Ruthenium-catalyzed oxidative cyclization of 1,7-dienes. A novel diasteroselective synthesis of 2,7-disubstituted trans-oxepane diols

Article abstract of DOI:10.1016/j.tetlet.2007.05.078

The ruthenium-catalyzed oxidation of some representative 1,7-dienes has been investigated. Tetrasubstituted 1,7-dienes are transformed into the corresponding trans-2,7-bis-hydroxyalkyl-oxepanes through an oxidative cyclization process. The process proceeds with an excellent stereoselectivity level.

Full text of DOI:10.1016/j.tetlet.2007.05.078

Tetrahedron Letters 48 (2007) 5131–5135
Ruthenium-catalyzed oxidative cyclization of 1,7-dienes. A novel
diasteroselective synthesis of 2,7-disubstituted trans-oxepane diols
Vincenzo Piccialli,a,* Nicola Borboneb and Giorgia Olivierob
a
`
Dipartimento di Chimica Organica e Biochimica, Universita degli Studi di Napoli ‘Federico II’, Via Cynthia 4, 80126, Napoli, Italy
b
`
Dipartimento di Chimica delle Sostanze Naturali, Universita degli Studi di Napoli ‘Federico II’,
Via D. Montesano 49, 80131, Napoli, Italy
Received 5 April 2007; revised 8 May 2007; accepted 11 May 2007
Available online 18 May 2007
Abstract—The ruthenium-catalyzed oxidation of some representative 1,7-dienes has been investigated. Tetrasubstituted 1,7-dienes
are transformed into the corresponding trans-2,7-bis-hydroxyalkyl-oxepanes through an oxidative cyclization process. The process
proceeds with an excellent stereoselectivity level.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Ruthenium tetroxide is known to catalyze the stereo-
selective formation of 2,5-bis-(hydroxyalkyl)-substituted
THF and THP rings from 1,5-1 and 1,6-dienes,2 respec-
tively (Scheme 1), in the presence of sodium periodate as
the reoxidant. Related oxidative cyclization processes,
mediated by other transition metal-oxo species such as
OsO4, MnO4ꢀ, RuO4ꢀ, are also known;3 on the other
hand, the ruthenium-mediated oxidation of 1,7-dienes
has never been investigated. Therefore, we decided to
probe the possibility of obtaining 2,5-disubstituted oxe-
pane diol products under conditions causing the oxida-
tive cyclization of other diene types. Seven-membered
oxacycles are present in many biologically active natural
products such as Laurencia acetogenin metabolites4 and
polyether marine toxins.5 In these compounds the oxe-
pane ring is very often 2,7-dialkylsubtituted. While some
efficient methods toward the stereoselective synthesis of
2,7-cis-oxepanes have been developed,6 few methods
have been so far devised to generate the 2,7-trans-oxe-
pane system.6
We report here the first successful ruthenium-catalyzed
oxidative cyclization of 1,7-dienes to trans-oxepane diol
products and related results on the oxidation of less
substituted 1,7-dienes. Starting dienes 1–37 were synthe-
sized as shown in Scheme 2. The parent diene 1,7-octadi-
ene is commercially available.
Os, Ru, Mn
oxo-species
R1
R4
R1
R2
R6
R5
OH
R6
R2
O
Taking into account the electrophilic character of RuO4,
and precedents from the oxidation of 1,5-1 and 1,6-
dienes,2 the substituted diene 2,9-dimethyldeca-2,8-diene
(1) was initially selected as a good substrate to probe the
effectiveness of the cyclization process. The first attempt
to cyclize diene 1 was carried out under the conditions we
previously employed for THF and THP formation
(5 mol % RuO22H2O as pre-catalyst, NaIO4 (4 equiv),
EtOAc/CH3CN/H2O (3:3:1)) (Table 1, entry 1).
Although TLC analysis revealed a clean conversion, as
indicated by the presence of a single spot at Rf = 0.25
(hexane/EtOAc, 7:3), the reaction failed to go to comple-
tion and a 60% mass recovery resulted after work-up at
ca 60% conversion. Preparative HPLC8 afforded the
cyclization product 4a9 (Scheme 3) in an encouraging
R3 R4
HO
R3
R5
Ru and Mn
oxo-species
R3
R4
R1
R2
HO
R1
R3
R4
O
R2
H
H
OH
Ru: trans-THP
Mn: cis-THP
Scheme 1. Formation of THF and THP diols by oxidative cyclization
of 1,5- and 1,6-dienes with metal-oxo species.
Keywords: Oxidative cyclization; 1,7-Dienes; trans-Oxepanes; Ruthe-
nium-catalyzed process.
*
Corresponding author. Tel.: +39 81 674111; fax: +39 81 674393;
e-mail: vinpicci@unina.it
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.078

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V. Piccialli et al. / Tetrahedron Letters 48 (2007) 5131–5135
i,ii
iii
O
O
1
iv,v,vi
vii, viii, ix
BzO
AcO
OBz
OAc
3
2
Scheme 2. Synthesis of 1,7-dienes. Reagents and conditions: (i) OsO4 (2 mol %)/NMO (1.2 equiv), acetone/H2O (9:1), 1 h; (ii) NaIO4 (2 equiv),
dioxane/H2O (7:3), 15 min (90%, for two steps); (iii) Me2CPPh3 (2.2 equiv), THF, ꢀ78!0 ꢁC, 2 h (50%); (iv) (EtO)2POCH2CO2Et, NaH, THF, rt;
(v) DIBAL–H, THF, ꢀ78ꢁC; (vi) BzCl, py, rt, 2 h; (vii) SeO2 (0.5 equiv), t-BuOOH (2 equiv), CH2Cl2; (viii) NaBH4, EtOH, 0.5 h; (ix) Ac2O–py,
50 ꢁC, 2 h (58% for three steps).
Table 1. Optimization of the reaction conditions for the cyclization of diene 1
Entry
Co-oxidant (equiv)
Solvent
Ru pre-catalyst (mol %)
Temperature (ꢁC)
Yield (%)
Time
1
2
3
4
NaIO4 (4)
NaIO4 (7)
NaIO4 (7)/wet silica
NaIO4 (7)/wet silica
EtOAc/CH3CN/H2O (3:3:1)
EtOAc/CH3CN/H2O (3:3:1)
THF/CH2Cl2 (9:1)
RuO2Æ2H2O (5)
RuO2Æ2H2O (20)
RuCl3 (10)
0
ꢀ10
0
26a
38b
24
1.5 h
2 h
24 h
EtOAc/CH3CN (1:1)
RuCl3 (5)
0
63
15 min
a Based on reacted 1 at 60% conversion.
b Based on reacted 1 at 90% conversion.
RuCl3 (5 mol%)
NaIO4/wet SiO2 (7 equiv.)
O
OH
+
HO2C
O
H
H
CH3CN/EtOAc (1:1), 0ºC,
15 min, (dr >95:5)
OR
1
HO
5 (9%)
4a R=H, 63%
p
BrBzCl (14 equiv.)-
DMAP (7.5 equiv.)
CH2Cl2, r.t., 6h, 50%
4b R=pBrBz
RuCl3 (5 mol%)
NaIO4/wet SiO2 (7 equiv.)
O
AcO
OAc
AcO
HO2C
+
OAc
O
OAc
CH3CN/EtOAc (1:1), 0ºC,
15 min, (dr >95:5)
OH
H
H
OH
7 (20%)
2
HO
6 (40%)
Scheme 3. RuO4-catalyzed oxidative cyclization of 1,7-dienes.
26% yield (based on reacted 1) and, most importantly, as
a single diastereoisomer.
Derivatization of 4a, carried out with p-bromobenzoyl
chloride/DMAP in CH2Cl2, afforded mono p-bro-
mobenzoate 4b10 (Scheme 3) suitable for NMR studies.
The proton spectrum of this material showed a good
proton dispersion allowing to collect unambiguous ste-
reostructural evidence from a set of 2D NMR experi-
ments. Aided by the strong tendency of 4a to
crystallize, we could confirm the stereostructure of this
compound by X-ray diffraction analysis (Fig. 1)11 car-
ried out on a single crystal of 4a obtained from CHCl3
by slow evaporation of the solvent. The collected data
confirmed the trans-configuration of 4a and showed that
the oxepane ring adopts the twisted-chair conformation,
as usually found in the X-ray structures of other oxe-
pane derivatives.12 This conformation also appears to
be the one adopted by 4b in solution as indicated by
NOE data and J values.
Figure 1. ORTEP drawing of oxepane 4a.
Further attempts to improve the yields of the process
were carried out as shown in Table 1. In an attempt to
force the process to completion the oxidation was con-
ducted by raising the RuO2 amount to 20% and initially
using 4 equiv NaIO4. However, two further amounts of

V. Piccialli et al. / Tetrahedron Letters 48 (2007) 5131–5135
5133
co-oxidant (20%+10%; overall NaIO4 7 equiv; consecu-
tive additions within 16 h) and an additional 20 mol %
of pre-catalyst were required to cause a complete con-
sumption of the substrate; nevertheless, still a modest
yield (24%, HPLC) of oxepane diol 4a was obtained.
When the 7 equiv amount co-oxidant was added all at
once at ꢀ10 ꢁC (Table 1, entry 2) the yield was improved
to 38% with a <10% recovered starting diene. Successive
reactions were carried out employing this amount of co-
oxidant. The need for such a quantity of NaIO4 is diffi-
cult to explain in view of our own experience,1b,2a,3 and
results reported by others,1a–d,2b which show the amount
of co-oxidant required to force to completion the cycli-
zations of 1,5- and 1,6-dienes to be 2.5–4 equiv.
6:4), were obtained as the main reaction products (ca.
70% overall yield, 9/10, 8:1). This result is in good agree-
ment with the results reported by this author for the oxi-
dation of simple alkenes and indicates a preference for
ketone group formation at the internal carbons of each
double bond. As far as we know this is the first report of
the ketohydroxylation of a diene and, due to the good
regiocontrol, this process, when suitably tuned, may
have synthetic value.
From a mechanistic point of view, we presume a path-
way similar to that proposed by Baldwin et al.15 for
the analogous MnO4ꢀ-mediated oxidative cyclization
of 1,5-dienes (Scheme 5). Thus, the initial [3+2] cycload-
dition16 between RuO4 and one of the double bonds of
the diene lead to the formation of a ruthenium(VI) dies-
ter. Next, this one intercepts the distal double bond
through a second, intramolecular, [3+2] cycloaddition
involving an O–Ru@O portion. This is a diasteroselec-
tive step that sets the trans junction of the oxepane ring.
Release of the products by hydrolysis then follows with
concomitant production of a low-valent Ru-species
whose reoxidation by NaIO4 regenerates RuO4.
Exclusion of water from the reaction mixture has
recently been demonstrated to increase yields of the
THF diols obtained from the Ru-catalyzed oxidation
of 1,5-dienes.1d However, running the process in THF/
CH2Cl2 (9:1), with RuCl3 as pre-catalyst and NaIO4
(7 equiv) supported on wet silica (entry 3), as reported,1d
4a was obtained in a diminished 24% yield along with
ketol 5 (50%) and scission products, among which adipic
acid was the most abundant one (ca. 20%). Gratifyingly,
an improved 63% yield of 4a was eventually obtained
when the oxidation of 1 was carried out in EtOAc/
CH3CN (1:1) by using the same NaIO4 (7 equiv)/wet
SiO2 pair (entry 4);2b the yield of ketol side product 5
was also reduced to 9%.
It is probable that both the increased conformational
freedom and the stability of the first-formed ruthe-
nium(VI) diester play a role in determining the success of
the cyclization step. We presume that for less substituted
dienes, the Ru(VI) diester intermediate is more suscepti-
ble to decompose (Scheme 5) hydrolytically, generating
a diol that can undergo successive oxidative scission to
carbonyl compounds. Alternatively, the direct fragmen-
tation of the intermediate may occur giving rise to
carbonyl compounds that are further oxidized to
carboxylic acids. a-Hydroxy ketones 9 and 10 may form
from the same intermediate according to Plietker’s
mechanistic proposal (ketohydroxylation pathway).14
Next, the process was tested on other 1,7-dienes under
the optimized conditions. 1,8-Diacetoxy-diene 2 gave
trans-oxepane 6 (Scheme 3)13 in a 40% yield along with
the scission product 7 (20%). Commercially available
1,7-octadiene only gave adipic acid in >90% yields
through the scission pathway. All-trans diene 3 could
not be persuaded to cyclize under a variety of conditions
(Scheme 4). In particular, oxidation of 3 under opti-
mized conditions gave a mixture of oxidation products
including scission products and di- and tetra-hydroxyde-
rivatives. Oxidation with RuO2/NaIO4 gave alkene diol
8 in a 40% yield along with small amounts of scission
products. A further attempt was carried out using
Oxoneꢂ as the co-oxidant, according to the procedure
recently reported by Plietker14 for the oxidation of
alkenes. In this case regioisomeric bis-ketols 9 and 10,
isolated as acetylderivatives (HPLC, hexane/EtOAc,
It is also to be noted that the above results are in line
with those reported for the oxidative cyclization of
1,5- and 1,6-dienes with RuO4 for which the best yields
of cyclized products are usually obtained with more
substituted substrates.1c,d,2
In conclusion we have shown for the first time that the
closure of oxepane rings through the RuO4-catalyzed
oxidative cyclization of an 1,7-diene is a possible
RuCl3/wet silica
Mixture of
oxidation products
OAc
O
O
BzO
BzO
BzO
OBz
OBz
RuCl3 (1 mol%)-
Oxone (5 equiv.)
NaHCO3 (2.5 eqiv.),
OAc
3
9 (60%)
RuO2/NaIO4
+
O
OAc
OH
AtOAc/CH3CN/H2O
(6:6:1), r.t
BzO
OBz
OBz
OAc
10 (8%)
O
OH
8 (40%)
Scission products
+
Scheme 4. Ru-catalyzed oxidation of a disubstituted 1,7-diene.

5134
V. Piccialli et al. / Tetrahedron Letters 48 (2007) 5131–5135
[3+2]
cycloaddition
Alternative pathways:
hydrolysis,
O
2
O
oxidative scission,
Ru
O
ketohydroxylation
Ru
Diols, tetrols,
carbonyl compounds,
α-ketols
O
O
O
O
O
Ru(VI) diester
trans-diasteroselective
[3+2] cycloaddition
(see arrows)
NaIO4
(reoxidation)
RuO2
or
RuCl3
low-vlent
Ru species
O
hydrolysis (H2O)
O
O
Ru
O
O
OH
OH
Scheme 5. Proposed catalytic cycle for the ruthenium-catalyzed oxidative cyclization of 1,7-diene.
Ed. 2001, 40, 4496–4498; (f) Cecil, A. R. L.; Brown, R. C.
D. Tetrahedron Lett. 2004, 45, 7269–7271; RuO4 Picci-
alli, V.; Caserta, T. Tetrahedron Lett. 2004, 45, 303–308.
4. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2003, 20, 1–48, and
earlier reviews in the same series.
process. This represents a novel approach to the forma-
tion of seven-membered oxacycles17 that further amplify
the knowledge of Ru-catalyzed oxidative cyclization of
dienes.
ꢀ
5. See, for example, (a) Hirama, M.; Oishi; Tuehara, H.;
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therein.
Acknowledgement
We are grateful to the ‘Centro di Metodologie Chimico-
`
Fisiche dell’Universita Federico II di Napoli’ for NMR
facilities.
References and notes
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