Oxidation with PCC/AcONa, followed by a final deprotection step with BCl3, afforded gabosine I in 12 steps and 10.8 % overall yield fromd-glucose... Oxidation followed by deprotections g
Trang 1DOI: 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).
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
Trang 2nature 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-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]
Total Synthesis of Gabosines
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 fromd-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) Ph 3 PCHBr, 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 fromd-glucose
Trang 3A 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 fromd-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 fromd-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 fromd-glucose)
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) POCl 3 , 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),
CH 2 Cl 2 , 100 %, (ii) TFA, H 2 O, CH 2 Cl 2 , 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 fromd-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 fromd-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, CH 2 Cl 2 , 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
Trang 4by 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 %) fromd-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
HWE reaction gave enone 28 and, after deprotection,
ga-bosine I in a higher yield (five steps and 65 % overall yield fromd-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 acetyladeprotec-tion, 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 reacprotec-tions 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 fromd-glucose
Scheme 7 Alternative synthesis of gabosine I through the use of an intramolecular HWE reaction as key step (a) (i) EOMCl, DIPEA,
CH 2 Cl 2 , r.t., 16 h, 99 %, (ii) H 2 , 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, H 2 O, 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, BF 3·Et2 O, MS (4 Å), CH 3 CN, 48 %.
Trang 5Benzoate 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 fromd-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 ofd-ribose as starting material (Scheme 9
and Scheme 10, below)
Scheme 9 Synthesis of gabosine C and COTC through the use of
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, CH 2 Cl 2 , 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-%),
CH 2 Cl 2 , 80 °C, 48 h, 56 %; (e) PDC, CH 2 Cl 2 , 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 fromd-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 fromd-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 fromd-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 fromd-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 fromd-glucose in four steps and 62% yield, was
Trang 6Scheme 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, H 2 O, 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 %.
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 fromd-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(OCOCF 3 ) 2 , (CH 3 ) 2 CO/H 2 O (1:1), 8 h, (ii) MsCl, CH2Cl2, Et3N, 0 °C to room temp., 2 h, 72 % for
(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 fromd-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, fromd-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, fromd-galactose.[29]
Trang 7Scheme 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]
Scheme 15 Synthesis of gabosine C and COTC through the use of
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 fromd-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, Et3 N, CH 2 Cl 2 , 60 %; (e) H 2 , 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 fromd-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 fromd-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 fromd-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 fromd-mannose
Trang 8Scheme 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/H 2 O/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
fromd-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) H 2 ,
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/H2
O/1,4-di-oxane (8:2:1), room temp., 12 h, 97 % from 102; (f) TFA, H2O,
CH 2 Cl 2 , room temp., 2 h, 100 %.
The oxime 99 was prepared froml-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 hydrogeelimi-nation,
possibly directed by the free OH group, followed by
depro-tection, afforded gabosine F in 12 steps and 23 % overall
yield froml-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 methyld-mannoside by
known procedures in six steps and 41.6 % yield Upon
con-densation with methylhydroxylamine the intermediate nitrone underwent the desired 1,3-dipolar cycloaddition to
afford isoxazolidine 106 plus its diastereoisomer at position
C2in 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 fromd-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),
K 2 CO 3 , THF, 24 h, (ii) DMP oxidation, CH 2 Cl 2 , 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/H 2 O (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,
Trang 9followed 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), H 2 , 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 (0.1n) 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 Hydrogeβ-elimi-nation 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
Trang 10Scheme 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, CH 2 Cl 2 , 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
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, CH 2 Cl 2 , 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/H 2 O (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 dehydracetyl-ation, to
yield a mixture of alkenes 150 and 151 in a 2:1 ratio
Aceto-nide 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