Intramolecular TiCl4-mediated cyclization reaction of β-hydroxyalkynyl acetals

Article abstract of DOI:10.1016/S0040-4039(01)02249-3

Intramolecular TiCl₄-mediated cyclization reaction of 1,1-dimethoxy-3-hydroxy-hex-5-yne derivatives produced anti-1-hydroxy-3-methoxy-cyclohex-5-ene derivatives with high diastereoselectivity via antiperiplanar manner on pseudo six-membered chair like conformation (transition state A).

Full text of DOI:10.1016/S0040-4039(01)02249-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 837–841
Intramolecular TiCl4-mediated cyclization reaction of b-hydroxy
alkynyl acetals
Yong-Hyun Kim,a Kee-Young Lee,a Chang-Young Oh,a Jae-Gwon Yangb and Won-Hun Hama,*
aCollege of Pharmacy, SungKyunKwan University, Suwon 440-746, Republic of Korea
bKolon Central Research Park 207-2, Mabuk-ri, Guseong-eup, Yong-in, Republic of Korea
Received 19 October 2001; revised 19 November 2001; accepted 22 November 2001
Abstract—Intramolecular TiCl4-mediated cyclization reaction of 1,1-dimethoxy-3-hydroxy-hex-5-yne derivatives produced anti-1-
hydroxy-3-methoxy-cyclohex-5-ene derivatives with high diastereoselectivity via antiperiplanar manner on pseudo six-membered
chair like conformation (transition state A). © 2002 Elsevier Science Ltd. All rights reserved.
The preparation of both carbocycles and heterocycles
using the Lewis acid-mediated cyclization reaction of
acetals with the participation of alkynes as nucleophiles
has been well documented,1 notably through the exten-
sive investigations of the Johnson group.1,2 More
recently, the Lewis acid-mediated cleavage3 of acetals
and chiral acetals has been the subject of numerous
investigations and has become a useful tool for the
asymmetric synthesis of secondary alcohols and the
preparation of medium and large ring compounds.4
cyclization reaction by alkyne could diastereoselectively
proceed via antiperiplanar attack on oxocarbenium ion
generated from chelation of b-hydroxy moiety and ace-
tal with Lewis acid. Consequently, we decided to inves-
tigate the stereochemical course of the intramolecular
Lewis acid-mediated cyclization reaction of b-hydroxy
alkynyl acetals. In the initial study testing of our
hypothesis, the combination of alkyne and TiCl4 or
SnCl4 was chosen for investigation in conjunction with
b-hydroxy acetal electrophiles. We are delighted to
report herein on the reaction of TiCl4 and b-hydroxy
alkynyl acetal, which, in most cases, proceeds with
excellent diastereoselectivity (Scheme 1).
The mechanism of the Lewis acid-mediated nucleophilic
substitution of acetals is a recent topic of interest.
Denmark reported that sterically unhindered aliphatic
acetals underwent intramolecular SN2-type substitution
with the aid of a mild Lewis acid.3i In contrast, Sam-
makia observed that dimethyl acetals underwent inter-
molecular allylation via an oxocarbenium ion using any
kind of Lewis acid.3g To our knowledge, however, there
has been one example4b reported on the intramolecular
Lewis acid-mediated cyclization of alkynyl acetals.
Overman et al. reported a ring-enlarging cyclopentane
annulation that involves the reaction of an alkynyl
acetal with SnCl4. This is believed to proceed by a
cationic cyclization–pinacol rearrangement sequence
but its stereoselectivity is not satisfactory.
Scheme 1.
We speculated that when the hydroxy group is present
at the b-position of the acetal, a Lewis acid-mediated
The first, when readily available b-hydroxy alkynyl
acetal 1 was treated with TiCl4 at −78°C, anti-1,3-dihy-
droxycyclohexene compound 2 was obtained as a single
diastereomer in 85% yield. The anti-orientation of the
two hydroxy moieties of 2 was confirmed by a single-
crystal X-ray diffraction study (Fig. 1). But, the treat-
ment of 1 with SnCl4 at −78°C afforded an allene
Keywords: 1,3-diaxial alcohol; b-hydroxy alkynyl acetal; intramolecu-
lar cyclization; Lewis acid; stereocontrol.
* Corresponding author. Tel.: 82 31 290 7706; fax: 82 31 292 8800;
e-mail: whham@speed.skku.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02249-3

838
Y.-H. Kim et al. / Tetrahedron Letters 43 (2002) 837–841
bond is formed. In the case of TiCl4, the single
diastereomer 2 may suggest highly diastereoselective
cyclization via antiperiplanar manner on pseudo six-
membered chair like conformation (transition state A).
In contrast to TiCl4, when the alkynyl acetal is reacted
with SnCl4, an allene compound 3 is produced as a
diastereomeric mixture (1:1).5 It demonstrates that the
reaction proceeds via an oxocarbenium ion intermedi-
ate B by a slow chloride trap. In an effort to investigate
the scope and limitation of this methodology, several
1,1-dimethoxy-3-hydroxy-hex-5-yne derivatives6 were
treated with TiCl4 or SnCl4. The results of this reaction
are summarized in Table 1.
All reactions of entries 1–6 with TiCl4 at −78°C
afforded
anti-1-hydroxy-3-methoxy-cyclohex-5-ene
Fig. 1. X-Ray crystal structure of 2.
1
derivatives as a single diastereomer on H NMR (500
MHz). To our knowledge, these present the first exam-
ples of intramolecular TiCl4-mediated cyclization reac-
tion that form anti-1,3-dihydroxy-cyclohexene products
with high diastereoselectivity. However, not all sub-
strates could be induced to undergo cyclization, even
though the structures were quite similar. In the case of
the alkynyl acetal containing the TMS group attached
to the terminal alkyne carbon, it did not undergo
cyclization (entry 7) and this unreactivity might be due
to the steric hindrance between TMS-alkyne and acetal
group.
compound 3 as a diastereomeric mixture (1:1) in 87%
yield.
The mechanistic basis for these results of the Lewis
acid-mediated intramolecular nucleophilic cyclization is
unclear; however, we propose the following mechanism
shown in Scheme 2.
When b-hydroxy alkynyl acetal is treated with Lewis
acid, oxocarbenium ion is generated from the chelation
of b-hydroxy moiety and acetal with Lewis acid. As the
alkyne attacks the oxocarbenium, a carbenium ion
develops which has to be trapped by chloride in order
to produce the desired cyclization product. If the trap-
ping by chloride is slow, then push–pull fragmentation
to the allene compound could be observed. This differ-
entiation could be due to a difference in the availability
of halogen, which in turn could depend on the Lewis
acid, as such, both reactions could proceed via a com-
mon intermediate with the difference in product arising
from a different course for the reaction after the CꢀC
In conclusion, we provided the first example of highly
diastereoselective
intramolecular
TiCl4-mediated
cyclization reaction of b-hydroxy alkynylacetal deriva-
tives. The reaction can be realized by an appropriate
condition of nucleophile (alkyne) and the Lewis acid
(TiCl4) and lend itself to the synthesis of a variety of
substituted anti-1,3-dihydroxycyclohexane systems.
Further studies and applications of this reaction will be
reported in due course.
Scheme 2.

Y.-H. Kim et al. / Tetrahedron Letters 43 (2002) 837–841
839
Table 1. Intramolecular Lewis acid-mediated cyclization of 1,1-dimethoxy-3-hydroxy-hex-5-yne derivates7
a
A: 1.0 M TiCl4 (1.1 equiv. in CH2Cl2, −78°C), B: 0.1 M SnCl4 (1.1 equiv. in CH2Cl2, −78°C).
b
Yield refer to isolated and chromatographically pure products.
c
The stereochemistry was confirmed by NOE experiment.8
d No reaction.
Acknowledgements
Am. Chem. Soc. 1988, 110, 612; (c) Fleming, I.;
Dunogue`s, J.; Smithers, R. Org. React. 1989, 37, 57; (d)
Funk, R. L.; Fitzgerald, J. F.; Olmstead, T. A.; Wos, J.
A. J. Am. Chem. Soc. 1993, 115, 8849. For oxacycles,
see: (e) Melany, M. L.; Lock, G. A.; Thomspon, D. W.
J. Org. Chem. 1985, 50, 3925; (f) Lolkema, L. D. M.;
Hiemstra, H.; Semeyn, C.; Speckamp, W. N. Tetra-
hedron. 1994, 50, 7115.
We are grateful for the financial support provided by
the KOSEF (98-0403-12-01-3).
References
2. For reviews, see: (a) Johnson, W. S.; Kinnel, R. B. J.
Am. Chem. Soc. 1966, 88, 3861; (b) Johnson, W. S. Bio-
org. Chem. 1976, 5, 51; (c) Johnson, W. S.; Ward, C. E.;
1. For reviews, see: (a) Mukaiyama, T.; Murakami, M.
Synthesis 1987, 1043; (b) Overman, L. E.; Sharp, M, J. J.

840
Y.-H. Kim et al. / Tetrahedron Letters 43 (2002) 837–841
Boots, S. G.; Gravestock, M. B.; Markezich, R. L.;
McCarry, B. E.; Okorie, D. A.; Parry, R. J. J. Am. Chem.
Soc. 1981, 103, 88, and other papers in this series.
the aqueous phase was extracted Et2O (20 mL×3). The
combined organic layers were washed with brine, dried
over MgSO4, filtered, and rotary evaporated. The residue
was purified by flash chromatography. Data for 2: 85%
yield; white crystal; mp 112–113°C; IR (neat); 3432, 2928,
3. (a) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 7371; (b) Sekizaki, H.; Jung, M.; McNamara, J. M.;
Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7372; (c) Bartlett,
P. A.; Johnson, W. S.; Elliott, J. D. J. Am. Chem. Soc.
1983, 105, 2088; (d) Mori, I.; Ishihara, K.; Flippin, L. A.;
Nozaki, K.; Yamamoto, H.; Bartlett, P. A.; Heathcock, C.
H. J. Org. Chem. 1990, 55, 6107; (e) Corcoran, R. C.
Tetrahedron Lett. 1990, 31, 2101; (f) Molander, G. A.;
Haar, J. P., Jr. J. Am. Chem. Soc. 1993, 115, 40; (g)
Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116,
7915. For recent review, see: (h) Alexakis, A.; Mangency,
P. Tetrahedron: Asymmetry 1990, 1, 477; (i) Denmark, S.
E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089; (j)
Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1992, 114,
10998; (k) Kinugasa, M.; Harada, T.; Oku, A. J. Am.
Chem. Soc. 1997, 119, 9067; (l) Harada, T.; Nakamura, T.;
Kinugasa, M.; Oku, A. J. Org. Chem. 1999, 64, 7594, and
reference cited therein.
4. (a) Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110,
6556; (b) Johnson, T. O.; Overman, L. E. Tetrahedron
Lett. 1991, 32, 7361; (c) Johnson, W. S.; Plummer, M. S.;
Reddy, S. P.; Bartlett, W. R. J. Am. Chem. Soc. 1993, 115,
515; (d) Hirst, G. C.; Johnson, T. O.; Overman, L. E. J.
Am. Chem. Soc. 1993, 115, 2992; (e) Trost, B. M.; Chen,
D. W. C. J. Am. Chem. Soc. 1996, 118, 12541; (f) Ando,
S.; Minor, K. P.; Overman, L. E. J. Org. Chem. 1997, 62,
6379; (g) Morihira, K.; Hara, R.; Kuwasara, S.; Nisimori,
T.; Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am.
Chem. Soc. 1998, 120, 12980; (i) Hara, R.; Furukawa, T.;
Kashima, H.; Kusama, H.; Horiguchi, Y.; Kuwajima, I. J.
Am. Chem. Soc. 1999, 121, 3072.
1660 cm−1 1H NMR (500 MHz): l 1.19–1.33 (m, 2 H),
;
1.36–1.47 (m, 3 H), 1.52–1.70 (m, 2 H), 1.31 (s, 3 H),
2.02–2.11 (dd, J=6.9, 6.0 Hz, 1 H), 2.17–2.26 (d br t,
J=J=18.0, 2.5 Hz, 1 H), 2.47–2.52 (dt, J=18.0, 2.5 Hz, 1
H), 3.37 (s, 3 H), 3.65 (dd, J=9.5, 1.0 Hz, 1 H), 6.00 (t,
J=1.0 Hz, 1 H); 13C NMR (125 MHz): l 21.9, 25.1, 26.0,
39.8, 45.1, 48.6, 57.1, 72.3, 80.5, 125.0, 132.0; HRMS (CI+,
NH3) calcd for C11H16ClO (M-OH)+ 199.0890, found
199.0890; 3: 87% yield (diastereomeric ratio=1:1). Data
1
for 3a: colorless oil; IR (neat); 3614, 3447, 1707 cm−1; H
NMR (400 MHz): l 1.60–1.74 (m, 3 H), 1.91 (m, 1 H),
1.98 (m, 1 H), 2.17 (m, 1 H), 2.28 (m, 1 H), 2.39 (m, 1 H),
2.47 (ddd, J=9.9, 6.4, 5.0 Hz, 1 H), 3.34 (s, 3 H), 4.13 (dd,
J=7.3, 6.4 Hz, 1 H), 4.79 (dd, J=11.0, 6.6 Hz, 2 H), 5.14
(dd, J=7.3, 6.6 Hz, 1 H); 13C NMR (125 MHz): l 25.1,
28.0, 28.6, 30.4, 42.9, 56.4, 57.5, 76.7, 90.5, 209.2, 211.2.
Data for 3b: colorless oil; IR (neat); 3614, 3447, 1707
1
cm−1; H NMR (400 MHz): l 1.57–1.69 (m, 3 H), 1.85 (m,
1 H), 1.96–2.07 (m, 2 H), 2.34 (m, 1 H), 2.41 (m, 1 H), 2.56
(ddd, J=10.5, 5.2, 3.6 Hz, 1 H), 3.34 (s, 3 H), 4.10 (dd,
J=7.2, 5.2 Hz, 1 H), 4.80 (dd, J=11.0, 8.2 Hz, 2 H), 4.98
(dd, J=8.2, 7.2 Hz, 1 H); 13C NMR (125 MHz): l 24.8,
28.6, 30.2, 42.6, 56.3, 57.3, 76.3, 79.4, 89.6, 210.1, 211.6;
HRMS (CI+, NH3) calcd for C11H16O2 (M)+ 180.1150,
found 180.1153. Data for 11: 88% yield; white crystal; mp
176–178°C; IR (neat); 3676, 2954, 1660 cm−1 1H NMR
;
(300 MHz): l 0.89 (s, 9 H), 1.04–1.09 (m, 2 H), 1.37–1.49
(m, 2 H), 1.61–1.65 (m, 1 H), 1.73–1.79 (m, 1 H), 2.02 (m,
2 H), 2.23–2.29 (d br t, J=17.4, 2.7 Hz, 1 H), 2.44–2.52
(dt, J=17.4, 2.7 Hz, 1 H), 3.37 (s, 3 H), 3.65 (dd, J=9.3,
1.5 Hz, 1 H), 6.01 (t, J=2.4 Hz, 1 H); 13C NMR (125
MHz): l 22.8, 26.0, 28.3, 33.2, 40.2, 45.5, 47.9, 48.4, 57.0,
71.9, 80.5, 124.9, 132.1; HRMS (CI+, NH3) calcd for
C15H24ClO (M–OH)+ 255.1516, found 255.1513. Data for
12: 74% yield; colorless oil; IR (neat); 3420, 2969, 2826,
5. For a similar discussion, see: Nokami, J.; Yoshizane, K.;
Matsuura, H.; Sumida, S. J. Am. Chem. Soc. 1998, 120,
6609.
6. 1,1-Dimethoxy-3-hydroxy-hex-5-yne derivatives (1, 4, 6–9)
were prepared in good yields from keto compounds
according to Scheme 3. Substrate 5, 10 were synthesized
from commercially available acetylacetaldehyde dimethyl
acetal by addition of propargyl magnesium bromide and
1-(trimethylsilyl)-1-propyne lithium salt, respectively. All
1
1657 cm−1; H NMR (300 MHz): l 1.35 (s, 3 H), 1.52 (dd,
J=12.8, 9.1 Hz, 1 H), 2.11 (dd, J=12.8, 5.9 Hz, 1 H),
2.27–2.34 (dt, J=17.8 Hz, 1 H), 2.48–2.56 (dt, J=17.8 Hz,
1 H), 3.38 (s, 3 H), 4.09 (ddd, J=9.1, 5.9, 2.0 Hz, 1 H),
6.01 (br s, J=2.0 Hz, 1 H); 13C NMR (100 MHz): l 30.3,
40.0, 46.9, 56.1, 70.9, 74.9, 124.7, 132.0; HRMS (CI+,
NH3) calcd for C7H10ClO (M−OH)+ 145.0420, found
145.0427. Data for 13: 68% yield; colorless oil; IR (neat);
1
substrates were fully characterized by H, 13C NMR and
IR spectroscopy.
7. General procedure for Lewis acid-mediated cyclization
reaction: The cyclization reaction was performed by addi-
tion of TiCl4 (1.1 equiv. in CH2Cl2, 1.0 M)/SnCl4 (1.1
equiv. in CH2Cl2, 0.1 M) to the 0.1 M solution of the
alkynyl acetals in CH2Cl2 at −78°C. The reaction mixture
1
3429, 2930, 1654 cm−1; H NMR (400 MHz): l 2.18 (s, 3
H), 2.56–2.61 (dd, J=15.8, 4.9 Hz, 1 H), 2.75–2.81 (dd,
J=15.8, 8.0 Hz, 1 H), 3.32 (s, 3 H), 4.18 (ddd, J=8.0, 6.8,
4.9 Hz, 1 H), 4.79–4.87 (dd, J=11.0, 7.0 Hz, 2 H), 5.08
was stirred for 10 min, quenched with
a saturated
NaHCO3 (10 mL). The organic layer was separated and
Scheme 3. (a) LDA, TMS-Cl, THF, −78°C for 1,4,6,7; (b) TMS-Cl, TEA, DMF, 80°C for 8,9; (c) MeLi, CH(OCH3)3, BF3-OEt2,
Et2O, −78°C; (d) propargyl magnesium bromide, Et2O, 0°C for 1,4–9; (e) 1-(trimethylsilyl)-1-propyne, t-BuLi, THF, −78°C for 10.

Y.-H. Kim et al. / Tetrahedron Letters 43 (2002) 837–841
841
(dd, J=7.0, 6.8 Hz, 1 H); 13C NMR (125 MHz): l 30.4,
31.6, 50.0, 57.1, 76.3, 77.2, 91.1, 207.0, 209.1; HRMS (CI+,
NH3) calcd for C8H13O2 (M+H)+ 141.0915, found
141.0918. Data for 14: 75% yield; colorless oil; IR (neat);
H), 1.28 (s, 3 H), 1.48–1.63 (dd, J=9.0, 6.6 Hz, 1 H),
2.30–2.36 (d br t, J=17.7, 2.7 Hz, 1 H), 2.51–2.59 (dt,
J=17.7, 2.7 Hz, 1 H), 3.39 (s, 3 H), 3.62 (ddd, J=9.0, 2.7,
2.4 Hz, 1 H), 6.01 (t, J=2.4 Hz, 1 H); 13C NMR (125
MHz): l 11.1, 28.5, 42.5, 48.3, 57.0, 73.3, 81.2, 124.7,
132.3. Data for 17: 67% yield; colorless oil; IR (neat);
1
3439, 2965, 2930, 2829 cm−1; H NMR (500 MHz): l 0.95
(t, 7.5 Hz, 3 H), 1.40–1.44 (dd, J=13.0, 9.0 Hz, 1 H),
1.57–1.62 (q, 15.0, 9.5 Hz, 2 H), 2.07–2.11 (dd, J=13.0,
6.0 Hz, 1 H), 2.21–2.25 (dt, J=18.0 Hz, 1 H), 2.48–2.53
(dt, J=18.0 Hz, 1 H), 3.38 (s, 3 H), 4.08–4.13 (ddd,
J=9.0, 6.0, 2.0 Hz, 1 H), 6.02 (br s, J=2.0 Hz, 1 H); 13C
NMR (125 MHz): l 8.0, 36.3, 38.7, 45.5, 56.8, 73.8, 75.7,
125.6, 132.6; HRMS (CI+, NH3) calcd for C7H10ClO (M)+
190.0761, found 190.0759. Data for 15: 72% yield; color-
1
3362, 2973, 2897, 1659 cm−1; H NMR (300 MHz): l 0.85
(d, J=6.9 Hz, 3 H), 1.31 (s, 3 H), 2.02–2.11 (dd, J=6.9,
6.0 Hz, 1 H), 2.17–2.26 (d br t, J=17.8, 2.6 Hz, 1 H),
2.46–2.54 (dt, J=17.8, 2.6 Hz, 1 H), 3.38 (s, 3 H), 4.17
(ddd, J=6.0, 2.6, 1.1 Hz, 1 H), 5.85 (t, J=1.1 Hz, 1 H);
13C NMR (125 MHz): l 11.2, 28.1, 40.3, 49.4, 71.0, 74.0,
127.1, 134.2; HRMS (CI+, NH3) calcd for C9H14ClO (M−
OH)+ 173.0733, found 173.0737.
1
less oil; IR (neat); 3450, 2967, 2883, 2826 cm−1; H NMR
(500 MHz): l 0.94–0.98 (m, 7.0 Hz, 6 H), 1.38–1.41 (dd,
J=14.0, 7.0 Hz, 1 H), 1.69–1.72 (m, 7.0 Hz, 1 H), 2.08–
2.12 (dd, J=13.0, 6.0 Hz, 1 H), 2.14–2.18 (dt, J=18.0 Hz,
1 H), 2.50–2.55 (dt, J=18.0 Hz, 1 H), 3.39 (s, 3 H),
4.09–4.12 (ddd, J=8.0, 5.5, 2.0 Hz, 1 H), 6.02 (br s, J=2.0
Hz, 1 H); 13C NMR (125 MHz): l 17.2, 17.3, 37.0, 38.9,
43.0, 56.8, 75.9, 125.7, 132.7; HRMS (CI+, NH3) calcd for
C7H10ClO (M–OH)+ 204.0917, found 204.0916. Data for
16: 70% yield; colorless oil; IR (neat); 3447, 2977, 2825,
8. The axial orientation of the hydroxy group at C1 of 2 was
confirmed by the existence of NOE between Ha, He and
OH at C1. The key interactions are illustrated here:
1
1664 cm−1; H NMR (300 MHz): l 1.06 (d, J=6.6 Hz, 3