Synthesis of a functionalized furan via ozonolysis-further confirmation of the Criegee mechanism

Article abstract of DOI:10.1016/j.tetlet.2010.05.129

A new method for the synthesis of a tetrahydrofuran ring is described which involves ozonolysis of a diene possessing a free hydroxy group in the γ-position. The reaction proceeds via ozone attack on the terminal double bond, cleavage, and intramolecular cyclization through the free hydroxy group. The cyclization event can be rationalized through formation of Criegee's carbonyl oxide, but not through the 'unified' mechanism, thereby lending support to the Criegee mechanism as a method of producing oxygen-containing heterocycles.

Full text of DOI:10.1016/j.tetlet.2010.05.129

Tetrahedron Letters 51 (2010) 4079–4081
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a functionalized furan via ozonolysis—further confirmation
of the Criegee mechanism
b
b
b
Veaceslav Kulcißtki a, , Andrea Bourdelais , Tomas Schuster , Daniel Baden
*
a
˘
Institutul de Chimie al ASßM, str. Academiei, 3, MD-2028, Chißsinau, Republic of Moldova
b Center for Marine Sciences (CMS), University of North Carolina at Wilmington, 5600 Marvin K. Moss Lane, Wilmington, NC 28409, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the synthesis of a tetrahydrofuran ring is described which involves ozonolysis of a
Received 7 April 2010
Revised 11 May 2010
Accepted 28 May 2010
Available online 1 June 2010
diene possessing a free hydroxy group in the c-position. The reaction proceeds via ozone attack on the
terminal double bond, cleavage, and intramolecular cyclization through the free hydroxy group. The
cyclization event can be rationalized through formation of Criegee’s carbonyl oxide, but not through
the ‘unified’ mechanism, thereby lending support to the Criegee mechanism as a method of producing
oxygen-containing heterocycles.
Keywords:
Ozonolysis
Criegee
Ó 2010 Elsevier Ltd. All rights reserved.
Tetrahydrofurans
Terpenoids
Oxygen-containing heterocycles are structural motifs widely
found in natural products of different origins. A range of biologi-
cally active compounds such as C-nucleosides, ionophore antibiot-
ics, acetogenins, and brevetoxins incorporate cyclic polyether
moieties in their structural backbone. Consequently, considerable
effort has been undertaken to elaborate new and efficient synthetic
methods to access cyclic ethers of different ring sizes.1 Functional-
ized polyethers are of particular interest in synthetic organic meth-
odology, because their synthesis often requires considerable effort.
Historically, different strategies have been undertaken in order
to access functionalized O-heterocycles. The most common strat-
egy is based on a biomimetic approach and consists of assembling
the specifically functionalized aliphatic chain, followed by a C–O
cyclization reaction, promoted by different electrophilic or radical
initiators.1 Typically, the formation of cyclic ethers is a two-step
process involving the formation of a carbocation through electro-
philic addition to an olefin, followed by intramolecular nucleo-
philic attack of an oxygen substituent on the carbocation
(Scheme 1). This strategy works well for the synthesis of tetrahy-
drofuran ring systems. On the other hand, the utility of a conju-
gated diene system in such a transformation is under explored.
In our opinion, the conjugated system can contribute to an alterna-
tive reaction course and may result in greater flexibility for build-
ing functionalized oxygen heterocycles.
polyethers containing conjugated dienes.2 We envisioned that this
functionality could be used for further functionalization of natural
ladder frame polyethers.
In order to check the feasibility of this approach, we designed a
model compound to mimic the lateral chain with conjugated dou-
ble bonds that incorporates a free hydroxy group at the c-position
with respect to the olefinic bond. Based on the general mechanism
of tetrahydrofuran formation (Scheme 1), one can assume that the
generation of a carbonium ion in the lateral chain would inevitably
lead to a cyclization event involving the free hydroxy group to pro-
vide a functionalized furan ring. The synthesis of the model sub-
strate 1 is presented in Scheme 2.3 The bicyclic system of 1
possesses a conjugated double bond in an equatorial position and
a tertiary hydroxy group trans-configured relative to the lateral
chain. It is noteworthy that an isoprenoid polycycle has recently
been used as a model to support an alternative mechanism for
the synthesis of marine polyether toxins.4
Functionalization of conjugated double bonds can be performed
by selective ozonolysis, and this type of transformation is well doc-
umented for similar substrates.5,6 In particular, it was demon-
strated that the ozonolysis of conjugated double bonds proceeds
X+
Research on the isolation of polyethers from the marine dinofla-
gellate Karenia brevis has delivered various families of ladder frame
+
-R+
OR
O
O
R
X
X
X=I or Br
* Corresponding author. Tel.: +373 22 739769; fax: +373 22 739954.
E-mail address: kulcitki@yahoo.com (V. Kulcißtki).
Scheme 1. Formation of tetrahydrofurans through carbocation generation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.129

4080
V. Kulcißtki et al. / Tetrahedron Letters 51 (2010) 4079–4081
12
13
CHO
14
15
[Ph3PCH2-CH=CH2]+Br-
1. KOH/EtOH
OAc
OAc
OH
n-BuLi, THF
2. HPLC
76%
3 13-Z (70%)
4 13-E (30%)
2
1
Scheme 2. Synthesis of model substrate 1.
12
12
11
OH
OH
19
10
17
15
14 O
1
15
1. O3/CH2Cl2; 0 ºC
1. O3/CH2Cl2; -70 ºC
10
8
OH
OH
3
2. NaBH4
70%
2. NaBH4
60%
5
17
18
16
6
1
5
Scheme 3. Ozonolysis reactions of 1.
+
+
-
O
-
O
O
O
O
O
O3/CH2Cl2; 0 ºC
O
1
OH
OH
OH
7
8
9
O
OH
O
O
O
O
O
O
~H+
NaBH4
6
10
11
Scheme 4. Proposed mechanism for the synthesis of tetrahydrofuran 6.
sequentially,5 and we also planned to transform selectively the lat-
eral chain of 1 under different ozonolysis conditions.
sodium borohydride to form the alcohol 6. Similar ‘abnormal’
ozonolysis has been reported and explained on the basis of the
intramolecular involvement of the free hydroxy group during the
reaction.12
Tetrahydrofurans similar in structure to alcohol 6 are well
known but their formation was based on a different mechanism,
suggested on the basis of involvement of iodine in the reaction se-
quences.13 From a synthetic point of view, the presence of the
hydroxymethylene group at C12 in alcohol 6 represents an alterna-
tive opportunity for further functionalization.
In summary, a new method for the synthesis of tetrahydrofu-
rans has been demonstrated. The procedure based on a tandem
ozonolysis-cyclization reaction provides a good yield of the hetero-
cyclic compound, possessing a lateral chain for further functional-
ization. To the best of our knowledge, this is the first example of
ozonolysis of a conjugated diene with simultaneous cyclization,
through utilization of an appropriately positioned hydroxy group,
to prepare oxygen-containing heterocycles. The practical utility
of the newly synthesized compound is currently under
investigation.
Following these hypotheses, alcohol 1 was submitted to ozonol-
ysis (Scheme 3). Ozone was added in slight excess and the reaction
was performed at different temperatures. At À70 °C, the major
product, after borohydride reduction, was the known diol 5—a
product of C12–C13 double bond cleavage. Performing the ozonol-
ysis at 0 °C provided a compound containing two carbon atoms less
than the initial diene side-chain suggesting cleavage of the C13–
C14 bond.7 The structure of this compound was determined as 6
using 1D and 2D NMR experiments.
The formation of alcohol 6 was quite unexpected, but the reac-
tion course can be explained on the basis of the Criegee mecha-
nism.8 It is well known that this mechanism was the subject of
controversial discussions and the most relevant alternative is the
so-called unified concept.9
Recent work on this subject, employing labeled atoms,10 has
shown the viability of the Criegee scheme. Our current work brings
further experimental evidence for this conclusion. In fact, the for-
mation of alcohol 6 is only possible via Criegee’s carbonyl oxide
8 (Scheme 4). Its stabilization by conjugation with the adjacent
double bond leads to a partial positive charge at C12, intramolecu-
lar attack by the hydroxy group then forms the corresponding het-
erocycle 10. Since the stability of the formed vinylic hydroperoxide
is extremely low,11 it decomposes to the aldehyde 11, (possibly via
a strained four-membered cyclic peroxide) which is reduced with
Acknowledgments
V.K. is grateful to MRDA/CRDF for a travel grant MTFP-04-05.
Dr. Allan Goodman (CMS) and Dr. Nicon Ungur (ASßM) are acknowl-
edged for valuable help during manuscript preparation.

V. Kulcißtki et al. / Tetrahedron Letters 51 (2010) 4079–4081
4081
1H); 5.61 (m, 1H); 5.96 (t, J = 11 Hz, 1H); 6.77 (dt, J = 6, 5 Hz, 1H). 13C NMR
(125 MHz, CDCl3): dC = 15.61 (C17); 18.78 (C2); 20.53 (C1); 21.77 (C18); 23.84
(C11); 24.54 (C16); 33.49 (C4); 33.67 (C19); 36.53 (C10); 40.42 (C6); 42.05
(C7); 44.38 (C3); 56.31 (C5); 62.42 (C9); 74.39 (C8); 117.35 (C15); 128.04
(C13); 132.37 (C14); 135.79 (C12). IR (cmÀ1): 598; 903; 1122; 1387; 1462;
2928; 3336.
References and notes
1. Elliott, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303. and previous
reviews in this series.
2. Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M., Jr.; Baden, D. G. J.
Nat. Prod. 2005, 68, 2.
4. Giner, J. L. J. Org. Chem. 2005, 70, 721.
3. Compounds 3 and 4. Triphenylphosphonium allyl bromide (2.20 g, 5.72 mmol)
was suspended in 15 mL of dry THF and treated with 3.5 mL of n-BuLi solution
in hexanes (1.6 M, 5.72 mmol) at 0 °C under argon. The obtained solution was
gradually warmed to room temperature over 30 min, then cooled to À30 °C,
and a solution of 561 mg (1.91 mmol) of 214 in 12 mL of THF was added
dropwise. Stirring was continued at rt for 2 h, after which TLC analysis showed
no remaining starting material. Diluting the reaction mixture with H2O (50 mL)
was followed by work-up, consisting of extraction with Et2O (3 Â 25 ml) and
washing the organic phase successively with dilute H2SO4, saturated sodium
bicarbonate solution, and brine to bring the pH to neutral. Drying over
anhydrous Na2SO4 and evaporation of the solvent under reduced pressure gave
the crude product which was submitted to column chromatography over silica
gel. Elution with 5% EtOAc in petroleum ether gave 400 mg of a mixture of 3
and 4 as an oil, in a 7:3 ratio. 1H NMR (500 MHz, CDCl3, selected): dH = 0.807 (s),
0.811 (s), 0.87 (s), 0.89 (s), 0.90 (s)—all 9H; 1.48 (s), 1.50 (s)—all 3H; 1.91 (s),
1.92 (s)—all 3H; 4.94 (d, J = 10 Hz, 0.4H); 5.07 (d, J = 10 Hz, 0.4H), 5.09 (d,
J = 16.5 Hz, 0.6H); 5.18 (d, J = 16.5 Hz, 0.6H); 5.51 (m, 0.6H); 5.75 (m, 0.4H);
5.91 (t, J = 11 Hz, 0.6H); 6.01 (dd, J = 10, 15 Hz, 0.4H); 6.31 (dt, J = 10, 17 Hz,
0.4H); 6.73 (dt, J = 10, 17 Hz, 0.6H). IR (cmÀ1): 1250; 1728; 2933. A mixture of 3
and 4 (260 mg, 0.82 mmol) was treated with a solution of KOH (448 mg,
8 mmol) in EtOH (5 mL) for 2 h at gentle reflux. Dilution with H2O and usual
work-up gave a mixture of 1 and its corresponding E-isomer. This mixture was
5. Griesbaum, K.; Zwick, G. Chem. Ber. 1985, 118, 3041.
6. Aricu, A.; Vlad, P. Russ. Chem. Rev. 1992, 61, 1303.
7. Preparation of 6. Diene 1 (10 mg, 0.036 mmol) was dissolved in CH2Cl2 (0.5 mL)
and treated with 1.5 mL of a saturated O3 solution in CH2Cl2 at 0 °C for 10 min.
Removal of excess O3 with a stream of argon was followed by addition of excess
NaBH4 and stirring was continued at rt for 2 h. Dilution with H2O and usual
work-up (see Ref. 3) gave the crude product which was submitted to column
chromatography over silica gel. Elution with 25% EtOAc in petroleum ether
gave 6 mg of 6 (yellow liquid). 1H NMR (500 MHz, CDCl3): dH = 0.84 (s, 3H);
0.85 (s, 3H); 0.88 (s, 3H); 0.95–1.10 (m, 3H); 1.16 (s, 3H); 1.30 (m, 1H); 1.40–
1.60 (m, 6H); 1.70–1.77 (m, 3H); 1.95 (m, 1H); 3.56 (dd, J = 7.5, 15 Hz, 1H); 3.67
(dd, J = 3.5, 10 Hz, 1H); 4.15 (m, 1H). 13C NMR (125 MHz, CDCl3): dC = 15.73
(C17); 18.61 (C2); 21.12 (C1); 21.24 (C15); 25.07 (C14); 25.41 (C11); 33.30
(C4); 33.72 (C16); 36.53 (C10); 40.20 (C7); 40.60 (C6); 42.65 (C3); 57.28 (C5);
60.90 (C9); 67.20 (C13); 79.30 (C12); 81.10 (C8). IR (cmÀ1): 827; 912; 1009;
1376; 2921; 3430.
8. Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 745.
9. Story, P. R.; Alford, J. A.; Burgess, J. R.; Ray, W. C. J. Am. Chem. Soc. 1971, 93,
3044.
10. Geletneky, C.; Berger, S. Eur. J. Org. Chem. 1998, 1625.
11. Richardson, W. H. J. Org. Chem. 1995, 60, 4090.
12. Everest, D. J.; Grant, P. K.; Slim, G. C. Aust. J. Chem. 1988, 41, 1025.
13. Barton, D. H. R.; Taylor, D. K.; Tse, C. Tetrahedron Lett. 1994, 51, 9505.
14. Barrero, A. F.; Manzaneda, E. A.; Altarejos, J.; Salido, S.; Ramos, J. M.; Simmonds,
M. S. J.; Blaney, W. M. Tetrahedron 1995, 51, 7435.
submitted to HPLC separation on
a Phenomenex Luna 5 lm C18 semi-
preparative column (9:1 MeOH–H2O) to provide pure 1 (yellow liquid). 1H
NMR (500 MHz, CDCl3): dH = 0.81 (s, 3H); 0.86 (s, 3H); 0.88 (s, 3H); 0.91–0.99
(m, 2H); 1.16 (m, 1H); 1.20 (s, 3H); 1.23–1.49 (m, 5H); 1.51–1.75 (m, 4H); 1.87
(m, 1H); 2.25 (m, 1H); 2.46 (m, 1H); 5.13 (d, J = 10 Hz, 1H); 5.21 (d, J = 17 Hz,