Total Synthesis of Gabosines

MICROREVIEW
DOI: 10.1002/ejoc.201200477
Total Synthesis of Gabosines
Dinh Hung Mac,[a,b]
Srivari Chandrasekhar,[c]
and René Grée*[a]
Keywords: Natural products / Total synthesis / Secondary metabolites / Carbocycles / Cyclohexanones / Cyclohexenones /
Carbasugars / Chiral pool / Stereoselective synthesis
This review reports on the total synthesis of gabosines, a fam-
ily of secondary metabolites containing trihydroxylated cy-
clohexanone or cyclohexenone cores. Analysis of the dif-
ferent stategies used to prepare these natural products and
their stereoisomers has been carried out with special atten-
Introduction
Gabosines are a family of secondary metabolites isolated
from various Streptomyces strains. The first compounds –
KD16-U1 (identical to gabosine C)[1a]
and COTC[1b]
– were
[a] Université de Rennes 1, Institut des Sciences Chimiques de
Rennes CNRS UMR 6226,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
Fax: +33-2-23236978
E-mail: rene.gree@univ-rennes1.fr
[b] Hanoi University of Sciences, Medicinal Chemistry Laboratory,
19 Le Thanh Tong, Ha Noi, Viet Nam
[c] Indian Institute of Chemical Technology, Division of Natural
Products Chemistry,
Hyderabad 500607, India
Dinh Hung Mac born in Hai Phong, Viet Nam, in 1982, graduated (BSc degree in Chemistry) at the Hanoi University of
Science, VNU, Viet Nam in 2004 and obtained his Master’s degree in Molecular Chemistry at the Université du Maine,
France in 2006. He did his doctoral studies on the tandem isomerisation/aldolisation of allylic alcohol in the presence of
pentacarbonyliron as catalyst under the supervision of Dr René Grée at the University of Rennes 1 (2006–2009). After
postdoctoral work at the University of Paris-Sud in 2010 in the group of Prof Jean-Daniel Brion, he came back to HUS
as lecturer in Medicinal Chemistry, faculty of Chemistry.
Srivari Chandrasekhar was born in 1964 in Hyderabad, India. He underwent all his primary education in Hyderabad. After
obtaining his PhD under the supervision of Dr. A. V. Ramarao at IICT, he moved to the University of Texas Southwestern
Medical School for postdoctoral study with Prof. J. R. Falck and then to the University of Göttingen, Germany as Alexander
von Humboldt fellow in the group of Prof. L. F. Tietze. His research interests include total synthesis of marine natural
products, new solvent media for organic synthesis and process development of APIs. He is a recipient of the NASI-Reliance
Platinum Jubilee award and Ranbaxy Research award and a Fellow of the Indian Academy of Sciences.
René Grée graduated from ENSCR in 1970, and after a PhD with Prof. R. Carrié at the University of Rennes, he moved
to Ohio State University for postdoctoral study with Prof. L. A. Paquette. He holds a position as Directeur de Recherche
Classe Exceptionelle CNRS. The major research interests of his group are organometallic catalysis and asymmetric synthe-
sis, fluorine chemistry, chemistry in and with ionic liquids and total synthesis of bioactive natural products and structural
analogues for applications in medicinal chemistry. He won the award of the Organic Chemistry Division of the French
Chemical Society in 1985, and from 1990 to 2002 he also held a part-time professor position at the Ecole Polytechnique
(Paris).
Eur. J. Org. Chem. 2012, 5881–5895 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5881
tion paid to the methods employed for the formation of the
carbocyclic ring. The different methods are compared in a
table, and a discussion of future directions of research in this
area is presented.
isolated by Umezawa’s group in the early 1970s. Gabosine B
was isolated about ten years later from Actinomycetes
strains.[1c]
Since then, extensive studies have been performed
by Thiericke, Zeeck and co-workers, starting from 1993,[2]
and to date 15 gabosine derivatives have been characterised;
their structures are given in Figure 1. These natural prod-
ucts can be classified into the family of carbasugars.[3]
These base-sensitive ketocarbasugars each contain a tri-
hydroxylated cyclohexanone or cyclohexenone core with a
methyl or hydroxymethyl substituent. Their structural di-
versity is due to variations of relative and absolute configu-
ration at their two to four asymmetric centres and/or the

D. H. Mac, S. Chandrasekhar, R. Grée
MICROREVIEW
nature of substituents on the carbon chain (Me, CH2OH or
substituted hydroxymethyl).
Figure 1. Gabosine family of secondary metabolites.
The stereochemical configurations of natural gabosines,
including their absolute configurations, were first estab-
lished mainly on the basis of spectroscopic methods for ga-
bosines A,[2]
B,[1c]
C,[1]
D,[2]
E,[2]
F,[2]
G,[2]
H,[2]
I,[2,4]
J,[2]
K,[2]
L,[5]
N,[5]
and O.[5]
These assignments were confirmed
later by total syntheses except in the case of gabosine K, in
which a first synthesis indicated that the originally assigned
structure needed to be corrected,[6]
which was achieved
through a new total synthesis.[7]
On the other hand, gabos-
ine I was found to be identical to valienone, an intermediate
in the biosynthesis of validamycin A.[8]
Interestingly, gabosine-type metabolites have been de-
tected in a large number of Streptomycetes strains. Their
biosynthesis has been studied in detail by Thiericke, Zeeck
and co-workers.[9]
Although their structures seem to be re-
lated to that of shikimic acid, they are obtained in a process
different from the shikimate pathway. These secondary me-
tabolites are formed by a pentose phosphate pathway
through cyclisation of heptulose phosphate intermediates.
Further, it is worthy of note that enantiomeric gabosines
can be obtained from different strains and that gabosine B
is the enantiomer of gabosine F.
Up to now, most of the gabosines have not shown very
significant biological activities. They have so far displayed
no antibacterial, antifungal, antiviral, herbicidal or insecti-
cidal properties but have exhibited weak antiprotozoal ac-
tivity, and gabosine E is also a weak inhibitor of de novo
cholesterol biosynthesis.[2]
Furthermore, gabosines A, B, F,
N and O, but not gabosines E, H and J, exhibit weak DNA-
binding properties.[10]
Plant growth regulating effects[11]
and
inhibition of glycosidases[12]
have also been reported.
Gabosine C and its crotonyl ester (COTC) were envis-
aged as potential anticancer agents, because they exhibit
cytotoxic and cancerostatic activities with low toxicities.[13]
In this context COTC was established to be an inhibitor of
glyoxalase I, but only in the presence of reduced glutathi-
www.eurjoc.org © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 5881–5895
5882
one.[14]
Later, it was demonstrated that COTC acts as a pro-
drug and that the active inhibitor was the corresponding
glutathionyl-substituted derivative.[15]
The use of COTC to
reverse anticancer drug resistance has also been de-
scribed.[16]
It inhibits alkaline phosphodiesterase and DNA
polymerase α.[17]
It acts synergistically with aclarubicine as
an anticancer drug.[1b,13,17]
Several strategies for elegant total synthesis of gabosines
have been designed. The most obvious way to access these
carbasugars is to start from carbohydrates. This so-called
“sugars-to-carbasugars” strategy has been the most com-
monly used approach and is therefore presented first. The
emphasis here is on the key reaction(s) employed to build
the carbocycle. In the second part, use of other molecules
from the chiral pool – essentially quinic and tartaric acids –
is discussed. Asymmetric syntheses from non-natural chiral
starting materials are then reviewed, followed by very inter-
esting examples of chemoenzymatic approaches. Finally, a
table reporting all syntheses of gabosines and their stereo-
isomers is presented and used for analysis of these synthetic
efforts as well as possible directions for future research.
Total Synthesis of Gabosines Starting from Carbohydrates
Intramolecular 1,2-addition to a carbonyl group, in an
acyclic system, is the first possibility for building the carbo-
cycle. This strategy was used by Lubineau and Billaut for
the synthesis of gabosine I (Scheme 1).[4]
Intermediate 1 was
easily prepared in five steps and 67% yield from d-glucose.
Scheme 1. Synthesis of gabosine I with an intramolecular Nozaki–
Kishi reaction as key step. (a) PCC, AcONa, MS (4 Å), CH2Cl2,
90%; (b) Ph3PCHBr, THF, 74%; (c) (i) TBAF, THF, 80%,
(ii) Swern oxidation, 89%; (d) CrCl2, NiCl2 (0.1%), DMF, 61%;
(e) (i) PCC, AcONa, MS (4 Å), CH2Cl2, 76%, (ii) BCl3, CH2Cl2,
74%.
Oxidation to 2, followed by a Wittig reaction, gave the
(Z)-vinyl bromide 3 with high stereoselectivity. After
alcohol deprotection and oxidation, key aldehyde interme-
diate 4 was obtained. Although the cyclisation of the de-
rived organomagnesium reagent under Barbier’s conditions
failed, a Nozaki–Kishi reaction gave the desired cyclohex-
enols 5 as a 1:1 mixture of stereoisomers. Oxidation with
PCC/AcONa, followed by a final deprotection step with
BCl3, afforded gabosine I in 12 steps and 10.8% overall
yield from d-glucose.
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A second useful strategy for the preparation of such cy-
clohexenones is intramolecular aldolisation followed by de-
hydration. A first example was described by Corsaro et al.
in the synthesis of 2-epi-3-epigabosine B and di-O-benzyl-
protected ent-gabosine A (Scheme 2).[18]
Scheme 2. Synthesis of di-OBn-ent-gabosine A and 2-epi-3-epiga-
bosine B with use of an intramolecular aldol reaction as key step.
(a) CH2I2, Et2Zn, Et2O, quantitative; (b) Hg(OCOCF3)2, anhy-
drous MeOH, room temp., then NaCl/H2O, 98%; (c) NaBH4, THF,
room temp., 71% from 6; (d) CF3CO2H, CH3CN/H2O, room
temp., 20% (9) and 65% (10); (e) Pd/C, H2, MeOH, 92%.
The starting sugar derivative 6 was prepared in two steps
and 26% yield from d-galactose. The first key point in this
strategy was the introduction of the methyl group necessary
for gabosines. This was done in two steps. Firstly, cyclo-
propanation was performed on 6 to afford 7 in high yield
and with excellent stereocontrol. Mercury-mediated ring
opening, followed by reductive demercuration with NaBH4
then gave intermediate 8. Hydrolysis to the bis(carbonyl)
intermediate, followed by the key intramolecular aldol and
dehydration reactions, gave a mixture of di-O-benzyl-ent-
gabosine A (9) and its diastereoisomer 10, which were sepa-
rated by chromatography. Stereoselective hydrogenation of
10 afforded 2-epi-3-epigabosine B (11, 11% overall yield in
seven steps from d-galactose).
Other examples of intramolecular aldol condensations
for the synthesis of ent-gabosine A and of gabosines D and
E were reported by Shing’s group.[19]
These derivatives have
the same trihydroxycyclohexenone framework and so could
be obtained from the same sugar, d-glucose (Scheme 3). Di-
ketone 12, prepared in six steps and 37% yield, was sub-
jected to the key l-proline-mediated intramolecular aldol
reaction, followed by dehydration to afford the first impor-
tant intermediate: enone 13. With such a mixed acetal as
protective group, this molecule seems best suited for the
preparation of gabosines with allylic CH2OH (R) groups,
but it can also be used for molecules with methyl groups in
those positions.
Stereoselective reduction of 13 with K-selectride, fol-
lowed by alcohol protection to afford 14 and removal of
the isopropylidene protective group, gave the second key
intermediate 15. Simple functional-group transformations
then afforded the target molecules. Mesylation of the pri-
mary alcohol and subsequent reduction gave derivative 16
with the required allylic methyl group. Oxidation followed
by deprotections gave ent-gabosine A (15 steps and 14.4%
overall yield from d-glucose).
Eur. J. Org. Chem. 2012, 5881–5895 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 5883
Scheme 3. Synthesis of ent-gabosine A and of gabosines D and E
through the use of an intramolecular aldolisation reaction as key
step. (a) (i) l-Proline, DMSO, 82%, (ii) POCl3, pyridine, 99%;
(b) (i) K-Selectride, THF, –78 °C, 99%, (ii) TBSCl, imidazole,
DMF, 95%; (c) AcOH (80%), 88%; (d) (i) MsCl, 2,4,6-collidine,
CH2Cl2, –78 °C, (ii) LiEt3BH, THF, –78 °C, 84% for two steps;
(e) (i) PDC, MS (3 Å), CH2Cl2, 92%, (ii) TFA, H2O, CH2Cl2, 90%;
(f) TBSCl, imidazole, CH2Cl2, 97%; (g) (i) PDC, MS (3 Å),
CH2Cl2, 100%, (ii) TFA, H2O, CH2Cl2, 87%; (h) AcCl, 2,4,6-colli-
dine, CH2Cl2, –78 °C, 94%; (i) (i) PDC, MS (3 Å), CH2Cl2, 91%,
(ii) TFA, H2O, CH2Cl2, 89%.
On the other hand, gabosine D was obtained from 15
after three steps: acetylation, oxidation and deprotections
(14 steps and 15.8% overall yield from d-glucose). Similarly,
gabosine E was prepared in three further steps from 15
and obtained in 14 steps and 17.5% overall yield from
d-glucose.
The synthesis of gabosine K, a diastereoisomer of gabos-
ine D, was performed by starting from the same intermedi-
ate 13 (Scheme 4).[7]
Reduction of 13, under Luche condi-
tions gave (after alcohol protection) silyl ether 19. The same
reactions as described above then afforded gabosine K in 15
steps and 13.5% overall yield from d-glucose.
Scheme 4. Synthesis of gabosine K through the use of an intramo-
lecular aldolisation reaction as key step. (a) (i) NaBH4, MeOH,
CeCl3·7H2O, (ii) Ac2O, DMAP, Et3N, CH2Cl2, (iii) K2CO3,
MeOH, (iv) TBSCl, imidazole, CH2Cl2, 81% for four steps;
(b) AcOH (80%), 84%, (c) (i) AcCl, 2,4,6-collidine, CH2Cl2,
–30 °C, (ii) TFA, H2O, CH2Cl2, 79% for two steps.
Another fruitful alternative for the preparation of desired
cyclohexenones is the intramolecular Horner–Wadsworth–
Emmons (HWE) reaction, developed mainly by Shing’s
group. Their starting material was δ-d-gluconolactone (21,
Scheme 5), an industrial product obtained from d-glucose
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MICROREVIEW
by bio-oxidation. Different protective groups were used for
the alcohol functions. Firstly, the synthesis of gabosines G
and I was described.[20]
Lactone 22, obtained by treatment
of 21 with 2-methoxypropene, was first treated with the lith-
ium derivative of diethyl methylphosphonate to afford 23.
A one-pot oxidation/cyclisation sequence gave the desired
enone 24 in 43% yield, after optimisation of conditions for
this key reaction. Deprotection afforded gabosine I (four
steps, 20.3%), and regioselective acetylation gave gabos-
ine G (five steps, 13.2%) from d-glucolactone.
Scheme 5. Synthesis of gabosines G and I through the use of an
intramolecular HWE reaction as key step. (a) 2-methoxypropene,
CSA, DMF, 72%; (b) (i) LDA, THF, (EtO)2POCH3, (ii) H3O+
,
78% for two steps; (c) TPAP, NMO, MS (3 Å), CH3CN, K2CO3,
43%; (d) TFA, H2O, CH2Cl2, 95%; (e) AcCl, collidine, –40 °C to
room temp., 65%.
Gabosine I and gabosine K were prepared by same strat-
egy but with different protection – the EOM group – on
the gluconolactone (Scheme 6).[21]
Scheme 6. Synthesis of gabosines I and K through the use of an
intramolecular HWE reaction as key step. (a) EOMCl, 2,6-lutidine,
93%; (b) (MeO)2POCH2Li, THF, –78 °C, 15 min, 95%; (c) NaBH4,
MeOH, 96%; (d) (i) TFAA, DMSO, CH2Cl2, –78 °C, (ii) Et3N,
–78 °C to room temp., 80% for two steps; (e) TFA, H2O, room
temp., 5 min, 96%; (f) NaBH4, MeOH, CeCl3·7H2O, 82%;
(g) (i) TFA, H2O, 89%, (ii) AcCl, 2,4,6-collidine, CH2Cl2, –30 °C,
80%.
Addition of phosphonate anion to 25 afforded 26 in ex-
cellent yield. A two-step reduction/oxidation protocol was
found to afford ketophosphonate 27 in best yields. The
5884
HWE reaction gave enone 28 and, after deprotection, ga-
bosine I in a higher yield (five steps and 65% overall yield
from d-glucose) than in the previous synthesis. On the other
hand, reduction of 28 under Luche’s conditions gave 29
with a high stereoselectivity (82:9). Subsequent deprotec-
tion, followed by selective acetylation, gave gabosine K in
seven steps and 40% overall yield from δ-d-gluconolactone
21.
A third variant, with a combination of protective groups,
was proposed by the same group and used for another syn-
thesis of gabosine I, as shown in Scheme 7.[22]
A mixed
acetal was employed to protect the OH groups in the 2- and
the 3-positions in glucose, together with an EOM group to
protect that in the 4-position. Intermediate 30 and lactone
31 were obtained from d-glucose through selective protec-
tion steps. The same sequence of reactions as described
above was then used to prepare hydroxyphosphonates 32
and 33. The same key one-pot oxidation/HWE reaction
procedure was used to obtain enone 34, and a final depro-
tection step afforded gabosine I in 10 steps and 27% overall
yield from d-glucose.
Scheme 7. Alternative synthesis of gabosine I through the use of an
intramolecular HWE reaction as key step. (a) (i) EOMCl, DIPEA,
CH2Cl2, r.t., 16 h, 99%, (ii) H2, Pd/C, EtOH, r.t., 12 h, 94%,
(iii) PDC, MS (3 Å), CH2Cl2, 6 h, room temp., 92%; (b) LDA,
THF, CH3PO(OMe)2 –78 °C, 15 min, 96%; (c) NaBH4, MeOH,
0 °C, r.t., 15 min, 96%; (d) (i) TFAA, DMSO, CH2Cl2, –78 °C, 5 h,
(ii) DIPEA, –78 °C, 15 min, (iii) TEA, LiCl, r.t., 15 min, 78% for
three steps; (e) TFA, H2O, r.t., 5 min, 96%.
A synthesis of gabosine C and COTC by Vasella’s group
was also based on an intramolecular HWE reaction to build
the carbocycle (Scheme 8).[23]
Scheme 8. Synthesis of gabosine C and COTC through the use of
an intramolecular HWE reaction as key step. (a) (i) PDC, MS
(3 Å), CH2Cl2, (ii) Et3N, CH2Cl2, (iii) NaBH4, iPrOH, (iv) O3,
–78 °C, CH2Cl2; (b) TBSCl, DMF, imidazole, 72% from 35;
(c) CH3PO(OMe)2, nBuLi, THF, –78 °C, 62%; (d) Me3Al, HSPh,
CH2Cl2, –78 °C, then HCHOgas bubbled through mixture at
–50 °C, NH4Claq, 66% of a mixture of diastereoisomers, (e) m-
CPBA, CH2Cl2, 0 °C, 91%; (f) TFA (60%), 100%; (g) crotonic
acid, BF3·Et2O, MS (4 Å), CH3CN, 48%.
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Benzoate 35 was obtained in three steps and 78% yield
from d-mannose. It was converted into 36 by treatment
with Et3N to perform β-elimination and subsequent re-
duction with NaBH4 and ozonolysis. Protection afforded
silyl ether 37 in 72% yield from 35 without isolation of un-
stable intermediates. The first key step was treatment with
the anion of dimethyl methylphosphonate to give cyclohex-
enone 38 directly. The second key step, the introduction of
the CH2OH chain, was then carried out by treatment with
Me2AlSPh, followed by trapping with formaldehyde to give
39. The corresponding sulfoxide underwent β-elimination
to afford 40. Deprotection afforded gabosine C (21% over-
all yield in 11 steps from d-mannose), and COTC was then
obtained by esterification with crotonic acid.
Ring closing metathesis (RCM) is another very fruitful
strategy for accessing carbocycles. It has been successfully
used to prepare some gabosines, starting from different
sugars. The first examples were described by Rao’s group,
in preparations of gabosine C, ent-gabosine N and ent-ga-
bosine O with use of d-ribose as starting material (Scheme 9
and Scheme 10, below).
a ring closing metathesis reaction as key step. (a) Vinylmagnesium
bromide, THF, –78 °C to 0 °C, 2 h, 70%; (b) (i) Piv-Cl, 2,6-lutidine,
DMAP, CH2Cl2, 0 °C to room temp., 12 h, 74%, (ii) MOMCl,
DIPEA, TBAI, CH2Cl2, 0 °C to room temp., 24 h, 83%,
(iii) NaOMe, MeOH, 0 °C to room temp., 5 h, 75%; (c) (i) Swern
oxidation, (ii) A, CrCl2, NiCl2, DMF, room temp., 24 h, 84% for
two steps; (d) second-generation Grubbs catalyst (10 mol-%),
CH2Cl2, 80 °C, 48 h, 56%; (e) PDC, CH2Cl2, 0 °C to room temp.,
24 h, 78%; (f) Amberlyst®
15, THF/H2O (2:1), 70 °C, 5 h, 50%.
Lactol 41, easily obtained in three steps and 74% yield
from d-ribose, gave diol 42 after treatment with a vinyl
Grignard reagent. After protection and deprotection steps,
followed by oxidation, a Nozaki–Kishi reaction was per-
formed on the intermediate aldehyde to give diene 44. The
key RCM reaction, in the presence of the second-generation
Grubbs catalyst, afforded cyclohexenone 45 in 86% yield.
Oxidation to 46, followed by deprotection reactions, af-
forded gabosine C in 12 steps and 4.4% overall yield from
d-ribose.[24]
ent-Gabosine N and ent-gabosine O were prepared by a
similar strategy, as indicated in Scheme 10.[25]
Protected lactol 47 was easily prepared in two steps from
d-ribose (61% yield). A Wittig reaction gave 48, and in
three classical steps intermediate aldehyde 49 was obtained.
Scheme 10. Synthesis of ent-gabosines N and O through the use of
a ring closing metathesis reaction as key step. (a) (i) Ph3P=CH2,
THF, –78 °C to room temp., 4 h, (ii) MOMCl, DIPEA, DMAP
(cat.), CH2Cl2, –15 °C to room temp., 12 h, 71% for two steps;
(b) (i) TBAF, THF, 4 h, 95%, (ii) Swern oxidation; (c) 2-bromopro-
pene, CrCl2, NiCl2, 12 h, 72%; (d) second-generation Grubbs cata-
lyst, toluene, reflux, 12 h, 85%; (e) PDC, CH2Cl2, MS (4 Å), 12 h,
82%; (f) Amberlyst®
15, THF/H2O (2:1), 70 °C, 5 h, 75%; (g) H2,
Pd/C, MeOH, 1 h, 95%; (h) Amberlyst®
15, THF/H2O (2:1), 70 °C,
5 h, 85%.
This was submitted to a Nozaki–Kishi reaction to afford
allylic alcohols 50 (3.8:1 mixture of stereoisomers). Under
the same conditions as above, the key RCM reaction
yielded cyclohexenols 51 in 85% yield. Oxidation to 52, fol-
lowed by deprotection, afforded ent-gabosine N in 10 steps
and 18.2% overall yield from d-ribose. On the other hand,
hydrogenation of 52 was fully stereoselective (reaction oc-
curring from the face anti to the bulky protecting groups),
affording 53 and, after deprotection, ent-gabosine O (11
steps and 19.5% overall yield from d-ribose).
RCM was also employed by Madsen’s group for the syn-
thesis of gabosines A and N (Scheme 11).[26]
Iodo derivative
54 was prepared from d-ribose in two steps and 78% yield.
On treatment of 54 with zinc, an interesting tandem reac-
tion occurred, affording an intermediate aldehyde, which
was trapped by an allylmetal reagent derived from 55. This
sequence afforded a 2:1 mixture of alcohol 56 and its dia-
stereoisomers, which were separated by chromatography.
The sequence was continued with 56. RCM in the pres-
ence of the second-generation Grubbs catalyst afforded 57
in excellent yield, and two protection/deprotection steps
yielded 58. Oxidation, followed by a final deprotection,
gave gabosine N (eight steps and 17.1% yield from d-ri-
bose). On the other hand, inversion of the configuration in
57 was performed on the free alcohol, and the same reac-
tion sequence afforded gabosine A in nine steps and 18.5%
overall yield from d-ribose.
Ferrier carbocyclisation (also known as Ferrier II re-
arrangement) is a widely used method for transformation
of pyranoses into six-membered carbocycles. It was used by
Shaw’s group to prepare four examples of gabosines
(Scheme 12 and Scheme 13, below).[27]
Iodo derivative 61,
obtained from d-glucose in four steps and 62% yield, was
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MICROREVIEW
Scheme 11. Synthesis of gabosines A and N through the use of a
ring closing metathesis reaction as key step. (a) Zn, THF, H2O,
40 °C, sonication 58%; (b) second-generation Grubbs catalyst,
CH2Cl2, 40 °C, 97%; (c) (i) DHP, PPTS, CH2Cl2, room temp. 75%,
(ii) NaOMe, MeOH, room temp., 83%; (d) PDC, CH2Cl2, room
temp., 71%; (e) AcOH, H2O, room temp. to 40 °C, 88%;
(f) (i) Tf2O, pyridine, CH2Cl2, –20 °C to room temp., then NaNO2,
DMF, room temp., (ii) DHP, PPTS, CH2Cl2, room temp. 85%;
(g) (i) NaOMe, MeOH, room temp., (ii) PDC, CH2Cl2, room temp.,
(iii) AcOH, H2O, 40 °C, 40% for three steps.
subjected to dehydrohalogenation followed by protection of
the free hydroxy group to afford exopyranoside 62. This
intermediate was ready for the key Ferrier carbocyclisation
in the presence of mercury(II) trifluoroacetate, followed by
mesylation to afford enone 63 in 70% yield. To introduce
the required methyl group on the double bond, a two-step
sequence was then employed: iodination to 64, followed by
a Stille cross-coupling reaction with Me4Sn to give 65. A
final deprotection step gave 4-epigabosine A in 11 steps and
12.9% yield from d-glucose. The same sequence of reac-
Scheme 12. Synthesis of gabosine A and 4-epigabosine A through
the use of a Ferrier carbocyclisation reaction as key step.
(a) (i) tBuOK, THF, 0 °C to room temp., 24 h, (ii) BnBr, NaH,
DMF, 0 °C to room temp., 2 h, 64% for two steps; (b) (i) Hg(OC-
OCF3)2, (CH3)2CO/H2O (1:1), 8 h, (ii) MsCl, CH2Cl2, Et3N, 0 °C
to room temp., 2 h, 70% for two steps; (c) I2, DMAP, CCl4/pyridine
(1:1), 0 °C to room temp., 2 h, 90%; (d) Me4Sn, AsPh3, Pd2(dba)3,
CuI, sealed tube, THF, 80 °C, 36 h, 72%; (e) BCl3, CH2Cl2, 0 °C,
4 h, 64%.
5886
tions was followed starting from d-mannose, affording ga-
bosine A in 11 steps and 10.8% overall yield.
A similar approach was followed for the synthesis of two
other derivatives, 2-epi-3-epigabosine E and ent-gabosine E.
In that case, however, a CH2OH group had to be intro-
duced on the double bond, and the authors considered the
possible use of a Morita–Baylis–Hillman reaction
(Scheme 13). However, this reaction did not work when
starting from the above benzyl-protected intermediate 63,
affording only an aromatised product, so a change to an
acetate-protected derivative was considered. Enone 69, pre-
pared by same route as described above, reacted with form-
aldehyde in the presence of DMAP to give the desired ad-
duct 70. After deprotection steps, 2-epi-3-epigabosine E was
obtained in 11 steps and 6.4% overall yield from glucose.
Similar reactions gave ent-gabosine E in 11 steps and 6.5%
overall yield from d-mannose.
Scheme 13. Synthesis of ent-gabosine E and 2-epi-3-epigabosine E
through the use of a Ferrier carbocyclisation reaction as key step.
(a) (i) tBuOK, THF, 24 h, 0 °C to room temp., (ii) Ac2O, pyridine,
0 °C, 5 h, 64%; (b) (i) Hg(OCOCF3)2, (CH3)2CO/H2O (1:1), 8 h,
(ii) MsCl, CH2Cl2, Et3N, 0 °C to room temp., 2 h, 72% for
two steps, (c) HCHO, DMAP, THF, –10 °C, 2 d, 49%;
(d) (i) pTsOH·H2O, CH2Cl2/MeOH (9:1), (ii) BCl3, CH2Cl2, 0 °C,
4 h, 46% for two steps.
A new iron-catalysed reaction, complementary to the
Ferrier carbocyclisation, was developed by us to prepare six
gabosine derivatives.[28,29]
It was first demonstrated by the
synthesis of 4-epigabosine A and 4-epigabosine B, starting
from d-glucose (Scheme 14). Vinylic pyranoside 73 was pre-
pared from glucose by known reactions in six steps and
26% overall yield. The key carbonyliron-catalysed tandem
isomerisation/aldolisation sequence produced aldols 74, as
a mixture of stereoisomers, in 95% yield. Treatment of this
mixture with MsCl and Et3N gave enone 75. One of the
interesting aspects of this approach is that it directly intro-
duces the required methyl group in the appropriate position
on the carbocycle.
Deprotection of 75 afforded 4-epigabosine A, whereas
hydrogenation gave 76 and then 4-epigabosine B. These two
target molecules were obtained in nine and ten steps and
9.4% and 14.5% overall yields, respectively, from d-glu-
cose.[28]
Similar reactions were performed from mannose to
afford gabosine A and 6-epigabosine O in nine steps and in
5.7% and 6.9% overall yields, respectively, from d-mannose.
4-Epigabosine N and 4-epi-6-epigabosine B were similarly
prepared in nine steps and 8.8% and 5.5% overall yields,
respectively, from d-galactose.[29]
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Scheme 14. Synthesis of six gabosine derivatives through the use of
an iron-catalysed carbocyclisation reaction as key step. (a) Fe(CO)5
(10 mol-%), THF, hν, 1 h, 95%; (b) MsCl, Et3N, CH2Cl2; (c) FeCl3,
CH2Cl2, 0 °C, 15 min; (d) H2, Pd/C, EtOH, 3 h; (e) H2, Pd/C,
EtOH, 3 d.
Another aldol-like condensation was used for the prepa-
ration of gabosine C and COTC (Scheme 15).[30]
a SnCl4-mediated aldol-like cyclisation as key step. (a) (i) TBSOTf,
2,6-lutidine, (ii) H2, Pd/C, (iii) DCC Py·TFA, DMSO/Et2O,
(iv) HC(OMe)3, CSA/MeOH, 64% for four steps; (b) MeSO3Ph,
nBuLi/THF, 90%; (c) TBSOTf, 2,6-lutidine, 74%; (d) SnCl4,
CH2Cl2, 85%; (e) (i) Bu3SnLi, THF then HCHOgas bubbling
through mixture, (ii) SiO2/PhH, 70% for two steps; (f) 90% TFA,
86%; (g) crotonic acid, BF3·Et2O, MeCN, 71%.
The trityl-protected lactone 77, easily obtained from d-
ribose in two steps and 81% yield, was transformed in a few
classical steps [bis(silylation), deprotection of the primary
alcohol followed by oxidation and acetal formation] into
intermediate 78. Addition of lithiated methyl sulfone af-
forded 79, which, after silylation, gave the labile silyl enol
ether 80. In the key step, an SnCl4-induced aldol-like cycli-
sation yielded cyclohexenone 81. The sulfonyl group was
used again to solve the second problem, the introduction of
the CH2OH group. Treatment with (tributylstannyl)lithium,
followed by trapping with formaldehyde, afforded (after
treatment with silica gel) the protected gabosine derivative
82. Deprotection gave gabosine C in 11 steps and 19.8%
overall yield from ribose.
The use of intramolecular 1,3-dipolar cycloadditions was
another very attractive strategy to access gabosines. Three
syntheses have been reported; the first two used nitrile ox-
ides as 1,3-dipoles, whereas the last employed nitrones. The
first involved the preparation of ent-gabosine C and gabos-
ine E from d-ribose (Scheme 16).[31]
Scheme 16. Synthesis of ent-gabosine C and gabosine E through
the use of an intramolecular nitrile oxide cycloaddition reaction as
key step. (a) Vinylmagnesium bromide (10 equiv.), THF, room
temp., 90%; (b) (i) TBSCl, pyridine, DMAP, (ii) BzCl, pyridine,
(c) (i) 2,3-dihydrofuran, PPTS, CH2Cl2, (ii) TBAF, THF, room
temp., (iii) Swern oxidation, (iv) HCl·H2NOH, pyridine, MeOH,
room temp., 59% from 84; (d) NaOCl, Et3N, CH2Cl2, 60%; (e) H2,
Raney-Ni, EtOH, AcOH, 89%; (f) DABCO, THF, 80% (mixture
2:1 of 89/90); (g) TFA, CH2Cl2 (95% from 89, 100% from 90).
Lactol 83 was prepared from d-ribose in one step and
70% yield. Treatment with vinyl Grignard reagent gave all-
ylic alcohol 84. Selective protections of the three alcohols
(TBS, benzoate and tetrahydrofuranyl) gave the key inter-
mediate 85. In particular, the benzoate protection in the
allylic position proved to be important for the success of
the next steps. From oxime 86, the key intramolecular ni-
trile oxide cycloaddition (INOC) gave isoxazoline 87 in
60% yield. Hydrogenolysis then afforded ketone 88 in 89%
yield. The next step, elimination of benzoic acid, was not
straightforward because of possible aromatisation, as well
as epimerisation reactions. A DABCO-mediated reaction
gave mixtures of 90 (formed first) and 89 with a 2:1 ratio
at equilibrium. After separation, treatment with trifluoro-
acetic acid yielded ent-gabosine C (12 steps and 10% overall
yield from d-ribose) and gabosine E (12 steps and 5.4%
overall yield from d-ribose), respectively.
A second example of the use of INOC reactions was de-
veloped by Shing’s group for the preparation of gabosine O
and 4-epigabosine O from d-mannose, as well as of gabos-
ine F from l-arabinose (Scheme 17 and Scheme 18, be-
low).[32]
The oxime 92 was easily prepared from d-mannose
in four steps and 60% yield. The key INOC reaction, medi-
ated by silica gel/chloramine, then afforded a mixture of
isoxazolines 93α (65%) and 93β (14%). Mitsunobu inver-
sion of configuration afforded alcohols 94α and 94β. Hy-
drogenolysis of 94α or 94β (or mixtures of both) with
Raney-nickel/acetic acid yielded the same 6:1 mixture of
95α/95β, due to equilibrium under the reaction conditions.
Water elimination could be performed with Martin’s sulf-
urane, under carefully controlled conditions, to give enone
96, which was hydrogenated from the less hindered face to
97. A final deprotection afforded 4-epigabosine O in 11
steps and 38% yield from d-mannose.
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MICROREVIEW
Scheme 17. Synthesis of 4-epigabosine O and gabosine O through
the use of an intramolecular nitrile oxide cycloaddition reaction as
key step. (a) (i) H5IO6, Et2O, room temp., 18 h, 79%, (ii) NH2OH,
MeOH, room temp., 2 d, 100%; (b) chloramine-T, silica gel, EtOH,
room temp., 15 min, 79%, α/β = 4.6:1; (c) (i) PPh3, DIAD, p-
NO2BzOH, room temp., 15 h; (ii) LiOH (aq), 98%; (d) H2, Raney-
Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 93%,
α/β = 6:1; (e) Martin’s sulfurane, THF, –78 °C, 10 min; (f) H2,
Raney-Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), –78 °C, 10 h,
88% from 95; (g) TFA, H2O, CH2Cl2, room temp., 5 min, 100%;
(h) H2, Raney-Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room
temp., 12 h, 97%, α/β = 5:1.
By the same series of reactions, gabosine O was prepared
from the 93α/93β mixture (nine steps, 41% overall yield
from d-mannose).
On the other hand, the same strategy was also followed
for the preparation of gabosine F (Scheme 18).
Scheme 18. Synthesis of gabosine F through the use of an intramo-
lecular nitrile oxide cycloaddition reaction as key step. (a) Chlor-
amine-T, silica gel, EtOH, room temp., 5 min, 94%; (b) H2, Raney-
Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 90%;
(c) AcCl, 2,4,6-collidine, CH2Cl2, –78 °C, 12 h, 87%; (d) Et3N,
CH2Cl2, reflux, 11 h; (e) H2, Raney-Ni, AcOH, EtOH/H2O/1,4-di-
oxane (8:2:1), room temp., 12 h, 97% from 102; (f) TFA, H2O,
CH2Cl2, room temp., 2 h, 100%.
The oxime 99 was prepared from l-arabinose by known
procedures in six steps and 34% yield. INOC afforded isox-
azoline 100 in 94% yield. Ring opening to give 101, fol-
lowed by regioselective acetylation to afford 102 and elimi-
nation, gave enone 103. Stereoselective hydrogenation,
possibly directed by the free OH group, followed by depro-
tection, afforded gabosine F in 12 steps and 23% overall
yield from l-arabinose.
An intramolecular nitrone cycloaddition as a key step for
the synthesis of ent-gabosine E from d-mannose was also
reported by the group of Gallos (Scheme 19).[33]
The vinylic
derivative 105 was prepared from methyl d-mannoside by
known procedures in six steps and 41.6% yield. Upon con-
5888
densation with methylhydroxylamine the intermediate
nitrone underwent the desired 1,3-dipolar cycloaddition to
afford isoxazolidine 106 plus its diastereoisomer at position
C2
in a 2:1 ratio. After separation by chromatography, the
N–O bond of 106 was cleaved by hydrogenolysis to afford
107, and the primary alcohol was selectively protected to
give 108. The final steps included quaternarisation of the
amine, followed by oxidative elimination and deprotection.
By this route, ent-gabosine E was obtained in 11 steps and
12% overall yield from d-mannose.
Scheme 19. Synthesis of ent-gabosine E through the use of an intra-
molecular nitrone cycloaddition reaction as key step.
(a) MeNHOH·HCl, EtONa, EtOH then 20 °C, 24 h, 80% (mixture
of isomers); (b) Zn, AcOH, reflux, 1 h; (c) TBSOTf, 2,6-lutidine,
CH2Cl2, –78 °C, 45 min, 77% from 106; (d) (i) MeI (excess),
K2CO3, THF, 24 h, (ii) DMP oxidation, CH2Cl2, 20 °C, 30 min,
80% for two steps; (e) BBr3, CH2Cl2, –78 °C, 45 min, 85%.
Total Synthesis of Gabosines Starting from Other Natural
Products
Several gabosines have been prepared from quinic acid,
whereas gabosine H has been obtained by starting from tar-
taric acid. In the first case, a large proportion of the gabos-
ine skeleton is already present in the starting material, but
functional modifications have to be performed selectively.
Ganem’s group has described the synthesis of gabosine C
and COTC (Scheme 20).[34]
Scheme 20. Synthesis of gabosine C and COTC starting from
quinic acid. (a) Tf2O (2.2 equiv.), pyridine, CH2Cl2, 65%;
(b) CsOAc, DMF; (c) (i) NBS/H2O, DMF, (ii) Dibal-H, benzene/
toluene, 47% from 112; (d) LiN(TMS)2, THF, –78 °C, 87%;
(e) MeSO3H, DMSO, room temp., 1.5 h, then Et3N, room temp.,
5 min, 71%; (f) TFA/H2O (1:1), 88%.
They started from acetonide 110, obtained in two steps
and 77% yield from quinic acid. On treatment with triflic
anhydride and base the intermediate bis(triflate) first spon-
taneously eliminated 1 mol-equiv. of triflic acid to give 111,
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followed on treatment with a second base with a second,
affording conjugated diene 112. The bromohydrin 113 was
obtained in a two-step sequence: formation of a bromo for-
mate by treatment with NBS in a mixture of DMF and
water, followed by reduction of ester groups with Dibal-
H. Cyclisation to epoxide 114 was performed under basic
conditions in good yield. The desired opening of this epox-
ide was not straightforward but could be achieved under
carefully controlled conditions (MeSO3H/DMSO and then
Et3N) to give 115. Deprotection gave gabosine C in nine
steps and 12.7% overall yield from quinic acid.
Other examples were reported later by Ohfune’s group
(Scheme 21).[35]
Scheme 21. Synthesis of gabosines A and B and of ent-gabosines D
and E starting from quinic acid. (a) (i) (EtO)3P, EtOH, reflux, 16 h,
98%, (ii) MOMCl (2 equiv.), iPr2NEt, CH2Cl2, 16 h, 90%: (b) SeO2
(1 equiv.), pyridine N-oxide (0.5 equiv.), 1,4-dioxane, reflux, 16 h,
54%; (c) Ac2O, DMSO (3:2), 18 h, 65%; (d) NaOH (0.1 n)/THF
(1:9), 40 min, 68%; (e) AcONa, AcOH, 110 °C, 2.5 h, 71%;
(f) TFA/H2O (1:20), CH2Cl2, 2–4 h, 59% from 120, 62% from 121;
(g) Pd/C (10%, 50% w/w), H2, MeOH, 6 h, 60%; (h) DMP
(1.2 equiv.), CH2Cl2, 67%; (i) NaOH (0.1 n), THF, 3 h, 81%;
(k) TFA/H2O (1:20), CH2Cl2, 0.5 h, 90%; (l) Pd/C (10%, 50% w/
w), H2, MeOH, 6 h, 80% (1:1 mixture of isomers); (m) DBU
(0.5 equiv.), benzene, reflux, 16 h, 89%.
The synthesis started from sulfoxide 116, prepared in
four steps and 40% overall yield from quinic acid. Thermol-
ysis in the presence of P(OEt)3 afforded the allylic alcohol
in excellent yield, and this was protected as the MOM ether
117. After allylic oxidation, the alcohols 118 were oxidised
to give the ketone 119. The next step, conjugate addition of
water, followed by β-elimination of the MOM group, could
be performed with NaOH solution (0.1 n) to afford 120 in
68% yield. On the other hand, addition of an acetoxy group
yielded 121. Final deprotection steps gave ent-gabosine E
and ent-gabosine D in 11 steps and 11.7% and 13.3% yields
respectively from quinic acid.
Ketone intermediate 119 was considered as a possible
precursor for gabosines A and B but all investigated meth-
ods for 1,4-addition of hydride were unsuccessful, so an al-
ternative strategy was used. Catalytic hydrogenation of 118
to afford 122 and subsequent oxidation gave 123 as a mix-
ture of stereoisomers. On treatment with NaOH, β-elimi-
nation occurred to give 124. Hydrogenation of 124 gave 125
in 80% yield but as a 1:1 mixture of α- and β-stereoisomers.
However, DBU-mediated epimerisation afforded the desired
molecule 125β. Final deprotection steps afforded the desired
gabosines A and B in 11 and 13 steps, respectively, in 8.3%
and 4.5% overall yields from quinic acid.
Another useful chiral pool molecule is tartaric acid, em-
ployed by Prasad’s group for a short synthesis of gabos-
ine H (Scheme 22).[36]
The bis(amide) 126 was obtained
from tartaric acid in two steps and 27% overall yield. A
first selective addition of a Grignard reagent gave the
monoketo monoamide 127 in good yield. Reduction under
Luche’s conditions gave the allylic alcohol 128 with good
stereocontrol (9:1), and the major isomer was isolated by
crystallisation.
Scheme 22. Synthesis of gabosine H starting from tartaric acid.
(a) CH2=CMeMgBr, THF, –15 °C, 0.5 h, 84%; (b) NaBH4, CeCl3,
MeOH, –78 °C, 1.5 h, 93% (dr = 9:1), 83% after recrystallisation;
(c) CH2=CHMgBr, THF, –15 °C, 0.5 h, 65%; (d) second-genera-
tion Grubbs catalyst (5 mol-%), CH2Cl2 (0.03 m), 50 °C, 6 h, 62%;
(e) PPTS, MeOH, r.t., 6 h, 92%.
Addition of a second Grignard reagent afforded the
ketone 129 in 65% yield. Ring closing metathesis in the
presence of the second-generation Grubbs catalyst gave the
desired cyclohexenone 130 in 62% yield. Final deprotection
gave gabosine H in seven steps and 7% overall yield from
tartaric acid.
A very recent synthesis of three gabosine derivatives by
Krishna’s group started from 2,3-O-isopropylidene-l-thre-
itol (131, Scheme 23), available from different sources, in-
cluding from tartaric acid (two steps and 82% yield).[37]
Se-
lective protection gave 132, which upon oxidation, followed
by a Morita–Baylis–Hilman reaction under optimised con-
ditions, afforded 133 as an inseparable mixture of stereoiso-
mers.
Reduction of the ester to afford alcohol 134, followed by
acetonide formation, gave 135. Deprotection of the primary
alcohol afforded isomers 136 and 137, which were separated
by chromatography.
The next reactions were performed independently on
each stereoisomer. Firstly, from minor isomer 137, oxi-
dation of the primary alcohol and subsequent addition of
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MICROREVIEW
Scheme 23. Synthesis of gabosines I and G and of 4-epigabosine I
starting from tartaric acid. (a) TBDPSCl, imidazole, CH2Cl2, 79%;
(b) (i) Swern oxidation, 96%, (ii) ethyl acrylate, DABCO, DMSO,
85% (30% de); (c) Dibal-H, CH2Cl2, –20 °C, 91%; (d) 2,2-DMP,
PTSA, CH2Cl2, 0 °C, 94%; (e) TBAF, THF, room temp. (57.8%
for 136 and 31.2% for 137); (f) (i) Swern oxidation, (ii) vinylMgBr,
–20 °C, 87% for two steps; (i) second-generation Grubbs catalyst,
toluene, reflux, 5 h, 83%; (k) DMP oxidation, CH2Cl2, 0 °C, 96%;
(l) TFA, CH2Cl2, 0 °C, 2 h.
vinyl Grignard reagent gave 138, as a mixture of isomers,
but that was of no consequence, because the corresponding
alcohol was to be oxidised later. A ring closing metathesis
was then performed, yielding 139 and, after oxidation, the
desired enone 140. Final deprotection gave gabosine I in 11
steps and 11.8% yield from 131. Gabosine G was also pre-
pared from gabosine I, by literature procedures.
The same sequence of reactions starting from dia-
stereoisomer 136 was followed, affording 4-epigabosine I in
11 steps and 21.8% yield from 131.
Total Synthesis of Gabosines Starting from Non-Natural
Products
Several gabosines have also been prepared by starting
from non-natural products. The first two examples used bi-
cyclic systems obtained through Diels–Alder cycloaddition
reactions. The first, shown in Scheme 24, was described by
Mehta’s group.[6]
It started from bicyclic derivative 144, obtained in five
steps and 60% overall yield from 1,2,3,4-tetrachloro-5,5-di-
methoxycyclopentadiene. A key Grob-type fragmentation
furnished the cyclohexene 145, which was transformed into
146 by a four-step sequence (dihydroxylation followed by
protection as acetonide, reduction of the ester and tosyl-
ation). Elimination via the corresponding iodide gave the
key intermediate alkene 147. Rhodium trichloride mediated
isomerisation of the double bond then gave cyclohexene
148, which on hydrolysis afforded gabosine F, in racemic
5890
Scheme 24. Synthesis of gabosine F and 1-epi-4-epigabosine K
starting from 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene.
(a) MeONa, MeOH, 3 h, 70°%; (b) (i) LAH, THF, 0 °C, 90%,
(ii) TsCl, pyridine, CH2Cl2, 94%; (c) NaI, acetone, Δ, 30 h, 92%,
(ii) tBuOK, Δ, 20 h, 70%; (d) RhCl3, NaHCO3, EtOH, Δ, 20 h,
60%; (e) HCl (5%), H2O/Et2O (4:1), room temp., 90%; (f) OsO4,
NMO, acetone/H2O (4:1), room temp., 2 d, 95%; (g) Ac2O, DMAP,
0 °C, 30 min, SOCl2, pyridine, CH2Cl2, room temp., 6 h, 45% (mix-
ture of isomers); (h) Amberlyst®
15, THF/H2O (2:3), room temp.,
48 h, 85% from 150.
form. The stereoselectivity of the protonation step in this
reaction is remarkable.
On the other hand, dihydroxylation of 147 gave diol 149
in a 70:30 ratio with its diastereoisomer. After separation
by chromatography, 149 was subjected to selective acetyl-
ation of the primary alcohol, followed by dehydration, to
yield a mixture of alkenes 150 and 151 in a 2:1 ratio. Acet-
onide deprotection, under controlled conditions, then af-
forded a compound with spectral properties that did not
match those of the natural product. These results led to
revision of the structure of gabosine K; the compound ob-
tained in this synthesis was (⫾)-1-epi-4-epigabosine K.
These syntheses were later extended to optically active
derivatives,[38a]
because very efficient resolution processes
(⬎48% yield for each enantiomer) to obtain the starting
Diels–Alder adducts in optically active form have been de-
scribed.[38b]
The second example, by Koizumi’s group, used chiral
sulfinylacrylate 152 (Scheme 25) as a dienophile.[39]
This optically active alkene 152 was prepared in four
steps and 14% overall yield from (+)-camphor. The first
key step was a high-pressure Diels–Alder reaction, at
1.2 GPa. It was stereoselective with regard to the sulfur ste-
reocentre, with additions on the face anti to the bulky R
group, but gave a 71:29 mixture of endo isomer 153 and the
corresponding exo derivative. After dihydroxylation of the
mixture, diol 154, now containing a sulfonyl group, was iso-
lated in 53% overall yield from 152. Acetonide formation
to provide 155 was followed by reduction to alcohol 156.
Treatment with aqueous trifluoroacetic acid then directly
afforded gabosine C by removal of the acetonide, opening
of the bicyclic system and hydrolysis to the keto group. On
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Scheme 25. Synthesis of gabosine C and COTC starting from a chi-
ral sulfinylacrylate. (a) Room temp., CH2Cl2, 3 d (71:29 endo/exo);
(b) OsO4 (cat.), Me3NO, acetone, 0 °C then room temp., 53% from
152; (c) 2,2-dimethoxypropane, pTsOH, acetone, reflux, 64%;
(d) LiAlH4, THF, room temp.; (e) 80% TFA, –20 °C, gabosine C
(51% from 155).
the other hand, esterification of 156 with crotonic anhy-
dride, followed by the same reaction with trifluoroacetic
acid, yielded COTC in nine steps and 2.4% overall yield
from (+)-camphor.
Other chiral sulfoxides have proved to be useful starting
materials for the synthesis of gabosines. The chiral quinone
159 (Scheme 26) was used by Carreno’s group for the syn-
thesis of gabosine O and 4-epigabosine A.[40]
They started
from chiral sulfoxide 157, easily available in two steps and
48% yield from menthol. Treatment of the lithium anion
of 157 with the benzoquinone monoketal 158, followed by
hydrolysis, gave 159. An interesting desymmetrisation pro-
cess was then performed by treatment of this quinone with
AlMe3 (4 equiv.), affording enone 160. This compound was
the result of an exclusive addition on the pro-S carbon
Scheme 26. Synthesis of gabosine O and 4-epigabosine A starting
from a chiral sulfoxide. (a) (i) (S,S)-157, LDA, THF, –78 °C, (ii) ox-
alic acid, THF, H2O, room temp., 78% for two steps; (b) AlMe3
(4 equiv.), CH2Cl2, –78 °C, 76%; (c) mCPBA, CH2Cl2, 0 °C, 1 h,
98%; (d) Dibal-H, THF, –78 °C, 30 min, 95%; (e) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 93%; (f) Cs2CO3, CH3CN, room temp.,
89%; (g) TBAF, THF, 0 °C, 80%; (h) OsO4 (1 equiv.), TMEDA,
CH2Cl2, –78 °C, 60%; (i) (i) (S,R)-131, LDA, THF, –78 °C, (ii) ox-
alic acid, THF, H2O, room temp., 76% for two steps;
(j) (i) mCPBA, CH2Cl2, 0 °C, (ii) TBHP, Triton B, THF, 0 °C, 72%
for two steps; (k) Dibal-H, THF, –78 °C, 67% (de ⬎ 98%);
(l) Cs2CO3, CH3CN, room temp., 54%; (m) NaOAc, H2O, reflux,
45%.
atom of quinone 159. In order to provide a better leaving
group, quinone 160 was oxidised to the sulfone 161. Selec-
tive reduction to alcohol 162 was then achieved with Dibal-
H. After protection of the secondary alcohol to give 163, a
retroaddition process was performed with Cs2CO3 to give
enone 164. From this compound, RuCl3/OsO4-mediated di-
hydroxylation occurred but only with a moderate yield
(31%) and a low diastereoselectivity (58:42). Deprotection
to afford alcohol 165 was therefore carried out, and treat-
ment with OsO4 (1 equiv.) gave gabosine O in a fully
stereocontrolled manner.
On the other hand, a one-pot, three-step sequence (1,4-
addition of AlMe3, followed by trapping of the resulting
enolate by NBS and then a base-mediated HBr elimination)
starting from 159 was used to prepare 166. Oxidation fol-
lowed by epoxidation stereoselectively gave 167.
Dibal-H reduction gave a 77:23 mixture of 168 plus its
diastereoisomer, and these were separated by chromatog-
raphy. Treatment of 168 with Cs2CO3 gave 169, a natural
product known as epiepoformin. Finally, heating of this
compound with aqueous NaOAc gave 4-epigabosine A in
45% yield. This strategy thus afforded gabosine O and 4-
epigabosine A in eight and ten steps, respectively, and in
21.8 and 4% overall yields from menthol.
Another series of masked p-benzoquinones was used by
Figueredo’s group for the preparation of several gabosine
derivatives (Scheme 27).[41]
They started from 171, easily
prepared in three steps and 50% yield from 170. The first
key step was the efficient enzymatic resolution of 171, af-
fording alcohol 172 in 45% yield and 98% ee together with
acetate 173 in 48% yield and 90% ee.
From the acetate 173, ent-172 was obtained in 75% yield
and 97% ee after saponification and crystallisation. After
protection of ent-172 as 174, alkylation mediated by potas-
sium tert-butoxide afforded a mixture of 175 (67%) and 176
(30%), which were separated by chromatography. Dihy-
droxylation of major isomer 175 gave diol 177 with full
stereocontrol. Desulfurisation gave 178, and after deprotec-
tion 4-epigabosine O was obtained.
On the other hand, again starting from 177, oxidation
followed by pyrolysis gave 179, which was deprotected to
afford 2-epi-3-epigabosine N.
Further, dihydroxylation of 176 gave a 2.8:1 mixture of
180 and its diastereoisomer. They could not easily be iso-
lated in pure form by chromatography, so the next reaction
was performed with this mixture. Desulfurisation gave 181
in 53% yield together with a small amount (11%) of its
diastereoisomer. After deprotection, ent-gabosine O was
obtained.
On the other hand, the same oxidation/pyrolysis protocol
as above gave 182 in 60% yield, with a small amount (8%)
of its diastereoisomer. A final deprotection step afforded
ent-gabosine N in ten steps and 2.8% overall yield.
The enantiomers of these gabosines were obtained in the
same way, by starting from 172.
This group completed these studies by also preparing
ent-gabosine A, 4-epigabosine A and gabosine F by use
of these versatile masked benzoquinone intermediates
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MICROREVIEW
Scheme 27. Synthesis of ent-gabosines N and O and of epigabos-
ines N and O starting from a masked p-benzoquinone. (a) Ac-
OCH=CH2, Novozyme®
435, iPr2O, 32 °C, 3 h (45% for 172 and
48% for 173); (b) MeONa, MeOH, room temp., 30 min, then
recrystallisation, 75%; (c) TBSCl, imidazole, CH2Cl2, room temp.,
5 d, then montmorillonite K10, CH2Cl2, room temp., 18 h, 62%;
(d) (i) tBuOK, THF, –78 °C, 15 min, (ii) MeI, –78 °C to room
temp., 2 h (67% for 175 and 30% for 176); (e) OsO4/NMO, H2O/
acetone, room temp., 4 h (70% for 177 and 62% for a mixture of
diastereoisomers for 180); (f) Bu3SnH/AIBN, toluene, reflux, 4 h,
83%; (g) TBAF, THF, room temp., 3 d, 66%; (h) (i) mCPBA,
CHCl3, 0 °C, 1 h then reflux in 2 h, (ii) TFA, CHCl3, room temp.,
3 h, 84%; (i) TBAF, THF, room temp., 1 h, 73%; (j) Bu3SnH/
AIBN, toluene, reflux, 4 h, 53%; (k) TBAF, THF, room temp.,
30 min, 51%; (l) mCPBA, CHCl3, 0 °C, 1 h then reflux in 2 h, 60%;
(m) TBAF, THF, room temp., 30 min, 83%.
(Scheme 28).[42]
The synthesis started from enones 175 and
176; epoxidation with potassium tert-butyl hydroperoxide
was fully stereocontrolled, affording the epoxides 183 and
184, respectively, in excellent yields. The same oxidation/
thermolysis protocol as above was followed to give a mix-
ture of 185 and 186. Desilylation of this mixture with
Et3N·3HF directly gave epiepoformin 169, a known precur-
sor of 4-epigabosine A.
ent-Gabosine A could be also prepared from this versa-
tile intermediate in a few steps; acetylation to 187 followed
by BF3·Et2O-induced ring opening afforded a mixture of
regioisomers 188 and 189. On treatment with MeONa, this
mixture gave ent-gabosine A in excellent yield. The same
sequence of reactions starting from ent-175 and ent-176
gave gabosine B in 14 steps and 23.7% yield from p-meth-
oxyphenol.
Finally, a synthesis of gabosine F starting from interme-
diates 183 and 184 was described (Scheme 28). Bu3SnH-me-
diated desulfonylation of either isomer, or of the mixture of
5892
Scheme 28. Synthesis of gabosines B and F and of ent-gabosine A
and 4-epigabosine A starting from a masked p-benzoquinone.
(a) tBuOOH/Triton B, THF (96% for 157, 98% for 158);
(b) mCPBA, CHCl3, Δ, 87%; (c) Et3N·3HF, THF, 86%;
(d) NaOAc, H2O reflux, 45%; (e) Ac2O, DMAP, CH3CN;
(f) BF3·Et2O toluene; (g) MeONa, MeOH, 77% from 187;
(h) Bu3SnH, AIBN, toluene (80% for 190, 90% for 191);
(i) (i) Et3N·3HF, THF, (ii) Ac2O, DMAP, CH3CN, 65% for two
steps; (k) (i) BF3·Et2O, toluene, (ii) MeONa/MeOH, 88%.
both, gave the same 6.6:1 mixture of epoxides 190 and 191.
Desilylation followed by acetylation gave acetates 192 and
193. The same two-step protocol as described above for ga-
bosine A then gave gabosine F in 13 steps and 13.9% over-
all yield. The enantiomer, gabosine B, was prepared simi-
larly.
Total Synthesis of Gabosines by Chemoenzymatic Methods
Two innovative syntheses of gabosine A using biotrans-
formation of aromatic systems have been reported. The
first, from Banwell’s group, used the dihydroxylation of
iodobenzene, mediated by toluene dioxygenase, as the key
step (Scheme 29).[43]
This reaction afforded a cyclohexadi-
enediol, which was immediately selectively protected on the
less hindered alcohol to give silyl ether 194. Dihydrox-
ylation of this iodo derivative was achieved in a regiocon-
trolled and stereoselective fashion on the face anti to the
two substituents to give 195. After protection to afford acet-
onide 196, oxidation was performed to give enone 197. The
last key step was the introduction of the desired methyl
group. After several unsuccessful attempts, the authors
found that the coupling of 197 with methylmagnesium
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chloride in the presence of FeCl3 was very efficient, afford-
ing 198 in 93% yield. Final deprotection gave gabosine A
in six steps and 42.3% overall yield from iodobenzene.
Scheme 29. Synthesis of gabosine A using the dihydroxylation of
iodobenzene mediated by toluene dioxygenase as a key step. (a) (i)
Pseudomonas putida UV4, 80% (ee ⬎ 98%), (ii) TBDPSCl
(1.1 equiv.), imidazole, CH2Cl2, 18 °C, 1.5 h; (b) OsO4 (cat.), NMO
(1.5 equiv.), acetone/H2O (1:1), 60 °C, 1 h; (c) 2,2-dimethoxy-
propane (neat), pTsOH (cat.), 18 °C, 3 h, then Et3N (0.27 equiv.);
(d) Swern oxidation; (e) MeMgCl (2.2 equiv.), FeCl3 (10 mol-%),
NMP (9 equiv.), THF, 0 °C, 0.5 h; (f) HCl (trace of a 2 m solution),
MeOH, 18 °C, 96 h, then (Me2N)3S+
F2SiMe3
–
(4.8 equiv.).
A similar approach was followed more recently by Pan-
dolfi’s group, starting from toluene in order to avoid the
iodo to methyl group transformation (Scheme 30).[44]
Scheme 30. Synthesis of gabosine A using the dihydroxylation of
toluene mediated by Pseudomonas putida as a key step. (a) Pseu-
domonas putida F39/D, 60% (ee ⬎ 99%); (b) DMP, acetone,
pTsOH, 0 °C, 80%; (c) OsO4 (cat.), NMO, H2O/acetone (1:5), room
temp., 70% (7:3 ratio of 201/202); (d) BzCl, Et3N, CH2Cl2, quant.;
(e) CuCl2·H2O, CH3CN, quant.; (f) IBX, DMF, 92%; (g) K2CO3,
MeOH, 54%.
The known dihydroxylation of toluene mediated by Pseu-
domonas putida afforded enantiopure cis-diol 199 in 60%
yield and acetonide 200 after protection. As already men-
tioned by Banwell et al.,[43]
the key step was the non-selec-
tive dihydroxylation of this intermediate, affording a 70:30
mixture of the two regioisomers 201/202. After separation
by chromatography, the minor isomer 202 was dibenzoyl-
ated to give 203. After deprotection to provide diol 204,
oxidation of the allylic alcohol afforded enone 205 and after
final deprotection gabosine A. This compound was ob-
tained in seven steps and 5% overall yield from toluene.
It appears interesting to compare the different ap-
proaches to gabosines and their isomers. To this end,
Table 1 lists the different syntheses that have been reported.
We have indicated the yields and the number of steps start-
ing from similar structures, such as the different sugars in
the chiral-pool approaches.
Conclusions
The fifteen natural gabosines have been synthesised, as
well as some of their enantiomers and various diastereoiso-
mers. Many elegant strategies for the total synthesis of these
derivatives have been developed. From the analysis of litera-
ture data several aspects are worthy of note:
– Although these natural products have relatively simple
structures, the numbers of steps required to prepare them
are still high (around 10), and the overall yields for the syn-
theses are in general only moderate (around 4–20%). Direct
comparison between the different syntheses is, of course,
extremely difficult, because it would require taking into ac-
count a number of other factors such as availability and
cost of starting materials and reagents, time to perform the
total synthesis and so on... Furthermore, the versatility of
an approach to obtain other isomers and/or chemical li-
braries could be an important point, for study of structure/
activity relationships, for instance. In any case, it is clear
that new synthetic strategies to improve access to these mo-
lecules still need to be designed.
– The first total syntheses were performed in order to
establish the stereostructures of these derivatives unambigu-
ously, but the corresponding molecules were later selected
as excellent models to demonstrate the scopes and limita-
tions of methodologies developed by synthetic chemists.
Further, these routes are also of interest for the preparation
of other derivatives, especially in the carbasugar family.
– The chiral-pool approach has, as usual, been efficient
for establishing the structures and absolute configurations
of these derivatives but requires further synthetic steps, or
changes in starting material, to allow access to their stereo-
isomers.
– In contrast, approaches through chiral molecules ob-
tained by resolution processes might have lower yields due
to the first resolution steps, but they are flexible and can
afford the two enantiomeric series more directly.
– Although they have not yet been much developed, ap-
proaches based on bioconversion methodologies appear
very attractive, because they are very short in terms of num-
bers of steps and clearly open a new avenue in this field.
– It is very interesting to remark that, with the exception
of the bioconversions mentioned above, no synthesis of ga-
bosine based on asymmetric catalysis, neither through orga-
nometallic nor through organocatalytic processes, has been
reported to date. However, these natural products would
appear to be well suited for the use of the corresponding
methodologies, and it can be expected that powerful devel-
opments in this direction should arise in the near future.
– As indicated above, these gabosines have not so far
demonstrated very significant biological properties. How-
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MICROREVIEW
Table 1. Synthesis of gabosine derivatives from 1994 to 2012.
Gabosine derivative Starting material Number of steps Overall yield Reference
Gabosine A d-ribose 9 steps 13.9% [26]
Gabosine A d-mannose 11 steps 10.8% [27]
Gabosine A d-mannose 9 steps 5.7% [29]
Gabosine A quinic acid 11 steps 8.3% [35]
Gabosine A iodobenzene 6 steps 58% [43]
Gabosine A toluene 7 steps 5% [44]
ent-Gabosine A d-glucose 15 steps 14.4% [19]
ent-Gabosine A p-methoxyphenol 13 steps 11.6% [42]
Di-OBn-ent-gabosine A galactose 5 steps 3.7% [18]
4-Epigabosine A d-glucose 11 steps 12.9% [27]
4-Epigabosine A d-glucose 9 steps 9.4% [28]
4-Epigabosine A menthol 10 steps 4% [40]
4-Epigabosine A p-methoxyphenol 11 steps 3.7% [42]
Gabosine B quinic acid 13 steps 4.5% [35]
4-Epigabosine B d-glucose 10 steps 14.5% [28]
2-Epi-3-epigabosine B d-galactose 7 steps 11% [18]
4-Epi-6-epigabosine B d-galactose 9 steps 5.5% [29]
Gabosine B p-methoxyphenol 13 steps 13.9% [42]
Gabosine C d-mannose 11 steps 21% [23]
Gabosine C d-ribose 12 steps 4.4% [24]
Gabosine C d-ribose 11 steps 19.8% [30]
Gabosine C quinic acid 9 steps 12.7% [34]
Gabosine C (+)-camphor 9 steps 2.4% [39]
ent-Gabosine C d-ribose 12 steps 10% [31]
COTC gabosine C 1 step 48–71% [23,24,30,34,39]
Gabosine D d-glucose 14 steps 15.8% [19]
ent-Gabosine D quinic acid 11 steps 13.3% [35]
Gabosine E d-glucose 14 steps 17.5% [19]
Gabosine E d-ribose 12 steps 5.4% [31]
ent-Gabosine E d-mannose 11 steps 6.5% [27]
ent-Gabosine E d-mannose 11 steps 12% [33]
ent-Gabosine E quinic acid 11 steps 11.7% [35]
2-Epi-3-epigabosine E d-glucose 11 steps 6.4% [27]
(⫾)-Gabosine F cyclopentadiene derivatives 9 steps 13.4% [6]
Gabosine F l-arabinose 12 steps 23% [32]
Gabosine F p-methoxyphenol 13steps 13.9% [42]
Gabosine G δ-d-gluconolactone 5 steps 13.2% [20]
Gabosine G tartaric acid 12 steps 7.7% [37]
Gabosine H tartaric acid 7 steps 7% [36]
Gabosine I d-glucose 12 steps 10.8% [4]
Gabosine I δ-d-gluconolactone 4 steps 20.3% [20]
Gabosine I δ-d-gluconolactone 5 steps 65% [21]
Gabosine I d-glucose 10 steps 27% [22]
Gabosine I tartaric acid 11 steps 11.8% [37]
4-Epigabosine I tartaric acid 11 steps 21.8% [37]
Gabosine K d-glucose 15 steps 13.5% [7]
Gabosine K δ-d-gluconolactone 7 steps 40% [21]
(⫾)-1-Epi-4-epigabosine K cyclopentadiene derivatives 11 steps 8.9% [6]
Gabosine N d-ribose 8 steps 17.1% [26]
ent-Gabosine N d-ribose 10 steps 18.2% [25]
ent-Gabosine N p-methoxyphenol 10 steps 2.8% [41]
4-Epigabosine N d-galactose 9 steps 8.8% [29]
2-Epi-3-epigabosine N p-methoxyphenol 11 steps 8.6% [41]
Gabosine O d-mannose 9 steps 41% [32]
Gabosine O menthol 10 steps 13% [40]
ent-Gabosine O d-ribose 11 steps 19.5% [25]
ent-Gabosine O p-methoxyphenol 11 steps 0.9% [41]
4-Epigabosine O d-mannose 11 steps 38% [32]
4-Epigabosine O p-methoxyphenol 11 steps 4.6% [41]
6-Epigabosine O d-mannose 9 steps 6.9% [29]
ever, it would not be surprising if these molecules, or their
derivatives, might be of use for some of the numerous new
biological targets discovered every day. This is exemplified
by a recent example; it has been shown that gabosine deriv-
5894
atives, and in particular 4-O-decyl-gabosine D, are glutathi-
one S-transferase M1 inhibitors. Through this action, they
have demonstrated synergistic effects with cisplatin against
a lung cancer cell line to overcome resistance.[45]
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Note Added in Proof (July 3, 2012): After acceptance of this manu-
script, a paper was published to describe a stereoselective synthesis
of gabosine J and to correct the stereochemistry previously as-
signed to this molecule.[46]
Acknowledgments
This research has been performed as part of the project Indo-
French “Joint Laboratory for Sustainable Chemistry at Interfaces”.
We thank the Centre National de la Recherche Scientifique
(CNRS), the University of Rennes 1, the French Ministry for For-
eign Affairs and the Council of Scientific and Industrial Research
(CSIR) for support of this research. D. H. M. thanks the Vietnam
Nation Foundation for Science and Technology Development
(NAFOSTED) (grant number 104.01-2011.52).
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Received: April 13, 2012
Published Online: July 5, 2012
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