Versatile method for the synthesis of 4-substituted 6-methyl-3- oxabicyclo[3.3.1]non-6-ene-1-methanol derivatives: Prins-type cyclization reaction catalyzed by hafnium triflate

Article abstract of DOI:10.1016/j.tetlet.2009.08.120

A versatile method for the synthesis of 4-substituted 6-methyl-3- oxabicyclo[3.3.1]non-6-ene-1-methanol derivatives has been developed using Prins-type cyclization reaction between aldehydes and O-protected/unprotected cyclohex-3-ene-1,1-dimethanol. Under

Full text of DOI:10.1016/j.tetlet.2009.08.120

Tetrahedron Letters 50 (2009) 6462–6465
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Versatile method for the synthesis of 4-substituted
6-methyl-3-oxabicyclo[3.3.1]non-6-ene-1-methanol derivatives:
Prins-type cyclization reaction catalyzed by hafnium triflate
*
Masayuki Nakamura , Kenji Niiyama, Takeru Yamakawa
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Company, Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2009
Revised 27 August 2009
Accepted 31 August 2009
Available online 2 September 2009
A versatile method for the synthesis of 4-substituted 6-methyl-3-oxabicyclo[3.3.1]non-6-ene-1-metha-
nol derivatives has been developed using Prins-type cyclization reaction between aldehydes and O-pro-
tected/unprotected cyclohex-3-ene-1,1-dimethanol. Under optimized reaction conditions using hafnium
triflate, various substrates, including functionalized benzaldehydes and heteroaromatic carbaldehydes,
afforded cyclization products in high yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Prins-type cyclization reaction
Hafnium triflate
Catalytic reaction
Oxabicyclo[3.3.1]nonene
Prins-type cyclization reaction is one of the most important
carbon–carbon bond-forming reactions in organic synthesis,1 and
has been used as a powerful tool in synthetic and medicinal chem-
istries. Typically, an aldehyde and an unsaturated alcohol (e.g.,
homoallyl alcohol) are reacted in the presence of an acid catalyst
to form five- and six-membered oxygen-containing heterocyclic
rings, which are present in various bioactive compounds. The
outcome of the reaction depends on the substrate structure and
reaction conditions due to the nature of the generated cationic
intermediates.
The Bayer2 and Ligand3 groups independently reported com-
pound 2 as an estrogen receptor ligand, and described the synthe-
sis and the structure–activity relationships (SARs) of its analogues.
Although they only prepared 4-hydroxyphenyl derivatives, which
should contain the key functional group for the estrogen activity,
we planned to modify the aryl ring to produce more diverse struc-
tures. Initially, we ran the TsOH-catalyzed cyclization according to
a previously described procedure,3,4 but using 4-phenoxybenzalde-
hyde 4 instead of 4-hydroxybenzaldehyde, the reaction did not
proceed smoothly (Scheme 1).
In the course of our extensive efforts toward the discovery of
new drugs for metabolic disorders, oxabicyclo[3.3.1]nonene deriv-
atives represented by the structure 1 were identified as a lead class
(Fig. 1).
We then attempted harsher conditions, such as higher temper-
ature and prolonged reaction time, but this resulted in a complex
mixture presumably due to extensive decomposition of the sensi-
tive intermediates or products. The use of other acid catalysts
(SnCl4, BF3OEt2, and TMSOTf) also gave a complex mixture (data
not shown). We therefore began to explore effective reaction con-
ditions to carry out the cyclization reaction forward.
Herein, we report a novel method for the synthesis of 4-substi-
tuted 6-methyl-3-oxabicyclo[3.3.1]non-6-ene-1-methanol deriva-
tives in high yield under mild conditions. Under our optimal
reaction conditions using hafnium triflate, various aldehydes,
including substituted benzaldehydes and heteroaromatic carbalde-
hydes, gave the target cyclization products.
HO
R1
O
O
OR2
H
OH
H
1
2
A plausible mechanism for this cyclization is proposed in
Scheme 2. The first step of the reaction would be the formation
of acetal A or hemiacetal B from diol 35 and aldehyde 4. The acid
in the system promotes the cleavage of the C–O bond to afford
oxonium cation C, and its addition to the double bond gives the
Figure 1.
* Corresponding author. Tel.: + 81 29 865 4527; fax: +81 29 865 2170.
E-mail address: masayuki_nakamura2@oasis.ocn.ne.jp (M. Nakamura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.120

M. Nakamura et al. / Tetrahedron Letters 50 (2009) 6462–6465
6463
PhO
OH
OH
PhO
TsOH (20 mol%)
O
H
toluene
reflux, 14 h
OH
O
H
4 (1.5 eq)
5 (18%)
3
Scheme 1. Prins-type reaction between aldehyde and diol using TsOH.
PhO
OH
OH
PhO
O
+
H
OH
H
O
3
4
5
H
H
O
O
Ar
M
Ar
O+
O
Ar
Ar
O
OH
O
OH
M
Me
OH
+
Me
Me
B
D
A
C
Scheme 2. Mechanistic proposal for Prins-type cyclization reaction.
tertiary cation intermediate D. Finally, deprotonation gives the
desired product 5.6 This reaction generates one molar equivalent
of water, which may deactivate the catalyst or decompose the
intermediates. We assume that there are two approaches to opti-
mize the reaction conditions; the first is the use of an acid catalyst
that is more effective in the presence of water, and the second is
accelerating the conversion of stable acetal A or unstable hemiac-
etal B into C.7
Table 1
Optimization of Prins-type reaction conditionsa
OH
OH
PhO
catalyst
H
+
CH3CN
O
3
4
Metal triflates have received increasing attention recently as
a water-tolerant catalyst with Lewis acid activity,8 and a Prins-
type cyclization reaction using metal triflates has been
reported.9 We thus assumed that metal triflate would be a suit-
able catalyst for this reaction. Our initial attempt using ytter-
bium triflate at room temperature gave the desired
oxabicyclo[3.3.1]nonene 5 in 14% yield and the acetal 8 in 66%
yield (Table 1, entry 1). These results prompted further screen-
ing of the metal triflates.
As shown in Table 1, zinc and lanthanum triflates (10 mol %)
mainly gave the acetal 6 in 75% and 68% yields, respectively, with
a low yield of the desired product 5 (entries 3 and 4). On the other
hand, the use of scandium, bismuth, or hafnium triflates (10 mol %)
afforded the desired product 5 in excellent yields (entries 2, 5, and
6).10 Hafnium triflate showed the best yield (97%) among the
tested catalysts, and when we decreased the amount of catalyst
to 1 and 5 mol %, the chemical yield was largely maintained (en-
tries 7 and 8).
PhO
PhO
O
O
OH
H
O
6
5
Entry
Catalyst
x (mol %)
5b (%)
6b (%)
1
2
3
4
5
6
7
8
Yb(OTf)3
Sc(OTf)3
Zn(OTf)2
La(OTf)3
Bi(OTf)3
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
10
10
10
10
10
10
5
14
89
10
2
92
97
94
89
66
—
75
68
—
—
—
4
1
a
All reactions were carried out at room temperature with 1.2 equiv of 4 and
1 equiv of 3.
b
Isolated yield.
Next we reacted diol 3 with various aldehydes using 5 mol %
hafnium triflate11 in order to examine the scope of this Prins-type
cyclization reaction, as shown in Table 2.
Substituted benzaldehydes gave excellent yields of cyclization
products (entries 1, 2, and 5). Heteroaromatic aldehydes 9 and
10 worked very well under optimized conditions (entries 3 and
4). However, in the case of pyridine aldehyde (entry 6), the major
product was acetal 17 and no desired rearranged products were
observed, even with higher temperatures and prolonged reaction
times. We therefore continued optimization of the reaction condi-
tions for compound 12.
Based on these results, conversion of the acetal into the oxo-
nium cation would be slow for this pyridine derivative. We there-
fore protected one of the two hydroxy groups to redirect the
reaction to a Prins-type cyclization through the hemiacetal forma-
tion. When we used TBDPS-protected alcohol 18, the cyclization

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M. Nakamura et al. / Tetrahedron Letters 50 (2009) 6462–6465
Table 2
Table 3
Representative examples of Prins-type reaction of aldehydes and diol 3a
Representative examples of Prins-type reaction of aldehydes and diol 18a
OH
Ar
O
OH
OTBDPS
Ar
O
Aldehyde
Aldehyde
TBAF, AcOH
Hf(OTf)4 (20 mol%)
OH
Hf(OTf)4 (5 mol%)
OH
OH
H
H
THF, 55 °C, 14 h
CH3CN, 14 h
CH3CN, 14 h
18
3
Yieldb
Entry Aldehyde
Product
Yieldb
Entry Aldehyde
Product
Br
Br
N
O
O
N
H
H
1
47
57
57
1
95
OH
OH
O
H
H
O
7
12
24
13
Cl
MeO2C
Cl
MeO2C
N
O
O
N
H
H
O
2
2
96
81
93
90
72
OH
OH
H
H
O
8
19
25
14
N
O
O
O
N
O
O
H
O
O
N
O
3
N
H
H
OH
3
O
H
OH
H
O
O
9
15
20
26
AcN
AcN
O
N
N
H
N
N
O
O
O
4
OH
O
H
O
4
5
6
54
57
89
OH
OH
OH
10
H
16
HO
21
27
HO
O
H
5
OH
N
H
H
O
N
O
11
H
H
2
O
O
22
N
N
O
28
N
H
6
O
O
O
N
12
17
O
a
All reactions were carried out at room temperature with 1.2 equiv of aldehyde
and 1 equiv of 3.
H
b
Isolated yield.
23
29
a
All reactions were carried out at room temperature with 1.2 equiv of aldehyde
reaction proceeded smoothly in the presence of 20 mol % of
hafnium triflate. The TBDPS group was gradually cleaved under
these reaction conditions, and we subsequently treated the reac-
tion mixture with TBAF to complete the deprotection of silyl
groups and to obtain the desired product 24. We applied this meth-
od to other substrates. A variety of nitrogen-containing aromatic
aldehydes gave the oxabicyclo[3.3.1]nonene structure in moderate
to good yield (Table 3; entries 2–6).
In summary, we have developed a versatile method for the syn-
thesis of 4-substituted 6-methyl-3-oxabicyclo[3.3.1]non-6-ene-1-
methanol derivatives using Prins-type cyclization reaction under
mild conditions. Under our optimized reaction conditions using
hafnium triflate, various aldehydes and diols react to give cycliza-
tion products in high yield, which will broaden the scope of Prins-
type reactions. For pyridine-containing aldehydes, acetal formation
and 1 equiv of 18.
b
Isolated yield.
prevailed over Prins-type cyclization; however, mono-protected
diols were effective in redirecting the reaction. Biological activities
of the synthesized compounds are currently being tested and will
be reported in due course.
References and notes
1. (a) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925; (b) Adams, D. R.;
Bhatnagar, S. P. Synthesis 1977, 661; (c) Arundale, L. A.; Mikeska, L. A. Chem. Rev.
1952, 51, 505.

M. Nakamura et al. / Tetrahedron Letters 50 (2009) 6462–6465
6465
2. Hamann, L. G.; Meyer, J. H.; Ruppar, D. A.; Marschke, K. B.; Lopez, F. J.;
Allegretto, E. A.; Karanewsky, D. S. Bioorg. Med. Chem. Lett. 2005, 15,
1463.
3. Sibley, R.; Hatoum-Mokdad, H.; Schoenleber, R.; Musza, L.; Stirtan, W.;
Marrero, D.; Carley, W.; Xiao, H.; Dumas, J. Bioorg. Med. Chem. Lett. 2003, 13,
1919.
4. (a) Chauzov, V. A.; Parchinskii, V. Z. Russ. J. Org. Chem. 1997, 67, 160; (b)
Chauzov, V. A.; Parchinskii, V. Z. Russ. J. Org. Chem. 1996, 66, 2006.
5. Gramenitskaya, V. N.; Golovkina, V. S.; Vul’fson, N. S. J. Org. Chem. USSR (Engl.
Transl.) 1975, 11, 4654.
6. The trans relationship between the aryl group and the hydroxymethylene
group on bicyclic core was confirmed by 1H NMR (including NOE) analysis. This
stereochemistry is consistent with that suggested from the proposed
mechanism.
19, 104; For Sc(OTf)3, see: (d) Zhang, W.-C.; Viswanathan, G. S.; Li, C.-J. Chem.
Commun. 1999, 291; (e) Zhang, W.-C.; Li, C.-J. Tetrahedron 2000, 56, 2403; For
In(OTf)3, see: (f) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005, 12, 1912;
(g) Chan, K.-P.; Loh, T.-P. Tetrahedron Lett 2004, 45, 8387; (h) Chan, K.-P.; Loh,
T.-P. Org. Lett 2005, 7, 4491.
10. The formation of the acetal 6 was rapidly observed in a few miniatures by TLC,
and the desired product was gradually formed.
11. General procedure: To a mixture of diol 3 (103 mg, 0.659 mmol) and aldehyde 4
(0.13 mL, 0.79 mmol) in acetonitrile (3.2 mL) was added hafnium triflate
(25.5 mg, 0.033 mmol) at room temperature and the reaction mixture was
stirred at room temperature for 14 h. After completion of the reaction as
indicated by TLC, the reaction was quenched with satd NaHCO3 aq and the
reaction mixture was extracted with ethyl acetate (2 Â 10 mL), the combined
organics were washed with brine, dried over anhyd Na2SO4, and evaporated.
The resulting residue was purified by silica gel chromatography (hexane:ethyl
acetate) to give the desired compound (205 mg, 93%) as a colorless solid.
Compound 5: 1H NMR (400 MHz, CDCl3) d: 7.33–7.25 (4H, m), 7.09–7.04 (1H,
m), 6.99–6.93 (4H, m), 5.60–5.56 (1H, m), 4.55 (1H, d, J = 1.7 Hz), 3.97 (1H, dd,
J = 10.7, 2.7 Hz), 3.64 (1H, dd, J = 10.7, 1.5 Hz), 3.40 (2H, s), 2.38–2.34 (1H, m),
2.25–2.17 (1H, m), 2.12–2.04 (1H, m), 1.86–1.80 (1H, m), 1.71–1.65 (1H, m),
1.06–1.03 (3H, m). ESI-MS 337 [M+H]+.
7. Acetals could be isolated by silica gel chromatography, while hemiacetal could
not be monitored by TLC.
8. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. L. Chem. Rev. 2002, 102, 2227.
9. For Bi(OTf)3, see: (a) Sabitha, G.; Bhikshapathi, M.; Nayak, S.; Yadav, J. S.; Ravi,
R.; Kunwar, A. C. Tetrahedron Lett. 2008, 49, 5727; (b) Yadav, J. S.; Subba Reddy,
B. V.; Chaya, D. N.; Narayana Kumar, G. G. K. S. Can. J. Chem. 2008, 86, 769; (c)
Murty, M. S.; Rajasekhar, K.; Harikrishna, V.; Yadav, J. S. Heteroat. Chem 2008,