A substrate-based approach to skeletal diversity from dicobalt hexacarbonyl (C1)-alkynyl glycals by exploiting its combined ferrier-nicholas reactivity

Article abstract of DOI:10.1002/chem.201402149

Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose-derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C-1)-alkynyl glycals with BF₃ ^.Et₂O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O-6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson-Khand cyclization leading to a single tricyclic derivative.

Full text of DOI:10.1002/chem.201402149

DOI: 10.1002/chem.201402149
Full Paper
&
Synthetic Methods
A Substrate-Based Approach to Skeletal Diversity from Dicobalt
Hexacarbonyl (C1)-Alkynyl Glycals by Exploiting Its Combined
Ferrier–Nicholas Reactivity**
Fernando Lobo, Ana M. Gꢀmez,* Silvia Miranda, and J. Cristꢀbal Lꢀpez*[a]
In Memory of Robert J. Ferrier
Abstract: Novel substrates that combine dicobalt hexacar-
bonyl propargyl (Nicholas) and pyranose-derived allylic (Fer-
rier) cations have been generated by treatment of hexacar-
panes), ring contraction (tetrahydrofurans), or branched
pyranoses, by incorporation of nucleophiles, can be ob-
tained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, re-
spectively. The use of a 6-O-allyl alkynyl glycal led to a suita-
ble funtionalized oxepane able to experience an intramolec-
ular Pauson–Khand cyclization leading to a single tricyclic
derivative.
.
bonyldicobalt (C-1)-alkynyl glycals with BF3 Et2O. The study
of these cations has resulted in the discovery of novel reac-
tion pathways that have shown to be associated to the
nature of O-6 substituent in the starting alkynyl glycals. Ac-
cordingly, compounds resulting from ring expansion (oxe-
Introduction
On the other hand, carbohydrates have already shown their
usefulness in DOS. For instance, the Ferrier,[8] and Pauson–
Khand,[9] reactions were exploited early on with a glycal tem-
plate to gain access to a library of tricyclic compounds,[10]
a glycal-derived scaffold was also used to generate highly sub-
stituted tetrahydrofurans,[11] and more recently the reaction of
2-C-formyl glycals[12] with various dinucleophiles has led to pyr-
imidine-, pyrazole- and pyrazolopyrimidine-based “carbohy-
brids” on route to fused triazole scaffolds.[13]
Diversity-oriented synthesis (DOS), as formulated by Schreiber
and co-workers,[1] emerged as the chemists’ response to the
need to generate libraries of structurally diverse small mole-
cules in an efficient manner.[2] This development had followed
the recognition of the ability of small molecules to interact
with macromolecules, and to function as critical components
on a variety of cellular processes.[3] From a synthetic stand-
point, the DOS central aim is the efficient generation of struc-
tural diversity and complexity.[4] Structural diversity, in its turn,
has been divided into four main components: appendage,
functional group, stereochemical, and skeletal diversities.[3] The
latter, skeletal diversity,[5] can be achieved mainly by two strat-
egies: the “reagent-based approach”, which involves exposure
of one common starting material to different reagents,[6] or the
“substrate-based approach” in which different starting materi-
als, containing pre-encoded information,[5a] are subjected to
a common set of reaction conditions resulting in different skel-
etal outcomes.[5d,7]
Our research group has been interested in the generation of
carbohydrate-based libraries, and we have already addressed
the issue of appendage diversity in furanose templates.[14,15]
More recently, we have turned our attention to the generation
of skeletal diversity from pyranose-derived glycals.[16] Our ap-
proach, to skeletal diversity, relies on a substrate-based strat-
egy of pre-encoded starting materials rather than on a re-
agent-based protocol.[1e]
In this work, we have studied the behavior of Nicholas-
type[17,18] Ferrier (allylic) cations 2,[8] generated from differently
(O-6)-substituted dicobalt hexacarbonyl (C-1)-alkynyl glycals,
that is, 1, by treatment with BF3·Et2O, in the context of the
generation of skeletal diversity (Scheme 1). The design of com-
[a] Dr. F. Lobo, Dr. A. M. Gꢀmez, S. Miranda, Prof. Dr. J. C. Lꢀpez
Department of Bio-Organic Chemistry
Instituto de Quꢁmica Orgꢂnica General (IQOG-CSIC)
Consejo Superior de Investigaciones Cientꢁficas
Juan de la Cierva 3, 28006 Madrid (Spain)
E-mail: ana.gomez@csic.es
jc.lopez@csic.es
[**] The results described in this manuscript have in part been communicated
in a conference paper: J. C. Lꢀpez, F. Lobo, S. Miranda, C. Uriel, A. M.
Gꢀmez, Pure Appl. Chem. 2014, DOI: 10.1515/pac-2014–0402.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402149.
Scheme 1. Ferrier allylic cation (boxed) and Nicholas cation (circled), gener-
ated from C-1-alkynyl glycal 1, are connected in a single molecule 2.
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pound 1 was based on previous findings from our research
group, which had shown that stabilization of the anomeric ox-
ocarbenium ion by an adjacent Nicholas-type dicobalt hexacar-
bonyl alkyne group, might lead to unexpected reaction path-
ways.[19] In fact, we have found that the O-6 substituent in
these glycals (1) can play a key role in determining the out-
come of the transformations, and we disclose herein how com-
pounds 1 can react, in a stereocontrolled manner, to give oxe-
panes, substituted tetrahydrofurans, tetrahydropyrans contain-
ing two distinct heterocycles, as well as bicyclic or tricyclic
compounds, by changes in the R2-O-6 substituent.
Table 1. Synthesis of C-1 alkynyl glycal derivatives 11 a–g from 9a.
Results and Discussion
Synthesis of the starting alkynyl glycals
The alkynyl glycal precursors of the corresponding dicobalt
hexacarbonyl derivatives 1, were readily prepared from tri-O-
acetyl-d-glucal (3) by synthetic sequences consisting of four or
five steps, depending on the substituent at O-6 (Scheme 2). Ac-
cordingly, C-1-alkynyl tri-O-benzyl-d-glucal derivatives 6, and 6-
O-silyl derivatives 9, were prepared by PCC oxidation of inter-
Figure 1. Dicobalt hexacarbonyl alkynyl glycals 12–15 obtained by cobalta-
tion of 6, 9, 10 and 11 (Co2(CO)8, CH2Cl2, room temperature, 1 h).
Reactivity and transformations of 6-O benzyl derivatives
We first examined the reaction of 12a with allyltrimethylsilane
in the presence of BF3·Et2O (ꢀ208C, CH2Cl2). Two compounds
were obtained in this reaction, a C-3-allyl derivative 16, and an
oxepane 17a, devoid of any allyl substituent (Scheme 3). The
structural assignment of compound 17a was based on its
NMR spectroscopy data, and the stereochemistries at C-2 and
C-3 (oxepane numbering) were determined on the basis of
a large coupling constant J2,3 =10.2 Hz, and observed NOEs be-
tween H-2, H-7ax, H-4ax and C6-OH (Scheme 3).[22] The C-3 con-
figuration in compound 16 was based on a NOESY experiment
carried out on a derivative obtained therefrom, vide infra.[23]
Scheme 2. Synthesis of C-1 alkynyl glycal derivatives 6 and 9 from tri-O-
acetyl-d-glucal 3.
mediates 4 and 7, leading to lactones 5 and 8, respectively,[20]
followed by a sequence of lithium acetylide-addition/POCl3-
mediated elimination.[21]
Additional substrates were prepared from compound 9a, by
tetrabutylammonium fluoride (TBAF)-mediated silyl deprotec-
tion leading to 6-hydroxy derivative 10a and subsequent alky-
lation. In this manner, a range of benzyl-type protecting
groups with different electronic properties in the aromatic ring
were introduced by conventional etherification, to afford deriv-
atives 11 a–g (Table 1).
Scheme 3. Reaction of C-1 alkynyl glycal 12a with allyltrimethylsilane in the
presence of BF3·Et2O.
Finally, incorporation of the dicobalt hexacarbonyl group
was carried out by treatment of the corresponding alkynyl
glycal with Co2(CO)8 in dichloromethane at room temperature
(1 h, >70% yield; Figure 1).
Owing to our interest in oxepane 17a, we repeated the re-
action of 12a with BF3 Et2O in the absence of allyltrimethylsi-
lane (Table 2).[24,57] This reaction led to two compounds, oxe-
pane 17a and 1,6-anhydro-derivative 18a. By comparing these
derivatives, we noticed that both were C-3-deoxy derivatives
whose O-6 benzyl groups had suffered an alteration. In com-
.
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that oxepane 17a can evolve to 1,6-anhydro derivative 18a
upon treatment with BF3·Et2O (Scheme 5a), thus implying re-
versibility in the steps 17a!23!22!18a, which could be re-
garded as a retroketalization followed by a retro-Prins frag-
mentation (Scheme 4).[34] Furthermore, treatment of 6-hydroxy
derivative 20 with benzaldehyde in the presence of BF3·Et2O
led to compounds 17a and 18a (Scheme 5b), then demon-
strating the reversibility in the transformation 19!20, and the
feasibility of the Prins cyclization in an intermolecular variant.
Finally, treatment of 18a with benzaldehyde in the presence of
BF3·Et2O did not result in any transformation, leaving the 1,6-
anhydro derivative unchanged (Scheme 5c).
Table 2. Reaction of C-1 alkynyl glycal 12a with BF3·Et2O.[a]
Entry
Reaction conditions
17a [%][b]
18a [%][b]
1
2
CH2Cl2/4 ꢂ MS (powder)
CH2Cl2/H2O (2 equiv)
61
18
23
67
[a] Reaction conditions: 12a (0.1 mmol), BF3·Et2O (1.2 equiv), ꢀ208C,
CH2Cl2, 1 h. [b] Isolated yield.
Two new stereogenic centers are generated in the overall
process leading to oxepane 17a, both of them in the Prins-
type cyclization (Scheme 4): the stereogenic center at C-2 (car-
bohydrate numbering) is dictated by geometric restrictions,
whereas the stereocenter at C-6’ (carbohydrate numbering) is
consequence of a preferred rotamer (as displayed in 19,
Scheme 4), which locates the aryl residue away from the bulky
dicobalt hexacarbonyl alkynyl moiety in the transition state
leading to cyclization, that is, 19!22 (Scheme 4).
pound 17a the 6-O-benzyl group had been involved in a cycli-
zation process, whereas the benzyl group in derivative 18a
had been lost. These observations led us to consider a hydrolyt-
ic step in the genesis of 18a. In agreement with our hypothe-
sis, the relative ratio 17a/18a proved to be highly dependent
on the water content in the reaction media. For instance,
when the reaction was carried out in the presence of molecu-
lar sieves, oxepane 17a was the major reaction product (61%
yield), whereas addition of H2O
In agreement with the proposed reaction pathway, the ex-
periments outlined in Table 3 serve to illustrate the effect of
(2.0 equiv) reversed this situation
and bicyclic derivative 18a
became the major reaction prod-
uct (67% yield; Table 2, compare
entries 1 and 2). In this context,
the basicity of the molecular
sieves along with its dehydrative
effect might be responsible for
the increase in oxepane forma-
tion.[25] From these considera-
tions we have been able to ad-
vance a preliminary mechanistic
rationale, which has now been
completed with data from addi-
tional experiments (Scheme 4).[57]
The transformation begins
with a 1,6-hydride transfer from
Scheme 4. Proposed reaction pathways for the formation of 17a and 18a.[57]
the 6-O-benzyl group to C-3 in
cation 2 (R1 =Bn, R2 =Ph),[26,27] to
generate an oxocarbenium ion, 19. The latter might evolve
through two different routes: 1) hydrolysis and loss of benzal-
dehyde to give 6-hydroxy derivative 20, (which in some instan-
ces has been isolated from the reaction media) that by proto-
nation, onto the activated enol-ether-type bond, would give
a pyranosidic Nicholas-oxocarbenium ion 21, the cyclization of
which would lead to 1,6-anhydro derivative 18a; 2) a Prins-
type cyclization,[28–30] will give raise to bicyclic Nicholas-oxocar-
benium ion 22, and thence hemiketal 23, the ring opening of
which could lead to oxepane hydroxy-ketone 17a.[31] The cycli-
zation step followed by hemiketal formation, that is, 19!22!
23, can be formally considered as a two-step electrophilic addi-
tion (AdE) to an alkene bearing an adjacent cation stabilizing
group.[32,33] In recent supporting experiments, we have shown
Scheme 5. Supporting experiments regarding the proposed reaction path-
way.
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fluence in the outcome of the reaction (Table 4).[57] Accordingly,
by replacing the terminal phenyl group in the alkyne, as in
12a, by a hexyl group, 12c, or a H atom, 12d, we have ob-
served an increase in the amount of oxepane formed as well
as in the ratio oxepane/1,6-anhydro derivative, going from
2.6:1, to 4:1 and to 11:1, respectively (Table 4).
Table 3. BF3·Et2O induced reaction of alkynyl glycals 13 leading to oxe-
panes 24 and 1,6-anhydro derivative 18a.[a]
In our opinion, this effect seems to be related with the re-
version step of oxepane!1,6-anhydro derivative (e.g., 23!
22!19, Scheme 4). In favor of this hypothesis is the fact that
whereas oxepane 17a undergoes a complete transformation
into 1,6-anhydro derivative 18a in a few hours (Schemes 4 and
6), oxepane 17d does not evolve completely to 1,6-anhydro
derivative 18d, even after 7 days of reaction (18d/17d, 7:1
ratio, Scheme 6). We hypothesize that the higher electrophilici-
ty of the Nicholas cation arising from the unsubstituted alkyne
compared to the cation from the alkyne with the terminal
phenyl substituent,[35] would render the ionization of hemike-
tal, leading back to the corresponding Nicholas cation, more
difficult, for example, 23!22 (Scheme 4).
Entry
Glycal
Aryl
24 (%)[b]
18a (%)[b]
Total [%]
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13 f
13g
p-OMe-Ph
m-OMe-Ph
p-Me-Ph
naphthyl
p-F-Ph
24a (–)
79
64
46
30
30
24
21
79
88
84
92
93
78
75
24b (24)
24c (38)
24d (62)
24e (63)
24 f (54)
24g (54)
p-Br-Ph
p-I-Ph
[a] Reaction conditions: 13 (0.1 mmol), BF3·Et2O (1.2 equiv), 4 ꢂ MS,
ꢀ208C, CH2Cl2, 1 h. [b] Isolated yield.
the O-6 substituent in the ratio oxepane (24)/1,6-anhydro de-
rivative (18a). Thus, in general, better yields of oxepane are
observed with electron-withdrawing substituents in the aro-
matic residue at O-6 (Table 3, entry 5). Conversely, electron do-
nating substituents in the aromatic ring cause a reduction in
the amount of oxepane formed (Table 3, entries 1–3). p-Iodo-
and p-bromo-benzene derivatives 13g and 13 f, respectively,
gave moderate yields of oxepanes (Table 3, entries 6 and 7).
Naphthyl derivative 13d, displayed a behavior similar to that
of the parent phenyl derivative 12a in terms of yields (Table 3,
entry 6). These results are in agreement with the proposed re-
action pathway, in which even though the electron-donating
group will favor the 1,6-hydride transfer step, that is, 2!19
(Scheme 4), they will also render oxocarbenium ion 19, less
electrophilic, thus disfavoring the cyclization step, that is, 19!
22.
Scheme 6. Reaction of oxepanes 17a and 17d in the presence of BF3·Et2O.
Skeletal diversity from oxepanes: tandem Ferrier–Nicholas
reaction/Pauson–Khand cyclization
Even though hexacarbonyl dicobalt complexes are now ac-
cepted as a new class of cytotoxics,[36] these cobalt adducts of
alkynes are rarely intended as the final synthetic targets. Thus,
they are normally submitted to decobaltation to regenerate
the alkyne moiety. However, a more appealing strategy, which
has been used in some instances, involves their use in further
synthetic endeavors, such as the Pauson–Khand reaction.[37]
In this context, and considering the cation-stabilizing ability
of allyl groups in hydride-transfer processes, we decided to
test the reaction of complexes 26a and 26d obtained by co-
baltation of 6-O-allyl derivatives 25a and 25d (Scheme 7).
When submitted to our standard reaction conditions, allyl de-
rivatives 26a and 26d were consumed in less than 1 h, and
Improving the oxepane yield: the effect of the substituent
at the alkyne terminal position
Even though enhanced electron density at the aromatic O-6
substituent in glycals 12a and 13a–g, could improve oxepane/
1,6-anhydro-derivative ratios (Table 3), we have found that sub-
stitution at the terminal alkyne position also has a marked in-
Table 4. Effect of substitution at the alkyne terminal position.[a]
Glycal
Oxepane (%)[b] Anhydro (%)[b] Combined % Ratio 17/18
12a
12c
12d
17a (61)
17c (80)
17d (89)
18a (23)
18c (16)
18d (8)
84
96
97
2.6:1
5:1
11:1
[a] Reaction conditions: 12 (0.1 mmol), BF3·Et2O (1.2 equiv), 4 ꢂ MS,
ꢀ208C, CH2Cl2, 1 h. [b] Isolated yield.[57]
Scheme 7. Synthesis of dicobalthexacarbonyl alkynyl 6-O allyl glycals 26.
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provided the corresponding oxepane 27 and 1,6-anhydro de-
rivative 18 in good combined yields. Consistent with the previ-
ously observed effect of the substituent at the alkyne terminal
position, compound 26d, with an unsubstituted terminal
alkyne, gave rise to a higher amount of oxepane 27d (oxe-
pane/1,6-anhydro derivative, 10.5:1) than that generated from
Finally, it was of interest to test whether the synthetic se-
quence Ferrier–Nicholas/Prins cyclization/Pauson–Khand reac-
tion, that is, 26a!27a!28, could be carried out in a one-pot
operation.[41] To this end, we treated hexacarbonyl dicobalt de-
rivative 26a, with BF3·Et2O and, after acid quenching (NEt3)
with TMANO·2H2O. Eventually, after some tuning of reaction
conditions, tricyclic derivative 27 could be obtained in 7%
yield (Scheme 8). Although the yield obtained is low, it is
worth mentioning that the overall process involves the forma-
tion of three new rings, four carbonꢀcarbon bonds, and three
new stereogenic centers.
Table 5. Effect of substitution at the alkyne terminal position in allyl de-
rivatives.[a]
Glycal Oxepane (%)[b] Anhydro (%)[b] Combined %[b] Ratio 27/18
26a
26d
27a (50)
27d (73)
18a (44)
18d (16)
94
80
1.1:1
10.5:1
Scheme 8. One-pot transformation of 26a into tricyclic derivative 28.
[a] Reaction conditions: 26 (0.1 mmol), BF3·Et2O (1.2 equiv), 4 ꢂ MS,
ꢀ208C, CH2Cl2, 1 h. [b] Isolated yield.
Attempted tandem Ferrier–Nicholas/Friedel–Crafts reactions
Related to tandem Nicholas/Pauson–Khand processes, some
groups have also reported Friedel–Crafts reactions in combina-
tion with Nicholas transformations to gain access to cyclic de-
rivatives.[42] In order to explore this avenue we first studied the
reduction of ketone 17a to the corresponding hydroxy-deriva-
tive. However, even though related transformations have been
described using DIBAL-H as the reducing agent,[43] we were
unable to obtain such diol upon treatment with DIBAL-H,
NaBH4 or HSnBu3.
Table 6. Pauson– Khand reaction of hexacarbonyl dicobalt derivative
27a.
Entry
Reaction conditions
t [min]
28 [%][a]
1
2
3
4
5
6
7
CyNH2
NMO, CH2Cl2, 08C
5
15
30
60
30
60
60
–
9
20
7
9
36
49
Alternatively, treatment of ketones 17a and 24b with a re-
ducing system composed of a Lewis acid and a hydride donor,
which could have led directly to tricyclic derivative 30, resulted
instead in the formation of bicyclic derivatives 31 and 32
(Table 7). Compound 31 could be obtained as single derivative
(Table 7, entry 1) or as a diastereomeric mixture at C-1 (carbohy-
drate numbering) depending on the reagents system (Table 7,
entries 2–4).
NMO·H2O, CH2Cl2, 08C
TMANO, CH2Cl2, 08C
TMANO·2H2O, CH2Cl2, RT
TMANO·2H2O, CH2Cl2, 08C
TMANO·2H2O, CH2Cl2, ꢀ208C
[a] Isolated yield.
The formation of compounds 29 and 30 from oxepanes 17a
and 24b, respectively, can be explained, according to our pro-
the aryl-substituted alkynyl derivative 27a (oxepane/1,6-anhy-
dro derivative, 1.1:1; Table 5).
Table 7. Reduction of keto-oxepanes with Lewis acid/hydride donors.
With these compounds in hand, we tackled the intramolecu-
lar Pauson–Khand reaction of oxepane 27a. The thermal reac-
tion in the presence of cyclohexylamine (CyNH2) did not result
in the formation of any tricyclic derivative (Table 6, entry 1).
The use of N-methylmorpholine N-oxide (NMO), which has
been recommended for Pauson–Khand reactions of electron-
deficient alkynes,[38] gave better results, with the hydrated re-
agent giving improved yields (Table 6, compare entries 2 and
3). Finally, best results were obtained with trimethyl-amine N-
oxide (TMANO; Table 6, entries 4–7),[39,40] and again the use of
the hydrated reagent at low temperature led to improved
yields (Table 6, entry 7, 49% yield). On the contrary, treatment
of hexacarbonyl dicobalt compound 27d, under similar reac-
tion conditions did not give any Pauson–Khand adduct.
Entry
Oxepane
Reagents
Product
Yield [%] (C-1)[a]
1
2
3
4
5
17a
17a
17a
17a
24b
TMSOTf/Et3SiH[b]
InCl3/BH3·SMe2
InCl3/Et3SiH[b]
TMSOTf/BH3·SMe2
TMSOTf/BH3·SMe2
29
29
29
29
30
10 (0:1)
15 (3:1)
37 (5:1)
60 (1:1)
56 (1:1)
[b]
[c]
[c]
[a] Diastereomeric ratio at C-1. [b] This reaction was conducted at RT.
[c] This reaction was conducted at ꢀ508C.
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posed general pathway (Scheme 4), by reduction of hemiketal
intermediates formed by a keto-alcohol/hemiketal equilibrium
(e.g., 17a!23, Scheme 4). Despite the fact that we have been
unable to develop a tandem Ferrier–Nicholas/Friedel–Crafts re-
actions to access tricyclic derivatives, the bicyclic derivatives
obtained from these oxepanes are valuable compounds dis-
playing skeletal diversity.
Reactivity and transformations of 6-O-triisopropylsilyl
derivatives
Scheme 9. Reaction of hexacarbonyl dicobalt derivative 14 with trimethoxy-
benzene and trimethylsilyl cyanide.
Since the formation of oxepanes, and derivatives therefrom,
appeared to be triggered by benzyl- or allyl-type substituents
at O-6 in hexacarbonyl dicobalt alkynyl glycals, a whole differ-
ent reactivity could be induced in these derivatives by modify-
ing the substituent at O-6. In this context, we studied the reac-
tion of 6-O-triisopropylsilyl hexacarbonyl dicobalt derivative 14
towards nucleophiles in the presence of BF3·Et2O, at ꢀ208C.
The reaction of 14 with hetaryl derivatives or allyltrimethylsi-
lane proceeded in a completely regioselective manner to give
3-C-substituted glycal derivatives 31a–e, in moderate to good
yields (Table 8).[57] The stereoselectivity of the process proved
to be high, leading almost exclusively to 3-C-a-isomers
(Table 8). The reaction of 14 with pyrrole was carried out at
ꢀ788C (Table 8).
ment of 14 with TMSCN to furnish bis-C,C-glycoside 33 in
good yield (Scheme 9b). Treatment of 14 with TMSN3 generat-
ed a complex mixture.
Some studies dealing with the influence of the nucleophile
in its site-selective incorporation to allylic/propargylic Nicholas-
type cations have appeared.[45,46] In particular, reports from
Green’s group on cyclic allylic/propargylic cations have shown
that even though the site remote to the alkyne-Co2(CO)6
moiety (g-site, C-3 substitution in our study) was the kinetically
preferred one for most nucleophiles, increasing amounts of a-
products (C-1 derivatives) were obtained with more nucleophil-
ic reagents.[46] Accordingly, the higher nucleophilicity of TMSCN
(along with its small size)[47] will be responsible for the ob-
served regioselectivity in the formation of 33.
On the other hand, treatment of trimethoxybenzene with
14, under identical reaction conditions to those in Table 8, af-
forded open-chain derivative 32 in moderate yield
(Scheme 9a). The formation of 32 might be explained through
a regio- and stereoselective substitution at C-3 followed by hy-
dration of the glycal double-bond and subsequent ring-open-
ing. In this connection, we had previously noted a related be-
havior in the C-glycosylation of C-ketosides with trimethoxy-
benzene leading to open-chain derivatives, more likely related
with the bulkiness of the reagent and the tertiary nature of C-
1.[44] Nucleophilic substitution at C-1 was observed upon treat-
Three-component reactions of 6-O-triisopropylsilyl deriva-
tives: access to carbohydrate frameworks containing two
distinct heterocycles
Some of the transformations disclosed in this work have em-
phasized the high nucleophilic nature of the glycal double-
bond on hexacarbonyl dicobalt alkynyl containing compounds,
for example, 20!21, 19!18a (Scheme 4). In this context, C-3
branched derivatives 31 still possess a reactive glycal
double-bond, and we have explored its reactivity in
two-step electrophilic addition processes (AdE).[48] We
first came across this possibility when treatment of
glycal 14 with pyrrole (2.9 equiv) in the presence of
BF3·Et2O (1.0 equiv) at ꢀ208C, afforded a mixture of
monopyrrole and dipyrrole derivatives 31 f and 34,
respectively (Table 9, entry 3). Higher temperatures
led to decomposition of the reaction mixture
(Table 9, entry 4), whereas lowering the reaction tem-
perature permitted access to increasing amounts of
monosubstituted 31 f (Table 9, compare entries 1–3).
Compound 34 was isolated as a unique stereoisomer,
thus indicating that the AdE takes place in a com-
pletely regio- and stereoselective manner.
Table 8. Reaction of 14 with nucleophiles at ꢀ208C in the presence of BF3·Et2O.[a]
The potential of pyrrole to act as a “second” nucle-
ophile (C-1), was tested in acid-catalyzed reactions of
C-3 substituted derivatives 31a–e (Table 10). Accord-
ingly, C-3-allyl derivative 31a, reacted with pyrrole in
the presence of BF3·Et2O to give C-3-allyl bis-C,C-gly-
coside 35a in 74% yield (Table 10, entry 1). The struc-
[a] Reaction conditions: 14 (0.1 mmol), BF3·Et2O (1.0 equiv), Nu (3 equiv), ꢀ208C,
CH2Cl2, 1 h. [b] This reaction was conducted at ꢀ788C. [c] Compound 31e consisted
of a 3.5:1 mixture of C-3 epimers that could not be separated, the major isomer is
shown.[57]
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Table 9. Reaction of hexacarbonyl dicobalt alkynyl glycal 14 with pyrrole
at different temperatures.[a]
Scheme 10. One-pot sequential synthesis of branched pyranosides 35d,e
from 14.
Entry
T [8C]
t [min]
31 f [%]
34 [%]
1
2
3
4
ꢀ78
ꢀ50
ꢀ20
0
20
10
15
1
51
29
15
–
34
48
Reactivity and transformations of 6-OH derivatives
[a]
[b]
–
–
The study of 6-hydroxy derivatives was also of interest since
one of the most extended applications of the Nicholas reaction
consists in the intramolecular trapping of hydroxyl groups to
obtain oxacycles of various sizes.[17d] On the other
hand, according to literature precedents and our
above-mentioned results, Ferrier-type substrates, e.g.
15, could give rise upon treatment with BF3·Et2O to
isomeric allylic oxacycles A[52] or B[53] by intramolecu-
lar trapping at either end of the allylic cation by the
6-OH nucleophile (Scheme 11).
[a] Reaction conditions: 14 (0.1 mmol), BF3·Et2O (1.0 equiv), Nu (2.9 equiv),
CH2Cl2. [b] Decomposition of the reaction mixture was observed.
Table 10. Reaction of 33 with pyrrole at ꢀ208C in the presence of BF3·Et2O.
Treatment of hydroxy-derivative 15 with BF3·Et2O
in CH2Cl2 at ꢀ208C, however, did not produce any of
the expected allylic oxacycles but resulted in the for-
mation of C-3 epimeric-1,6-anhydro, derivatives (36
and 37) along with ring contraction product 38
(Scheme 12). The relative proportion of these three
derivatives proved to vary with the reaction time
(Scheme 12). Prolonged reaction times seemed to
favor formation of higher amounts of 38 (45 min,
70% yield compared to 15 min, 36% yield) over 36
and 37, whereas short reaction times led to a more
uniform distribution of reaction products 36, 37, 38
(Scheme 11). In addition, the formation of branched
tetrahydrofuran 38 proved to be irreversible, since it
remained unchanged upon treatment with BF3·Et2O.
[a] The reaction was conducted at RT. [b] When BF3·Et2O was replaced by triphenyl-
phosphine hydrobromide (TPHB) compound 35c was obtained, after 6 h at ꢀ208C, in
20% yield.[57]
ture of 35a was unambiguously assigned on the basis of 2D
NMR spectroscopy experiments. The stereochemistries at C-3
and C-1, in compound 35a were unequivocally assigned based
on NOESY correlations of H-5 with the C-3 allyl protons and
the pyrrol NH. Likewise, treatment of C-3-hetaryl glycals 31b–
e, with pyrrole yielded derivatives 35b–e, which contain two
distinct heterocycles, in moderate to low yields. The low yields
in the generation of some of the derivatives are probably asso-
ciated with side-reactions of furan and pyrrole due to their ten-
dency to polymerize in acid-catalyzed processes.[49] No system-
atic screening of Lewis acids has been made to optimize these
results, however, replacement of catalyst BF3·Et2O with triphe-
nylphosphine hydrobromide (TPHB)[50] resulted in an increased
yield in the preparation of 35c (Table 10).[51,57]
On the contrary, treatment of bicyclic derivative 37 under relat-
ed reaction conditions generated a reaction mixture analogous
to that of 15.[54]
The reaction pathway accommodating these results would
occur by Lewis-acid activation of glycal 15, which induces the
departure of benzyl alcohol to generate Ferrier–Nicholas cation
39 (Scheme 12). The latter can then react with either the de-
parted benzyl alcohol or with the 6-OH group. Intramolecular
cyclization at C-3 in cation 39 will yield bicyclic glycal 41,
which after hydration to hemiketal 42, and retroketalization
Finally, we have found that the addition of two nucleophiles
to dicobalt hexacarbonyl glycal 14, can be carried out as one-
pot sequential operations. Accordingly, glycal 14 was treated
with N-methyl pyrrole or furan and, after TLC showed com-
plete disappearance of 14, with pyrrole to give branched pyra-
nosides 35d or 35e, respectively, with yields comparable to
those obtained in the two-step synthesis (Scheme 10).
Scheme 11. Hypothetical Ferrier reaction of 6-OH derivative 15, leading to
1,6- or 1,3-anhydro derivatives A or B, respectively.
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unable to undergo 1,6-hydride
transfers and where the 6-OH
group would behave as an inter-
nal
nucleophile,
produces
branched tetrahydrofuran deriv-
atives ensuing from a ring con-
traction process.
Experimental Section
General procedure for the
preparation of cobalt-com-
plexed enynes 12–15 and 26
A solution of Co2(CO)8 (1.2 equiv)
in anhydrous CH2Cl2 (1 mLmmolꢀ1
)
was added to a solution of the cor-
responding enyne in CH2Cl2
(10 mLmmolꢀ1). The dark solution
was stirred at room temperature
Scheme 12. Proposed reaction pathway for the formation of 36, 37 and 38 from 6-hydroxy glycal 15.
will, irreversibly, produce branched tetrahydrofuran 38. On the
until TLC showed complete formation of the complex (ca. 1–2 h).
The solvent of the resulting reaction mixture was then removed
under vacuum, and the residue was purified by flash chromatogra-
phy. Dicobalt hexacarbonyl complexed enynes 13, 15 and 26 were
used after chromatography without further characterization (12a:
86%; 12c: 69%; 12d: 70%; 13a: 80%; 13b: 77%; 13c: 98%; 13d:
83%; 13e: 76%; 13 f: 70%; 13g: 90%; 14: 87%; 15: 75%; 26a:
70%; 26d: 70%).
other hand, stereorandom intermolecular Ferrier-type reaction
of 39 with benzyl alcohol will give rise to epimeric glycals 15
and 40, from which 1,6-anhydro derivatives 36 and 37 could
be obtained, respectively, by intramolecular glycosylation.[55]
A comparison of the “expected”[52] versus observed results in
the reaction of compound 15 indicated that its reactivity was
again modified by the presence of the alkynylhexacarbonyl di-
cobalt substituent at C-1.
General procedure for the preparation of oxepanes 17, 24
and 27 from cobalt-complexed enynes
Conclusion
A solution of the corresponding cobalt complex (1 equiv) in dry
CH2Cl2 (100 mLmmolꢀ1) under an argon atmosphere and in the
presence of 4 ꢂ molecular sieves was cooled to ꢀ208C, and treat-
ed with BF3·Et2O (1.2 equiv). The mixture was kept at this tempera-
ture until no further progress was revealed by TLC analysis, and
then quenched with saturated aqueous NaHCO3. The cooling bath
was removed and the layers were separated. The aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated,
in vacuo. The crude product was purified by silica gel chromatog-
raphy.
We have shown that vinylogous Nicholas cations[56] construct-
ed from dicobalt hexacarbonyl (C-1)-alkynyl glycals, lead to
novel Ferrier-Nicholas cations that can be used to generate
skeletal diversity.[57] The overall process, is then a substrate-
based approach where the substituent at C-6 carries the pre-
encoded information. The reaction of 6-O-benzyl alkynyl-glycal
derivatives mediated by BF3·Et2O granted access to a mixture
of oxepane and 1,6-anhdro derivatives. The overall process has
been demonstrated to proceed by 1,6-hydride transfer fol-
lowed by a multistep sequence of reversible reactions involv-
ing, Prins cyclization, retroketalization of the ensuing hemike-
tal, and ring expansion. Appropriate structural modifications at
the terminal alkyne position have been found that led almost
exclusively to the formation of oxepane derivatives. Likewise,
6-O-allyl derivatives undergo a related transformation leading
to a polyfunctionalized oxepane that have been used in an in-
tramolecular Pauson–Khand cyclization leading to a single tri-
cyclic compound. If the triggering 1,6-hydride transfer step is
avoided, e.g. by use of 6-O-TIPS derivative, the system behaves
as “normal“ Ferrier substrate able to react with heteroaryl nu-
cleophiles to generate C-3 branched glycal pyranosides. An ad-
ditional transformation was still possible in these substrates
owing to the highly nucleophilic nature of the Nicholas-activat-
ed glycal double bond, and then C-3 branched, bis-C-C-glyco-
sides can be accessed by reaction in the presence of a second
nucleophile. The use of 6-hydroxy derivatives as systems
Procedure for Pauson–Khand cyclization of 27a
A solution of dicobalt-enyne complex 27a (78 mg, 0.12 mmol) in
CH2Cl2 (2 mL) under an argon atmosphere was cooled to ꢀ208C,
and treated with TMANO·2H2O in five lots (7 mg, 0.06 mmol) in
30 min intervals. Stirring was maintained until complete disappear-
ance of the dicobalt-enyne complex (TLC monitoring), and the re-
action mixture was filtered through Celiteꢃ, and washed with
CH2Cl2. The solvent was removed under vacuum and the residue
was purified by column chromatography (silica gel, hexanes/ethyl
acetate 7:3 to 1:1) to give the tricyclic compound 28 (24 mg. 49%).
Data for compound 28: [a]2D5 =ꢀ143.4 (c 0.8, CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.03–7.92 (m, 2H), 7.49–7.26 (m, 8H), 4.76 (d,
J=11.1 Hz, 1H, CH2Ph), 4.45 (d, J=11.2 Hz, 1H, CH2Ph), 4.13–4.04
(m, 2H, H-4, H-9b), 3.86–3.70 (m, 2H, H-2, H-3), 3.52–3.40 (m, 1H,
H-2), 3.33 (ddd, J=9.2, 6.6, 3.0 Hz, 1H, H-9a), 3.18 (ddd, J=10.4,
8.7, 2.3 Hz, 1H, H-5a), 3.10 (dd, J=18.7, 6.5 Hz, 1H, H-9), 2.62 (dd,
J=18.6, 3.1 Hz, 1H, H-9), 2.44 (ddd, J=14.7, 6.3, 2.1 Hz, 1H, H-5),
Chem. Eur. J. 2014, 20, 10492 – 10502
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2.01 ppm (dd, J=14.6, 12.8 Hz, 1H, H-5); 13C RMN (101 MHz,
CDCl3): d=207.7, 201.9, 161.0, 141.2, 137.2, 131.0, 130.6 (ꢄ2), 128.8
(ꢄ2), 128.8, 128.4, 128.3 (ꢄ2), 128.2 (ꢄ2), 83.0, 75.7, 72.1, 71.0, 69.1,
48.2, 46.6, 43.2, 26.0 ppm; HMRS: m/z calcd for [C25H24O5 +H]+:
405.1697; found 405.1706.
General procedure for the electrophilic addition to cobalt-
complexed enynes 31 to branched pyranoses 35
To a solution of the dicobalt-enyne complex 31 in dry CH2Cl2
(50 mLmmolꢀ1) and cooled to ꢀ208C, BF3·Et2O (1 equiv) and pyr-
role (2 equiv) were added. The mixture was kept at this tempera-
ture for the times shown in Table 7, and then quenched with satu-
rated aqueous NaHCO3. The cooling bath was removed and the
layers were separated. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo and the resi-
due was purified by column chromatography.
Procedure for tandem Nicholas–Ferrier reaction/Pauson–
Khand cyclization
A solution of dicobalt-enyne complex 26a (64 mg, 0.085 mmol) in
dry CH2Cl2 (5 mL) under an argon atmosphere and in the presence
of 4 ꢂ molecular sieves was cooled to ꢀ208C, and treated with
BF3·Et2O (14.5 mg, 0.10 mmol). The mixture was kept at this tem-
perature for 1 h, quenched by addition of Et3N (18 mL, 0.13 mmol)
at ꢀ208C and then stirred for an additional 30 min. While keeping
the temperature at ꢀ208C, TMANO·2H2O was added in five lots
(7 mg, 0.06 mmol) in 30 min intervals and then the mixture was
stirred for 1 h, filtered through Celiteꢃ, and washed with CH2Cl2.
The solvent was removed under vacuum and the residue was puri-
fied by column chromatography (silica gel, hexanes/ethyl acetate
7:3 to 1:1) to give tricyclic compound 28 (2 mg, 7%).
General procedure for the sequential one-pot synthesis of
branched pyranoses 35
A solution of the dicobalt-enyne complex 14 in dry CH2Cl2
(50 mLmmolꢀ1) and cooled to ꢀ208C, was treated with the appro-
priate nucleophile (3 equiv) and BF3·Et2O (1 equiv). The mixture
was kept at this temperature for 30 min, and then pyrrole (3 equiv)
and BF3·Et2O (1.2 equiv) were added. The mixture was kept at this
temperature until complete disappearance of the starting material
(TLC monitoring) and then the reaction mixture was diluted with
CH2Cl2 and washed with aqueous NaHCO3, water and brine. The
solvent was removed under vacuum and the residue was purified
by column chromatography.
Procedures for reaction of keto-oxepane 17a with Lewis
acid/hydride donors
Method A: A solution of dicobalt enine complex 17a (55 mg.
0.08 mmol) in dry CH2Cl2 (2 mL), under an argon atmosphere was
cooled to ꢀ508C and treated with BH3·SMe2 (0.09 mmol, 44 mL,
2.0m solution in THF) and TMSOTf (41 mg, 0.18 mmol). The mixture
was kept at this temperature until complete disappearance of the
starting material (TLC monitoring) and then the reaction mixture
was diluted with CH2Cl2 and washed with aqueous NaHCO3, water
and brine. The solvent was removed under vacuum and the resi-
due was purified by column chromatography (silica gel, hexanes/
ethyl acetate 95:5) to give compound 29 as an inseparable 1:1
mixture of diastereomers (32 mg, 60%). Method B: A solution of di-
cobalt enine complex 17a (42 mg, 0.06 mmol) in dry CH2Cl2 (2 mL),
under an argon atmosphere was treated with Et3SiH (14 mg,
0.12 mmol) and InCl3 (41 mg, 0.18 mmol). The mixture was kept at
this temperature until complete disappearance of the starting ma-
terial (30 min) and then the reaction mixture was diluted with
CH2Cl2 and washed with aqueous NaHCO3, water and brine. The
solvent was removed under vacuum and the residue was purified
by column chromatography (silica gel, hexanes/ethyl acetate 95:5)
to give compound 29 (15 mg, 37%).
Acknowledgements
The authors are grateful to the MInisterio de Economꢅa y Com-
petitividad for grant CTQ2012-32114. F.L. and S.M. are grateful
to Consejo Superior de Investigaciones Cientꢅficas (CSIC) and
Ministerio de Economia y Competitividad, respectively, for pre-
doctoral scholarships.
Keywords: Ferrier reaction · glycals · Nicholas reaction ·
synthesis design · synthetic methods
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Received: February 12, 2014
Published online on July 10, 2014
Chem. Eur. J. 2014, 20, 10492 – 10502
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10502
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim