Acceleration effect of allylic hydroxy group on ring-closing enyne metathesis of terminal alkynes: scope and application to the synthesis of isofagomine

Article abstract of DOI:10.1016/j.tetlet.2007.11.098

An interesting allylic substituent effect on ring-closing enyne metathesis has been found. An allylic hydroxy group on enyne substrates accelerates ring-closing enyne metathesis of terminal alkynes. The reaction proceeds smoothly without ethylene atmosphere and/or more reactive newer generation Ru-carbene catalysts, which are generally necessary to promote the reaction. This efficient reaction was applied to the synthesis of isofagomine.

Full text of DOI:10.1016/j.tetlet.2007.11.098

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Tetrahedron Letters 49 (2008) 265–268
Acceleration effect of allylic hydroxy group on ring-closing
enyne metathesis of terminal alkynes: scope and application
to the synthesis of isofagomine
*
*
Tatsushi Imahori , Hidetomo Ojima, Hiroki Tateyama, Yukiko Mihara, Hiroki Takahata
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 24 October 2007; revised 7 November 2007; accepted 12 November 2007
Available online 22 November 2007
Abstract
An interesting allylic substituent effect on ring-closing enyne metathesis has been found. An allylic hydroxy group on enyne substrates
accelerates ring-closing enyne metathesis of terminal alkynes. The reaction proceeds smoothly without ethylene atmosphere and/or more
reactive newer generation Ru-carbene catalysts, which are generally necessary to promote the reaction. This efficient reaction was applied
to the synthesis of isofagomine.
Ó 2007 Elsevier Ltd. All rights reserved.
Enyne metathesis between an alkyne and an alkene is a
powerful and highly atom-economical carbon–carbon
bond forming reaction to generate 1,3-dienes,1 which can
be transformed into more complex organic molecules.2
With the advent of Ru-alkylidene catalysts,3 applications
of both intramolecular ring-closing and intermolecular
cross enyne metathesis have rapidly expanded.4 Despite
its usefulness, however, the development of enyne metath-
esis has lagged behind that of olefin metathesis,5 probably
due to its capricious efficiency. The ring-closing enyne
metathesis of terminal alkynes using Grubbs’ 1st genera-
tion catalyst (Fig. 1,6 cycle A) is often slow, and the
Ru-vinylcarbene intermediate (IM-2) is thought to prevent
the catalytic cycle because of its stability.7,8 This drawback
has been overcome by utilizing an ethylene atmosphere to
regenerate reactive Ru-carbene species into a new catalytic
cycle (Fig. 1, cycle B)7,9 and/or by developing new more
reactive catalysts.10 In this Letter, we report an interesting
substituent effect on ring-closing enyne metathesis, which
also can resolve the efficiency problem of enyne metathesis.
Introduction of an allylic hydroxy group into a variety of
enyne substrates smoothly promoted the enyne metathesis
of terminal alkynes without ethylene atmosphere and/or
more reactive newer generation catalysts. This efficient
reaction was applied to the synthesis of isofagomine.
In conjunction with our continuous studies on aza-sug-
ars,11 we investigated enyne metathesis of N-containing
enyne substrates (1a–d) to construct a 3-piperidene frame-
work. The enyne substrates were treated with Grubbs’ 1st
generation catalyst (4 mol %) in CH2Cl2 at rt. The results
Ru
Ring-closing
Ru
Ru
st
Grubbs' 1
gen. cat.
A
B
Initiation
IM-2
IM-1
Regeneration of
Ru-carbene
Ru
Slow
st
Grubbs' 1
gen. cat.
Initiation
*
Corresponding authors. Tel./fax: +81 22 727 0144 (T.I.); tel.: +81 22
727 0145 (H.T.).
Fig. 1. Catalytic cycle of ring-closing enyne metathesis of terminal alkynes
and the acceleration effect of ethylene.6,9
E-mail addresses: takahata@tohoku-pharma.ac.jp (T. Imahori),
imahori@tohoku-pharm.ac.jp (H. Takahata).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.098

266
T. Imahori et al. / Tetrahedron Letters 49 (2008) 265–268
Table 1
Table 2
Acceleration effect of allylic hydroxy group
Scope of the acceleration effect of allylic groupa
Entry Substrate
Time
(h)
Products
Yieldb,c
(%)
Grubbs' 1st gen. cat.
Cy3P
Cl
R
R
(4 mol %)
Ru
Cl
Cy3P
Ph
CH2Cl2, rt
Time
under Ar
N
Boc
2a-d
N
Boc
1a-d
HO
HO
Grubbs' 1st gen. cat.
1
1.5
>99
1b
2b
2e
N
Boc
N
Entry
R
Time (h)
Products
Yielda,b (%)
Boc
1
2c
3
4
5
a
H (1a)
H (1a)
OH (1b)
OBn (1c)
OTBDPS (1d)
41
2a
2a
2b
2c
2d
32 (41)
96
>99
44 (32)
7 (73)
HO
HO
HO
2
1.5
99
1.5
1.5
41
1e
1f
O
O
HO
41
3
4d
44.5
1
74 (17)
66
Isolated yield.
2f
b
Figures in parentheses are recovery yields estimated from 1H NMR
spectrum of crude reaction mixture.
c
HO
HO
The reaction was performed under ethylene atmosphere.
5
6d
32
5
>99
66
1g
2g
are summarized in Table 1. An interesting effect of the
allylic hydroxy group has been highlighted from them.
Compared with the substrate without an allylic substituent
(1a), enyne metathesis of the substrate with an allylic
hydroxy group (1b) proceeded rapidly (Table 1, entries 1
and 3). This acceleration effect of an allylic hydroxy group
is comparable to the effect of an ethylene atmosphere
(Table 1, entry 2). Also, the acceleration is specific for an
allylic hydroxy group. Protection of the allylic hydroxy
group decreased the reaction rate and efficiency (Table 1,
entries 4 and 5). These results clearly indicate an accelera-
tion effect of the allylic hydroxy group.
HO
HO
7
48.5
3
76
77
1h
tBuOOC COOtBu
2h
tBuOOC COOtBu
8d
9
4
79
1i
1j
HO
HO
2i
10
44
16.5
1.5
15
45
61
11d
12e
HO
HO
HO
HO
2j
13
1
>99f
We then investigated the scope of this acceleration effect
of an allylic hydroxy group. Using 4 mol % of Grubbs’ 1st
generation catalyst, ring-closing metathesis of various N-,
O-, C-tethered enynes containing an allylic hydroxy group
was investigated in CH2Cl2 at rt (Table 2). The enyne
metathesis of an O-tethered enyne that constructs a six-
membered cyclic 1,3-diene proceeded with excellent yield
(99%) in a short time (Table 2, entry 2). C-Tethered enynes
with and without substituents on the tethered chain
smoothly promoted ring-closing enyne metathesis to afford
five- and six-membered cyclic products (Table 2, entries
3–12). Although some reactions took a long time and
had low efficiency, with higher catalyst loading almost all
of these reactions were completed in a short time and gave
cyclic products in good yields. The reaction of a benzene
ring-tethered enyne also proceeded smoothly to yield a
bicyclic product (2k) in excellent yield (Table 2, entry 13).
Unfortunately, seven-membered ring products were not
obtained from corresponding N-, O-, C-tethered enynes
(Table 2, entries 14–16). Although there are some limita-
tions, the enyne metathesis of terminal alkynes with an
allylic hydroxy group proceeds smoothly without ethylene
atmosphere and/or more reactive newer generation cata-
lysts. The acceleration effect is applicable to a wide range
of substrates.
1k
2k
14
15
16
1l: X = NBoc, Y = CH2 48
1m: X = CH2, Y = O
1n: X = CH2
2l
ndg
ndg
ndg
30
40
2m
2n
Y = C(COOEt)2
a
The reactions were performed with 0.002 M of Grubbs’ 1st generation
catalyst.
b
Isolated yield.
Figures in parenthesis are recovery yields estimated from 1H NMR
spectrum of crude reaction mixture.
c
d
8 mol % of the catalyst (0.002 M) was used.
12 mol % of the catalyst (0.002 M) was used.
nd = not detected.
e
g
f Since 2k is easily transformed to 2-vinylnaphthalene, the yield was cal-
culated from the sum of 2k and 2-vinylnaphthalene (2k: 2-vinylnaphtha-
lene = 74:26). After 14 h, 2k was completely converted to 2-
vinylnaphthalene.
received much attention in Gaucher’s disease therapy.12
The hydroxy group of dienol 2b given by the ring-closing
metathesis (>99%) was protected with a tert-butyldiphenyl-
silyl (TBDPS) group (99%). Then the TBDPS-protected
product 2d was treated with AD-mix-aÒ. Highly regioselec-
tive dihydroxylation of terminal olefin proceeded to pro-
vide diol 3 (78%). Oxidative cleavage of the diol with
NaIO4 followed by reduction with NaBH4 gave allylalco-
hol 4 (98% for two steps). Hydroboration of the internal
olefin and the introduction of a hydroxy group provided
Utilizing this efficient reaction, the synthesis of isofago-
mine was demonstrated (Scheme 1). Isofagomine is a
potent selective b-glucosidase inhibitor that has recently

T. Imahori et al. / Tetrahedron Letters 49 (2008) 265–268
267
1) propargylamine
H2O(cat.)
100 °C, 6 h
2) (Boc)2O, NaOH
1,4-dioxane/H2O (5:1)
r.t., overnight
Grubbs' 1st catalyst
RO
HO
TBDPSCl
imidazole
DMAP (cat.)
CH2Cl2
O
(4 mol %)
R =
H (2b)
TBDPS (2d)
CH2Cl2
r.t., 1.5 h
>99%
N
N
Boc
Boc
rt, 3 h:99%
1b
71%
under Ar
OH
OH
1) NaIO4
EtOH / H2O, r.t., 2.5 h
®
TBDPSO
AD-mix-α
TBDPSO
OH
methanesulfonamide
2) NaBH4
N
t
-BuOH / H2O
r.t., 15h
78%
N
EtOH / H2O, r.t., 1.5 h
Boc
Boc
98 %
4
3
OH
OH
OH
OH
1) 10% HCl
1) BH3⋅THF
HO
dioxane
HO
TBDPSO
THF, 40-50 °C, 18 h
OH
OH
reflux, 2 h
+
2) 3 mol/L NaOH
30% H2O2
THF, r.t., 3.5 h
72%
N
H
7
2) NH4OH
N
H
6
N
Boc
5
10 %
89 %
Total Yield 34 %
Scheme 1. Application to isofagomine synthesis.
Am. Chem. Soc. 1997, 119, 12388–12389; (f) Zuercher, W. J.;
Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 8305–
8314.
diol 5 (72% for two steps). After deprotection of the
TBDPS and the tert-butoxycarbonyl (Boc) group with
10 mol % HCl, isofagomine (6, 89%) and 3-epi-isofagomine
(7, 10%) were obtained.13 Isofagomine (6) was synthesized
in 34% total yield from commercially available 1,3-butadi-
ene monoxide.14,15
2. For selected examples, see: (a) Bentz, D.; Laschat, S. Synthesis 2000,
1766–1773; (b) Katritzky, A. R.; Nair, S. K.; Khokhlova, T.;
Akhmedov, N. G. J. Org. Chem. 2003, 68, 5724–5727.
3. Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997,
119, 3887–3897.
In summary, we have found an interesting acceleration
effect of an allylic hydroxy group on ring-closing enyne
metathesis.16–18 The ring-closing enyne metathesis of vari-
ous terminal alkynes containing an allylic hydroxy group
proceeded smoothly without ethylene atmosphere and/or
more reactive newer generation Ru-carbene catalysts.19
We believe that enyne metathesis would be more helpful
and would act as familiar tool in organic synthesis using
this acceleration effect. Further investigations of the mech-
anism of the acceleration are currently under way.20 Also,
the application of this acceleration effect to other systems
and the development of selective molecular transforma-
tions using this acceleration effect are proceeding in our
laboratory.
4. (a) Diver, S. T.; Gissert, A. J. Chem. Rev. 2004, 104, 1317–1382; (b)
Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55–66; (c)
Maifeld, S. V.; Lee, D. Chem. Eur. J. 2005, 11, 6118–
6126.
5. (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (b)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4449.
6. In Figure 1, the ‘ene-then-yne’ pathway is described provisionally
because some mechanistic and computational studies on ring-closing
enyne metathesis support the ‘ene-then-yne’ pathway, see: (a) Hoye,
T. R.; Donaldso, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277–279; (b)
Lloyd-Jones, G. C.; Margue, R. G.; de Vries, J. G. Angew. Chem., Int.
Ed. 2005, 44, 7442–7447; (c) Lippstreu, J. J.; Straub, B. F. J. Am.
Chem. Soc. 2005, 127, 7444–7457; The ‘yne-then-ene’ pathway is also
proposed, see: (d) Kinoshita, A.; Mori, M. Synlett 1994, 1020–1022;
(e) Vedrenne, E.; Royer, F.; Oble, J.; Ka¨ım, L. E.; Grimaud, L.
Synlett 2005, 2379–2381; (f) Dieltiens, N.; Moonen, K.; Stevens, C. V.
Chem. Eur. J. 2007, 13, 203–214.
7. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082–6083.
Acknowledgments
8. Ru-g3-vinylcarbene species are not so reactive for metathesis, see:
Trnka, T. M.; Day, M. W.; Grubbs, R. H. Organometallics 2001, 20,
3845–3847.
We are grateful for the financial supports provided by a
Grant-in-Aid for Scientific Research from Japan Society
for the Promotion of Science (JSPS) (No. 18570012) and
High Technology Research Program from the Ministry of
Education, Culture, Sports, Sciences and Technology,
Japan (MEXT).
9. It is suggested that ethylene can accelerate ring-closing enyne
metathesis by diversion of Ru-vinylcarbene intermediate (Scheme 1,
cycle B) to re-entry reactive Ru-carbene species into catalytic cycle,
see Ref. 6b,c.
10. (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L. J. Am.
Chem. Soc. 1999, 121, 2674–2678; (b) Weskamp, T.; Kohl, F. J.;
Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem., Int. Ed.
1999, 38, 2416–2419; (c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R.
H. Org. Lett. 1999, 1, 953–956; (d) Garber, S. B.; Kingsbury, J. S.;
Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–8179;
(e) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973–9976.
References and notes
1. For representative early examples, see: (a) Kats, T. J.; Sivavec, T. M.
J. Am. Chem. Soc. 1985, 107, 737–739; (b) Trost, B. M.; Tanoury, G.
J. J. Am. Chem. Soc. 1991, 110, 1636–1638; (c) Kim, S.-H.; Bowden,
N.; Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801–10802; (d)
Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem. Soc.
1994, 110, 6049–6050; (e) Kinoshita, A.; Sakakibara, N.; Mori, M. . J.
11. For selected examples, see: (a) Takahata, H.; Suto, Y.; Kato, E.;
Yoshimura, Y.; Ouchi, H. Adv. Synth. Catal. 2007, 349, 685–693; (b)
Ouchi, H.; Mihara, Y.; Takahata, H. J. Org. Chem. 2005, 70, 5207–

268
T. Imahori et al. / Tetrahedron Letters 49 (2008) 265–268
5214; (c) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.;
Diver, S. T. J. Am. Chem. Soc. 2005, 127, 5762–5763; (b) Kinoshita,
T.; Sato, Y.; Mori, M. Adv. Synth. Catal. 2002, 344, 678–693.
19. An interesting acceleration effect of phenol as an additive for olefin
metathesis has been reported. See: Forman, G. S.; McConnell, A. E.;
Tooze, R. P.; Janse van Rensburg, W.; Meyer, W. H.; Kirk, M. M.;
Dwyer, C. L.; Serfontein, D. W. Organometallics 2005, 24, 4528–4542.
In the present enyne metathesis, the allylic hydroxy group might act in
the same way as phenol.
Adachi, I.; Kato, I.; Ouchi, H.; Takahata, H.; Feet, G. W. J.
Tetrahedron: Asymmetry 2005, 16, 223–229; (d) Kato, A.; Kato, N.;
Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48,
2036–2044; (e) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org.
Lett. 2003, 5, 2527–2529; (f) Takahata, H.; Banba, Y.; Ouchi, H.;
Nemoto, H.; Kato, A.; Adachi, I. J. Org. Chem. 2003, 68, 3603–
3607.
20. General procedure for allylic hydroxy group accelerated ring-closing
enyne metathesis: To a solution of an enyne substrate containing an
allylic hydroxy group in CH2Cl2 was added 4, 8 or 12 mol % of
Grubbs’ 1st generation catalyst at rt under Ar atmosphere. The
concentration of Grubbs’ 1st generation catalyst was kept at 0.002 M.
The mixture was stirred for the indicated reaction time. Then the
reaction mixture was concentrated in vacuo and the residue was
purified with silica gel column chromatography to obtain cyclic 1,3-
dienes. Spectroscopic data for representative examples: Compound
12. Zhu, X. Z.; Sheth, K. A.; Li, S.; Chang, H.-H.; Fan, J.-Q. Angew.
Chem., Int. Ed. 2005, 44, 7450–7453.
13. This anti-selectivity would be induced by steric repulsion of TBDPSO
group in the hydroboration step.
14. The use of AD-mix-aÒ would induce slight kinetic resolution of 3 and
27
½aꢀD ꢁ1.8 (c 1.43, CHCl3) was indicated for the final product 6.
27
Compound 6: ½aꢀD ꢁ1.8 (c 1.43, CHCl3); 1H NMR (600 MHz, D2O) d
(ppm): 1.61–1.68 (m, 1H), 2.33–2.38 (m, 2H), 3.05 (dd, J = 13.0,
3.5 Hz, 1H), 3.10 (dd, J = 12.1, 4.8 Hz, 1H), 3.27 (t, J = 9.9 Hz, 1H),
3.43–3.48 (m, 1H), 3.59 (dd, J = 11.4, 7.0 Hz, 1H), 3.78 (dd, J = 11.4,
3.3 Hz, 1H); 13C NMR (100 MHz, D2O/CH3CN) d (ppm): 43.9, 45.7,
48.8, 59.8, 71.4, 73.1; EI-Ms (m/z): 147 (M+); HRMS: calcd for
C6H13NO3: 147.0895, found: 147.0845.
1
2b: H NMR (600 MHz, CDCl3/TMS) d (ppm): 1.48 (s, 9H), 2.23 (s,
2H), 3.55 (br s, 2H), 3.95 (d, J = 17.6 Hz, 1H), 4.10–4.26 (m, 2H),
5.12 (d, J = 11.0 Hz, 1H), 5.22–5.25 (m, 1H), 5.87 (br s, 1H), 6.30 (dd,
J = 17.6, 11.0 Hz, 1H); 13C NMR (67.5 MHz, C6D6, 60 °C) d (ppm):
28.5, 43.0, 48.2, 64.2, 79.8, 113.1, 130.3, 135.7, 136.7, 155.1; IR (neat):
15. Other examples of isofagomine syntheses, see: (a) Ouchi, H.; Mihara,
Y.; Watanabe, H.; Takahata, H. Tetrahedron Lett. 2004, 45, 7053–
7056; (b) Banfi, L.; Guanti, G.; Paravidino, M.; Riva, R. Org. Biomol.
Chem. 2005, 3, 1729–1737.
16. A similar acceleration effect of an allylic hydroxy group has been
observed in olefin metathesis with Grubbs’ 1st generation catalyst,
though details are not clear. See: (a) Hoye, T. R.; Zhao, H. Org. Lett.
1999, 1, 1123–1125; (b) Schmidt, B.; Nave, S. Adv. Synth. Catal. 2007,
349, 215–230; (c) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.;
Asai, N.; Mizui, Y.; Abe, S.; Kotake, Y. Angew. Chem., Int. Ed. 2007,
46, 4350–4355.
17. Effects of a hydroxy group at other positions in Ru-carbene catalyzed
enyne metathesis, see: (a) Mori, M.; Tonogaki, K.; Nishiguchi, N. J.
Org. Chem. 2002, 67, 224–226; (b) Smulik, J. A.; Diver, S. T. Org.
Lett. 2000, 2, 2271–2274.
18. Effects of other substituents on the rate of Ru-carbene catalyzed
enyne metathesis, see: (a) Galan, B. R.; Giessert, A. J.; Keister, J. B.;
1683, 3406 cmꢁ1 EI-Ms (m/z): 225 (M+); HRMS: calcd for
;
C12H19NO3: 225.1365, found: 225.1370. Compound 2f: 1H NMR
(400 MHz, CDCl3) d (ppm): 1.56–1.64 (m, 2H), 1.71 (br s, 1H), 1.79–
1.90 (m, 2H), 2.11–2.15 (m, 2H), 4.29 (br s, 1H), 5.04 (d, J = 10.7 Hz,
1H), 5.20 (d, J = 17.6 Hz, 1H), 5.75 (br s, 1H), 6.34 (dd, J = 17.6,
10.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d (ppm): 18.8, 23.7, 32.0,
66.2, 112.9, 130.8, 138.6, 139.2; IR (neat): 909, 991, 1049, 1607, 2863,
2935, 3308 cmꢁ1; EI-Ms (m/z): 124 (M+); HRMS: calcd for C8H12O:
124.0888, found: 124.0889. Compound 2h: 1H NMR (400 MHz,
CDCl3) d (ppm): 1.42 (s, 9H), 1.46 (s, 9H), 2.20–2.28 (m, 2H), 2.53 (d,
J = 16.9 Hz, 1H), 2.68 (d, J = 16.9 Hz, 1H), 3.07 (d, J = 9.2 Hz, 1H),
4.31 (br s, 1H), 5.10 (d, J = 10.6, 1 H), 5.30 (d, J = 17.9 Hz, 1H), 5.76
(br s, 1H), 6.53 (dd, J = 17.4, 11.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d (ppm): 27.7, 27.8, 29.3, 36.6, 53.8, 64.2, 81.7, 82.1, 113.5,
130.1, 134.4, 138.4, 170.3; IR (neat): 1147, 1257, 1369, 1608, 1716,
1729, 2934, 2978, 3522 cmꢁ1; EI-Ms (m/z): 324 (M+); HRMS: calcd
for C18H28O5: 324.1937, found: 324.1947.