The alkaloids, volume 75

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ISBN: 978-0-12-803434-7
ISSN: 1099-4831
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CONTRIBUTORS
Joseph P. Michael
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
Johannesburg, Gauteng, South Africa

vii

j


PREFACE
Since the appearance of its first volume in 1950, the book series The Alkaloids
has become the leading publication forum for alkaloid chemistry. The
present book is the 75th volume and thus represents a jubilee for The
Alkaloids. In the long history of this series, single-topic volumes have been
very rare: Volume 25, published in 1985, described “Antitumor Alkaloids”;
Volume 37, published in 1990, compiled “Bisindole Alkaloids from Catharanthus roseus (L.)”; Volume 65, published in 2008, reviewed the “Chemistry
and Biology of Carbazole Alkaloids”; and in 2010, Volume 69 summarized
“The C19-Diterpenoid Alkaloids.” Volume 75 represents another singlechapter volume and is dedicated to “Simple Indolizidine and Quinolizidine
Alkaloids.”
The author, Joseph P. Michael from the Molecular Sciences Institute
at the University of the Witwatersrand in South Africa, had already written two of the three previous reviews on this topic for The Alkaloids. In
Chapter 3 of Volume 28, published in 1986, Arthur S. Howard and
Joseph P. Michael presented the first full coverage of “Simple Indolizidine
and Quinolizidine Alkaloids” within this series. In Chapter 3 of Volume
44, published in 1993, Hiroki Takahata and Takefumi Momose gave an
update on “Simple Indolizidine Alkaloids”. In Chapter 1 of Volume 46,
published in 1995, David J. Robins described the “Biosynthesis of Pyrrolizidine and Quinolizidine Alkaloids”. The last overview on “Simple
Indolizidine and Quinolizidine Alkaloids” in this series was compiled

again by Joseph P. Michael and published in 2001 as Chapter 2 of Volume
55. Thus, there could have been no better expert for the present review
which is covering the tremendous development in this field from the
middle of 1999 till the end of 2013. This view of the editor has been confirmed by Jo Michael’s remarkably extensive compilation of exceptional
quality.
Hans-Joachim Kn€
olker
Technische Universit€at Dresden, Dresden, Germany

ix

j


CHAPTER ONE

Simple Indolizidine and
Quinolizidine Alkaloids
Joseph P. Michael
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg,
Gauteng, South Africa
E-mail:

Contents
1. Introduction
2. Indolizidine Alkaloids from Fungal and Microbial Sources
2.1 Slaframine
2.2 Cyclizidine and JBIR-102
2.3 Streptomyces Metabolites
2.4 Pantocins A and A2

3. Hydroxylated Indolizidine Alkaloids
3.1 General Reviews
3.2 1-Hydroxyindolizidines
3.3 Lentiginosine and Related Compounds

3
5
5
12
15
16
19
19
21
26

3.3.1 Isolation and Biological Activity
3.3.2 Synthesis

28
28

3.4 Steviamine
3.5 Swainsonine

64
69

3.5.1 Occurrence, Isolation, and Characterization
3.5.2 Synthesis

3.5.3 Biological Activity

69
73
116

3.6 Castanospermine and Related Compounds

122

3.6.1 Isolation and Structure
3.6.2 Synthesis
3.6.3 Biological Activity

122
123
140

3.7 The Putative Uniflorines
4. Plant Indolizidine and Quinolizidine Alkaloids Bearing Alkyl, Functionalized Alkyl,
or Alkenyl Substituents
4.1 Dendroprimine
4.2 Prosopis Alkaloids
4.3 5,6,7,8-Tetrahydroindolizine Alkaloids
4.4 Anibamine

The Alkaloids, Volume 75
ISSN 1099-4831
/>
© 2016 Elsevier Inc.

All rights reserved.

146
148
148
153
159
162

1

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2

Joseph P. Michael

4.5 Elaeocarpus Alkaloids
4.5.1 Isolation and Characterization
4.5.2 Biogenesis
4.5.3 Synthesis

4.6 Lupin Alkaloids
4.6.1 Occurrence and Characterization
4.6.2 Structural Investigations
4.6.3 Synthesis

4.7 Myrtine and Epimyrtine
4.8 Lycopodium Alkaloids

4.8.1 Isolation and Characterization
4.8.2 Synthesis

4.9 Porantheridine
4.10 Plumerinine
5. Plant Indolizidine and Quinolizidine Alkaloids Bearing Aryl or Heteroaryl
Substituents
5.1 Ipalbidine and Related Alkaloids
5.1.1 Isolation and Characterization
5.1.2 Synthesis

5.2 Septicine, Julandine, and Related Alkaloids
5.2.1 Isolation, Characterization, and Biological Properties
5.2.2 Synthesis

5.3 Ficuseptine
5.4 Lythraceae Alkaloids
5.4.1 Isolation and Characterization
5.4.2 Synthesis

5.5 Nuphar Alkaloids
5.5.1 Isolation and Biological Activity
5.5.2 Syntheses of Nuphar Quinolizidines
5.5.3 Syntheses of the Nuphar Indolizidine

5.6 QuinolizidineeQuinazoline Alkaloids
6. Indolizidine and Quinolizidine Alkaloids from Terrestrial Animals
6.1 Indolizidine and Quinolizidine Alkaloids from Arthropods
6.1.1
6.1.2

6.1.3
6.1.4

Isolation and Characterization
Monomorine I
Solenopsis Alkaloids
(3S,5R,8S,8aS)-3-Butyl-5-Propyl-8-Hydroxyindolizine

6.2 Indolizidine and Quinolizidine Alkaloids from Amphibians
6.2.1
6.2.2
6.2.3
6.2.4
6.2.5

Occurrence: The “Dietary Hypothesis”
Isolation and Characterization
5-Alkylindolizidines
3,5-Disubstituted Indolizidine Alkaloids
5,8-Disubstituted Indolizidine Alkaloids

165
165
169
169

179
179
181
184

207
215
215
216

221
229
229
229
229
230

235
237
238

247
248
248
250

275
275
276
280

283
286
286

286
292
309
312

314
315
319
325
326
344


Simple Indolizidine and Quinolizidine Alkaloids

6.2.6
6.2.7
6.2.8
6.2.9
6.2.10
6.2.11
6.2.12

5,6,8-Trisubstituted Indolizidine Alkaloids
Epiquinamide
1,4-Disubstituted Quinolizidine Alkaloids
4,6-Disubstituted Quinolizidine Alkaloids
Pumiliotoxins and Allopumiliotoxins
Homopumiliotoxins
Biological Activity

7. Indolizidine and Quinolizidine Alkaloids from Marine Sources
7.1 Clathryimines and Callyimine A
7.2 Stellettamides
7.3 Piclavines
7.4 Clavepictines and Pictamine
7.5 Bis(quinolizidine) Alkaloids
References

3
374
384
406
420
424
442
447

451
451
452
456
460
465
468

1. INTRODUCTION
It has been over 13 years since the simple indolizidine and quinolizidine alkaloids were surveyed in Volume 55 of this treatise.1 That survey,
which updated prior coverage of the indolizidine alkaloids in Volume
44,2 and of both indolizidine and quinolizidine alkaloids in Volume 28,3

aimed for comprehensive treatment up to the middle of 1999. This review
covers publications from mid-1999 to the end of 2013.
Once again it is necessary to emphasize that the concept of a “simple”
izidine alkaloid is subjective. Because the indolizidine and quinolizidine motifs are so widely distributed in natural products, some limitations have had
to be imposed in order to keep the chapter to a manageable length. Thus,
with very few exceptions, only those alkaloids that possess an isolated azabicyclic nucleusdi.e., one not embedded within a fused polycyclic assemblagedare considered. The numbering systems for the two motifs are
shown in Figure 1. In general, the IUPAC numbering system for the parent
octahydroindolizine (1) and octahydro-2H-quinolizine (2) ring systems is
used. Some authors also label the bridgehead positions 8a and 9a as 9 and
10, respectively. One also occasionally encounters indolizidines and quinolizidines with the 1-azabicyclo[4.3.0]nonane (3) or 1-azabicyclo[4.4.0]
decane (4) numbering systems, respectively.


4

Joseph P. Michael

Figure 1 Alternative numbering systems for the indolizidine and quinolizidine ring
systems.

The two classes of alkaloids are of such widespread occurrence in living
systems that the organization of the voluminous material in this chapter presents some problems. Relevant alkaloids have been isolated from microorganisms and fungi, higher plants, and both terrestrial and marine animals.
For convenience, these broad categories are used in the presentation of
the subject matter. In addition, since alkaloids from higher plants constitute
the majority of compounds of interest, they are further categorized according to the substituents on the bicyclic core. In view of the diversity of the
families and genera in which the alkaloids are found, it is a little surprising
that so few have merited chapters of their own in this series of reviews in
the intervening years. References to these chapters are provided in the
appropriate sections.
Several other general reviews dealing with aspects of indolizidine and

quinolizidine alkaloid chemistry were published during the period under
consideration. The series of annual reports in the Royal Society of Chemistry’s journal Natural Product Reports, which provided regular coverage of
both simple and various more complex indolizidine and quinolizidine alkaloids, ended in 2008.4e11 Another important review that dealt principally
with pertinent alkaloids from ants and amphibians, slaframine, polyhydroxylated indolizidine alkaloids, and the lupin quinolizidine alkaloids was published in the series Studies in Natural Product Chemistry in 2002, and covered
the period 1994 to 1999.12


Simple Indolizidine and Quinolizidine Alkaloids

5

As is to have been expected, a substantial portion of this chapter is
devoted to total synthesis. A number of useful reviews describing general
strategies for the synthesis of alkaloids, among them radical cyclizations,13
asymmetric aza-Michael reactions,14 and palladium-mediated total syntheses,15 include examples of simple indolizidine and quinolizidine alkaloid targets. Also valuable are the overviews from individual research groups on
their own approaches to the construction of nitrogen heterocycles, with examples illustrating applications to alkaloid synthesis in general and izidines in
particular. These include Jefford’s use of pyrroles derived from a-amino
acids as building blocks for various indolizidines16; the CN(R,S) method
of Husson and Royer based on the use of chiral non-racemic N-cyanomethyloxazolidines as masked iminium ion intermediates17; the numerous contributions of Toyooka and Nemoto to the syntheses of marine and
amphibian alkaloids18,19; allylsilaneeN-acyliminium ion cyclizations as
exploited by Remuson for the synthesis of a wide variety of relevant alkaloids20; Mori’s approach to the use of molecular nitrogen as the nitrogen
source in alkaloid synthesis21; Martin’s applications of imines as key intermediates in Mannich and related reactions22; and developments by Rovis and
others of multicomponent cycloadditions for the catalytic asymmetric synthesis of alkaloidal targets.23 Other surveys of specific classes of alkaloids
are highlighted in the appropriate sections.
As will becomes apparent in subsequent sections, synthetic strategies
that use metathesis, especially ring-closing metathesis, have assumed prominence during the period covered by this review. Ruthenium-containing
catalysts are especially important. Since they are mentioned repeatedly in
the ensuing discussion, the most widely used catalysts are illustrated in
Figure 2. They include the Grubbs first- and second-generation catalysts
(5) and (6), the HoveydaeGrubbs catalyst (7), and the GrubbseNolan

catalyst (8).24

2. INDOLIZIDINE ALKALOIDS FROM FUNGAL AND
MICROBIAL SOURCES
2.1 Slaframine
The parasympathomimetic slaframine (9), isolated from the fungus
Rhizoctonia leguminicola, received little attention in the primary literature
during the review period. Four asymmetric total syntheses were reported,
the earliest of them by Comins and Fulp, who made use of the recyclable


6

Joseph P. Michael

Figure 2 Metathesis catalysts: Grubbs first-generation catalyst (5), Grubbs secondgeneration catalyst (6), HoveydaeGrubbs catalyst (7), and GrubbseNolan catalyst (8).

auxiliary (À)-trans-2-(a-cumyl)cyclohexanol (10) to control the absolute
configuration at the alkaloid’s C-8a site (Scheme 1).25 Reaction between
4-methoxy-3-(triisopropylsilyl)pyridine (11) and the chloroformate of the
auxiliary produced the N-acylpyridinium salt, to which was added the
mixed 1-propenylcuprate 12. The reaction proceeded in only 87% diastereomeric excess (de), but the chiral dihydropyridone intermediate 13 could
be isolated in 61% yield after radial preparative layer chromatography. After
several functional group transformations to the vinyl triflate 14, the stereogenic center at C-1 was introduced by intramolecular phenylselenocarbamation, which yielded the bicyclic oxazolidinone 15 as the only
diastereomer. Further functional group manipulations, including a problematic chemoselective defunctionalization of the vinyl triflate, provided 16,
basic hydrolysis and decarboxylation of which led to formation of the indolizidine skeleton by in situ cyclization. The bicyclic product was isolated as
the acetate 17, which has the requisite absolute configurations at both C-1
and C-8a. As a prelude to introducing the final stereogenic center at C-6,
the difficult transformation of vinyl bromide 17 into the vinyl acetate 18
required heating with freshly prepared copper(I) acetate in N-methylpyrrolidone (NMP) at 202  C for 14 h. The product, formed in 66% yield, was

converted directly into oxime 19, a known intermediate in previous syntheses of (À)-slaframine.26,27 When the authors repeated the reported hydrogenation of the oxime over platinum dioxide, however, a mixture of


Simple Indolizidine and Quinolizidine Alkaloids

7

Scheme 1 Synthesis of (À)-slaframine (9) and (À)-N-acetylslaframine (20) by Comins
and Fulp.25 Reagents and conditions: (a) ClCO2-(À)-TCC; (b) cuprate 12; (c) H3Oþ,
then chromatography; (d) NaOMe, MeOH, heat; (e) HCl (6 M); (f) n-BuLi; (g) CbzCl; (h)
NBS, CH2Cl2; (i) L-Selectride; (j) 2-N(Tf)2-5-Cl-py; (k) PhSeCl, MeCN; (l) H2O2, THF; (m)
(C6H11)2BH; (n) NaBO3; (o) Pd(OAc)2 (10%), dppf (10%), Et3SiH, NEt3; (p) NCS, Ph3P,
CH2Cl2,À35  C to rt; (q) Ac2O, py; (r) CuOAc (10 equiv.), NMP, 202  C, 14 h; (s)
NH2OH$HCl (4.5 equiv.), EtOH, py, 80  C; (t) H2 (40 psi), PtO2, aq. HCl, 6 h.

(À)-slaframine (9) and its O-deacetyl analog was obtained. Acetylation of
this crude mixture yielded (À)-N-acetylslaframine 20 in 20% overall yield
based on oxime 19.
An unusual synthesis of (À)-slaframine (9) by Greene and coworkers
proceeds via a cyclobutanone formed in a [2 þ 2] ketene cycloaddition in
which (R)-(þ)-1-(2,4,6-triisopropylphenyl)ethanol 21 functions as a chiral
auxiliary (Scheme 2).28 This alcohol was incorporated into the dichloro


8

Joseph P. Michael

Cl
a

HO

b, c

O

81%
Cl
(R )-(+)-21

(+)-22

O

Ar

O

d

Cl
24

Ar
O

e, f
50%
from 22

Cl

O

23

Ar

Ar
O

g-i

j-l

64%

HN
(+)-25 O

Ar
O

H

m-o
HO

85%

N
Cbz
TsO (+)-27
H

63%

N
Cbz
(+)-26

O

Ar
O

p, q
87%

N
(+)-28

OAc

H

OAc

r, s

O

N
(+)-29

39%

H2N

N

(–)-Slaframine (9)

Scheme 2 Synthesis of (À)-slaframine (9) by Greene and coworkers.28 Reagents and
conditions: (a) KH, THF, rt, 3 h, then Cl2C]CHCl, À50 to 20  C, 1 h; (b) n-BuLi, THF,
À78 to À40  C, then H2C]CHCH2CH2OTf, À28  C, 20 h; (c) H2 (1 atm), 10% Pd/
BaSO4, 1-hexene, py, 0  C, 4 h; (d) Zn/Cu, Et2O, Cl3CCOCl, 2.5 h; (e) H2NOSO2C6H2Me3,
Na2SO4, CH2Cl2, 20  C, 2 h; (f) Zn/Cu, NH4Cl, MeOH, 20  C, 3 h, then recrystallization;
(g) n-BuLi, CbzCl, THF, À78 to 0  C, 1 h; (h) LiBHEt3, THF, À78  C, 30 min; (i) Et3SiH,
BF3$OEt2, CH2Cl2, À78  C, 2.5 h; (j) OsO4, Me3NO, tBuOHeH2O, reflux, 12 h, then
Na2SO3; (k) Bu2SnO, MeOH, reflux, 45 min; (l) p-TsCl, NEt3, 20  C, 10 min; (m) H2
(1 atm), Pd(OH)2, MeOH, 20  C, overnight; (n) NEt3, CH2Cl2, reflux, 2.5 h; (o) Swern oxidation; (p) TFA, CH2Cl2, rt, 1 h; (q) Ac2O, NEt3, DMAP, CH2Cl2, 20  C, 4 h; (r) NH2OH$HCl,
EtOHepy (2:1), reflux, 4 h; (s) H2 (3 atm), PtO2, conc. HCl, EtOH, 6 h, then aq. Na2CO3.

enol ether (þ)-22, which is a masked alkyne precursor for the sensitive enol
ether 23. Cycloaddition of dichloroketene to 23 proceeded with facial
discrimination and total chemoselectivity for the electron-rich double
bond as well as high diastereoselectivity (95:5) to give the cyclobutanone
24. The strained ring was expanded regioselectively in a Beckmann rearrangement, after which dechlorination gave lactam (þ)-25, the structure

Simple Indolizidine and Quinolizidine Alkaloids

9

of which was predicted by molecular modeling and confirmed by X-ray
crystallography. After protection as the benzyloxycarbonyl (Cbz) derivative,
reduction gave the pyrrolidine (þ)-26. The pendent terminal alkene was
dihydroxylated and tosylated at the primary alcohol site to give (þ)-27,
cyclization of which to the indolizidine skeleton was initiated by selective
hydrogenolysis of the Cbz group, leaving the chiral auxiliary in place to protect the alcohol at C-1. This useful result permitted Swern oxidation to be
effected solely at the C-6 alcohol to give the protected indolizidinone
(þ)-28 in 85% overall yield based on 27. At this stage the C-1 protecting
group was removed with trifluoroacetic acid and the product was immediately acetylated to give the keto-ester (þ)-29, which had featured in several
previous syntheses of (À)-slaframine. The authors chose to complete the
synthesis of (À)-9 by following reported procedures that entailed oxime formation and hydrogenation over platinum dioxide.26,27
The key step in the synthesis of (À)-slaframine (9) by Cossy et al. was the
enantioselective allyltitanation of (þ)-aldehyde 30 with the (R,R)-titanium
complex 31 to give adduct (þ)-32 almost exclusively (dr >95:5) in 69%
yield (Scheme 3).29 Silylation of the alcohol to give (þ)-33 was followed
by hydroborationeoxidation and deprotection to afford the diol 34 (61%)
as well as a small quantity of the secondary alcohol regioisomer (12%).
The primary alcohol of 34 was protected by silylation, while the secondary
alcohol was converted into an azide under Mitsunobu conditions with
inversion of configuration followed by removal of the PMP protecting
group to give (þ)-35 in 38% overall yield. After several protecting group
manipulations, both hydroxy groups of the functionalized diol (À)-36
were mesylated. Catalytic hydrogenation of the azide substituent then produced a primary amine, which underwent spontaneous double cyclization
to give the indolizidine (þ)-37 in 67% yield. The synthesis of (À)-slaframine
was completed by appropriate functional group interconversions at the

1-hydroxy and 6-amino groups.
The mixed dicarbamate (À)-38, prepared in several steps from the glutamic acid-derived diol (S)-39, was a crucial intermediate in the synthesis of
(À)-N-acetylslaframine (20) by Hoppe and coworkers (Scheme 4).30 A delicate competition between the complexing ability of the carbamoyl groups
was apparent in the kinetically-controlled regioselective (À)-sparteinemediated lithiation of this intermediate with sec-butyllithium, with the less
bulky remote carbamoyl group apparently favoring internal complexation
in the putative intermediate 40. Under optimized conditions, this regioselective and stereoselective monolithiation followed by treatment with


10

Joseph P. Michael

CHO

OPMP
PMPO

+
BocN
O

Ti O Ph
a
O
Ph
Ph
69% BocN
O dr >95:5
Ph
O

(+)-30

O
(+)-32

(R,R)-31
OPMP

OPMP
b

c, d

87%

OH

OSiEt3

BocN

61% + BocN
isomer

O

e-g

OH

OH

34

(+)-33
OH

N3

BocN

OBn
h, d, i
OTBDPS

60%

O

BocNH

N3

OH

OH
(–)-36

(+)-35

H

OBn

H

OAc

l-n

j, k
67%

38%

O

BocNH

N
(+)-37

73%

H2N

N

(–)-Slaframine (9)

Scheme 3 (PMP ¼ p-MeO-C6H4). Synthesis of (À)-slaframine (9) by Cossy et al.29 Reagents and conditions: (a) Et2O, À78  C, 4 h; (b) Et3SiCl, imidazole, CH2Cl2, 0  C to rt,
overnight; (c) BH3, THF, 0  C, 2 h, rt, 2 h, then NaOH (3 M), aq. H2O2 (30%), rt; (d)
Bu4NF, THF, 0  C, then rt, overnight; (e) TBDPSCl, imidazole, CH2Cl2, 0  C, then rt, overnight; (f) Ph2P(]O)N3, Ph3P, DIAD, THF, 0  C to rt, 12 h; (g) CAN, MeCNeH2O (4:1), 0  C,
10 min; (h) BnBr, NaH, THF, 0  C, then rt, 2 day; (i) AcOHeTHFeH2O (5:1:1), 55e60  C,
12 h; (j) MsCl, DMAP, py, 0  C, 2 h; (k) H2 (1 atm), 10% Pd/C, MeOH, NEt3 (5 equiv.), rt,
overnight, then reflux, 4 h; (l) H2 (1 atm), 10% Pd/C, MeOHeHCl (50:1), rt, 1 h; (m)
Ac2O, THF, NEt3 (5 equiv.), DMAP (cat.), rt; (n) TMSI, CDCl3, rt, 10 min.

ethylene oxide and boron trifluoride etherate gave the diastereomerically
pure alcohol (þ)-41 in 66% yield. Subsequent double deprotonation with
the same base/ligand combination and quenching with methyl chloroformate produced the diester (À)-42 in 57% yield. Reduction with DIBAL
afforded diol (þ)-43 in 98% yield, opening the way to the double cyclization required for creating the alkaloid’s indolizidine core. Although mesylation followed by hydrogenolysis over Pearlman’s catalyst proved to be a
poor choice for the desired transformation, the structure and stereochemistry
of the product (þ)-44, formed in only 29% yield, was confirmed by X-ray


11

Simple Indolizidine and Quinolizidine Alkaloids

O

O

4 steps
HO

OH
NBn2
(S)-39

NR2

a

O

L
Li

O

i

72%

Pr2N

66%
d.r. >97:3

NR'2

OCO2Me

a, d

OCby

OH

H

98% CbO

OCby
f, g

O

OH

OH
h, i

m, n 93%
H

NBn2

29% CbO

(+)-44

92%
OCby

OH
j-l

o-q

N

56%
CbO
OTr

59%

CbO

N
H

(–)-47

HN
OH

(+)-46

r
95%

OCby

OCby

N

CbO

H

OH

e
NBn2
(+)-43

Cby =
N

OCby
NBn2

NBn2
(–)-42

Cb = CONiPr2

O

CbO

(+)-41

OMe

O

O

OH

b, c

NBn2
40

57% CbO
d.r. >97:3

N

NBn2
(–)-38

O
O

O

O

O

OTr

H

Boc OH
(–)-45
OAc

s, t
N
OH

N
(–)-48

86%

AcNH

N

(–)-N-Acetylslaframine (20)

Scheme 4 Synthesis of (À)-N-acetylslaframine (20) by Hoppe et al.30 Reagents and conditions: (a) sec-BuLi, (À)-sparteine, Et2O, À78  C, 7 h; (b) ethylene oxide, À78  C; (c)
BF3∙OEt2,À78 to 20  C, 14 h; (d) ClCO2Me,À78 to 20  C, 14 h; (e) DIBAL-H, THF, 0  C,
2 h; (f) MsCl, DMAP, py, 0  C, 2 h; (g) Pd(OH)2/C, NEt3, H2, MeOH, 20  C, 14 h, then
60  C, 5 h; (h) Pd/C, H2, MeOH, 20  C, 14 h, then 65  C, 5 h; (i) (Boc)2O, NEt3, MeOH,
40  C, 3 h, then 20  C, 14 h; (j) MsCl, NEt3, CH2Cl2,À20  C, 14 h; (k) TFA, CH2Cl2, 20  C,
14 h; (l) K2CO3, MeOH, 65  C, 14 h; (m) HCl (5 N), THF, MeOH, 65  C, 14 h; (n) NaOH
(5 N), 65  C, 14 h; (o) Ph3CCl, DBU, CH2Cl2, 20  C, 48 h; (p) DIBAL-H, THF,À78  C, 2 h,
then 20  C, 14 h; (q) Swern oxidation; (r) NH2OH$HCl, py, EtOH, 80  C, 4 h; (s) PtO2,
H2, EtOH, HCl, 20  C, 14 h; (t) Ac2O, py, 20  C, 2 h.

12

Joseph P. Michael

crystallography. Cyclization was more effectively achieved via the N-Boc
derivative (À)-45, mesylation of which followed by treatment with trifluoroacetic acid yielded the 1-hydroxyindolizidine (þ)-46 in which the
more labile 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyl (OCby) group
had also been cleaved. For the replacement of the alcohol at C-6 by amine
with inversion of configuration, a series of protection and deprotection steps
preceded oxidation to the ketone (À)-47, the corresponding oxime (À)-48
of which underwent stereoselective hydrogenation and hydrogenolysis. Immediate acetylation of the amino alcohol intermediate completed the synthesis of (À)-N-acetylslaframine (20) in 86% yield from oxime 48.

2.2 Cyclizidine and JBIR-102
A new derivative of the actinomycete metabolite cyclizidine (49) has been
isolated from a culture of Saccharopolyspora sp. RL78, found in a mangrove
soil sample from Nosoko, Ishigaki Island, Okinawa Prefecture, Japan.31
This compound, given the code name JBIR-102, was identified as 50, the
isopentanoic acid ester of the parent alkaloid (Figure 3). The compound
was isolated as an optically active amorphous solid (½aŠ25
D e52.7, c 0.1,
MeOH) and characterized thoroughly by spectroscopic techniques in which
one- and two-dimensional NMR spectroscopic methods played a major
role in elucidating the skeletal connectivities. Hydrolysis with aqueous sodium hydroxide solution gave (À)-cyclizidine, the NMR spectra of which
agreed with those reported by Leeper et al.32 In addition, the specific rotation of the hydrolysis product matched that reported for the levorotatory
natural product by Hanessian et al.,33 whose synthesis of (þ)-ent-cyclizidine
(vide infra) established the parent alkaloid’s absolute configuration. Thus the
absolute configuration of JBIR-102 is as shown in 50. The new compound
displayed cytotoxic activity against human mesothelioma MPM ACCMESO-1 cells (IC50 39 and 32 mM), and against human cervical carcinoma
HeLa cells (IC50 29 and 16 mM) in colorimetric assays.
O

H

OH
OH

N

O

H

OH
O

N
O

49

50

Figure 3 Structures of (À)-cyclizidine (49) and (À)-JBIR-102 (50).


Simple Indolizidine and Quinolizidine Alkaloids

13

In both, the original article describing the isolation of (À)-cyclizidine34

and the subsequent biosynthetic investigations of Leeper’s team,32 cyclizidine was represented as the enantiomer of 49, namely, ent-49, although it
was explicitly stated that the structural diagram was meant to represent relative configuration only. Thus this was the enantiomer that Hanessian and
coworkers set out to synthesize, choosing readily available N-Boc-D-serine
(51) as a convenient source of the target’s C-8a stereochemistry and the position of the nitrogen atom (Scheme 5).33 In tackling the challenge of
creating the six contiguous stereogenic centers, they next installed the correct C-1 stereochemistry by adding ethynylmagnesium bromide to the ketone (þ)-52, giving the tertiary alcohol (þ)-53 in 92% yield and a
diastereomeric ratio (dr) of better than 10:1. Partial reduction of the alkyne
to the alkene and dihydroxylation with AD-Mix-b then afforded triol
(þ)-54 with the correct C-2 orientation as the major isomer (dr >5:1).
Sequential protection of the primary and secondary alcohols as the tertbutyldiphenylsilyl and benzyloxymethyl ethers, respectively, yielded diastereomeric intermediates, the separable major isomer of which was converted
into the bicyclic carbamate (þ)-55, thereby also protecting the tertiary
alcohol. With all sites in the future five-membered ring protected, elaboration of the piperidine ring then commenced by cleavage of the acetal, oxidation of the liberated primary alcohol with DesseMartin periodinane, and
Wittig methylenation. The resulting terminal alkene (þ)-56 was alkylated
on nitrogen with 3-butenyl triflate, the resulting diene (þ)-57 subsequently
undergoing an efficient ring-closing metathesis to (À)-58 with the Grubbs
second-generation catalyst (6) after deprotection of the primary alcohol.
Once the carbamate had been hydrolyzed and the nitrogen protected as
the Fmoc derivative (þ)-59, the sensitive epoxide with the correct configurations at C-7 and C-8 was introduced by epoxidation with oxone in 83%
yield and excellent diastereoselectivity (dr >20:1). Oxidation of the primary
alcohol of the intermediate (þ)-60, again with DesseMartin periodinane,
afforded aldehyde 61, reaction of which with propynylmagnesium bromide
gave a 3:2 mixture of alcohols in favor of the readily separable product
(þ)-62. The undesired minor isomer 63 could be converted into 62 by
oxidation followed by reduction with sodium borohydride. The mesylate
of 62, which contains the target alkaloid’s final stereocenter, was then quantitatively cyclized by treatment with piperidine to create the indolizidine
(þ)-64. The final steps entailed palladium-catalyzed hydrostannylation followed by iodination to give the E-vinyl iodide (þ)-65, which underwent
SuzukieMiyaura coupling with the vinylboronate 66 to complete the


14

Joseph P. Michael

O
CO2H

HO

OH

a-c

d
O

52%

NHBoc
51

O

92%
dr >10:1

NBoc
(+)-52

NBoc
(+)-53

OH

OBOM

OH

e, f

g-i

O

74%
dr >5:1

NBoc

O

(+)-55

(+)-54
OBOM

j-l
51%

O

HN

O

N

O (+)-56

N

O

O

OH
81%

OBOM

k

(+)-60
OH
OBOM

O
N
Fmoc

OBOM

p, q

OH

OH

OH

O

100%

u, v

62 R1 = OH; R2 = H
63 R1 = H; R2 = OH

k, t
80%

OBOM

H

O

H

OH

N

+

O
O B

w, x

OBOM

N

73%

(+)-64
H

OH
OBOM

s
72%
(62:63 3:2)

CHO
N
Fmoc
61

O
O

r
83%
dr >20:1

N
OH
Fmoc
(+)-59

100%
from 62

R1 R2

n, o

OTBDPS 82%

O (+)-57

O
(–)-58
OH
N
Fmoc

OTBDPS

O

OBOM

m

OTBDPS 78%

OBOM

O

N

52%
OH

N

OH
OH

y, z
64%

I
(+)-65

66

(+)-Cyclizidine
(ent-49)

Scheme 5 Synthesis of (þ)-cyclizidine (ent-49) by Hanessian et al.33 Reagents and conditions: (a) EDC, N-methylmorpholine, NHMe(OMe)$HCl, THF, e10  C, 3 h; (b)
Me2C(OMe)2, Me2CO, BF3$OEt2; (c) MeLi$LiBr, THF, À78  C, 2 h; (d) HC^CMgBr, THF,
rt, 2 h; (e) LiAlH4, THF, rt, 4 h; (f) AD-Mix-b, tBuOHeH2O (1:1), MeSO2NH2, 0  C, 24 h;
(g) NEt3, TBDPSCl, DMAP (cat.), CH2Cl2, rt, 3 h; (h) BOM-Cl, iPr2NEt, ClCH2CH2Cl, Bu4NI,


Simple Indolizidine and Quinolizidine Alkaloids

15

assembly of the cyclopropyldienyl substituent. The very tricky removal of
the benzyloxymethyl (BOM) protecting group was eventually accomplished
with lithium di-tert-butyldiphenyl (LiDBB) to give the target in 26 steps and
an overall yield of 2.7% based on 51. This product proved to be dextrorotatory (½aŠD þ36.1, c 0.5, MeOH), whereas a sample of natural cyclizidine
was levorotatory ([a]D À29.51, c 0.5, MeOH); the Hanessian product was
thus the enantiomer of cyclizidine, namely, ent-49. By implication, naturally
occurring (À)-cyclizidine must have the absolute configuration shown in
49. However, to clinch matters, the X-ray crystal structures of both natural
(À)-cyclizidine and synthetic (þ)-cyclizidine were determined using a copper radiation source, anomalous scattering from which permitted the evaluation of Flack factors and hence the unambiguous determination of the
absolute configurations of both enantiomers.

2.3 Streptomyces Metabolites

:

The ethyl acetate extract from the fermentation broth of Streptomyces koyangensis BY-4, a Gram-positive actinomycete isolated from the gut of the

termite species Odontotermes formosanus, was the source of the unique alkaloid (7S)-(þ)-2-ethyl-7-hydroxy-6,7-dihydro-3(5H)-indolizinone (67)
(Figure 4).35 The standard spectroscopic techniques, including a range of
one- and two-dimensional NMR experiments, revealed the skeletal structure of the alkaloid (½aŠ20
D þ28.33, c 0.10, CHCl3). More interestingly, the
(S)-absolute configuration was inferred by comparing the computed electronic circular dichroism (ECD) spectra for both the (7R)- and (7S)-enantiomers with the recorded ECD spectrum of the natural product. The
new alkaloid was weakly active when tested against three fungi and six bacteria; a minimum inhibitory concentration value of 64 mg/mL was found in
tests with Staphylococcus aureus, Streptococcus pyogenes, Micrococcus luteus, Escherichia coli, and Candida albicans.
50  C, 12 h; (i) NaHMDS, THF, rt, 30 min; (j) p-TsOH, MeOH, rt, 2 h; (k) DesseMartin
periodinane, CH2Cl2, rt, 1 h; (l) Ph3P]CH2, THF, 0 to rt, 1 h; (m) NaHMDS, H2C]
CH(CH2)2OTf, THFeDMF (5:1), 0  C to rt, 2 h; (n) Bu4NF, THF, rt, 6 h; (o) Grubbs II catalyst
(6) (5 mol%), CH2Cl2, reflux, 2 h; (p) KOH (2 N)eEtOH (1:1), reflux, 12 h; (q) Fmoc-Cl, THF,
aq. satd. Na2CO3, 0  C, 3 h; (r) TFA, oxone, MeCN, H2O, 0  C, 3 h; (s) MeC^CMgBr, THF,
À78  C to rt; (t) NaBH4, MeOH, À78  C, 2 h; (u) MsCl, NEt3, CH2Cl2, 0  C to rt, 1 h; (v)
piperidine, MeCN, rt 12 h; (w) PdCl2(PPh3)2, Bu3SnH, THF, rt, 30 min; (x) I2, CH2Cl2 0  C
to rt; (y) 66, Pd(PPh3)4 (10 mol%), Tl2CO3, THFeH2O (4:1); (z), LiDBB (0.5 M in THF),
THF, À78  C, 1 h.


16

Joseph P. Michael

HO
N
O
67

Figure 4 (7S)-(þ)-2-Ethyl-7-hydroxy-6,7-dihydro-3(5H)-indolizinone (67) from Streptomyces koyangensis.35

The use of a short-lived carbonyl ylide in a [3 þ 2] dipolar cycloaddition

has been demonstrated by Padwa and coworkers36,37 in the synthesis of the
angiotensin converting enzyme (ACE) inhibitor (À)-A58365A (68), which
had been reported in 1985 as a metabolite in the fermentation broth of the
soil actinomycete Streptomyces chromofuscus NRRL 15098.38e40 Treatment
of the diazosulfone 69, prepared in four standard steps from L-pyroglutamic
acid (70), with rhodium(II) acetate in benzene at 80  C generated the transient isom€
unchnone intermediate 71 (Scheme 6). This underwent cycloaddition with methyl vinyl ketone followed by spontaneous elimination of
phenylsulfinic acid to give the bicyclic hydroxypyridone 72 in 86% yield.
The readily formed triflate of 72 participated in a Heck reaction with methyl
acrylate to give the enoate 73 in 82% yield over the two steps. Once the
alkene had been hydrogenated, a BaeyereVilliger oxidation of the acetyl
substituent, methyl-to-benzyl transesterification and hydrolysis of the acetate yielded the benzyl ester 74. Since Fang and Danishefsky had previously
converted this intermediate into (À)-A58365A by hydrogenolysis of the
benzyl esters,41 Padwa’s route constitutes a formal synthesis of the alkaloid.
Martin and coworkers have published the shortest enantioselective synthesis of (À)-A58365A (68) to date (Scheme 7).42 The known sulfoxidesubstituted lactone 75 was transformed in two steps into the butenolide
76, which was converted in situ into the trimethylsilyloxyfuran 77. This intermediate participated in a highly efficient vinylogous Mannich reaction
with pyroglutamate derivative 78 to give the adduct 79 as a mixture of
four diastereomers in 90% yield. Simply treating this mixture with lithium
methoxide in methanol effected rearrangement of the lactone to a lactam,
producing the indolizinone (À)-80 in 75% yield. Hydrolysis of the methyl
esters with an acidic ion-exchange resin completed the synthesis of (À)-68.

2.4 Pantocins A and A2
The epiphytic bacterium Erwinia amylovora is responsible for fire blight, a
contagious disease that affects apples, pears, and other members of the Rosaceae, with disastrous results for commercial producers. A report in 2001


17

Simple Indolizidine and Quinolizidine Alkaloids

O

N2

a-d

HN

52%

O

e
N

PhSO2

CO2H

–

O+
N

CO2Me

O

70

PhSO2

O

69

CO2Me
71

O

O
f, g

86%

N

HO
O

81%
CO2Me

OH

OH
h-j
N

BnO2C

k
96%
CO2Bn

O
74

CO2Me

O
73

72

94%

N

MeO2C

HO2C

N
CO2H
O
(–)-A58365A (68)

Scheme 6 Formal synthesis of (À)-A58365A (68) by Padwa et al.36,37 Reagents and conditions: (a) MeOH, Dowex 50WX2e200, reflux, 3 h; (b) PhSCH2COCl, C6H6, reflux, 24 h; (c)
oxone, MeOH, H2O, rt, 7 h; (d) p-MeCONHC6H4SO2N3, NEt3, MeCN, 0  C to rt, 18 h; (e)
H2C]CHCOMe, Rh2(OAc)4 (cat.), C6H6, reflux, 20 h; (f) PhN(Tf)2, NEt3, CH2Cl2, rt, overnight; (g) H2C]CHCO2Me, Pd(Ph3P)2Cl2 (20 mol%), NEt3, MeCN, reflux, 3 h; (h) H2
(50 psi), 10% Pd/C, CHCl3, rt, 5 h; (i) aq. H2O2 (30%), TFA, CH2Cl2, 0  C to rt, 4.5 h,
then aq. NaHCO3; (j) BnOH, ClBu2SnOSnBu2OH (Otera’s catalyst), PhMe, reflux, 15 h;
(k) H2, Pd/C, MeOH (Ref. 41).

noted that strain Eh318 of the related bacterium Pantoea agglomerans, an
opportunistic pathogen that often causes infections in humans, was able to
inhibit the growth of E. amylovora.43 This activity was traced to two antibiotics, pantocins A and B. The latter was readily identified as the sulfonylsuccinamic acid derivative (þ)-81 (Figure 5), but the lability of pantocin A
under basic, acidic, and thermal conditions as well as inconsistent and low
levels of production in liquid culture hampered its identification for some
time. The indolizinone structure (3S,6S,30 S)-(À)-82 e moderately stable
under neutral conditions, fortunatelydwas eventually elucidated by spectroscopic methods that included 15N NMR spectroscopy on an enriched
sample isolated from a culture medium containing 15N-labeled ammonium
sulfate.44 NOESY experiments helped to define the stereogenic centers, as
did hydrogenation to 83, hydrolysis of which afforded L-aspartic acid. This
established the (S)-absolute configuration at C-3’. The remaining stereogenic centers were assigned after chiral HPLC comparison of 83 with a synthetic sample of this compound and its (3,6,9R) diastereomer, both of which


18

Joseph P. Michael

SPh

SPh

O
S

O

Ph

c

a, b

O

MeO2C

73%

O
75

O

TMSO

O
76

77
SPh

MeO
N

Boc

CO2Me
78

O HN
H

MeO2C

d, 90%

O

e
75%

OH
f
97%

N
O
(–)-80

CO2Me

79

OH

MeO2C

R

CO2Me

HO2C

N

CO2H
O
(–)-A58365A (68)

Scheme 7 Martin’s synthesis of (À)-A58365A (68).42 Reagents and conditions: (a) NaH
(cat.), THF, rt, 15 min, then H2C]CHCO2Me, rt, 1 h, 50  C, 2 h; (b) TMSOTf, NEt3, CH2Cl2,
0  C, 1 h, then PhSCl, À78  C, 0.5 h; (c) TMSOTf, NEt3, CH2Cl2, 0  C, 1 h; (d) add 78,
TMSOTf (cat.), CH2Cl2, À78  C, 1 h, then TMSOTf (2 equiv.), À78 to 0  C, 2 h; (e) LiOMe
(1 M in MeOH), rt, 14 h; (f) Dowex 50WX8-200, H2O, reflux, 3 h.

were made from L- or D-dimethyl glutamate via the indolizidinones 84 and
ent-84; the natural L-amino acids proved to be the alkaloid’s precursors. A
minor inactive compound found during the isolation of pantocin A was
identified as the pyrrole 85, perhaps an unsurprising structure in view of
the relative instability of 82. (À)-Pantocin A2 (86), another active minor
antibiotic identified in a subsequent investigation, differs from (À)-pantocin
A in having an additional L-alanine residue attached to the C-terminus of the
pendent asparagine unit at C-3.45 This later investigation also reported the
identification of specific genes that encode for plausible peptide sequences

in the biosynthesis of pantocin A, and the involvement of a 30-residue upstream prepeptide with a Glu-Glu-Asn sequence near its midpoint. The
structural resemblance of this three amino acid sequence, shown in 87, to
pantocin A (86) is obvious. In support of this hypothesis, labeled glutamic
acid was efficiently incorporated into the antibiotic in feeding experiments.
The authors also reported the first results from site-directed mutagenesis of
the genes involved in the biosynthesis of this unusual group of antibiotics; an
inactive analog of 85 with an additional Ile-Thr residue at the N terminus
was isolated from an E. coli clone containing an altered gene. Further genetic
manipulation is expected to lead to the production of modified analogs of
the antibiotics.


19

Simple Indolizidine and Quinolizidine Alkaloids

H
N

H2N
O

6

H
N
O

N

H2N

CO2H

H2N

SO2Me

O

3

O

HN
3'

CO2H
O
(–)-Pantocin A (82)

(+)-Pantocin B (81)
H
H

9

N

H2N

H2N

O

H2N
O

HN

N

BocHN

H2N

CO2H

O

83

85

(Glu)

H2N
O

CO2H

84

N

H2N
O

HN

O
H
N

CO2H CO2H
H
N
(Glu)

N
H
O
H2N HN
CO2H

O
(–)-Pantocin A2 (86)

O

HN

O

CO2H

O

HN
CO2H

O

O
NH

(Asn) O
87

Figure 5 The pantocins and related compounds.43e45

3. HYDROXYLATED INDOLIZIDINE ALKALOIDS
3.1 General Reviews
The hydroxylated indolizidine alkaloids dealt with in this section
continue to receive an astounding amount of attention, mainly as a result
of their ability to inhibit a variety of glycosidases and, in consequence, their
potential uses as chemotherapeutic agents for the treatment of disorders
relating to glycoprotein processing, carbohydrate catabolism, lysosomal storage, cellular recognition, and allied processes, as well as anticancer and antiviral effects and immunomodulatory properties. Since the structures of these
alkaloids mimic those of monosaccharides, they are often referred to as azasugars, aminosugars, or iminosugars. Indeed, the latter name was adopted in
the titles of two important books that deal not only with the indolizidine
alkaloids of interest, but also with hydroxylated pyrrolidines, piperidines,

pyrrolizidines, and nortropanes and their synthetic analogs.46,47 Topics
introduced in these books include occurrence and distribution of the natural
products, approaches to their synthesis, and their activity as glycosidase


20

Joseph P. Michael

inhibitors as well as other aspects of their biological activity. Both books
conclude with impressive tabular surveys of polyhydroxy alkaloids and their
numerous synthetic analogs. The former set of tables includes references to
their isolation, synthesis, NMR spectroscopic characterization, as well as
quantitative data (IC50 or Ki values) on the inhibition of various glycosidases;
while the latter supplements the quantitative data with valuable information
on their potential as therapeutic agents for the treatment of various diseases,
including type 2 diabetes, viral infections, malaria, cancers, and lysosomal
storage disorders.
Many shorter reviews cover similar ground. Relevant book chapters may
be found in the multi-volume compilation Comprehensive Natural Products
Chemistry,48 and in a more recent monograph on modern alkaloids.49 Surveys by a group of the most prominent authors in the field also deal with
the natural occurrence and biological activity of iminosugars in general,
and provide more in-depth coverage of potential therapeutic applications,
especially in the case of swainsonine and castanospermine, arguably the
two most important hydroxyindolizidines (cf. Sections 3.5 and 3.6).50e52
The therapeutic applications of these and related alkaloids are treated in
another brief review,53 and are mentioned in a review that concentrates
on the structure and biological activity of a- and b-glucosidase inhibitors.54
These aspects are also covered in a more general review of the synthesis and
biological applications of azapyranose sugars.55

A somewhat different perspective is presented in reviews that take as
their starting point the toxicity of poisonous forage plants to livestockd
the factor that led to the discovery of many of the polyhydroxylated alkaloids in the first place. An important review in the current series of volumes
adopts this approach.56 Genera including Astragalus, Oxytropis (the infamous
North American “locoweeds”; see Section 3.5.1) and Castanospermum are
dealt with in similar reviews,57e59 the first of which also elaborates on the
development of animal models for human diseases and the resulting exploration of relevant alkaloids as drug candidates.
Since the synthesis of iminosugars is a perennially active area of research,
it is not surprising that general reviews devoted mainly or exclusively to the
synthesis of polyhydroxylated alkaloids and analogs of all classes have
appeared fairly regularly.60e65 While polyhydroxylated indolizidines form
a rather small subset of the compounds in the cited reviews, they are the
focus of yet another review that concentrates on total synthesis.66 The application of specific reactions to the synthesis of iminosugars and analogs has
also received attention in reviews that include examples drawn from the


21

Simple Indolizidine and Quinolizidine Alkaloids

literature of hydroxylated indolizidines; topics covered include the use of
2-silyloxypyrroles and related chalcogen heterocycles as vinylogous nucleophiles for aldol-type condensations,67 applications of 1,3-dipolar cycloadditions in general68e70 and nitrone cyloadditions in particular,71 and methods
involving the intermediacy of a,b-unsaturated diazoketones.72 Reviews that
highlight the personal contributions of the authors to the synthesis of relevant alkaloids are by Pyne,73 who has also presented an overview of his
use of the borono-Mannich reaction (the Petasis reaction) in pertinent syntheses74; and by Mariano, who has described his approaches based on alkene
metathesis and pyridinium salt photochemistry.75 Specific examples from
the published work of these authors are included in subsequent sections
(vide infra).
Among the miscellaneous general reviews of interest is one that contains
extensive tabulations of 1H and 13C NMR spectroscopic data for virtually all

of the naturally occurring polyhydroxylated alkaloids known at the time,
including the hydroxylated indolizidines.76 Another general review describes chromatographic techniques for the isolation, purification, detection,
and analysis of polyhydroxylated alkaloids.77

3.2 1-Hydroxyindolizidines
Both (1S,8aS)-(þ)-indolizidin-1-ol (88) and (1R,8aS)-(À)-indolizidin-1-ol
(89) are intermediates in the biosynthesis of slaframine (9) and swainsonine
(cf. Section 3.5) in the fungus Rhizoctonia leguminicola.78 The former has also
been isolated as the acetate from the diablo locoweed, Astragalus oxyphysus.79
A related compound, 8-methylindolizidin-1-ol (90), has been claimed as a
new toxic principle in extracts of Oxytropis kansuensis,80 but details are
sketchy (Figure 6). All recent publications in this area have dealt with the
synthesis of 88, 89, and the enantiomer of 89.
Greene and coworkers synthesized both 88 and 89 by introducing simple
modifications into the route they had previously employed for making
slaframine (9) (cf. Scheme 2; Section 2.1). A late-stage diversion in the
slaframine route saw hydroborationeoxidation of the previously featured
H

OH

H

OH

Me

N

N

N

88

89

90

Figure 6 1-Hydroxyindolizidine alkaloids.

OH


22

Joseph P. Michael

pyrrolidinone (þ)-25 producing the primary alcohol (þ)-91, mesylation of
which preceded cyclization to indolizidin-3-one (þ)-92 (Scheme 8). Treatment with trifluoroacetic acid was sufficient to cleave the chiral auxiliary,
after which reduction of the lactam with lithium aluminum hydride
completed the synthesis of (1S,8aS)-(þ)-indolizidin-1-ol (88).28 The modification in the route to (1R,8aS)-(À)-indolizidin-1-ol (89) entailed the
initial use of the (S,E)-protected enol ether (À)-93, which replaced the previously used (R,Z)-isomer 23 in the ensuing [2 þ 2] cycloaddition with
dichloroketene.81 The major cyclobutanone adduct in the diastereomeric
mixture (95:5) was 94, the structure of which was substantiated by means
of X-ray crystallography. Regioselective Beckmann rearrangement followed by dechlorination then yielded the 4,5-trans-disubstituted pyrrolidin-2-one (À)-95. The final stages of the synthesis paralleled those used
Ar
O

O

Ar
Scheme 2

a
75%

HN
23 Ar = C6H2-2,4,6-iPr3

(+)-25 O
Ar

Ar
O

H

OH (+)-91

H
66%

N

O

(+)-92

O

Ar
O

f

O

dr 95:5

94

O

H

O

a-c
66%
de >98%
O

Cl

g, h
82% from
93

Ar

Ar

(–)-95

Cl

O

(–)-93

HN

N
(+)-88

Ar

H

OH

d, e

b, c
88%

HN

O

H

OH

d, e
N
(–)-96

78%
O

N
(–)-89

Scheme 8 Greene’s routes to (1S,8aS)-(þ)-indolizidin-1-ol (88) and (1R,8aS)-(À)-indolizidin-1-ol (89).28,81 Reagents and conditions: (a) Sia2BH, THF, 0e20  C, 5 h, then
NaOH, H2O2, 0e20  C, 20 h; (b) MsCl, NEt3, CH2Cl2, 0  C, 1.5 h; (c) NaH, THFeDMF (3:
1), 20  C, 2 h; (d) TFA, CH2Cl2, 20  C, 2.5e3 h; (e) LiAlH4, THF, 20  C, 21e24 h; (f)
Cl3CCOCl, Zn/Cu, Et2O, 0  C, 1 h, 20  C, 2 h; (g) H2NOSO2C6H2Me3, Na2SO4, CH2Cl2,
20  C, 7 h; (h) Zn/Cu, NH4Cl, MeOH, 20  C, 11 h.