HCl at 0 °C, the layers were
separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were
washed with brine, dried, and concentrated. Flash chromatography (3:1 hexane–acetone) afforded 34
(80 mg, 78%) as a colourless oil: [α]23D + 92. 8 (c 0.79, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ (ppm):
0.96 (d, J = 6.8 Hz, 3H, CH3), 1.34-1.40 (m, 1H), 1.55-1.59 (m, 1H), 1.63-1.72 (m, 2H), 2.03-2.10 (m,
2H), 2.23-2.28 (m, 2H), 2.30-2.41 (m, 2H), 2.62 (dd, J = 12.4, 14.4 Hz, 1H), 2.99 (s, 3H, NCH3), 3.32-
3.33 (m, 1H), 3.66-3.68 (m, 1H); 13C-NMR (CDCl3, 100.6 MHz) δ (ppm): 20.1 (CH), 21.8 (CH3), 30.4
(NCH3), 31.3 (CH2), 33.0 (CH), 36.4 (CH), 38.1 (CH2), 38.9 (CH2), 42.7 (CH2), 55.8 (CH), 58.2 (CH),
167.7 (NCO), 205.8 (CO).
(+)-Luciduline: 1st step. LiAlH4 (1.25 mL, 1 M in THF, 5.88 mmol) was added to a stirring solution of
34 (55 mg, 0.248 mmol) in anhydrous Et2O (15 mL) at 0 °C, and the mixture was stirred at reflux
temperature for 1 h. After cooling, water was slowly added at 0 °C, and the resulting mixture was
diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The
combined organic extracts were dried and concentrated to give crude alcohol.
2nd step. A solution of the above residue in acetone (1.6 mL) was added at room temperature to Jones
reagent (2.5 mL) freshly prepared by dissolving CrO3 (700 mg) in water (5 mL), H2SO4 (1.2 mL), and
acetone (100 mL). After 30 min, water was slowly added at 0 °C, and the resulting mixture was basified
with 3 M aqueous NaOH. The aqueous solution was extracted with EtOAc, and the combined organic
extracts were dried and concentrated. Flash chromatography (KP-NH Biotage® SNAP cartridges, from
hexane to 8:2 hexane–AcOEt) afforded (+)-luciduline (37 mg, 72%) as an unstable light yellow oil:
[α]23D + 86.0 (c 0.13, MeOH) [Lit.11a + 87 (c 2.05, MeOH); Lit.11b + 85.3 (c 0.15, MeOH); Lit.11c + 87.3
1
(c 0.495, MeOH)]; H-NMR (CDCl3, 400 MHz) δ (ppm): 0.89 (d, J = 6.8 Hz, 3H, CH3), 0.95-1.02 (m,
1H), 1.21-1.29 (m, 1H), 1.50-1.56 (m, 1H), 1.69 (br s, 1H), 1.81-1.90 (m, 2H), 1.91-2.01 (m, 1H), 2.02-
2.08 (m, 1H), 2.12-2.18 (m, 1H), 2.13 (s, 3H, NCH3), 2.23-2.25 (m, 1H), 2.27-2.37 (m, 2H), 2.39-2.43
(m, 1H), 2.81-2.85 (m, 1H), 3.04 (dd, J = 11.8, 16.4 Hz, 1H).
26
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Supporting Information Available
8
9
1
Copies of the H and 13C NMR spectra of all new compounds, and X-ray crystallographic data 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
compound 3. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment
Financial support from the MINECO/FEDER (Project CTQ2015-65384-R) and the Generalitat de
Catalunya (Grant 2014-SGR-155) is gratefully acknowledged. We also acknowledge the networking
contribution from the COST Action CM1407, the MECD (Spain) for a fellowship to A. P., and the Serra
Hunter programme (R. G.).
References
(1) For reviews, see: (a) Ma, X.; Gang, D. R. The Lycopodium Alkaloids. Nat. Prod. Rep. 2004, 21,
752–772. (b) Hirasawa, Y.; Kobayashi, J.; Morita, H. The Lycopodium Alkaloids. Heterocycles, 2009,
77, 679–729. (c) Siengalewicz, P.; Mulzer, J.; Rinner, U. Lycopodium Alkaloids-Synthetic Highlights
and Recent Developments. In The Alkaloids; Knölker, H.-J., Ed.; Elsevier: San Diego, 2013; Vol. 72, pp
1–151. (d) Veerasamy, N.; Carter, R. G. Synthesis of Quinolizidine-Containing Lycopodium Alkaloids
and Related Natural Products. Tetrahedron, 2016, 72, 4989–5001.
(2) For reviews, see: (a) Daly, J. W. The Nature and Origin of Amphibian Alkaloids. In The Alkaloids;
Cordell, G. A, Ed.; Academic Press: New York, 1998; Vol. 50, pp 141–169. (b) Spande, T. F.; Jain, P.;
Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.;
Torres, J. A.; Snelling, R. R.; Jones, T. H. Occurrence and Significance of Decahydroquinolines from
1
Dendrobatid Poison Frogs and a Myrmicine Ant: Use of H and 13C NMR in Their Conformational
Analysis. J. Nat. Prod. 1999, 62, 5–21. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F. Alkaloids from
Amphibian Skins. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon:
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
New York, 1999; Vol. 13, pp 1–161. (d) Daly, J.W.; Spande, T. F.; Garraffo, H. M. Alkaloids from
5
6
Amphibian Skin: A Tabulation of Over Eight-Hundred Compounds. J. Nat. Prod. 2005, 68, 1556–1575.
7
8
9
(3) (a) Steffan, B. Lepadin A, A Decahydroquinoline Alkaloid from the Tunicate Clavelina lepadiformis.
Tetrahedron 1991, 47, 8729–8732. (b) Kubanek, J.; Williams, D. E.; de Silva, E. D.; Allen, T.;
Andersen, R. J. Cytotoxic Alkaloids from the Flatworm Prostheceraeus villatus and its Tunicate Prey
Clavelina lepadiformis. Tetrahedron Lett. 1995, 36, 6189–6192. (c) Wright, A. D.; Goclik, E.; König, G.
M.; Kaminsky, R. Lepadins D–F: Antiplasmodial and Antitrypanosomal Decahydroquinoline
Derivatives from the Tropical Marine Tunicate Didemnum sp. J. Med. Chem. 2002, 45, 3067–3072. (d)
Davis, R. A.; Carroll, A. R.; Quinn, R. J. Lepadins F–H, New cis-Decahydroquinoline Alkaloids from
the Australian Ascidian Aplidium tabascum. J. Nat. Prod. 2002, 65, 454–457.
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) For reviews, see: (a) Inubushi, Y.; Harayama, T. Total Synthesis of Lycopodium Alkaloids.
Heterocycles 1981, 15, 611–635. (b) Kibayashi, C.; Aoyagi, S. Recent Advantages in the Synthesis of
Dendrobatid Alkaloids. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 1997; Vol. 19, pp 3–88. (c) Pelss, A.; Koskinen, A. M. P. Stereocontrolled Construction of
Decahydroquinoline Ring Systems: the Case of Lepadin Alkaloids (Review). Chem. Heterocycl.
Compd. 2013, 49, 226–240. (d) See also refs 1b and 1c.
(5) (a) Amat, M.; Griera, R.; Fabregat, R.; Molins, E. Bosch, J. A Biomimetic Enantioselective
Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids. Angew. Chem. Int. Ed. 2008, 47,
3348–3351. (b) Amat, M.; Fabregat, R.; Griera, R.; Florindo, P.; Molins, E.; Bosch, J. Biomimetic
Construction of Hydroquinoline Ring System. Diastereodivergent Enantioselective Synthesis of 2,5-
Disubstituted cis-Decahydroquinolines. J. Org. Chem. 2010, 75, 3797–3805.
(6) (a) Amat, M.; Pinto, A.; Griera, R.; Bosch, J. Stereoselective Synthesis of (–)-Lepadins A-C. Chem.
Commun. 2013, 49, 11032–11034. (b) Amat, M.; Pinto, A.; Griera, R.; Bosch, J. Enantioselective
Synthesis of Lepadins A-D from a Phenylglycinol-Derived Hydroquinolone Lactam. Chem.–Eur. J.
2015, 21, 12804–12808.
28
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(7) Amat, M.; Ghirardi, E.; Navío, L.; Griera, R.; Llor, N.; Molins, E.; Bosch, J. Enantio- and
Diastereoconvergent Cyclocondensation Reactions. Synthesis of Enantiopure cis-Decahydroquinolines.
Chem.–Eur. J. 2013, 19, 16044–16049.
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
(8) Piccichè, M.; Pinto, A.; Griera, R.; Bosch, J. Amat, M. Enantioselective Total Synthesis of (+)-
Gephyrotoxin 287C. Org. Lett. 2017, 19, 6654–6657.
(9) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. A General Synthetic Route to Enantiopure 5-
Substituted cis-Decahydroquinolines. J. Org. Chem. 2009, 74, 1794–1797.
(10) (a) Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H. Asymmetric Total
Syntheses of Two Phlegmarine-Type Alkaloids, Lycoposerramines-V and -W, Newly Isolated from
Lycopodium serratum. Org. Lett. 2007, 9, 4069–4072. (b) Tanaka, T.; Kogure, N.; Kitajima, M.;
Takayama, H. Asymmetric Total Synthesis of Cyclic Nitrone-Containing Phlegmarine-Type
Lycopodium Alkaloids, Lycoposerramines-X and -Z. J. Org. Chem. 2009, 74, 8675–8680. (c) Wolfe, B.
H.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.; Comins, D. L. Asymmetric Synthesis of All the Known
Phlegmarine Alkaloids. J. Org. Chem. 2010, 75, 8564–8570. (d) Bradshaw, B.; Luque-Corredera, C.;
Bonjoch, J. cis-Decahydroquinolines via Asymmetric Organocatalysis: Application to the Total
Synthesis of Lycoposerramine Z. Org. Lett. 2013, 15, 326–329. (e) Bradshaw, B.; Luque-Corredera, C.;
Bonjoch, J. A Gram-Scale Route to Phlegmarine Alkaloids: Rapid Total Synthesis of (–)-Cermizine B.
Chem. Commun. 2014, 50, 7099–7102. (f) Zhang, L.-D.; Zhou, T.-T.; Qi, S.-X.; Xi, J.; Yang, X.-L.;
Yao, Z.-J. Total Synthesis of Lycoposerramine-V and 5-epi-Lycoposerramine-V. Chem.–Asian J. 2014,
9, 2740–2744. (g) Bosch, C.; Fiser, B.; Gómez-Bengoa, E.; Bradshaw, B.; Bonjoch, J. Approach to cis-
Phlegmarine Alkaloids via Stereodivergent Reduction: Total Synthesis of (+)-Serratezomine E and
Putative Structure of (–)-Huperzine N. Org. Lett. 2015, 17, 5084–5087. (h) Zhang, L.-D.; Zhong, L.-R.;
Xi, J.; Yang, X.-L.; Yao, Z.-J. Enantioselective Total Synthesis of Lycoposerramine-Z Using Chiral
Phosphoric Acid Catalyzed Intramolecular Michael Addition. J. Org. Chem. 2016, 81, 1899–1904.
29
ACS Paragon Plus Environment