Highly efficient catalytic routes to spiroketal motifs

Article abstract of DOI:10.1016/j.tetlet.2008.12.075

The versatile and efficient synthesis of a variety of spiroketal motifs via the double intramolecular hydroalkoxylation of aliphatic and aromatic alkyne diols was achieved using simple and readily accessible Ir(I) and Rh(I) cyclooctadiene complexes as cat

Full text of DOI:10.1016/j.tetlet.2008.12.075

Tetrahedron Letters 50 (2009) 1125–1127
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient catalytic routes to spiroketal motifs
a,
Selvasothi Selvaratnam a, Joanne H. H. Ho b, Paul B. Huleatt a, Barbara A. Messerle b, , Christina L. L. Chai
*
*
a
*
Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (A STAR), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
b School of Chemistry, University of New South Wales, Kensington, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The versatile and efficient synthesis of a variety of spiroketal motifs via the double intramolecular hydro-
alkoxylation of aliphatic and aromatic alkyne diols was achieved using simple and readily accessible Ir(I)
and Rh(I) cyclooctadiene complexes as catalysts.
Received 3 November 2008
Revised 7 December 2008
Accepted 16 December 2008
Available online 24 December 2008
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hydroalkoxylation
Spiroketal
Catalysis
Coupling
The spiroketal functionality is an important structural motif
that is often found in biologically active natural products
including insect pheromones,1,2 polyether antibiotics,3 and
spongistatins/altohyrtins.4 In light of this, there is much inter-
est in the development of synthetic methodologies that will
enable rapid and efficient access to spiroketal skeletons under
the mildest possible reaction conditions. The latter is important
in view of the complexity of the functionalities that may be
present on the spiroketal moiety. Not surprisingly, a number
of synthetic routes to spiroketals have been reported. Most of
these routes utilize dihydroxyketones or equivalents as
intermediates.5,6
{PyP = 1-[(2-diphenylphosphino)ethyl]pyrazole} and [Rh(bim)-
(CO)2]BPh4 {bim = bis(N-methylimidazol-2-yl)methane}) can effi-
ciently catalyze the double hydroalkoxylation of both terminal
and internal alkyne diols.
As part of our ongoing program to develop efficient syn-
thetic routes to O,O-acetals, we report here a rapid and versa-
tile route to the construction of spiroketal skeletons via the
double intramolecular hydroalkoxylation of alkyl and aryl
internal alkyne diols, using the very simple Ir(I) and Rh(I)
cyclooctadiene catalysts 1–3. These catalysts can be easily pre-
pared in one step from the corresponding commercially avail-
able dimeric metal complexes.13
The limitations of these methods are that often multi-step syn-
theses are involved and they require purification of mixtures that
can be rather complex.
Our initial studies were performed with the alkyne diol 4,
which was easily prepared via the ring opening of methyloxira-
ne with the lithio derivative of 1-(2-tetrahydropyranyloxy)-4-
pentyne. Removal of the THP protecting group afforded the de-
sired diol 4.14 Treatment of the alkyne diol 4 with 1 mol % of
[Ir(COD)2]BARF (1) at room temperature in 1,1,2,2-tetrachloro-
ethane-d2, (CDCl2)2 gave the corresponding spiroketal 11 with
quantitative conversion in 0.5 h (Table 1, entry 1).15,16 Decreas-
ing the catalytic loading to 0.5 mol % gave the desired product
with similar high conversion in 1.5 h. The spiroketal 11 was
obtained as a mixture of two diastereomers in the ratio of
1.7:1. In contrast, Utimoto reported that the Pd(II)-catalyzed
cyclization of substrate 4 yielded the corresponding spiroketal
in a 1:1 diastereomeric ratio.7a The Rh(I) catalyst 2 proved to
be less efficient than its Ir(I) analogue 1 in promoting the dou-
ble hydroalkoxylation reaction of alkyne diol 4. Complete con-
version was only achieved in 2.5 h at 90 °C with a catalyst
loading of 5 mol %.
Surprisingly, examples of single-step transition metal-cata-
lyzed approaches to spiroketals are rather limited. Pd(II), Pt(II),
and Au(I) complexes have been utilized to catalyze the hydroalk-
oxylation of internal alkynols.7–9 [Ir(
l
-Cl)(COD)]2 (COD = 1,5-
cyclooctadiene) and Rh(I) complexes of the type [Rh(PR3)3Cl]
and [Rh(l-Cl)(COD)]2 have also been reported to promote the
tandem hydroalkoxylation of terminal propargylic alcohols.10,11
In the case of the rhodium complexes, the addition of excess
phosphine ligand (up to 55%) is necessary to suppress side reac-
tions. Recently, Messerle et al.12 demonstrated that Ir(I) and
Rh(I) complexes bearing N-donor ligands ([Ir(PyP)(CO)2]BPh4
* Corresponding authors. Tel.: +61 2 9385 4653; fax: +61 2 9385 6141 (B.A.M.),
tel.: +65 6796 3902; fax: +65 6316 6184 (C.L.L.C).
E-mail addresses: b.messerle@unsw.edu.au (B.A. Messerle), Christina_Chai@ices.
a-star.edu.sg (C.L.L. Chai).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.075

1126
S. Selvaratnam et al. / Tetrahedron Letters 50 (2009) 1125–1127
Table 1
[Ir(COD)2]BARF (1), [Rh(COD)2]BARF (2), and [Rh(COD)2]PF6 (3) catalyzed synthesis of spiroketals from alkyne diolsa
Entry
Substrate
Product(s)
Catalyst (mol %)
Temperature (°C)
>98% Conversion (h)
OH
1
1, 0.5
1, 1.0
2, 1.0
2, 5.0
25
25
90
90
1.5
0.5
20.0
2.5
O
11
O
O
OH
4
OH
2
3
4
1, 0.5
2, 5.0
3, 5.0
90
90
90
2.0
20.0
4.5
O
12b
OH
5
OH
O
O
O
1, 1.0
2, 5.0
3, 5.0
90
90
90
1.5
24.0
2.5
Ph
Ph
Ph
Ph
OH
13
6
OH
1, 1.0
2, 5.0
3, 5.0
25
90
90
0.5
O
24.0c
5.5
OH
14
7
OH
O
O
15
5
1, 5.0
2, 5.0
3, 5.0
90
90
90
16.0 15:16 = 3.1:1
N/Ad
42.0 15:16 = 3.4:1
OH
8
O
O
16
O
O
OH
6
1, 5.0
2, 5.0
3, 5.0
90
90
90
2.0 17:18 = 1:1.3
36.0 17:18 = 1:2.3
3.5 17:18 = 1:2.5
17
OH
9
O
O
18
HO
7
1, 5.0
2, 5.0
3, 5.0
90
90
90
3.5
24.0
4.5
O
O
OH
10
19
Reactions were performed in 1,1,2,2-tetrachloroethane-d2 on an NMR scale. The identities of the products were confirmed by GC–MS, 1H, and 13C NMR spectroscopy. All
new compounds have been characterized, while the physical and spectroscopic data of known compounds were compared with those reported in the literature.17
Pheromone component of the common wasp Paravespula vulgaris.
a
b
c
Time at 60% conversion. Reaction proceeded to completion in 8 days.
The reaction did not go to completion after 48 h and was aborted.
d

S. Selvaratnam et al. / Tetrahedron Letters 50 (2009) 1125–1127
1127
some of the examples above, excellent conversion to the spiroketals
is achieved with short reaction times and low catalyst loadings.
Work is currently underway in our laboratories to develop chiral
metal catalysts for the enantioselective synthesis of spiroketals.
X
CF3
CF3
M
B
BARF =
4
Acknowledgments
1: M = Ir, X = BARF
2: M =Rh, X = BARF
3: M =Rh, X = PF6
Financial support from the Agency for Science, Technology and
*
Research (A STAR) in the form of an institutional Grant is gratefully
Encouraged by these results, the transformation of a range of al-
kyl and aryl internal alkyne diols was examined (Table 1). The data
in Table 1 demonstrate the versatility of the spirocyclization reac-
tion as [4.4], [4.5], [5.5], and [4.6] spiroketal motifs can be synthe-
sized from appropriate precursors. In all cases, the iridium catalyst
1 was superior in promoting the double hydroalkoxylation of the
alkyne diols as compared to its rhodium analogue 2.
acknowledged. This work was also supported by the Australian Re-
search Council and the University of New South Wales. J.H.H.Ho is
grateful to the University of New South Wales for a University
International Postgraduate Award (UIPA).
References and notes
1. Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
It was noted that the efficiency of the Rh(I) complex 2 in cata-
lyzing the spirocyclization reaction decreased with increasing
chain length and/or bulkiness of the substituent present on the al-
kyne (substrates 5–7). For complete consumption of the starting
alkyne diols, reaction times of up to 24 h were frequently required.
However, when the counterion of the Rh complex was replaced
with the more coordinating counterion PF6À, complete conversions
to products were obtained in much shorter reaction times (catalyst
2. Hintzer, K.; Weber, R.; Schurig, V. Tetrahedron Lett. 1981, 22, 55.
3. (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309; (b) Brasholz, M.; Sörgel, S.; Azap,
C.; Reibig, H.-U. Eur. J. Org. Chem. 2007, 3801.
4. (a) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237; (b) Brimble, M. A.; Liu,
Y.-C.; Trzoss, M. Synthesis 2007, 1392.
5. (a) Doubsky´, J.; Streinz, L.; Šaman, D.; Zedník, J.; Koutek, B. Org. Lett. 2004, 6,
4909; (b) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003, 7, 227.
6. (a) Tursun, A.; Canet, I.; Aboab, B.; Sinibaldi, M.-E. Tetrahedron Lett. 2005, 46,
2291; (b) de Greef, M.; Zard, S. Z. Org. Lett. 2007, 9, 1773; (c) Sommer, S.; Kühn,
M.; Waldmann, H. Adv. Synth. Catal. 2008, 350, 1736.
7. (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845; (b) Patil, N. T.; Lutete, L. M.;
Wu, H.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270;
(c) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664.
8. Liu, B.; de Brabander, J. K. Org. Lett. 2006, 8, 4907.
9. Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 940.
10. Genin, E.; Antoniotti, S.; Michelet, V.; Genet, J.-P. Angew. Chem., Int. Ed. 2005, 44,
4949.
11. Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482.
12. (a) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006, 78, 385; (b) Messerle, B.
A.; Vuong, K. Q. Organometallics 2007, 26, 3031; (c) Elgafi, S.; Field, L. D.;
Messerle, B. A. J. Organomet. Chem. 2000, 607, 97.
13. (a) Dervisi, A.; Carcedo, C.; Ooi, L.-L. Adv. Synth. Catal. 2006, 348, 175; (b)
Guzel, B.; Omary, M. A.; Fackler, J. P., Jr.; Akgerman, A. Inorg. Chim. Acta
2001, 325, 45.
À
2 vs 3). The increased efficiency of the PF6 counterion could be
attributed to the stabilization of the reactive intermediates by
À
À
the PF6 anion or the enhanced stability of PF6 relative to the
BARF- counterion.
The cyclization of the unsubstituted alkyne diol, 4-nonyne-1,9-
diol (8) resulted in the formation of two regioisomers. With the
Ir(I) catalyst (1), [5.5] and [4.6] spiroketals, 15 and 16, were formed
in the ratio 3.1:1 within 16 h. The reaction was muchslower with the
Rh(I) catalyst 3. This reaction went to completion in 42 h, and the
products 15 and 16 were formed in a 3.4:1 ratio. By comparison, in
previous reports of the spiroketalization of 8 using PdCl2 as a cata-
lyst, the [4.6] spiroketal 16 was obtained selectively.7a de Brabander
et al.8 in turn found that the PdCl2-catalyzed cyclization of 8 resulted
in a 1:2.5 mixture of spiroketals 15 and 16. It is noteworthy that
these observations suggest that Pd(II) catalysts favor the formation
of the [4.6] spiroketal while the use of Ir(I) and Rh(I) catalysts 1
and 3, under our conditions, favors the [5.5] spiroketal.
The transition metal-catalyzed cyclization of 5-(2-(hydroxy-
methyl)phenyl)pent-4-yn-1-ol (9) led to the formation of the two
possible regioisomeric spiroketals 17 and 18. With the Ir catalyst
1 under our reaction conditions, almost equal amounts of 17 and
18 were formed. This is in contrast to the observations of Crabtree
et al.18 where the use of an Ir(III) hydride catalyst favored the for-
mation of spiroketal 18 over 17 in a ratio of 11:1. In our studies,
treatment of diol 9 with the Rh catalysts (2 or 3) gave a mixture
of spiroketals 17 and 18 in a 1:2.3 or 1:2.5 ratio. In comparison,
the treatment of substrate 9 with Ir(I) and Rh(I) catalysts bearing
N-donor ligands was recently reported to give the spiroketals 17
and 18 in 1:1 and 1.7:1 ratios, respectively.12
The substrate scope was also extended to diaryl alkyne diols.
Cyclization of the aromatic substrate 10 to spiroketal 19 proceeded
smoothly with all three catalysts 1–3. It should be noted that the
reaction times for the conversion of substrates 9 and 10 with the Ir
catalyst 1 are very much shorter than the corresponding reactions
with the Ir catalyst bearing N-donor ligands. The presence of N-do-
nor ligands on the Ir retards the hydroxyalkoxylation reaction.
In summary, we have demonstrated that easily prepared Ir(I)
and Rh(I) complexes efficiently promote the double cyclization
reaction of a range of aliphatic and aromatic alkyne diols. The ease
of preparation of these substrates combined with the simplicity of
the metal complexes provides a straightforward and valuable route
to the preparation of biologically active spiroketals. In addition, in
14. Lee, Y. B.; Folk, J. E. Bioorg. Med. Chem. 1998, 6, 253.
15.
A typical procedure is as follows: All the metal-catalyzed reactions were
performed on small scale in NMR tubes fitted with a concentric Teflon Young
top with (CDCl2)2 as solvent. All additions and weighings were carried out in a
glove box. In a typical experiment, the substrate (20–30 mg) was weighed into
an NMR tube and diluted with about 0.2 mL of solvent. The catalyst (1–
12 lmol, 0.5–5 mol %) was then weighed into a sample bottle and dissolved in
the same solvent (0.4 mL). It was then transferred to the NMR tube using a
syringe. The catalytic reaction was performed at elevated temperature (90 °C)
by heating in an oil bath. The conversion of starting material to product was
determined by integration of selected 1H NMR signals of the product relative to
selected 1H NMR signals of the substrate. The diastereomeric ratio of the
products was determined by 1H NMR spectroscopy, and GC analysis, in
comparison with data reported in the literature.
16. General procedure for the isolation of product from the NMR-scale reaction in
(CDCl2)2: Upon completion of the reaction, as determined by 1H NMR
spectroscopy, the content of the tube was poured into a small beaker, the
NMR tube rinsed with diethyl ether and the mixture was diluted with n-
pentane. The resulting solution was passed through a short pad of silica. The
solvent was removed in vacuo and the product characterized by 1H NMR, 13C
NMR spectroscopy and GC–MS (HP-5 column) analysis. New compounds have
been characterized.
17. Spectral data for selected compounds: (a) 1: reddish-brown solid, 1H NMR
(400 MHz, CD2Cl2) d 2.35 (m, 16H, CH2 of COD), 5.02 (br s, 8H, CH of COD), 7.48
(br s, 4H of BARF), 7.64 (m, 8H of BARF); 19F NMR (CD2Cl2) d À63.5 (s); Anal.
Calcd for C48H36IrBF24Á0.5CH2Cl2: C, 44.31; H, 2.82. Found: C, 44.69; H, 2.75. (b)
Compound 6: colorless oil, 1H (400 MHz, CDCl3) d 1.66 (m, 2H, CH2), 2.23 (m,
2H, CH2), 2.53 (m, 2H, CH2), 3.65 (t, J = 6 Hz, 2H, OCH2), 4.76 (dt, J = 6.2 Hz,
1.6 Hz, 1H, CH), 7.30 (m, 5H, Ar-H); 13C (100 MHz, CDCl3) d 15.5 (CH2), 29.9
(CH2), 31.3 (CH2), 61.9 (OCH2), 72.6 (CH), 76.7 („C), 82.5 (C„), 125.7 (Ar-CH),
127.8 (Ar-CH), 128.4 (Ar-CH), 142.8 (quart. C). HRMS (ESI): m/z calcd for
C13H16O2Na (M+Na)+ 227.10425, found 227.10512. (c) Compound 7: colorless
oil, 1H (400 MHz, CDCl3) d 1.57 (m, 4H, CH2 Â 2), 2.17 (m, 2H, CH2), 2.55 (m, 2H,
CH2), 3.60 (t, J = 6.2 Hz, 2H, OCH2), 4.70 (dt, J = 5.2 Hz, 2.4 Hz, 1H, CH), 7.28 (m,
5H, Ar-H); 13C (100 MHz, CDCl3) d 18.5 (CH2), 25.1 (CH2), 29.9 (CH2), 31.8 (CH2),
62.4 (OCH2), 72.6 (CH), 76.5 („C–), 83.1 (–C„), 125.8 (Ar-CH), 127.8 (Ar-CH),
128.4 (Ar-CH), 142.8 (quart. C). HRMS (ESI): m/z calcd for C14H18O2Na (M+Na)+
241.11990, found 241.12101. (d) Compounds 9–10 and 17–19: spectral data
have been reported in Refs. 12a and b.
18. Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437.