Ring-closing metathesis as a tool for the efficient preparation of chiral spirocyclic ethers from homoallylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2009.06.136

The preparation of chiral spirocyclic ethers via allylic etherification/olefin metathesis of homoallylic alcohols is investigated. This reaction sequence transforms the enantiopure substrate alcohols, synthesized by a one-pot asymmetric rhodium-catalyzed

Full text of DOI:10.1016/j.tetlet.2009.06.136

Tetrahedron Letters 50 (2009) 5305–5307
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Ring-closing metathesis as a tool for the efficient preparation of chiral
spirocyclic ethers from homoallylic alcohols
*
Sara Rosenberg, Reko Leino
Laboratory of Organic Chemistry, Åbo Akademi Univeristy, FI-20500, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of chiral spirocyclic ethers via allylic etherification/olefin metathesis of homoallylic alco-
hols is investigated. This reaction sequence transforms the enantiopure substrate alcohols, synthesized
by a one-pot asymmetric rhodium-catalyzed conjugate addition/metal-mediated allylation procedure,
into the desired spiro ethers with full conversions and in excellent isolated yields. The synthetic sequence
provides an efficient means for a rapid construction of functionalized spiro ethers in a stereoselective
manner.
Received 22 May 2009
Revised 11 June 2009
Accepted 26 June 2009
Available online 4 July 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Asymmetric synthesis
Conjugate addition
Allylation
Ring-closing metathesis
Spirocyclic ether
The frequent occurrence of the spiro framework in naturally
occurring and pharmaceutically active substances has made their
stereoselective preparation an important area of investigation in
organic synthesis.1 One of the commonly encountered members
of this family of compounds are spirocyclic ethers,2 exemplified
by natural products such as clementein (1),3 clerocidin (2),4 and
theaspirone (3)5 (Fig. 1).
Conversion of the homoallylic alcohols 1a–f into the spiro
ethers commenced by reaction with sodium hydride and allyl bro-
mide to afford the corresponding allyl ethers 2a–f (step 1, Table
1).9 As the deprotonation with sodium hydride and the subsequent
reaction with excess allyl bromide at room temperature provided
quantitative conversions, the allyl ethers 2a–f were used for the
next reaction step without further purification. Thus, on treating
´
As reported by us previously, the combination of enantioselec-
tive Rh-catalyzed conjugate addition of arylboronic acids to enon-
es, in the presence of the monodentate phosphoramidite ligand L,6
followed by Barbier-type indium-mediated allylation7 as the sec-
ond step in a one-pot sequence, in aqueous medium, afforded
1,3-disubstituted cyclic alcohols in excellent diastereoselectivities
and high yields (Scheme 1).8
In our earlier work, the potential for further derivatization of
the product alcohols was briefly explored by allylic etherifica-
tion/ring-closing metathesis (RCM) of a single compound to afford
the corresponding spiro ether in moderate yield.8
degassed dichloromethane solutions of 2a–f with Grubbs second
generation ruthenium catalyst at room temperature, chiral spiro-
cyclic ethers 3a–f were obtained in excellent isolated yields (step
H
O
O
OH
HO
O
H
O
O
clementein (1)
Here, we report optimized conditions for the conversion of dia-
stereomerically pure homoallylic alcohols, prepared via the one-
pot conjugate addition/allylation sequence (Scheme 1), into chiral
spirocyclic ethers via allylic etherification/RCM, quantitatively,
and in excellent isolated yields. The product spiro ethers can be
functionalized by, for example, dihydroxylation, as is also exempli-
fied in the present work.
H
O
Me
Me Me
Me
Me
Me
H
H
O
O
OH
O
Me
O
O
clerocidin (2)
theaspirone (3)
* Corresponding author. Tel.: +358 2 2154532; fax: +358 2 2154866.
E-mail address: reko.leino@abo.fi (R. Leino).
Figure 1. Naturally occurring spirocyclic ethers.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.136

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S. Rosenberg, R. Leino / Tetrahedron Letters 50 (2009) 5305–5307
Table 1
Synthesis of chiral spiro ethers 3a–f by allylation/RCM of 1a–fa
R4
R3
R4
R3
R2 R3
HO
Grubbs´ 2nd gen.
cat. (5 mol%)
R5 CH2Cl2, r.t.
O
O
NaH (5 equiv.)
allyl bromide (3.5 equiv)
R2
R2
R4
R5
R6
R5
R6
DMF, r.t.
R1
R1
R1
R6
1a, R1 = CH2, R2 = R3 = R4 = R5 = R6 = H
1b, R1 = CH2, R2 = R3 = R5 = R6 = H, R4 = Me
1c, R1 = CH2, R2 = Me, R3 = R4 = R5 = R6 = H
1d, R1 = CH2, R2 = R3 = Me, R4 = R5 = R6 = H
1e, R1 = NCbz, R2 = R3 = R4 = R5 = R6 = H
2a-f
3a-f
1f, R1 = CH2, R2 = R3 = R4 = H, R5 = R6 = OMe
Entry
Substrateb
Product
Yieldc (%)
HO
O
1
90
1a, >98% ee
3a
dr = 94:6 (a/b)
HO
O
2
3
4
5
89
89
95
80
84
1b, >98% ee
3b
dr = 95:5 (a/b)
HO
O
1c, >98% ee
3c
dr = 98:2 (a/b)
HO
O
1d, >98% ee
dr = >99:<1 (a/b)
HO
3d
O
N
Cbz
N
Cbz
1e, 99% ee
3e
dr = 73:27 (a/b)
HO
O
OMe
6
OMe
OMe
OMe
1f, 96% ee
3f
dr = >99:<1 (a/b)
a
Allylations were performed at rt on 0.10–0.20 mmol scale with 5 equiv of NaH and 3.5 equiv of allyl bromide, respectively. RCM was performed at rt with 5 mol % of
´
Grubbs second generation catalyst.
b
ee Values were determined by chiral HPLC. dr Values were determined by GC or 1H NMR spectroscopy (a: axial OH group; b: equatorial OH group). Pure single
diastereoisomers were used for further derivatization by allylation/RCM.
c
Isolated yields based on substrates 1a–f.
2, Table 1).10,11 The stereochemistry of the substrate alcohols 1a–f
was, in our earlier work, ascertained by NMR and, in the case of 1a,
also by single-crystal X-ray analysis.8
To demonstrate an example of further derivatization of the dou-
ble bond in the chiral spirocyclic ether products 3a–f, we reacted
the spiro ether 3a with osmium tetroxide and N-methylmorpho-
line N-oxide (NMO) in an acetone, water, and t-butanol solvent
mixture (1:1:0.4) at 40 °C. The highly functionalized dihydroxyspi-
ro ether 4 was obtained in 82% isolated yield as a 1:1 mixture of
cis-dihydroxy diastereoisomers (Scheme 2).12,13 In 2008, Carroll

S. Rosenberg, R. Leino / Tetrahedron Letters 50 (2009) 5305–5307
5307
O
O
References and notes
HO
Rh(acac)(C2H4)2
Ligand L
allyl bromide
indium
1. For recent reviews, see: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005,
105, 4406–4440; (b) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis
2009, 165–193.
dioxane/H2O
PhB(OH)2
dioxane/H2O
2. See, for example: (a) Bäckvall, J.-E.; Andersson, P. G. J. Org. Chem. 1991, 56,
2274–2278; (b) Lord, M. D.; Negri, J. T.; Paquette, L. A. J. Org. Chem. 1995, 60,
191–195; (c) Nilsson, Y. I. M.; Aranyos, A.; Andersson, P. G.; Bäckvall, J. E.;
Parrain, J.-L.; Ploteau, C.; Quintard, J.-P. J. Org. Chem. 1996, 61, 1825–1829; (d)
Wallace, D. J.; Goodman, J. M.; Kennedy, D. J.; Davies, A. J.; Cowden, C. J.;
Ashwood, M. S.; Cottrell, I. F.; Dolling, U.-H.; Reider, P. J. Org. Lett. 2001, 3, 671–
674; (e) Chen, P.; Wang, J.; Liu, K.; Li, C. J. Org. Chem. 2008, 73, 339–341. For a
review, see: Rosenberg, S.; Leino, R. Synthesis 2009, doi:10.1055/s-0029-
1216892.
1a, >98% ee
dr = 94:6
O
O
P
NEt2
L
3. Isolation: Massanet, G. M.; Collado, I. G.; Macías, F. A.; Bohlmann, F.; Jakupovic,
J. Tetrahedron Lett. 1983, 24, 1641–1642; Synthesis: Macías, F. A.; Molinillo, J.
M. G.; Massanet, G. M. Tetrahedron 1993, 49, 2499–2508.
Scheme 1.
4. Isolation: Andersen, N. R.; Rasmussen, P. R. Tetrahedron Lett. 1984, 25, 465–468;
Synthesis: Xiang, A. X.; Watson, D. A.; Ling, T.; Theodorakis, E. A. J. Org. Chem.
1998, 63, 6774–6775.
5. Isolation: Ina, K.; Sakato, Y.; Fukami, H. Tetrahedron Lett. 1968, 2777–2780;
Synthesis: Paquette, L. A.; Lanter, J. C.; Wang, H.-L. J. Org. Chem. 1996, 61, 1119–
1121.
6. See, for example: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (b)
Boiteau, J.-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681–
684; (c) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003, 68,
9481–9484.
7. For reviews on metal-mediated allylation, see: (a) Yamamoto, Y.; Asao, N.
Chem. Rev. 1993, 93, 2207–2293; (b) Russo, D. A. Chem. Ind. N.Y. 1996, 64, 405–
439; (c) Li, C.-J. Tetrahedron 1996, 52, 5643–5668; (d) Denmark, S. E.; Fu, J.
Chem. Rev. 2003, 103, 2763–2794.
8. Källström, S.; Jagt, R. B. C.; Sillanpää, R.; Feringa, B. L.; Minnaard, A. J.; Leino, R.
Eur. J. Org. Chem. 2006, 3826–3833.
OsO4 (5 mol%)
NMO (1.2 equiv)
Acetone/H2O/ -BuOH
(1:1:0.4), 40 °C
O
t
3a
OH
O
OH
OH
OH
9. Walters, M. A.; La, F.; Deshmukh, P.; Omecinsky, D. O. J. Comb. Chem. 2002, 4,
125–130.
O
+
10. Standard procedure (Table 1): A Schlenk tube flushed with argon was charged
with NaH (16.8 mg, 0.70 mmol) and anhydrous DMF (0.4 mL) and cooled in an
ice bath. To this slurry was added a solution of 1a (31.1 mg, 0.14 mmol) in
anhydrous DMF (0.2 mL). The reaction mixture was allowed to warm to rt over
the course of 1 h and then recooled in an ice bath and treated with freshly
purified allyl bromide (42 lL, 0.49 mmol, filtered through a basic alumina
4 (82% yield,
column). The reaction mixture was stirred at rt overnight. After 15 h the
mixture was again cooled using an ice bath and was quenched by slow addition
of water. The resulting mixture was extracted with diethyl ether, washed with
water and brine, and the combined organics were dried over MgSO4. Filtration
through a pad of silica gel followed by concentration in vacuo gave 2a (100%
conversion) as a colorless liquid.
dr = 50:50)
Scheme 2.
In the second step, a Schlenk tube flushed with argon was charged with a
solution of 2a (35.0 mg, 0.14 mmol) in anhydrous CH2Cl2 (0.7 mL) and
and co-workers reported the dihydroxylation of a similar unsatu-
rated spiro ether using a Sharpless one-pot procedure which affor-
ded the corresponding diol product in 74% yield and 1:4 cis/trans
selectivity.14
To summarize, we have shown that enantiopure homoallylic
alcohols, obtained by one-pot conjugate addition/allylation, are
easily converted into chiral spirocyclic ethers in excellent isolated
yields via an allylation/RCM reaction sequence. Furthermore, we
have shown that the obtained spiro ethers may be further utilized
for the preparation of highly functionalized spiro building blocks,
resembling spiroglycosides,15 by subsequent cis-dihydroxylation.
degassed using three evacuation/argon-fill cycles. In
a
separate tube
a
degassed solution of Grubbs´ second generation catalyst (5.9 mg, 7
lmol) in
anhydrous CH2Cl2 (0.3 mL) was prepared. The solution of 2a was cooled in an
ice bath and treated dropwise with the solution of catalyst over approximately
5 min. The reaction mixture was then removed from the ice bath, allowed to
warm to rt and stirred overnight. After 12 h, the reaction product was purified
by flash chromatography by passing the reaction mixture, as such, through a
silica gel column affording 3a (28.7 mg, 90% from 1a) as a light yellow oil. For
analytical data, see Supplementary data.
11. For a similar preparation of racemic spiro ethers, see: (a) Maier, M. E.; Bugl, M.
Synlett 1998, 1390–1392; (b) Brahma, S.; Maity, S.; Ray, J. K. J. Heterocycl. Chem.
2007, 44, 29.
12. (a) Compound 3a (22.8 mg, 0.10 mmol) was dissolved in a mixture of acetone,
water, and t-butanol (1:1:0.4, 1.10 mL), after which NMOÁH2O (14.1 mg,
0.12 mmol) and OsO4 (1.6 lL, 5 lmol) were added. The resulting mixture
was stirred for 16 h at 40 °C, then treated with Na2S2O5 (22.8 mg, 0.12 mmol)
and stirring was continued for an additional 1 h. Finally, the mixture was
extracted with EtOAc and the organic extracts were washed with 1 N HCl,
water, and brine, and dried over Na2SO4. After evaporation, the crude product
Acknowledgments
Financial support from the Academy of Finland (project
#203283) and the Graduate School of Organic Chemistry and
Chemical Biology is gratefully acknowledged. We thank Mr. Mark-
ku Reunanen for technical support. S. R. wishes to thank Mr. Filip
Ekholm for fruitful ideas in the laboratory.
was purified by silica gel flash chromatography (eluent:EtOAc) giving
4
(21.4 mg, 82%) as a colorless oil. For analytical data, see Supplementary data.
(b) Asymmetric dihydroxylation of 3a under Sharpless conditions using AD-
mix-a was also investigated providing only marginal diastereoselectivity and
yielding the cis-dihydroxy diastereoisomers 4a and 4b in a 1.5:1 ratio as
ascertained by NMR analysis.
13. (a) Doddi, V. R.; Kumar, A.; Vankar, Y. D. Tetrahedron 2008, 64, 9117–9122; (b)
Jones, G. B.; Guzel, M.; Heaton, S. B. Tetrahedron: Asymmetry 2000, 11, 4303–
4320.
14. McElroy, T.; Thomas, J. B.; Brine, G. A.; Navarro, H. A.; Deschamps, J.; Carroll, F.
I. Synthesis 2008, 943–947.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.136.
15. Forni, E.; Cipolla, L.; Caneva, E.; La Ferla, B.; Peri, F.; Nicotra, F. Tetrahedron Lett.
2002, 43, 1355–1357.