Total synthesis of Japanese Hop Ether using an efficient intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1055/s-2005-918459

The naturally occurring monoterpene Japanese Hop Ether has been synthesised in 14 steps in an overall yield of 29%. The key step of the synthesis, an intramolecular Pauson-Khand reaction, has been shown to proceed in good to excellent yield under mild N-oxide promotion conditions and with complete retention of alkene stereochemistry (for both cis- and trans-alkenes) in the product cyclopentenone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918459

PAPER
3293
Total Synthesis of Japanese Hop Ether Using an Efficient Intramolecular
Pauson–Khand Reaction
T
otal
S
ynt
o
hesis of Japa
h
nese
H
op Et
n
her J. Caldwell, Iain D. Cameron, Steven D. R. Christie, Alastair M. Hay, Craig Johnstone, William J. Kerr,*
Anthony Murray
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland G1 1XL, UK
Fax +44(141)5484246; E-mail: w.kerr@strath.ac.uk
Received 11 September 2005
We dedicate this paper with the utmost gratitude and respect to Professor Steven V. Ley as we celebrate the occasion of his 60th birthday.
H
H
Abstract: The naturally occurring monoterpene Japanese Hop
Ether has been synthesised in 14 steps in an overall yield of 29%.
The key step of the synthesis, an intramolecular Pauson–Khand re-
action, has been shown to proceed in good to excellent yield under
mild N-oxide promotion conditions and with complete retention of
alkene stereochemistry (for both cis- and trans-alkenes) in the prod-
uct cyclopentenone.
Ref 5b
+
O
+
HC CH
Co2(CO)6
O
O
C6H6, 60 °C
22%
H
4
H
5
O
O
2
3
3 : 2
Scheme 1
Key words: amine N-oxides, cyclopentenones, natural products,
Pauson–Khand cyclizations, stereoselectivity
Given the drawbacks in both yield and selectivity in the
key step, shown, towards Japanese Hop Ether, as well as
our interest in the application of the P–K reaction in natu-
ral product synthesis,10 we have embarked upon a total
synthesis programme towards this natural target, which
would incorporate an intramolecular P–K reaction as the
central synthetic transformation. The retrosynthetic plan
presented in Scheme 2 shows how the precursor to Japa-
nese Hop Ether 1, cyclopentenone 6, could be derived
from P–K annulation of enyne complex 7, which may be
assembled from the propargylic alcohol 8 and the mono-
protected (Z)-butenediol 9. This latter alkene would itself
be derived from alkyne 10, via hydrogenation.
Japanese Hop Ether 1 (Figure 1) is a monoterpene first
isolated from the Japanese hop ‘Shinshu-Wase’ in 1968.1
This natural product is also found to be present in Spalter
hops2 and, interestingly, it is believed to contribute to both
the taste and aroma of a number of beers in which it has
been identified in low concentrations.3 The first reported
synthesis of this deceptively simple molecule was by Ima-
gawa and co-workers in 1979,4 and since this time a small
number of alternative preparative pathways have also
been published.5
Co2(CO)6
H
H
O
O
O
O
O
6
7
1
H
H
OTHP
1
H
OTHP
Figure 1
+
HO
OTHP
Of particular note to the study presented here is the syn-
thesis reported by Billington et al,5b which employs an in-
termolecular Pauson–Khand (P–K) reaction6 of the
dicobalthexacarbonyl complex of acetylene 2 with the di-
hydrofuran 3. Although this approach provides a rapid en-
try into the desired carbon skeleton, the key P–K step
suffered from unselective alkene incorporation [3:2 ratio
of desired (4) to undesired (5) alkene regioisomers] and a
low yield of 22% (Scheme 1). However, it should be not-
ed that this cyclisation was carried out under more tradi-
tional thermal reaction conditions and none of the more
recently developed techniques, such as application of
amine N-oxides,7 sulfides,8 or ultrasonication,9 were ap-
plied to this particular transformation.
HO
OTHP
HO
10
9
8
Scheme 2
This proposed synthetic route also opens up the possibility
of investigating an interesting aspect of selectivity within
the P–K reaction, namely the translation of alkene stere-
ochemistry into product stereochemistry. Although the Z-
isomer of alkene 9 is pictured in Scheme 2, the corre-
sponding E-alkene could also be obtained from 10 by
Red-Al® reduction, and this material could be carried
through the same synthetic sequence as (Z)-9 to arrive at
the E-isomer of enyne complex 7. If stereochemistry
could be conserved, the Z-enyne complex 7 should cyclise
to the cis-cyclised product 6 and the E-enyne complex
should cyclise to the alternative trans-cyclic enone. How-
ever, Krafft found that, under thermal conditions, alkene
stereochemistry is usually lost, with a mixture of products
SYNTHESIS 2005, No. 19, pp 3293–3296
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918459; Art ID: C08005SS
© Georg Thieme Verlag Stuttgart · New York

3294
J. J. Caldwell et al.
PAPER
(b)
(c)
(a)
99%
HO
Br
OTHP
OTHP
92%
100%
OH
OTHP
HO
O
OTHP
11
12
10
9
(d) 85%
Co2(CO)6
(e)
(f)
HO
85%
8
O
95%
13
7
14
OTHP
OTHP
Scheme 3 Reagents and conditions: (a) 3,4-DHP, p-TsOH, < 60 °C, 45 min; (b) n-BuLi, THF, (CH2O)3, ))), 75 min; (c) Pd on CaCO3
poisoned with Pb, H2, toluene; (d) CBr4, PPh3, CH2Cl2, –70 °C; (e) NaH, DMF, 3,3-dimethylbut-1-yn-3-ol, 20 h; (f) Co2(CO)8, PE, 1.5 h.
resulting.11 Based on this, we felt that pursuing routes to 18 was achieved when TMANO·2H2O was, again, em-
Japanese Hop Ether 1 through both the Z- and E-isomers ployed as promoter, this time with a mixture of toluene
of enyne complex 7 would allow a timely evaluation of and MeOH as solvent, to deliver 19 in 78% yield. Whilst,
stereochemistry retention under milder methods of P–K use of brucine N-oxide12 did not lead to the optimum yield
reaction promotion, such as those employed with amine with either substrate, the rapid nature of the cyclisations
N-oxides.7
with this promoter is worthy of note. Additionally, in
terms of the potential stereoselectivity discussed within
the introductory section, it was gratifying and notable that,
by using such mild reaction protocols, the alkene stereo-
chemistry was retained in the product cyclopentenone in
both cases.13
To begin with, propargyl alcohol 11 was converted to the
THP-protected derivative 12 in 99% yield (Scheme 3).
Deprotonation of 12, using n-BuLi, followed by reaction
with solid para-formaldehyde in an ultrasound cleaning
bath, afforded the mono-protected ynediol 10 in 92%
yield. For the Z-olefin series, alkene 9 was obtained in
100% yield by hydrogenation over Lindlar’s catalyst and
this allylic alcohol was converted to the bromide 13 in
85% yield by treatment with CBr4 and PPh3. Allyl propar-
gyl ether 14 was then formed in 85% yield, by the action
of the alkoxide anion of dimethylpropargyl alcohol 8 on
bromide 13. Finally, complexation with octacarbonyldi-
cobalt occurred uneventfully to give 7 in 95% yield.
Co2(CO)6
O
O
O
H
OTHP
7
6
OTHP
Co2(CO)6
O
O
O
Turning to the E-alkene series, ynediol 10 was reduced us-
ing Red-Al® to give (E)-15 in 69% yield (Scheme 4). This
mono-protected enediol was then converted, in steps of
89% and 93% yield, to the (E)-allylpropargyl ether 17, us-
ing the same chemistry as for the Z-isomer. Likewise, E-
enyne complex 18 was obtained in an 87% yield.
H
OTHP
OTHP
18
19
7 → 6
18 → 19
Time Yield (%)
Reaction
conditions
Time Yield (%)
NMO⋅H2O,
CH2Cl2, THF
1 h
65
90
-
30 min
65
66
78
66
(a)
(b)
TMANO⋅2H2O,
3 h
1 h
OTHP
OTHP
10
HO
Br
HO
O
acetone
69%
89%
15
16
93%
TMANO⋅2H2O,
toluene, MeOH
-
4 h
(c)
8
Brucine N-oxide
acetone
< 1 min
70
< 1 min
Co2(CO)6
(d)
87%
Scheme 5
O
OTHP
OTHP
18
17
Having secured quantities of both isomeric cyclopenten-
ones, it was decided to continue the synthesis with the cis-
product 6. Thus, bicyclic enone 6 was reduced to ketone
20 in 100% yield by hydrogenation at 3 atm over Pd/C
(Scheme 6). The carbonyl function in 20 was then reduced
to the alcohol using LiAlH4, giving a 90% yield of 21 as a
10:1 mixture of diastereomers. Separation of these diaste-
reomers was deemed unnecessary since the alkanol stereo-
centre was to be removed in the following step. In this
respect, Barton–McCombie deoxygenation14 of alcohol
21 proceeded in 70% yield over the two steps of xanthate
formation and reduction to cyclic ether 23. Removal of the
Scheme 4 Reagents and conditions: (a) Red-Al®, THF, 0 °C, 1.5 h;
(b) CBr4, PPh3, CH2Cl2, –70 °C; (c) NaH, DMF, 3,3-dimethylbut-1-
yn-3-ol, 20 h; (d) Co2(CO)8, PE, 2 h.
With both cobalt complexes in hand, the key P–K cyclisa-
tions were examined, using amine N-oxide promotion at
room temperature (Scheme 5). Using a variety of N-ox-
ide-based conditions, all cyclisations were complete in, at
the most, a few hours and proceeded in good yields. Most
notably, use of TMANO·2H2O in acetone under air with
the Z-enyne complex 7 led to an excellent 90% yield of
product 6. The optimum yield with the E-enyne complex
Synthesis 2005, No. 19, 3293–3296 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Japanese Hop Ether
3295
S
H
H
H
H
H
SMe
(b)
(c), (d)
(a)
OH
O
O
O
O
O
O
O
22
90%
86%
100%
H
H
OTHP
OTHP
OTHP
OTHP
6
20
21
(e) 81%
H
H
H
H
H
H
(g)
(h)
(f)
O
O
O
O2N
O
99%
88%
94%
H
Se
OH
OTHP
25
24
23
1
H
Scheme 6 Reagents and conditions: (a) 10% Pd on C, H2 (3 atm), toluene, 75 min; (b) LiAlH4, Et2O, –78 °C, 10 min; (c) n-BuLi, CS2, THF,
3 h; (d) MeI; (e) n-Bu3SnH, AIBN, C6H6, reflux, 20 h; (f) PPTS, EtOH, 50 °C, 16 h; (g) 2-nitrophenylselenocyanate, PPh3, THF, 2.5 h; (h)
H2O2 (67%), THF, 5.5 h.
(m, 2 H), 3.91–3.95 (m, 0.5 H), 4.14–4.19 (m, 1 H), 4.46–4.56 (m,
1 H), 5.88–5.92 (m, 1 H).
THP group, to give alcohol 24, was effected using PPTS
in EtOH and proceeded in 88% yield. The transformation
of intermediate 24 into Japanese Hop Ether 1 makes use 13C NMR (100 MHz, CDCl3): d = 19.2, 19.5, 25.4, 26.5, 27.4, 30.6,
30.7, 48.6, 50.1, 50.6, 62.1, 62.5, 65.4, 66.3, 66.4, 78.0, 98.3, 99.8,
of selenyl oxides as intermediates in the conversion of pri-
121.9, 122.0, 192.5, 209.4.
mary alcohols to alkenes. This methodology, first devel-
HMRS–EI: m/z [M + H]+ calcd for C15H23O4: 267.15963; found:
267.15789.
oped by Sharpless and co-workers,15 has since been
applied to the formation of exocyclic alkenes by Grieco.16
Thus, the alcohol functionality in 24 was directly replaced
by treatment with o-nitrophenylselenyl cyanate and tri-n-
butylphosphine, delivering the organoselenium species 25
in 99% yield. Simply treating this compound with H2O2
allowed the in situ formation of the selenoxide, which un-
derwent elimination directly to give Japanese Hop Ether 1
in an excellent 94% yield. Pleasingly, this material dis-
played spectral characteristics, which were in agreement
with those published following the isolation of this natural
monoterpene.1,4,5
Cyclopentenone 19
IR (CH2Cl2): 2981, 2951, 2874, 1723, 1640, 1461, 1444, 1385,
1368, 1327, 1245, 1187, 1158, 1140, 1076, 1036, 1006, 977, 942,
919, 872 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 3 H), 1.44 (s, 3 H), 1.39–
1.75 (m, 6 H), 2.42–2.47 (m, 1 H), 3.33–3.51 (m, 3 H), 3.65–3.71
(m, 1 H), 3.74–3.82 (m, 1 H), 3.93–4.03 (m, 1 H), 4.26–4.30 (m, 1
H), 4.54–4.59 (m, 1 H), 5.88–5.91 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.3, 19.8, 25.5, 26.4, 27.4, 30.6,
30.7, 49.2, 49.8, 53.1, 53.4, 62.0, 62.8, 65.0, 65.2, 69.82, 69.84,
77.9, 98.6, 99.8, 122.05, 122.09, 190.5, 190.7, 208.3, 208.5.
In conclusion, the natural product Japanese Hop Ether 1
has now been successfully synthesised in 14 steps, using
an intramolecular P–K reaction as the key transformation.
The overall optimum yield of 29% represents an average
yield of 92% per step. Importantly, it has also been shown
that, by using mild N-oxide methodology, the stereochem-
istry of the alkenes used in the intramolecular P–K reac-
tion was retained in the cyclised product, for both the Z-
and E-alkenes used.
HMRS–EI: m/z [M]+ calcd for C15H22O4: 266.1518; found:
267.1509.
Acknowledgment
We thank the EPSRC for funding (C.J.), the Carnegie Trust for the
Universities of Scotland for a Postgraduate Scholarship (J.J.C.),
Pfizer Global Research and Development, Sandwich for generous
funding of our research, and the EPSRC Mass Spectrometry Ser-
vice, University of Wales, Swansea for analyses. We also thank Dr
D. M. Lindsay for assistance during the construction of this manu-
script.
Pauson–Khand Cyclisation; Typical Procedure
The cobalt complex 7 (4.15 g, 7.91 mmol) was dissolved in anhyd
acetone (150 mL), and TMANO·2H2O (5.63 g, 50.65 mmol) was
added in one portion. The reaction was stirred under an air atmo-
sphere for 3 h, after which time the reaction mixture was filtered
through a pad of silica, and the residues were washed with Et2O.
The solvents were removed in vacuo and the crude product was pu-
rified by flash column chromatography (Et2O–PE, 5:1) to give
1,3,3a,4-tetrahydro-1,1-dimethyl-4-{[(tetrahydro-2H-pyran-2-
yl)oxy]methyl}-5H-cyclopenta[c]furan-5-one (6; 1.89 g, 7.10
mmol, 90% yield) exclusively as the cis-isomer.
References
(1) Naya, Y.; Kotake, M. Tetrahedron Lett. 1968, 1645.
(2) Tressel, R.; Friese, L.; Fendesack, F.; Koeppler, H. J. Agric.
Food Chem. 1978, 26, 1426.
(3) (a) Peacock, V. E.; Deinzer, M. L. J. Am. Soc. Brew. Chem.
1981, 39, 136. (b) Tressel, R.; Friese, L.; Fendesack, F.;
Koeppler, H. J. Agric. Food Chem. 1978, 26, 1422.
(c) Peppard, T. L.; Ramus, S. A.; Witt, C. A.; Siebert, K. J.
J. Am. Soc. Brew. Chem. 1989, 47, 18. (d) Graves, I. R.;
Brier, M. B.; Chandra, G. S.; Alspach, P. A. Proceedings of
the 27th Convention, Institute of Brewing (Asia Pacific
Section) 2002, 10; Chem. Abstr. 2003, 138, 168942a.
(e) See also: Lam, K. C.; Deinzer, M. L. J. Am. Soc. Brew.
Chem. 1986, 44, 69.
IR (CH2Cl2): 3051, 2978, 2946, 2896, 2873, 1703, 1641, 1134,
1123, 1034, 1005 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3 H), 1.45 (s, 3 H), 1.39–
1.75 (m, 6 H), 2.90–2.97 (m, 1 H), 3.36–3.58 (m, 3.5 H), 3.62–3.82
Synthesis 2005, No. 19, 3293–3296 © Thieme Stuttgart · New York

3296
J. J. Caldwell et al.
PAPER
(4) Imagawa, T.; Murai, N.; Akiyama, T.; Kawanishi, M.
Tetrahedron Lett. 1979, 1691.
McLaughlin, M.; Pauson, P. L. J. Organomet. Chem. 2001,
630, 118. (f) Kerr, W. J.; McLaughlin, M.; Morrison, A. J.;
Pauson, P. L. Org. Lett. 2001, 3, 2945. (g) Kennedy, A. R.;
Kerr, W. J.; McLaughlin, M.; Pauson, P. L. Acta
Crystallogr., Sect. C 2001, 57, 1316.
(5) (a) Johnson, C. R.; Elliot, R. C.; Meanwell, N. A.
Tetrahedron Lett. 1982, 23, 5005. (b) Billington, D. C.;
Kerr, W. J.; Pauson, P. L. J. Organomet. Chem. 1987, 328,
223. (c) Linderman, R. J.; Godfrey, A. J. Am. Chem. Soc.
1988, 110, 6249. (d) Tanimori, S.; Nakayama, M. Agric.
Biol. Chem. 1990, 54, 1875. (e) Veselovsky, V. V.;
Moiseenkov, A. M. Russ. Chem. Bull. 1993, 42, 102.
(6) For reviews, see: (a) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (b) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297. (c) Schore, N. E. Org. React.
(N.Y.) 1991, 40, 1.
(7) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 5289. (b) Jeong, N.; Chung, Y.
K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204.
(c) Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann, S.;
Van Pelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199.
(d) Gordon, A. R.; Johnstone, C.; Kerr, W. J. Synlett 1995,
1083.
(8) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M.
Synlett 1999, 771.
(9) (a) Ford, J. G.; Kerr, W. J.; Kirk, G. G.; Lindsay, D. M.;
Middlemiss, D. Synlett 2000, 1415. (b) Billington, D. C.;
Helps, I. M.; Pauson, P. L.; Thomson, W.; Willison, D. J.
Organomet. Chem. 1988, 354, 233.
(10) (a) Johnstone, C.; Kerr, W. J.; Lange, U. J. Chem. Soc.,
Chem. Commun. 1995, 457. (b) Donkervoort, J. G.; Gordon,
A. R.; Johnstone, C.; Kerr, W. J.; Lange, U. Tetrahedron
1996, 52, 7391. (c) Clements, C. J.; Dumoulin, D.;
Hamilton, D. R.; Hudecek, M.; Kerr, W. J.; Kiefer, M.;
Moran, P. H.; Pauson, P. L. J. Chem. Res., Synop. 1998, 636;
J. Chem. Res., Miniprint 1998, 2658. (d) Kerr, W. J.;
McLaughlin, M.; Pauson, P. L.; Robertson, S. M. J.
Organomet. Chem. 2001, 630, 104. (e) Kerr, W. J.;
(11) (a) Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968.
(b) Krafft, M. E.; Scott, I. L.; Romero, R. H. Tetrahedron
Lett. 1992, 33, 3829. (c) Krafft, M. E.; Juliano, C. A.; Scott,
I. L.; Wright, C.; McEachin, M. D. J. Am. Chem. Soc. 1991,
113, 1693.
(12) (a) Kerr, W. J.; Lindsay, D. M.; Rankin, E. M.; Scott, J. S.;
Watson, S. P. Tetrahedron Lett. 2000, 41, 3229.
(b) Carbery, D. R.; Kerr, W. J.; Lindsay, D. M.; Scott, J. S.;
Watson, S. P. Tetrahedron Lett. 2000, 41, 3235.
(c) Kennedy, A. R.; Kerr, W. J.; Lindsay, D. M.; Scott, J. S.;
Watson, S. P. J. Chem. Soc., Perkin Trans. 1 2000, 4366.
(d) Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Synlett 1995,
1085.
(13) The identity of each cyclopentenone product was initially
elucidated by 1H NMR. In particular, the non-olefinic proton
a to the carbonyl in product 19 (from E-enyne 18), would be
in an endo-position and, hence, would be more shielded; this
proton appears as a multiplet at d = 2.42–2.47 ppm. The
equivalent non-olefinic proton a to the carbonyl in product 6
(from Z-enyne 7), would be in an exo-position and, hence,
would be more deshielded; this proton appears as a multiplet
at d = 2.90–2.97 ppm.
(14) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Hartwig, W. Tetrahedron 1983, 39,
2609.
(15) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40,
947.
(16) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485.
Synthesis 2005, No. 19, 3293–3296 © Thieme Stuttgart · New York