Efficient synthesis of 8,11-dimethylene-bicyclo[5.3.1]undecan-2-one

Article abstract of DOI:10.1016/j.tetlet.2005.07.108

We report here, an effective methodology for the preparation of 8,11-dimethylene-bicyclo[5.3.1]undecan-2-one. The key steps in these reactions were chloromethylation, cationic-alkyne cyclization and anionic fragmentation sequence.

Full text of DOI:10.1016/j.tetlet.2005.07.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6449–6451
Efficient synthesis of 8,11-dimethylene-bicyclo[5.3.1]undecan-2-one
Haining Gu,a,* Wei Ming Xua and Thomas H. Kinstleb,*
aCenter of Analysis and Measurement, Zhejiang University, Hangzhou 310028, PR China
bDepartment of Chemistry, Bowling Green State University, Bowling Green, OH 43403, USA
Received 13 May 2005; revised 22 July 2005; accepted 22 July 2005
Abstract—We report here, an effective methodology for the preparation of 8,11-dimethylene-bicyclo[5.3.1]undecan-2-one. The key
steps in these reactions were chloromethylation, cationic-alkyne cyclization and anionic fragmentation sequence.
Ó 2005 Elsevier Ltd. All rights reserved.
The bicyclo[5.3.1]undecane ring system is a substructure
of naturally occurring taxanes. Among them, the most
prominent representative compound is taxol,1 a clini-
cally useful anti-cancer drug. Due to its therapeutic
potential and its limited availability, enormous efforts
have been directed towards the chemical synthesis of
taxol in the past decade.2 The construction of the AB-
ring core of taxol, which involves the bicyclo[5.3.1]unde-
cane moiety, is among the most challenging facets of the
taxane synthesis and not yet practical. As a solution to
the problem, some efficient methods for the construction
of bicyclic undecanes have been developed recently.3 We
wish to report here, an efficient route for the construc-
tion of the AB-ring core with evident advantages of
good yields and scaleable to larger quantities.
formed the cyclopentenone 10, because the endo-double
bond is thermodynamically more stable than the exo-
double bond in the a,b-unsaturated five-membered
OR
b
a
Cl
OH
O
O
R= H 3a
R=THP 3b
c
2
1
OR
f
O
d
H
R=THP 4a
R= H 4b
e
5
We start our effect from 2-hydroxymethyl-tetrahydro-
pyran 1 (Scheme 1). An adaptation of the procedure
used by Jones4 to prepare tetrahydrofurfuryl chloride
was used to prepare 2-chloromethyl-tetrahydro-pyran
2. Whitingꢀs double elimination was used to prepare 5-
hexyn-1-ol 3a. Dihydropyran protection and C-methyl-
ation of the 5-hexyn-1-ol 3a gave the tetrahydropyranyl
ether of 5-heptyl-1-ol 4a, which was cleanly deprotected
and then oxidized with PCC to give aldehyde 5 for the
alkylation of the five-membered ring. The a,b-unsatu-
rated ketone 9 was synthesized by aldol condensation
of aldehyde 5 with enamine 8 made by the reaction of
cyclopentanone 6 with morpholine 7. Acid-catalyzed
isomerization of the exo-methylenecyclopentanone 9
O
O
O
O
g
5 + h
N
+
N
H
9
6
7
8
O
CH2Cl
HO
i
j
11
10
Scheme 1. Reagents and conditions: (a) SOCl2, pyridine, 45 °C, 8 h,
65%; (b) (1) NaNH2 (3 equiv)/NH3(l); Fe(NO3)3Æ9H2O (cat); (2)
NH4Cl, 85%; (c) DHP, H3O+; (d) NaNH2 (3 equiv)/NH3(l),
Fe(NO3)3Æ9H2O (cat); (2) CH3I; (3) NH4Cl, 69%; (e) p-toluenesulfonic
acid, 98%; (f) PCC, CH2Cl2, 70%; (g) reflux in toulene, 77%; (h) (1)
reflux in toluene; (2) 6 N HCl, 81%; (i) n-butanol, HCl (concd), reflux,
95 °C, 2 h, 75%; (j) n-BuLi, ClCH2I, THF, ether, À100 °C, 95%.
Keywords: 8,11-Dimethylene-bicyclo[5.3.1]undecan-2-one; Chloro-
methylation; Cationic-alkyne cyclization; Anionic fragmentation.
*
Corresponding authors. Fax: +86 571 88273515; e-mail addresses:
haining@zju.edu.cn; tkinstl@bgnet.bgsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.108

6450
HO
H. Gu et al. / Tetrahedron Letters 46 (2005) 6449–6451
CH Cl
2
CH Cl
2
+
B-
H
H O
Cl
11
12
O
17
14
Scheme 4.
CH Cl
CH Cl
2
2
The pre-settled chloromethyl group and the high energy
of its strained structure can be relieved with ring open-
ing, making compound 14 a good candidate for frag-
mentation to form the bicyclo[5.3.1]undecane ring.
Good proton trapper and proper solvent system were
found to be the best for conversion of the starting mate-
rial to the desired product (Scheme 4).8
12a
12b
Scheme 2.
rings. The key step in Scheme 1 was the addition of chlo-
romethyl lithium to the cyclopentenone 10 to form
chlorohydrin 11, which was crucial for the fragmenta-
tion reaction. We first adopted Sadhu and Mattesonꢀs
method5 to perform the chloromethylation reaction
but it did not give the satisfied result. Upon further
investigation, we found when the reaction temperature
descended to À100 °C and the amount of base (n-BuLi)
was no more than 1.5 equiv, the yield of the desired
chlorohydrin 116 was increased to 95%. The yield of
the product was dramatically decreased when excessive
base, longer reaction time and higher temperature
(above À78 °C) were used.
In summary, we have developed a methodology using a
chloromethylation reaction, cationic-alkyne cyclization
and anionic fragmentation sequence as key steps to syn-
thesize the bicyclo[5.3.1]undecane ring system. With
intensive experimentations, conditions for the last three
reactions have been well established. Thus, a useful syn-
thetic methodology with high expected yields and scale-
able to larger quantities, is now available for further
exploitation.
Acknowledgement
With this cyclopentenol precursor 11 in hand, test for
the feasibility of the proposed cationic-alkyne cycliza-
tion–anionic fragmentation strategy to form the
bicyclo[5.3.1]undecane skeleton was undertaken. Cyclo-
pentenol 11 can easily form an allyl-cation 12, an
equilibrium of 12a and b, under an acidic condition
(Scheme 2). We did not observe any cationic-alkyne
cyclization products of 12b, because the cation 12b is
less stable than the cation 12a.
We are grateful to the Department of Chemistry, Bowl-
ing Green State University.
References and notes
1. (a) Wall, M. Chronicles of Drug Discovery 1993, 3, 327; (b)
Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665.
2. (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.;
Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.;
Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J.
Nature 1994, 367, 630; (b) Holton, R. A.; Somoza, C.;
Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki,
Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.;
Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1597; (c) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young,
W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl.
1995, 34, 1723.
In our investigations of the cationic-alkyne cyclization
of cationic 12a, we found not only the exo-product 14
but also the endo-cyclization product, the 5,8-bicyclic
compound 16 was formed. Massive optimization
research shows that the sequential cyclization is a rapid
reaction, and the tricyclic cation 13 is rapidly reacted
with available nucleophiles. With proper acid, short
reaction time and fast workup, we obtained 147 as the
sole product (Scheme 3).
exo
CH2Cl
HO
CH2Cl
CH2Cl
13
14
endo
12a
CH2Cl
ClH2C
O
15
16
Scheme 3.

H. Gu et al. / Tetrahedron Letters 46 (2005) 6449–6451
6451
3. (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881, and
references cited therein; (b) Shimada, Y.; Nakamura, M.;
Suzuka, T.; Matsui, J.; Tatsumi, R.; Tsutsumi, K.; Mor-
imoto, T.; Kurosawa, H.; Kakiuchi, K. Tetrahedron Lett.
2003, 44, 1401.
4. Jones, E. R. H.; Eglinton, G.; Whiting, M. C. Organic
Syntheses, Collect.; John Wiley and Sons, Inc.: New York,
1963; Vol. IV, p 755.
tography with n-hexane–EtOAc (4:1, v/v) as the eluent gave
98 mg (98%) 8-chloromethyl-2-hydroxy-11-methylene-tri-
cyclo[5.3.1.0]undecane 14. Oil; 1H NMR (CDCl3) d 4.92
(1H, d, J = 2.4 Hz), 4.72 (1H, d, J = 2.4 Hz), 3.92 (1H, d,
J = 11.2 Hz), 3.74 (1H, d, J = 11.2 Hz), 2.59–2.55 (1H, m),
2.47–2.44 (1H, m), 1.24–2.20 (13H, m); 13C NMR (CDCl3)
d 157.8, 103.7, 85.5, 55.5, 54.0, 47.7, 46.6, 38.9, 34.9, 29.1,
28.1, 26.0, 22.9; MS m/z 226 (M+, 100), 228 (M++2, 33); IR
mmax 1623, 1470, 1411, 1095 (cmÀ1). Elemental analysis
calcd for C13H19ClO: C, 68.86; H, 8.45; Cl, 15.64. Found:
C, 69.03; H, 8.51; Cl, 15.56.
5. Sadhu, K. M.; Matteson, D. S. Tetrahedron Lett. 1986, 27, 795.
6. Typical preparation of chlorohydrin 11 is described as
follows: a solution of fleshly distilled 2-(5-heptynyl) cyclo-
pent-2-enone 10 (0.352 g, 2 mmol) and iodochloromethane
(0.512 g, 3 mmol) in 5 mL ethyl ether and 5 mL dry THF
was cooled to À100 °C under argon. 1.5 mL n-BuLi (2.0 M
in hexane, 3 mmol) was added dropwise over a period of
10 min. The mixture was allowed to set for another 10 min
at À100 °C before quenched with 1 mL water. The mixture
was treated with saturated ammonium chloride and
extracted with ether. Dryness followed by purification via
flash chromatography with n-hexane–EtOAc (4:1, v/v) as
the eluent gave 0.43 g (95%) chlorohydrin 11.
7. Typical preparation of 8-chloromethyl-2-hydroxy-11-meth-
ylene-tricyclo[5.3.1.0]undecane 14 is described as follows:
to a solution of 100 mg chlorohydrin 11 in 2 mL ether,
30 mL trifluoroacetic acid was added at 0 °C with stirring.
The mixture was neutralized with excess cold potassium
carbonate solution within a minute and extracted with
ether. Dryness followed by purification via flash chroma-
8. Typical preparation of 8,11-dimethylene-bicyclo[5.3.1]-
undecan-2-one 17 is described as follows: to a solution of
50 mg tricyclo[5.3.1.0]undecane 14 in 1.5 mL DMF, NaH
(0.3 g) was added with stirring. After about 45 s, the
mixture was neutralized with excess saturated ammonium
chloride and extracted with hexane. Dryness followed by
purification via flash chromatography with n-hexane–
CH2Cl2 (4:1, v/v) as the eluent gave 41 mg (98%) 8,11-
1
dimethylene-bicyclo[5.3.1]undecan-2-one 17. Oil; H NMR
(CDCl3) d 5.12 (1H, d, J = 1.4 Hz), 5.04 (1H, d, J =
1.4 Hz), 4.64 (1H, d, J = 2.0 Hz), 4.56 (1H, d, J = 2.0 Hz),
3.05–3.02 (1H, m), 2.94–2.90 (2H, m), 2.44–2.54 (2H, m),
1.98–2.10 (2H, m), 1.21–1.86 (7H, m); 13C NMR (CDCl3) d
195.9, 151.5, 147.6, 115.5, 107.4, 56.0, 54.5, 39.1, 32.1, 30.9,
29.7, 26.1, 24.2; MS m/z 190 (M+, 100); IR mmax 1711, 1627,
1466 (cmÀ1). Elemental analysis calcd for C13H18O: C,
82.06; H, 9.53. Found: C, 82.17; H, 9.58.