Syntheses of Galbulimima Alkaloids - Rinner Group - Universität Wien

22 Pages·2010·0.45 MB·English

REVIEW 3763
Syntheses of Galbulimima Alkaloids
SUyntheses of Galbuwlimima Alkaloidse Rinner,* Christoph Lentsch, Christian Aichinger
Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
Fax [phone]; E-mail: [email protected]
Received 28 May 2010; revised 1 July 2010
Abstract: The bark of the rain forest tree Galbulimima belgraveana
has been identified as a rich source of fascinating natural products
and so far 28 unique alkaloids have been isolated. The chemical in-
terest in Galbulimima alkaloids started with the discovery of the
promising biological activities of himbacine. Fifteen years after the
first total synthesis of himbacine, this class of natural product still
inspires, with the structurally more complex congeners himandrine,
himgaline, and G.B. 13 as highly challenging synthetic targets. This
review article summarizes and discusses all syntheses of Galbulimi-
ma alkaloids published to date.
1 Introduction
2 Syntheses of Galbulimima Alkaloids
2.1 Class I Alkaloids
2.2 Class II Alkaloids
2.3 Class III Alkaloids al.
3K ey woCrdosn:c Gluaslibounlimima alkaloids, natural products, total synthe- Figure 1 Galbulimima baccata11 materi
sis, Diels–Alder reaction, heterocycles, fused-ring systems d
Powdered bark in combination with wild tobacco and gin- hte
ger served as natural treatment for hair lice.7 yrig
p
In 1948, Webb recorded that the bark of Galbulimima o
1 Introduction C
baccata is rich in alkaloids and several compounds were n.
e
isolated.8 In the following years, a total of 28 alkaloids Wi
The rain forest tree commonly called white magnolia or were revealed, of which 22 were structurally character- ät
pliiag aenodn bPearpryu aa Nshe w(F Giguuirnee1a), ,w eansd feimrsitc b ointa Nniocratlhleyr dne Ascursibtread- ized. The newly isolated compounds were either named versit
in 1887 by F. Mueller and was originally named Eupoma- with the prefix ‘him’, as the authors were under the im- Uni
tia belgraveana.1 Ever since this first disclosure, botanists pression that the botanically correct name for white mag- y:
have argued about the correct taxonomic classification nolia was Himantandra belgraveana, or they were given d b
numbers. Based on their structural properties, the Galbu- de
and the plant was allocated different synonyms, the most a
limima alkaloids are subdivided in four classes; the struc- o
common name being Himantandra belgraveana.2,3 Today nl
turally characterized alkaloids (classes I to III) are w
the name Galbulimima belgraveana is used and this name Do
outlined in Figure2, and the miscellaneous compounds
has been given as synonym to Galbulimima baccata by
(class IV) include the alkaloids for which characterization
authors who consider the genus monotypic. Recently,
and thus categorization have not yet been achieved. Only
Jessup reported that Galbulimima belgraveana is endemic
recently, Mander published the structures of three Galbu-
to Papua New Guinea and Indonesia while Galbulimima
limima alkaloids which had not been characterized previ-
baccata is found in Northern Queensland, Australia.4 The
ously.9 While himgrine (5) possesses the structural
rain forest tree is categorized as a member of the family
features of a Galbulimima class I alkaloid, G.B. 16 (24) is
Himantandraceae in the order Magnoliales.
more complex and could be classified as a class III alka-
Traditional medicine of the native populations of Papua loid despite the missing C9–C20 bond. G.B. 17 (25) clear-
New Guinea, Malaysia, and Northern Australia made use ly stands out, as the structure of this natural product is
of this rain forest tree. The bark was chewed – often in unique among Galbulimima constituents.
combination with leaves of Homalomena sp. – to induce
Atoms and ring systems are labeled in Figure2. The num-
vision and dream-like states, for divination and religious
bering for class I alkaloids is consistent throughout the
rites, or it was swallowed to reduce abdominal pains.5–7
chemical literature with only a few exceptions. There is no
uniform system for the atom numbering of class II and
class III alkaloids, so we have adopted the method sug-
SYNTHESIS 2010, No. 22, pp3763–3784xx.xx.2010 gested by Ritchie and Taylor.10
Advanced online publication:15.09.2010
DOI: 10.1055/s-0030-1258251; Art ID:E27410SS
© Georg Thieme Verlag Stuttgart · New York
3764 U. Rinner et al. REVIEW
The synthetic interest in Galbulimima alkaloids began himbosine (7) was established via X-ray crystal structure
with the discovery of their biological properties. Himba- analysis of the corresponding hydrobromide21 and the
cine (2) was identified as a potent muscarinic receptor structures of himandrine (6) and himandridine (8) were
antagonist12,13 and a possible candidate for the treatment determined by degradation studies and X-ray crystal
of senile dementia associated with Alzheimer’s dis- structure analysis.22,23 The structurally related Galbulimi-
ease.14,15 Furthermore, derivatives of himbacine are cur- ma class II alkaloids were assigned based on these find-
rently in clinical trial as antithrombotic agents.16,17 ings without proof of the absolute configuration.10,24
Despite the high potential of himbacine, the biological Because of the similarity of the carbon skeleton, it was as-
properties of most other Galbulimima alkaloids remain sumed that subtypes of this family of natural products
unexplored. would also share the absolute configuration of the decalin
system and the structures of himbadine (23), himgaline
A characteristic feature of all the Galbulimima alkaloids
(21) and G.B. 13 (22) were assigned accordingly.25,26 In
is a trans-decalin system. While the piperidine ring is at-
2006, Movassaghi27 corrected the stereochemistry of G.B.
tached to the decalin moiety via a carbon tether in class I
13 from 2R to 2S and this report also motivated Willis and
alkaloids, the heterocycle is part of a complex fused-ring
Mander28 to reevaluate this group of natural products. Af-
system in the class II and class III alkaloids. Although
ter extensive X-ray studies, they were able to prove, un-
class II and III alkaloids are structurally more complex,
ambiguously, that the C2 stereochemistry is S in all of
the main carbon skeleton remains basically identical for
these alkaloids. Apart from that, they found the C10 and
all members of this family of natural products.
C15 stereocenters of more complex class II and class III
The structure of Galbulimima alkaloids has been inten-
alkaloids to be antipodal to those in himbacine (2) and re-
sively studied. Degradation studies revealed the structure
lated class I congeners. This highly interesting result is in
of himbacine (2)18,19 before the absolute configuration
full agreement with all total synthetic efforts published to
was determined by X-ray crystal structure analysis.20 Sub-
date.
sequently, the structure of Galbulimima class II alkaloid
al.
eri
Biographical Sketches at
m
d
e
ht
Uwe Rinner studied chem- 2003, he received is Ph.D. tive in the field of diterpene yrig
istry at the Technical Uni- from the University of Flor- chemistry before he started op
C
versity in Graz. After ida and moved to Brock his own research group in n.
graduation he moved to University, Ontario (Cana- 2007. His current interests Wie
Gainesville, Florida (USA) da) for postdoctoral studies. include the synthesis of ät
to pursue graduate studies in After returning to Austria, diterpenes and the prepara- sit
er
the area of total synthesis of Uwe Rinner joined the re- tion of other biologically in- v
ni
Amaryllidaceae constitu- search group of Prof. teresting natural products. U
ents with Prof. Hudlicky. In Johann Mulzer and was ac- by:
d
e
d
a
o
nl
Christoph Lentsch was in 2006 under the supervi- Johann Mulzer in the field w
o
born in 1981 in Zams, Aus- sion of Prof. Walther of natural product total syn- D
tria. He studied chemistry at Schmid. Currently he is car- thesis.
the University of Vienna, rying out his Ph.D. studies
where he received his M.Sc. under the guidance of Prof.
Christian Aichinger was Widhalm, working on im- cin. His research interests
born in 1984 in St. Pölten, proved methods to access include transition-metal-
Austria. He studied chemis- binaphthyl derivatives. Cur- mediated coupling reactions
try at the University of Vi- rently, he is working to- and the synthesis of biologi-
enna, where he received his wards his Ph.D. in the cally important natural
M.Sc. in 2008 under the su- Rinner group, studying the products and derivatives.
pervision of Prof. Michael total synthesis of euphosali-
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
REVIEW Syntheses of Galbulimima Alkaloids 3765
Class I Galbulimima alkaloids:
OH
O H H O H 8 O H 9 H O H
1 9a
O A B C O 3 2O 3a O
H H H H 5 H H H
12 11
R Me Me
N N HN N
D
17
1 himbeline; R = H 3 himgravine 4 himandravine 5 himgrine
2 himbacine; R = Me
Alkaloid R1 R2 R3 R4
Class II Galbulimima alkaloids:
7 himbosine OAc OCOPh OAc OAc
8 himandridine OCOPh OMe OH OH
OBz OMe R1 R2 9 G.B. 1 OAc OCOPh OAc OH
18 H H 10 G.B. 2 OAc OAc OAc OAc
MeO2C MeO2C R3 11 G.B. 3 OH OH OAc OAc
1 17 15 B A 12 G.B. 4 OH OH OCOPh OAc
13 G.B. 5 OH OH OH OAc
12
34 26N 7 89H E N C H 111456 GGG...BBB... 678 OOOCCHOOPPhh OOOMMMeee OOHAHc OOOHAHc
D 17 G.B. 9 OAc OMe H OH
20 18 G.B. 10 OAc OMe H OAc
HO R4 19 G.B. 11 OH OH H OAc
20 G.B. 12 OAc OAc H OAc
6 himandrine
Class III Galbulimima alkaloids: al.
eri
OHH O H O H HO H d mat
e
H HB A 19 H H H ght
N H E NRC H N H H N opyri
C
D 20 O en.
HO HO O O Wi
21 himgaline 22 G.B. 13; R = H 24 G.B. 16 25 G.B. 17 ät
23 himbadine; R = Me sit
Figure 2 Classification of Galbulimima alkaloids ver
ni
U
In a first speculation about the biosynthesis of Galbulimi- discussed within this article. Reports describing the prep- by:
ma alkaloids, Taylor and Ritchie18,26 suggested that these aration of derivatives or simplified models for biological ed
d
natural products are derived from either nine acetates and activity studies are not included. For clarity and better un- a
o
one pyruvate unit or ten acetates and a one-carbon unit. derstanding, key steps are depicted in blue color within wnl
Movassaghi27,29,30 published a hypothetical biogenesis the schemes. Do
which explains the generation of class II and class III Gal-
bulimima alkaloids. Mander suggested biosynthetic path-
2.1 Class I Alkaloids
ways for the formation of G.B. 16 and G.B. 17.9 Aside
from these reports, no further information about the bio- Syntheses of class I alkaloids are discussed in detail be-
synthesis of Galbulimima alkaloids has appeared. low. All synthetic efforts utilize Diels–Alder reactions as
the key step to establish the decalin unit of the natural
product. As each of the approaches varies by the bonds
2 Syntheses of Galbulimima Alkaloids formed during the cycloaddition step, different strategies
for the construction of the Diels–Alder precursors were
Several syntheses of Galbulimima alkaloids have ap- applied (Scheme1).
peared in the literature over the last few years and these ef-
forts are listed in Table1. Despite the growing interest in
Hart, Kozikowski, 1995 (Himbacine, Himbeline)
this highly fascinating class of natural products, syntheses
of Galbulimima alkaloids have not been summarized pre- In 1995, Hart and Kozikowski31,42 reported the first total
viously. synthesis of himbacine via himbeline, as outlined in
Scheme2. The key step in this synthetic effort is the for-
This review article concentrates on total and formal syn-
mation of the trans-decalin system by an intramolecular
theses of members of this interesting class of natural prod-
Lewis acid promoted Diels–Alder reaction of thioester 29.
ucts, and all of the syntheses outlined in Table1 are
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
3766 U. Rinner et al. REVIEW
Table 1 Syntheses of Galbulimima Alkaloids
Alkaloid class Compound Author Publication year Number of steps Overall yield
class I himbacine/himbeline Hart, Kozikowski31 1995 19 (himbeline) 5.4% (himbeline)
20 (himbacine) 3.8% (himbacine)
class I himbacine/himbeline Chackalamannil32 1996 11 (himbeline) 12.4% (himbeline)
12 (himbacine) 9.7% (himbacine)
class I himbacine (formal synthesis) Terashima33 1999 18 12.6%
class I himandravine Chackalamannil34 2001 12 17.0%
class I himbacine (formal synthesis) De Clercq35 2002 13 6.6%
class I himbacine (formal synthesis) Sherburn36 2003 26 2.4%
class I himbacine/himbeline Baldwin37 2005 12 (himbeline) 3.1% (himbeline)
13 (himbacine) 2.3% (himbacine)
class II himandrine Movassaghi29 2009 28 0.7%
class III (±)-G.B. 13 Mander38 2003 30 0.2%
class III G.B. 13/himgaline Chackalamannil39 2006 31 (G.B. 13) 0.5%
33 (himgaline) 0.3%
class III G.B. 13 Movassaghi27 2006 19 1.7%
al.
class III ent-G.B. 13/ent-himgaline Evans40 2007 31 (ent-G.B. 13) 1.0% (ent-G.B. 13) eri
32 (ent-himgaline) 0.9% (ent-himgaline) at
m
class III (±)-G.B. 13 Sarpong41 2009 18 1.2% ed
ht
g
The reaction sequence started with cycloheptene (26) rahydropyran group in methanol and elimination of the pyri
o
which was converted into 7,7-dimethoxyheptanal via ozo- hydroxy functionality. C
ndoeslycsriibs eind tbhye pSrcehsreenicbee ro.4f3 m Seutbhsaenqoul efonltl oWwiitntigg ao pleroficneadtuiorne Installation of the thioester and formation of the triene Wien.
gave a,b-unsaturated ester 27 as a 2:1 mixture of geomet- wolaesfi ancahtiioenv.e dD biyel cs–leAavldaegre coyf cthliez aatcioetna lo ffo ltlroiweneed b2y9 Wunitdteigr sität
rical isomers. Deprotonation of this material with lithium er
thermal conditions afforded a 3:2 mixture of the desired v
diisopropylamide afforded the corresponding enolate, ni
endo-cycloadduct 30 and the corresponding exo-deriva- U
which reacted with O-protected (S)-2-hydroxypropanal to tive. The endo/exo selectivity could be improved by addi- by:
give tetrahydropyranyl ether 28. By exposing alkene 28 to d
tion of Lewis acids. The best results (endo/exo=20:1) e
sunlight in the presence of iodine, the ratio of the desired were obtained with a heterogeneous promoter prepared oad
trans-isomer could be increased to 32:1. The unsaturated from diethyl aluminum chloride and silica gel. wnl
g-lactone was obtained by cleavage of the acid-labile tet- o
D
The synthetic strategy envisaged the introduction of the
piperidine ring via Julia–Lythgoe olefination and the fol-
lowing steps were devoted to the installation of the sul-
R fone required for this olefination reaction. Reduction of
R the thioester with Raney nickel under concomitant stereo-
O O selective hydrogenation of the remaining double bond in
H
N the decalin system (C9–C9a), and conversion of the pri-
O Me O mary alcohol into the corresponding tosylate and dis-
Hart/Kozikowski 1995 Chackalamannil 1996
De Clercq 2002 placement with thiophenol gave sulfide 31. In order to
Baldwin 2005 H H circumvent compatibility issues of a deprotonated sulfone
O and a lactone present in one species, the lactone moiety in
31 was converted into a methyl acetal by reduction with
H H
R O R R diisobutylaluminum hydride and exposure to boron tri-
2 himbacine fluoride etherate in methanol (the original erroneous ste-
O O reochemical assignment of the acetal carbon atom31 was
corrected in the full paper published in 1997).42 Subse-
O O quently, sulfur was oxidized by means of m-chloroperoxy-
Terashima 1999 Sherburn 2002 benzoic acid to afford sulfone 32 in good overall yield.
Scheme 1 Different strategies in the syntheses of himbacine (2) The required coupling partner for the Julia–Lythgoe olefi-
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
REVIEW Syntheses of Galbulimima Alkaloids 3767
COSEt
MeO OMe MeO OMe
12.. ONa3,H MCeOO3,H Me2S, MeOH 1 . L(SD)A-M, eTCHHF–(OHTMHPPA),CHO HO OTHP 12.. TMssOCHl, ,E Mt3eNOH
O
3. Ph3P=CHCO2Me O 2. I2, hν, CH2Cl2 O 3. Amberlyst-15
72% 4. Ph3P=CHCOSEt
OMe OMe 44% (from ) O
26 27 28 27 29
SiO2,
Et2AlCl 75%
PhO2S PhS 1. Raney-Ni O SEt
H H 1. DIBAL-H H H 2. TsCl, py H H
2. BF3·OEt2, MeOH 3. t-BuOK, DMSO, PhSH
O O O
3. MCPBA, NaHCO3 72% 9a
H H OMe 88% H H O H 9 O
32 31 30
1. n-BuLi;
36
46% 2. 6% Na(Hg),
MeOH, Na2HPO4
1. s-BuLi,
NBoc NR 12.. B(BHo3c⋅M)2Oe2,S NaOH 2 . TTMBAEFDA; MeI
NH NBoc NBoc
3. TBSCl, 3. TPAP, NMO
imidazole
H H 1. Jones reagent H H HO O OTBS 57% O al.
2. TFA 84% eri
O 87% O 34 35 36 mat
d
H H OMe H H O hte
g
33 1 hhiimmbbealcininee; ;R R = = H Me 3M7e%C Na,q N HaCBHHO3C,N; 70% pyri
2 o
C
Scheme 2 Hart and Kozikowski’s synthesis of himbacine (2) n.
e
Wi
nation reaction – aldehyde 36 – was prepared from com- ät
mercially available (R)-piperidinecarboxylic acid (34). ersit
Reduction followed by N- and O-protection gave tert-bu- NBoc niv
U
tyldimethylsilyl ether 35. After stereoselective methyla- O y:
tLioeyn’, s tphreo tsoiclyoll 4e4 tchoemr pwleatse dr ethmeo rveeadc tiaonnd s eoqxuideantcieo nto uasldineg- H H Joulelifain–aLtyiothngoe H H ded b
NBoc a
hyde 36. O + O o
nl
w
The first synthesis of himbacine was completed by the H H O SO2Ph H H OMe Do
coupling of sulfone 32 and aldehyde 36, which after treat- 37 38 33
ment with sodium-amalgam delivered trans-alkene 33. It Scheme 3 Attempted Julia–Lythgoe olefination of aldehyde 37 and
is interesting to note that the original synthetic plan de- sulfone 38
vised by Hart and Kozikowski proposed a Julia–Lythgoe
olefination between aldehyde 37 and sulfone 38 as shown
Chackalamannil, 1996 (Himbacine, Himbeline)
in Scheme3. When this protocol failed, the problem was
solved by preparing coupling partners with reversed func- Shortly after the publication of the first synthesis of him-
tionalities. bacine by Hart and Kozikowski, Chackalamannil32 report-
Oxidation of the protected lactol with Jones reagent and ed his route to the alkaloid. The key step is an
cleavage of the Boc group on the piperidine nitrogen af- intramolecular Diels–Alder reaction of a substrate which
forded himbeline (1) which was converted into himbacine bears the complete carbon framework of the natural prod-
(2) by N-methylation under reductive alkylation condi- uct as shown in Scheme4. The stereochemistry of this re-
tions. Overall, himbeline was prepared in 17 steps and action was controlled by the C3-methyl group attached to
5.4% yield and himbacine was obtained in 18 steps and the projected g-lactone. Conformation 45b is energetical-
3.8% yield. ly favored, as the methyl group in 45a adds considerable
allylic strain. In this intramolecular cyclization reaction,
the piperidinyl-substituted diene system acts as dieno-
phile. The authors suggest that the vinylcyclohexenyl
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
3768 U. Rinner et al. REVIEW
tone ring attached to the decalin system. As reaction
OH
1. (Boc)2O, NaOH conditions only afforded partial isomerization to the de-
2. s-BuLi, TMEDA, NBoc sired cis-fused material, the cycloaddition product was
Me2NCHO NBoc 41 treated with 1,8-diazabicyclo[5.4.0]undec-7-ene, result-
NH 3. CrCl2, CHI3 PdCl2(PhCN)2, ing in complete epimerization at C9a. Reprotection of the
41% piperidine, CuI piperidinyl nitrogen was necessary as the high reaction
39 I 40 42
81% temperature required for the Diels–Alder reaction also re-
sulted in thermally induced cleavage of the Boc function-
OH
ality. Stereoselective hydrogenation of the decalin double
Lindlar, H2 95% bond in 46 from the less hindered face of the molecule
with Raney nickel and cleavage of the Boc group afforded
NBoc
himbeline (1) which was converted into himbacine (2) fol-
NBoc lowing the reductive alkylation protocol applied by Hart
and Kozikowski.31
3 COOH
44 Chackalamannil thus presented a highly efficient route to
9a O
DEAC, DMAP, himbacine and the synthesis is the shortest and highest-
45 O TEMPO (1%) 43 OH yielding process published so far. Only 12 steps (11 from
91%
Boc-protected methyl piperidine) were required to elabo-
1. toluene, 186 °C,
60% TEMPO (1%) rate this piperidine alkaloid from inexpensive and readily
2. DBU
3. (Boc)2O, NaOH available starting materials, and the author reported a
9.7% overall yield.
NBoc NR
Terashima, 1999 (Himbacine) al.
H H 1. Raney-Ni, H2 H H In 1999, Terashima and co-workers14,33 reported a synthe- materi
3 2. TFA sis of himbacine (2) based on an intermolecular Diels– d
9aH OO 72% H H OO Abultdeenro rleidaec t5io8n a so fo utetltirnaehdy dinro Siscohbeemnezo5f.u ran 51 and chiral pyrighte
Following a procedure developed by Kanematsu,47 50 was o
46 HCHO, MeCN, 1 himbeline; R = H C
NaBH3CN; 78% 2 himbacine; R = Me obtained starting from propargyl ether 47 by an intramo- n.
e
lecular Diels–Alder reaction and base-catalyzed ring Wi
opening sequence of cycloadduct 49. The hydroxy func- ät
O O tionality in 50 was converted into a leaving group and ersit
eliminated. Hydrogenation finally delivered the coupling niv
O O partner for the key cycloaddition reaction. Butenolide 58 y: U
was accessible from tetrahydropyranyl-protected (S)-2- d b
R A1,3 R hydroxypropanal (56) by Still–Gennari olefination and de
a
acid-catalyzed cyclization in large quantities.48 Reaction o
45a 45b nl
of diene 51 and butenolide 58 in diethyl ether containing w
Scheme 4 Chackalamannil’s synthesis of himbacine (2) Do
lithium perchlorate afforded the exo-cycloadduct 52 as
sole product. Hydrogenation of the double bond from the
moiety is more likely to adopt the required cisoid confor-
sterically less hindered face of the decalin derivative 52
mation.
and base-mediated opening of the oxygen bridge gave alk-
Amine 39 was obtained by chiral resolution of commer- ene 53. Isomerization of the double bond and hydrogena-
cially available 2-methylpiperidine with L-tartaric acid. tion cleanly afforded alcohol 54.
Boc-protection of the nitrogen and installation of an alde-
Installation of the piperidinyl moiety was accomplished
hyde functionality via treatment of the carbamate with
via the Julia–Lythgoe olefination protocol which had al-
sec-butyllithium and addition of dimethylformamide was
ready proven successful in the work of Hart and
followed by Takai iodovinylation to afford vinyl iodide
Kozikowski. Therefore, a one-carbon elongation was re-
40.45 This material was used in a palladium-mediated cou-
quired, which, after protection of the lactone as methyl
pling reaction with (S)-but-3-yn-2-ol (41) and the triple
acetal, was carried out by oxidation of the secondary alco-
bond in alkyne 42 was reduced to the corresponding dou-
hol and subsequent Wittig olefination. Hydroboration of
ble bond via Lindlar hydrogenation. Esterification of alco-
the double bond delivered primary alcohol 55 which was
hol 43 with acid 44 (accessible in three steps from
converted into sulfone 32. The synthesis was completed in
cyclohexane carbaldehyde)46 cleanly gave key intermedi-
analogy to Hart and Kozikowski’s protocol with signifi-
ate 45 which was used in the intramolecular Diels–Alder
cantly higher reported yields.
reaction. As pointed out earlier, this intramolecular pro-
cess only afforded the exo-adduct with a trans-fused lac-
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
REVIEW Syntheses of Galbulimima Alkaloids 3769
1. MsCl, Et3N
t-BuOK, 83 °C 2. DBU, 80 °C
O O O O
O O O O 98% HO 3 . PHd2,/ C0 (°1C0%),
C
39%
47 48 49 50 51
5 M LiClO4,
Et2O, 58, r.t. 58%
OH 1. DIBAL-H
OH OH
H H 2. BF3·OEt2, MeOH H H 1. DBU, 100 °C H H 1. Pd/C (10%), H2 H
3. TPAP, NMO 2. PtO2, H2 2. LiN(TMS)2
O O O O O
4. Ph3P⋅CH3I, NaN(TMS)2 80% 88%
H H OMe 5. BH3THF; H2O2, NaOH H H O H O H O
55 54 53 52
44%
1. MsCl, Et3N
82% 2. PhSH, t-BuOK Still–Gennari
3. MCPBA NR olefination H3O+
OTHP OTHP O
SO2Ph 1. n-BuLi, 36 O COOMe
H H 2. 5% Na(Hg), H H 56 57 58 O
MeOH, Na2HPO4
O O
3. Jones reagent
4. TFA NBoc
H H OMe H H O
32 66%
1 himbeline; R = H 37% aq HCHO, CHO
2 himbacine; R = Me MeCN, NaBH3CN; 91% 36 al.
Scheme 5 Terashima’s synthesis of himbacine (2) eri
at
m
The natural product was obtained in 18 linear steps with DeClercq, 2002 (Himbacine) d
e
12.6% overall yield. As several steps of the endgame were ht
A Diels–Alder strategy similar to that already employed g
adopted from earlier studies, this synthetic effort consti- by Hart and Kozikowski31 in their first total synthesis of pyri
tutes a formal synthesis of the natural product. The ele- o
himbacine was used by DeClercq35,49 who presented a C
gance of the synthesis with a nice intermolecular Diels– n.
formal synthesis of the Galbulimima alkaloid in 2002 e
Alder key step suffers from the tedious C1 elongation se- Wi
quence. Terashima also employed the reaction sequence (Scheme7). ät
to prepare derivatives of the natural product for further Aldehyde 36 was converted into alkyne 60 with deproto- ersit
structure–activity relationship studies. nated (trimethylsilyl)diazomethane in good yield and sub- niv
jected to a Sonogashira coupling reaction with vinyl U
y:
iodide 66, easily obtained by syn-hydroalumination of b
Chackalamannil, 2001 (Himandravine) d
commercially available octa-1,7-diyne (65). Stille cou- e
d
a
As himandravine (4) and himbeline (1) only differ in the pling of iodide 61 with stannylated butenolide 68 deliv- o
nl
stereochemistry at C13, synthetic routes to himbeline (1) ered the precursor for the key cyclization reaction. The w
o
can be modified in a way to grant access to himandravine cycloaddition was accomplished in refluxing toluene after D
(4) as well. In 2001, Chackalamannil34 reported the first a reaction time of three days, resulting in a complex mix-
total synthesis of himandravine (4) based on results ob- ture of isomers in 80% total yield. The double bond be-
tained in his earlier work on the epimeric alkaloid. The tween C9 and C9a in conjugation to the ester functionality
preparation of 4 was carried out in complete analogy to was reduced with magnesium in methanol and intermedi-
the synthesis of himbacine (2) and the only difference was ate 64 was obtained in 31% yield over two steps.
the epimerization of starting material 36 with triethyl- DeClercq decided to convert the alkyne into an already
amine on silica gel to aldehyde 59 as outlined in known intermediate. Thus, the lactone moiety was re-
Scheme6. The alkaloid was obtained after 12 synthetic duced and converted into its methyl ketal before the triple
operations (11, if counting from Boc-protected piperidine bond was reduced under dissolving metal conditions af-
36) in 17.0% yield overall. fording alkene 33 in excellent yield. As this material was
described in Hart and Kozikowski’s synthesis of himba-
cine, the reduction concludes the formal synthesis of the
silica gel,
Et3N cf. Scheme 4 alkaloid.
himandravine (4)
NBoc NBoc DeClercq thus presented an approach towards Galbulimi-
83%
13 13
ma alkaloids that is highly valuable for obtaining various
CHO CHO
derivatives for SAR studies. All major isomers isolated
36 59
after the Diels–Alder/reduction sequence were further
Scheme 6 Epimerization of aldehyde 36 in Chackalamannil’s syn-
converted into himbacine analogues and used in biologi-
thesis of himandravine (4)
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
3770 U. Rinner et al. REVIEW
NBoc NBoc
NBoc
66, Pd(PPh3)4, toluene, 110 °C,
LDA, TMSCHN2 piperidine 68, CuCl, DMF 3 days
NBoc NBoc
75% 63% 80% total yield: 80%
(mixture of isomers)
CHO
9a O
O 9
36 60 I mixture of O
diastereomers
O
61 62 63
Mg, 31%
DIBAL-H, 50 °C; MeOH (from 62)
I2, –50 °C
I
4
86% I
65 66 NBoc
NBoc
1. DIBAL-H
OH Hseaert ,S Kchoezimkoew 2ski, H H 32.. LBiF, 3li·qOuEidt 2N, MH3e,OH H H
n-Bu3SnH, Pd(PPh3)4 himbacine t-BuOH
O (2) O 9a O
80% 92%
CO2Et Bu3Sn O H H OMe H 9H O
67 68 33 64
Scheme 7 DeClerq’s formal synthesis of himbacine (2)
al.
eri
cal investigations. However, the low selectivity of the radical cyclization reaction, different reaction conditions at
m
Diels–Alder reaction is a drawback and obstacle for an ef- and mediators were employed. The desired cyclization d
e
ficient preparation of himbeline (1) and himbacine (2). product 76 could be isolated without evidence of the C4 ht
g
epimer, thus indicating the high degree of stereocontrol in yri
this reaction. However, the main product in this key step op
Sherburn, 2003 (Himbacine) C
was identified to be a mixture of E- and Z-isomers of ke- n.
In 2003, Sherburn36 published a formal synthesis of him- tone 77. As the maximum yield of the desired product did Wie
bacine (2) with an intramolecular Diels–Alder reaction not exceed 13%, the approach was abandoned. ät
and a radical cyclization as key steps. The alkene moiety sit
As delocalized propargylic radicals react almost exclu- er
formed in the Diels–Alder reaction is utilized as reactive v
sively at the propargylic site, the modified approach asked ni
handle for the radical process. The synthesis is outlined in U
for the preparation of alkyne 80 which was achieved by y:
Schemes8 and9. b
coupling of stannane 79 with bromide 73 as outlined in d
e
Stille coupling of vinylstannane 69 and dibromide 70, de- Scheme9. In analogy to the procedure described above, d
a
rived from (S)-lactic acid in three steps,50 afforded diene the methoxymethyl group in 80 was cleaved and the hy- nlo
w
71. Protection of the free hydroxy functionality and cleav- droxy functionality was oxidized to the corresponding o
D
age of the silyl ether paved the way for the preparation of carboxylic acid by applying Swern and subsequent
Diels–Alder precursor 72 which was obtained after ester- Pinnick51 oxidation protocols. Esterification with diphe-
ification of the primary alcohol with acryloyl chloride. nyl diselenide and tributyl phosphine again proceeded
The thermal cycloaddition reaction was carried out in re- smoothly and selenoate 81 was isolated in 51% overall
fluxing chlorobenzene and delivered a mixture of cis- and yield from methoxymethyl ether 80. All cyclization ef-
trans-fused bicyclic reaction products; this mixture was forts resulted in approximately 1:1 mixtures of alkyne 83
converted into the desired cis-fused adduct 73 in quantita- and allene 82; the best results were obtained when the re-
tive yield by exposure to 1,8-diazabicyclo[5.4.0]undec-7- action was carried out in refluxing benzene with a total
ene. The piperidinyl side chain was attached by way of a yield of 90% and 43% yield of the desired alkyne 83.
Stille coupling between stannane 78 and the vinyl bro-
Epimerization of C4a by treatment of ketone 83 with 1,8-
mide moiety in 73 and the corresponding E-alkene 74 was
diazabicyclo[5.4.0]undec-7-ene was followed by Luche
obtained in high yield.
reduction. The Barton–McCombie deoxygenation proto-
The following steps were devoted to the installation of the col required installation of a thionocarbonate. Unexpect-
selenoate ester required for the radical cyclization. This edly, all attempts to introduce the thionocarbonate failed
was achieved by cleavage of the methoxymethyl ether fol- and when more forcing conditions were applied, the cor-
lowed by oxidation of the primary alcohol under Swern responding secondary chloride was obtained. As pointed
and Pinnick51 conditions and exposure of the carboxylic out by Sherburn, this transformation is unprecedented
acid to diphenyl diselenide and tributyl phosphine. For the with thionocarbonates but has been observed with xan-
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
REVIEW Syntheses of Galbulimima Alkaloids 3771
OH OH Br
Br Pd2(dba)3,
SnBu3 AsPh3 NBoc
+Br OTBS
OTBS 72%
71
69 70 NBoc MOMO
1. MOMCl, DIPEA Pd(PPh3)4, CuCl, H
2. TBAF LiCl, DMSO, 73
82%
3. acryloyl cloride,
O
Et3N 85%
MOMO Br 1. PhCl, reflux MOMO Br SnBu3 H H O
H BHT (0.05 equiv) 79 80
1. PPTS, t-BuOH,
2. DBU
2. (Boc)2O
O O 3. Swern ox. 51%
75% 4. Pinnick ox.
H H 5. Ph2Se2, n-Bu3P
73 O 72 O
86% C78u,C Pl,d L(PiCPl,h D3)M4,SO NBoc H NBoc
H
N
Boc
O O C PhSe
NBoc NBoc H H H H Bu3SnH, O H
AIBN
4a
MOMO H 213... (P(BCPoOTcCS)2l,)O 2t-,,B DCuMHO2SHCO,l 2r; eEfltu3Nx PhSe O H H H OO+ H H OO t o t a 9l 0y%ield: H H OO
O O 83 43% 82 47% 81
4. Pinnick ox.
H H O 5. Ph2Se2, n-Bu3P, DMF H H O 12.. DNBaBUH4, CeCl3⋅7H2O
74 75 65% 43.. BCu6F3S5OnHC,S ACIlB, NDMAP al.
42% Ph3SnH, Et3B, 6to5t%al yield ateri
air, PhH, reflux m
77/76 = 4:1 NBoc d
NBoc e
ht
g
yri
NBoc NBoc H H De Clercq, op
C
Sn7B8u3 O O 4a O see Scheme 7 himbacine (2) en.
H H H H Wi
himb(2a)cine 4 O + 4 O H64 H O sität
er
Scheme 9 Sherburn’s formal synthesis of himbacine (2) v
H H O H H O Uni
Scheme 8 Sherburn’s first appro77ach towards himbacine7 6(2) 26 operations are necessary to prepare the natural product by:
with a yield of 2.6% overall. ed
d
a
thates.52 As dechlorination proceeds under same reaction nlo
conditions as removal of the xanthate or thionocarbonate, Baldwin, 2005 (Himbacine, Himbeline, Himandravine) ow
D
the formation of a chloride might have easily been over-
The latest synthetic contribution to class I Galbulimima
looked in previous deoxygenation protocols.
alkaloids was published by Baldwin in 2005.37 The ap-
The formal synthesis of himbacine (2) was concluded by proach mimics the assumed biosynthetic pathway and fea-
such a radical dechlorination, resulting in the formation of tures an intramolecular Diels–Alder reaction similar to the
alkyne 64 which had been reported as intermediate in strategies presented by Hart and Kozikowski and by
DeClercq’s preparation of the natural product. DeClercq accompanied by simultaneous formation of the
Sherburn’s synthesis clearly suffered from unexpected piperidine ring.
problems such as migration of the double bond in the first Starting from cycloheptene (26), Baldwin repeated the
approach and formation of the allene in the second ap- first six steps of Hart and Kozikowski’s route to aldehyde
proach which significantly reduces the overall efficiency 84. Conversion into a,b-unsaturated aldehyde 86 was ef-
of the published formal synthesis. The utilization of both fected by reaction with aldimine 85, as traditional Wittig
bromines in the starting material for coupling reactions,
olefination protocols unexpectedly delivered the desired
and the use of the double bond generated in the Diels– product only in low yield. Chiral phosphonate 92 was de-
Alder reaction for the radical cyclization are worth men- rived from Boc-protected methyl piperidine 90 through
tioning. However, the installation of the selenoate ester re- ruthenium tetraoxide oxidation and reaction with lithiated
quires several synthetic operations and preparation of the dimethyl methylphosphonate. The key cyclization precur-
unfunctionalized six-membered ring is tedious. Counting, sor 87 was accessed via Horner–Emmons reaction of
aldehyde 86 and phosphonate 92. Exposure to trifluoro-
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York
3772 U. Rinner et al. REVIEW
acetic acid in dichloromethane, followed by cyanoboro- Movassaghi, 2009 (Himandrine)
hydride reduction, gave the desired tetracycle 88 as an
In 2006, Movassaghi reported the synthesis of G.B. 13
inseparable mixture of C13 epimers. Reprotection of the
which is outlined in the discussion of Galbulimima class
nitrogen and hydrogenation of the trisubstituted double
III alkaloids (section 2.3). The preparation of himandrine
bond afforded lactones 33 and 89 which were separated
(6) can be regarded as a follow-up project to build a
by column chromatography. The two diastereomers 33
structure of higher complexity and is closely related to
and 89 were then elaborated into himbacine (2; from lac-
Movassaghi’s earlier work. As similar strategies have
tone 33) and himandravine (4; from lactone 89) as out-
been applied, a direct comparison of these two syntheses
lined in Scheme10.
might be of interest.
In his effort to improve upon Hart and Kozikowski’s syn-
The synthesis of the natural product follows the assumed
thesis of himbacine, Baldwin presented a highly divergent
biosynthetic pathway as outlined by Movassaghi.27 Ac-
approach towards all class I Galbulimima alkaloids. The
cordingly, the N–C9 bond is formed at a late stage of the
key step not only establishes the decalin system but also
synthesis by spirocyclization of pentacycle 93 that is
delivers the piperidine unit of the natural products. Given
obtained by oxidation of a,b-unsaturated ester 94
that the key Diels–Alder cycloaddition delivers a mixture
(Scheme11). The heterocyclic ring is introduced through
of epimers, the strategy does not allow the preparation of
a formal [3+3]-cycloaddition reaction of tricyclic ketone
a single alkaloid in high yield.
95 and alaninol-derived piperidine derivative 96. The key
steps in the preparation of tricyclic ketone 95 are an aldol
2.2 Class II Alkaloids condensation and a Diels–Alder reaction.
Only one synthesis of a class II Galbulimima alkaloid has The starting material for this synthesis was obtained via
been presented to date. The preparation of himandrine, proline-catalyzed a-oxidation of hept-6-enal following
published by Movassaghi in 2009, is described below. the procedure developed by MacMillan.53 Monosilylation
of diol 97, methylation of the secondary hydroxy group al.
with Meerwein salt and subsequent desilylation delivered eri
at
m
d
e
NHBoc ht
O yrig
p
O Co
n.
6 steps, O Wie
Hsaerte, KSoczhiekmowes 2ki, (ZTnMBSr2);2 ZCnHCCl2H, =HN2Ot-Bu (85), 9L2iC, lD, MIPeECAN, sität
O O O er
49% 60% 50% v
ni
U
26 84 O 86 O 87 O y:
b
TFA; d
NaBH3CN de
a
o
nl
H w
NBoc NBoc NH Do
13 13 13
H H H H 1. (Boc)2O, Et3N H H
2. H2, PtO2
O + O O
22% from 87
H33 H O H89 H O H 88 O
1. TFA
60% 2. HCHO, NaBH3CN 80% TFA RuO4, NaIO4
NBoc 39% NBoc
O
N NH
90 91
BuLi
H H H H (MeO)2P(O)Me
O NHBoc
54%
O O
H H H H (MeO)2P 92
O O
O
himbacine (2) himandravine (4)
Scheme 10 Baldwin’s synthesis of himbacine (2) and himandravine (4)
Synthesis 2010, No. 22, 3763–3784 © Thieme Stuttgart·New York