Facile Synthesis of Spirocyclic Systems through the Intramolecular Addition of Ketyl Radicals via the Sodium/Ammonia Reduction of δ,ε-Unsaturated Carboxylic Esters

Full text of DOI:10.1021/jo972339i

J . Org. Chem. 1998, 63, 3141-3146
3141
F a cile Syn th esis of Sp ir ocyclic System s
Sch em e 1
th r ou gh th e In tr a m olecu la r Ad d ition of
Ketyl Ra d ica ls via th e Sod iu m /Am m on ia
Red u ction of δ,E-Un sa tu r a ted Ca r boxylic
Ester s
J anine Cossy,* Barbara Gille, and V e´ ronique Bellosta
Laboratoire de Chimie Organique Associ e´ au CNRS,
ESPCI,10 rue Vauquelin, 75231 Paris Cedex 05, France
Received December 31, 1997
Sch em e 2
Cyclization of δ,ꢀ-unsaturated radicals is a very fast
process that leads to cyclopentylmethyl or cyclohexyl
radicals. Convenient methods to prepare the key radical
intermediate include the reduction of functional groups
such as halides, haloketals, or thioethers. Similarly,
ketyl radicals arising from the reduction of δ,ꢀ-unsatur-
ated ketones and aldehydes, utilizing alkali metals in
1
2a
2b
SnH,3
liquid ammonia, TMSCl/Zn, TMSCl/Mg, Bu
3
4
5
SmI
2
, cathode reduction, or photochemically induced
6
electron transfer, are cyclized efficiently and lead to the
7
corresponding substituted cyclopentanols. Alternatively,
reduction14 of carboxylic esters and the acyloin condensa-
tion15 proceed via ketyl radical anion intermediates, these
latter have not yet been used in additions to alkenes or
alkynes.
Here, we report that δ,ꢀ-unsaturated carboxylic esters
3
react with Na in liquid ammonia (Na/NH ) and undergo
esters can be reduced by dissolved metals in liquid
8
7c
9
10
ammonia, amines, or HMPA, at the cathode, by
1
1
12
SmI
2
2
in the presence of H O, or by photochemically
1
3
induced electron transfer from HMPA. Although it has
been known for a long time that the Bouveault-Blanc
cyclization with the formation of cyclopentanols with good
diastereoselectivity (enantioselectivity) and that â-hy-
droxyesters of type II (Scheme 1) can be transformed to
spirocyclic diols with excellent regio- and stereoselectiv-
ity. The results are summarized Table 1.
(
*) To whom correspondence should be addressed. Tel.: (+33) 1 40
9 44 29. Fax: (+33) 1 40 79 44 25. E-mail: janine.cossy@espci.fr.
1) (a) Stork, G.; Malhotra, S.; Thompson, H.; Uchibayashi, M. J .
7
(
Am. Chem. Soc. 1965, 87, 1148. (b) Stork, G.; Boeckmann, R. K., J r.;
Taber, D. F.; Still, W. C.; Singh, J . J . Am. Chem. Soc. 1979, 101, 7107.
(
c) Pradhan, S. K.; Subhash, R. K.; Kohle, J . N.; Radhakrishnan, T.
V.; Sohani, S. V.; Thaker, V. B. J . Org. Chem. 1981, 46, 2622.
2) (a) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
b) Ikeda, T.; Yue, S.; Hutchinson, C. R. J . Org. Chem. 1985, 50, 5193.
3) (a) Ardisson, J .; Ferezou, J . P.; J ulia, M.; Pancrazi, A. Tetrahe-
Treatment of â-hydroxy ester 1 by Na (6 equiv) in NH
3
(
afforded the spirocyclic compound 10 (95%). The 300
(
1
MHz H NMR analysis of the crude reaction mixture did
(
dron Lett. 1987, 28, 2001. (b) Sugawara, T.; Otter, B. A.; Ueda, T.
Tetrahedron Lett. 1988, 29, 75.
not reveal any other product. The relative configuration
of centers C-6, C-5, C-1, and C-2 was determined by NOE
differences in the H NMR spectrum and was confirmed
by single-crystal X-ray diffraction studies. The high
regio- and stereoselectivity as well as the high yield
observed for this process led us to explore the synthetic
potential of this new reductive cyclization reaction.
(
4) (a) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem. Soc.
1
1
2
987, 109, 453. (b) Molander, G. A.; Kenny, C. Tetrahedron Lett. 1987,
8, 4367. (c) Molander, G. A.; Kenny, C. J . Org. Chem. 1991, 56, 1439.
(
5) (a) Allen, M. J .; Siragusa, J . A.; Pierson, W. J . Chem. Soc. 1960,
1
1
045. (b) Pallaud, R.; Nicolaus, M. C. R. Acad. Sci., Ser. C 1968, 267,
834. (c) Shono, T.; Nishigushi, I.; Ohmizu, H.; Mitani, M. J . Am. Chem.
Soc. 1978, 100, 545. (d) Sch a¨ fer, H. J . Angew. Chem., Int. Ed. Engl.
1
981, 20, 911.
6) Belotti, D.; Cossy, J .; Pete J . P.; Portella, C. J . Org. Chem. 1986,
1, 4196.
7) (a) Boar, R. B.; J oukhadar, L.; McGhie, J . F.; Misra, S. C.;
3
Reduction of esters 2-5 with Na/NH led to the corre-
(
sponding spirocyclic products 11-14,16 respectively, in
5
(
good yield and high diastereoselectivity. On the contrary,
Barrett, A. G. M.; Barton, D. H. R.; Prokopiou, P. A. J . Chem. Soc.,
Chem. Commun. 1978, 68. (b) Barrett, A. G. M.; Prokopiou, P. A.;
Barton, D. H. R.; Boar, R. B.; McGhie, J . F. J . Chem. Soc., Chem.
Commun. 1979, 1173. (c) Barrett, A. G. M.; Godfrey, C. R. A.;
Hollinshead, D. M.; Prokopiou, P. A.; Barton, D. H. R.; Boar, R. B.;
J oukhadar, L.; McGhie, J . F.; Mistra, S. C. J . Chem. Soc., Perkin Trans.
3
when compound 6 was treated with Na/NH , the spiro-
cyclic compound 15 was isolated (45%), accompanied by
17
a diastereoisomeric spirocyclic alcohol 15′ (30%). The
relative stereochemistry of the substituents in compound
11 was established by oxidation of 10 and 11, which led
to the same dione 19 (Scheme 2).
1
1981, 1501.
(8) Pinnick, H. W.; Fernandez, E. J . Org. Chem. 1979, 44, 2810.
9) (a) Deshayes, H.; Pete, J . P. J . Chem. Soc., Chem. Commun.
(
1
978, 567. (b) Mukhopadhyaya, J . K.; Mukhopadhyaya, C.; Ghatak,
U. R. Indian J . Chem. 1994, 33B, 132.
10) Chaussard, J .; Combellas, C.; Thiebault, A. Tetrahedron Lett.
987, 28, 1173.
11) (a) Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
(14) (a) Bouveault, L.; Blanc, G. C. R. Acad. Sci. Paris 1903, 136,
1676. (b) Chablay, E. C. R. Acad. Sci. Paris 1913, 156, 1020. (c) House,
H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park,
CA, 1972; pp 150-151.
(15) (a) McElvain, S. M. Org. React. 1948, 4, 256. (b) Finley, K. T.
Chem. Rev. 1964, 64, 573. (c) Ruhlmann, K. Synthesis 1971, 236. (d)
Bloomfield, J . J .; Owsley, D. C.; Nelke J . M. Org. React. 1976, 23, 259.
(16) By analogy to compound 10, the same configuration can be
assigned respectively, to compounds 12, 14 and 11, 13.
(
1
(
1
1
985, 28, 4437. (b) Reetz, M. T.; Lauterbach, E. H. Tetrahedron Lett.
991, 32, 4477. (c) Bartelts, A.; J ones, P. G.; Liebscher, J . Tetrahe-
dron: Asymmetry 1995, 6, 1539.
(
12) Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 1495.
(13) Portella, C.; Deshayes, H.; Pete, J . P.; Scholler, D. Tetrahedron
1
984, 40, 3635.
(17) The stereochemistry of compound 15′ could not be determined.
S0022-3263(97)02339-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

3
142 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
Ta ble 1. Red u ction of Un sa tu r ed â-Hyd r oxy Ester of
Sch em e 3
Typ e II
Sch em e 4
Sch em e 5
reduction conditions, 9 provided diol 18 (83%) as a unique
product, showing that cyclization may not compete with
Bouveault-Blanc reduction of the ester, possibly due to
steric reasons.
Discu ssion
Except for compounds 8 and 9, which underwent
Bouveault-Blanc reduction faster than cyclization, all
the products of cyclization followed an exo-trig mode. This
indicates that when one-electron transfer occurs, the
cyclization process is faster than hydrogen transfer from
the solvent. The reaction is very sensitive to steric effects
as the treatment of 9 led only to diol 18. We should point
out that no cyclized product was detected in the crude
reaction mixture. The cyclization of unsaturated esters
a
All compounds are racemic.
2
b
is sensitive to the Thorpe-Ingold effect as compound 21
provides the cyclic alcohol 2319 and the unsaturated
Furthermore, as the dimethoxy compound 20 could be
2
0
primary alcohol 24 in a ratio of 6/4 (yield ) 90%) in
contrast to the unsaturated ester 22,21 which led only to
a single spirocyclic alcohol 25 (83%) (Scheme 4).
In the case of the acetylenic hydroxy ester 8, the diol
17 and the spirocyclic diol 11 were formed (Scheme 5),
but no product resulting from a 5-exo-dig process was
detected. This result seems to indicate that under these
reaction conditions, the acetylenic functionality is slightly
more reducible than the ester group.
obtained from 10 [NaH (2.5 equiv), MeI (4 equiv)] as well
as from 15 [NaH (1.5 equiv), MeI (3 equiv)], the relative
stereochemistry of the substituents in spirocyclic com-
pound 15 has been established by comparison of the
spectral data of the dimethoxy compound obtained from
1
0 (Scheme 3).
Under similar conditions, mesylate 7 gave the spiro-
cyclic alcohol 16 in which the mesylate has been re-
duced.18 When several functional groups are present in
the starting ester, electron transfer from the donor might
occur selectively to the most reducible group. Not
unexpectedly, treatment of the acetylenic ester 8 with
(19) Partridge, J . J .; Chadha, N. K.; Uskokovic, M. R. J . Am. Chem.
Soc. 1973, 95, 532.
1
(
20) H and 13C NMR data of 23 and 24 were identical with the
Na/NH
7/11 (75% yield), the acetylenic moiety being reduced
concomitantly with the ester moiety. Under the same
3
furnished a 46/54 mixture of reduced products
literature values, and the structure of alcohol 23 was confirmed by
the reduction of 2-methylcyclopentanone. The ratio of 6:4 was deter-
mined by comparison of the integrals between CHCH and CH OH in
3 2
the proton NMR spectrum.
1
(
21) (a) Cossy, J .; Pete, J . P.; Portella, C. Tetrahedron Lett. 1989,
(
18) For a similar reduction by alkali metals in HMPA see: Cuvigny,
30, 7361. (b) Shono, T.; Masuda, H.; Murase, H.; Shimomura, M.;
Kashimura, S. J . Org. Chem. 1992, 57, 1061.
T.; Larcheveque, M. J . Organomet. Chem. 1974, 64, 315.

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3143
Sch em e 6
Sch em e 7
The relative stereochemistry of the newly created
stereocenters deserves further comments. In the special
case of a ketyl radical anion intermediate of type IV
(Scheme 7), the stereoselectivity is well rationalized
considering repulsive electrostatic interactions between
negative oxygen and partial negative charge carried by
2
the terminal sp carbon atom in the C5 cyclic transition
state, according to the stereoelectronic approach to this
transition state. In other words, the stereochemistry will
be governed by the size of the dihedral angle between
the C-O bond and the olefinic bond in the transition
state. The transition state5
c,23
that has the greater
dihedral angle will be favored. Furthermore, the relative
stereochemistry between the two hydroxy groups (in
compounds 1-5) is due to the complexation of the two
alcoholates by the sodium.
In summary, the readily available unsaturated â-hy-
droxy esters are reduced very efficiently to produce
substituted cycloalkanols or spirocyclic diols. The reac-
tion is general when an olefinic bond is present but is
somewhat sensitive to steric hindrance. Furthermore,
because unsaturated â-hydroxy esters can be synthesized
with good enantioselectivity,24 the spirocyclic compounds
could be obtained with good enantioselectivity.
Exp er im en ta l Section
Gen er a l. All experiments were run under an argon atmo-
sphere. Microanalyses were performed at the Service de Mi-
croanalyse de l’Universit e´ Pierre et Marie Curie. Mass spectra
were run on a coupled analysis GC-MS device and were
obtained at 70 eV. Uncorrected melting points were taken on a
Kofler bank. Flash chromatographies were carried out on
Kieselgel 60 (230-400 mesh) with petroleum ether (PE) and
ethyl acetate. Analytical thin layer chromatographies (TLC)
were accomplished on Merck silica Kieselgel 60 GF254. Solvents
3
When an ester is treated with Na/NH , an electron
transfer takes place in what might be considered as a
classical redox process (Scheme 6). In the treatment of
such as THF or Et O were freshly distilled from sodium/
2
benzophenone. Diisopropylamine, DMSO, dichloromethane,
propane-1,3-diamine (APA), and triethylamine were distilled
from CaH and MeOH from magnesium.
2
â-hydroxy esters of type II by Na/NH
should be formed and the ester group should be reduced
by Na/NH to produce intermediate b, which could be
transformed (path A) to aldehyde e via intermediates c
second electron transfer) and d (hydrogen abstraction
to NH ). The aldehyde e should be then reduced and the
3
, the alcoholate a
3
(22) Compound 26 was synthesized according to the following
scheme [(i) TBSCl, imidazole, DMF, rt; (ii) Dibal-H, CH Cl
Cl
2
2
, -78 °C
, rt; (iv)
(
to room temperature; (iii) PCC, molecular sieves 4 Å, CH
TBAF, THF, rt]:
2
2
3
ketyl radical f should cyclize to produce the observed
spirocyclic compound of type III. This hypothesis was
verified by the reduction of hydroxy aldehyde 2622 by Na/
3
NH , which led to the spirocyclic diol 11 in 67% yield. In
the case of 1 and 26, only one spirocyclic alcohol was
detected in the reaction mixture. This experiment seems
to be in favor of intermediate f.
However, a second mechanism (path B), where the
cyclization of the ketyl radical takes place to produce
intermediate g, cannot be excluded. The resulting hy-
droxy ketone h could be reduced to the spirocyclic diol of
type III via intermediates i and j.
(
23) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073.
(24) (a) Frater, G. Helv. Chim. Acta 1979, 62, 2825. (b) Frater, G.
Helv. Chim. Acta 1980, 63, 1383. (c) Cossy, J .; Ibhi, S.; Kahn, P. H.;
Tacchini, L. Tetrahedron Lett. 1995, 43, 7877. (d) Chitkul, B.; Pinyo-
pronpanich, Y.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron
Lett. 1994, 35, 1099.

3
9
144 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
Syn th esis of Sta r tin g Ma ter ia ls. Com p ou n d s 1-3 a n d
. Methyl 2-oxocyclopentanecarboxylate (6.0 mmol, 1.0 equiv)
mL). The solution was stirred at room temperature for 1 h, and
iodomethane (0.6 mL, 10.0 mmol, 2.0 equiv) was added. After
12 h at room temperature, the reaction mixture was diluted with
was added dropwise to a stirred solution of t-BuOK (0.7 g, 6.5
mmol, 1.1 equiv) in dry DMSO (30 mL). After the mixture was
stirred at room temperature for 1 h, the alkyl bromide (6.6 mmol,
Et
solution of NH
and dried over MgSO
washed with water, dried over MgSO
residue was purified by flash chromatography to give a yellow
oil (1 g, 95% yield): R 0.35 (PE/AcOEt 90/10); IR 1725, 1640
2
O (50 mL) and neutralized with an aqueous saturated
Cl. The organic layer was washed with water
The combined organic extracts were
, and concentrated. The
4
1
.1 equiv) was added dropwise. After 12 h at room temperature,
the solution was diluted with a saturated aqueous solution of
NH Cl and extracted with AcOEt. The organic layer was
washed with brine, dried over MgSO , and concentrated. The
residue was dissolved in MeOH (20 mL), and NaBH (0.3 g, 7.2
4
.
4
4
4
f
-
1 1
4
cm ; H NMR δ 1.15-1.30 (m, 1H), 1.40-1.78 (m, 6H), 1.80-
2.00 (m, 2H), 2.05-2.21 (m, 1H), 3.25 (s, 3H), 3.60 (s, 3H), 3.83
(dd, 1H, J ) 2.6, 5.1 Hz), 4.86-4.99 (m, 2H), 5.65-5.70 (m, 1H);
C NMR δ 20.8 (t), 29.4 (t), 29.9 (t), 31.6 (t), 33.0 (t), 51.6 (q),
56.9 (q), 58.9 (s), 85.5 (d), 114.1 (t), 138.5 (d), 176.7 (s); EI MS
, 3), 171 (11),
mmol, 1.2 equiv) was added at 0 °C in small portions. When
the reaction was complete, the reaction mixture was mixed with
water. After evaporation of MeOH, the aqueous layer was
acidified with an aqueous solution of HCl 10% and extracted
1
3
with Et
over MgSO
by flash chromatography.
()-(1RS,2SR)-Meth yl 1-(bu t-3-en yl)-2-h yd r oxycyclop en -
ta n e-1-ca r boxyla te (1). R 0.24 (petroleum ether (PE)/AcOEt
0/10); yellow oil; yield 72%; IR 3480, 1725, 1640 cm-1; 1H NMR
δ 1.45-1.72 (m, 5H), 1.82-2.00 (m, 4H), 2.02-2.15 (m, 1H), 2.55
2
O. The organic layers were washed with water, dried
C
12
H
20
O
3
m/z (relative intensity) 197 (M - CH
3
4
, and evaporated. The crude product was purified
158 (19), 141 (30), 139 (36), 126 (56), 121 (42), 111 (53), 109 (72),
79 (100), 72 (46), 71 (52), 67 (46), 53 (40). Anal. Calcd for
(
C
12
H
20
O
3
: C, 67.89, H, 9.49. Found: C, 67.80; H, 9.16.
f
(()-(1RS,2SR)-Meth yl 1-(bu t-3-en yl)-2-(m eth ylsu lfon yl-
9
oxy)cyclop en ta n e-1-ca r boxyla te (7). 4-DMAP (0.05 g, 0.04
mmol, 0.02 equiv) was added to a stirred solution of 2 (0.4 g,
2.0 mmol, 1.0 equiv) and triethylamine (0.35 mL, 2.50 mmol,
1.10 equiv) in CH Cl (1 mL). The reaction mixture was cooled
(
(
(
(
s, 1H), 3.64 (s, 3H), 4.25 (dd, 1H, J ) 5.8, 5.9 Hz), 4.75-4.94
13
m, 2H), 5.64-5.81 (m, 1H); C NMR δ 19.8 (t), 29.6 (t), 31.0
2
2
t), 31.2 (t), 32.2 (t), 51.6 (q), 57.3 (s), 76.8 (d), 114.3 (t), 138.2
d), 176.9 (s); EI MS C11
to -40 °C, and mesyl chloride (0.2 mL, 2.5 mmol, 1.1 equiv) was
added dropwise. The solution was warmed at room temperature,
diluted with Et O, and neutralized by a saturated aqueous
solution of NH Cl. The organic phase was washed with brine,
H
18
O
3
m/z (relative intensity) 166 (3, M
-
6
1
MeOH), 157 (64), 126 (40), 125 (100), 97 (55), 81 (65), 79 (86),
2
5 (55), 55 (81), 53 (64); HRMS calcd for C11
81.1229, found 181.1228.
H
17
O
2
(M - OH)
4
dried over MgSO , and concentrated. The crude product was
4
Com p ou n d s 5 a n d 29. These compounds were prepared as
purified by flash chromatography to give a yellow oil (0.4 g, 96%
-
1 1
compounds 1-3 and 9 from ethyl 2-oxocycloheptanecarboxylate
and were purified by flash chromatography (PE/AcOEt 90/10).
()-(1RS,2SR)-Eth yl 1-(bu t-3-en yl)-2-h yd r oxycycloh ep -
ta n e-1-ca r boxyla te (5): R 0.28 (PE/AcOEt 90/10); yellow oil;
yield 22%; IR 3500, 1730, 1640 cm ; H NMR δ 1.26 (t, 3H, J
yield): R 0.30 (PE/AcOEt 90/10); IR 1725, 1640, 1355 cm ; H
f
NMR δ 1.54-2.09 (m, 9H), 2.18-2.33 (m, 1H), 2.99 (s, 3H), 3.67
(s, 3H), 4.89-4.97 (m, 2H), 5.26 (dd, 1H, J ) 3.1, 4.9 Hz), 5.64-
5.80 (m, 1H); 13C NMR δ 20.5 (t), 29.5 (t), 31.8 (t), 32.1 (t), 32.5
(t), 38.3 (q), 52.1 (q), 58.2 (s), 86.0 (d), 114.7 (t), 137.5 (d), 174.6
(s); EI MS C12H20O S, m/z (relative intensity) 180 (M - CH -
(
f
-
1 1
)
7.0 Hz,), 1.30-1.60 (m, 7H), 1.60-1.88 (m, 4H), 1.88-2.20
m, 3H), 2.75-2.79 (m, 1H), 4.01 (dd, 1H, J ) 2.6, 7.0 Hz), 4.18
q, 2H, J ) 7.0 Hz), 4.85-5.00 (m, 2H), 5.73-5.77 (m, 1H); 13
5
3
(
(
SO H, 6), 151 (7), 126 (50), 121 (60), 93 (43), 79 (100), 77 (38),
67 (48), 55 (22). Anal. Calcd for C12H20O S: C, 52.16; H, 7.29.
3
C
5
NMR δ 14.0 (q), 22.3 (t), 22.3 (t), 24.8 (t), 28.8 (t), 31.7 (t), 32.2
Found: C, 52.06; H, 7.14.
(
(
(
(
(
t), 32.8 (t), 52.9 (s), 60.5 (t), 75.2 (d), 114.3 (t), 138.4 (d), 177.5
()-(1SR,2SR)-Meth yl 1-(bu t-3-yn yl)-2-h yd r oxycyclop en -
ta n e-1-ca r boxyla te (8). KH (1.2 g, 28.8 mmol, 4.0 equiv) was
•
+
s); EI MS C14
58), 168 (29), 153 (100), 107 (27), 83 (20), 81 (55), 79 (28), 67
26), 55 (43). Anal. Calcd for C14 : C, 69.96; H 10.06.
24 3
H O m/z (relative intensity) 240 (M , 1), 199
26
added to APA (25 mL) at 0 °C.
temperature, the reaction mixture was cooled at 0 °C and (()-
1SR,2SR)-methyl 1-(3-chlorobut-3-enyl)-2-hydroxycyclopentane-
After 30 min at room
24 3
H O
Found: C, 69.80; H, 10.18.
(
1
1
(
()-(1SR,2SR)-Eth yl 1-(bu t-3-en yl)-2-h yd r oxycycloh ex-
-carboxylate (1.7 g, 7.2 mmol, 1.0 equiv) (prepared as compound
with 1-iodo-3-chlorobut-2-ene ) was added. After 1 h at room
temperature, the reaction mixture was poured into a solution
of ice/water (50 mL), acidified with a solution of HCl 10%, and
24
a n e-1-ca r boxyla te (4).
Ethyl 2-oxocyclohexanecarboxylate
27
(1.0 g, 6.0 mmol, 1.0 equiv) was dissolved in MeOH (20 mL) and
4
NaBH (0.3 g, 7.2 mmol, 1.2 equiv) was added at 0 °C in small
portions. When the reaction was complete, the reaction mixture
was mixed with water (20 mL). MeOH was removed in vacuo,
and the remaining aqueous layer was acidified with an aqueous
solution of HCl 10% and extracted with Et
were washed with water, dried over MgSO
The residue was dissolved in THF (4 mL), and the solution was
added to a stirred solution of LDA [diisopropylamine (1.5 g, 14.4
mmol, 2.4 equiv) and n-BuLi (1.6 M hexane solution, 9.0 mL,
extracted with Et
washed with water and dried over MgSO
removed in vacuo. The crude product, identified as (()-
1SR,2SR)-1-(but-2-ynyl)-2-hydroxycyclopentanoic acid, was
isomerized to (() (1SR,2SR)-1-(but-3-ynyl)-2-hydroxycyclopen-
tane carboxylic acid by KAPA (Anal. Calcd for C10 : C,
5.92; H, 7.74. Found: C, 65.78; H, 7.84). The obtained alkyne
0.7 g, 3.6 mmol, 1.0 equiv) was dissolved in acetone (30 mL)
and was treated with anhydrous K CO (0.8 g, 5.4 mmol, 1.5
2
O. The combined organic extracts were
4
, and the solvent was
2
O. The organic layers
, and evaporated.
(
4
14 3
H O
6
(
1
4.3 mmol, 2.4 equiv)] in THF (6 mL) at - 70 °C. After 10 min,
2
3
a solution of 4-bromobut-1-ene (1.0 g, 7.6 mmol) in HMPA (5
mL) was added at -15 °C. The reaction mixture was stirred at
room temperature for 30 min, poured onto a cold aqueous
equiv) and iodomethane (1.5 g, 10.8 mmol, 3.0 equiv). After 12
h at 23 °C, the resulting mixture was quenched with an aqueous
solution of NH Cl and extracted with Et O. The combined
4 2
NH
4
Cl solution (10%), and extracted with Et
2
O. The organic
, and concen-
phase was washed with water, dried over MgSO
trated in vacuo to afford an oily residue. The crude product was
purified by flash chromatography and provided a colorless oil
4
(
25) The relative stereochemistry of the ester group and the hydroxy
groups was determined by NOE differences in the ketal 32 [(i) LiAlH
Et O, ∆; (ii) PhCHO, cat. PPTS, toluene, ∆, Dean-Stark]:
4
,
2
f
(0.4 g, yield ) 30%): R 0.25 (PE/AcOEt 90/10); IR 3510, 1700,
-
1
1
1
3
3
640 cm ; H NMR δ 1.24 (t, 3H, J ) 7.0 Hz), 1.02-1.29 (m,
H), 1.30-1.50 (m, 2H), 1.52-1.70 (m, 2H), 1.80-2.18 (m, 5H),
.44 (dd, 1H, J ) 9.9, 3.3 Hz), 3.41-3.55 (m, 1H), 4.19 (q, 2H,
J ) 7.0 Hz), 4.91-4.93 (m, 1H), 5.00-5.05 (m, 1H), 5.74-5.77
1
3
(m, 1H); C NMR δ 14.1 (q), 22.4 (t), 23.6 (t), 28.3 (t), 31.4 (t),
3
1
2
5
2.1 (t), 36.1 (t), 51.1 (s), 60.3 (t), 74.6 (d), 114.5 (t), 138.1 (d),
•
+
76.9 (s); EI MS C13
H
22
O
3
m/z (relative intensity) 226 (M , 2),
08 (M - H
5 (47).
2
O, 1), 185 (86), 154 (2), 139 (100), 93 (47), 67 (53),
(
()-(1RS,2SR)-Met h yl 1-(Bu t -3-en yl)-2-m et h oxycyclo-
p en ta n e-1-ca r boxyla te (6). To a stirred suspension of NaH
0.3 g, 7.5 mmol, 1.5 equiv) in THF (30 mL) at 0 °C was added
dropwise a solution of 2 (5 mmol, 1.2 g, 1.0 equiv) in THF (5
(
(26) Brown, C. A. J . Org. Chem. 1978, 43, 3083.
(27) Naf, F.; Decorzant, R. Helv. Chim. Acta 1974, 57, 1317.

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3145
organic phases were washed with brine, dried over MgSO
concentrated in vacuo. The residue was purified by flash
4
, and
in vacuo gave (()-(1SR,2SR)-1-(but-3-enyl)-2-hydroxypentane-
f
1-methanal (26) (0.11 g, 60% yield): R 0.30 (PE/AcOEt 80/20);
-
1 1
chromatography to provide a colorless oil (0.35 g, 25% yield):
IR 3400, 1720, 1640 cm ; H NMR δ 0.80-2.25 (m, 10H), 3.30
(m, 1H), 4.15 (t, 1H, J ) 5.9 Hz), 4.84-5.12 (m, 2H), 5.69-5.92
(m, 1H), 9.70 (s, 1H); 13C NMR δ 20.4 (t), 29.0 (t), 29.3 (t), 33.7
(t), 33.9 (t), 62.1 (s), 80.2 (d), 114.9 (q), 138.1 (d), 206.8 (d); EI
0.26 (PE/AcOEt 80/20); IR 3450, 3300, 2120, 1720 cm-1; H
1
R
f
NMR δ 1.52-1.91 (m, 6H), 1.92-2.02 (m, 2H), 2.13-2.28 (m,
H), 2.79 (s, 1H), 3.71 (s, 3H), 4.02 (dd, 1H, J ) 4.4, 6.2 Hz); 13
NMR δ 14.0 (t), 20.2 (t), 31.0 (t), 32.2 (t), 35.0 (t), 51.7 (q), 57.8
3
C
MS C10
H
16
O
2
m/z (relative intensity) 150 (M - H
2
O, 1), 127 (2),
(
(
(
s), 68.4 (d), 79.2 (d), 83.5 (s), 175.7 (s); EI MS C11
relative intensity) 164 (M - MeOH, 6), 157 (85), 139 (39), 125
100), 97 (44), 79 (72), 55 (31). Anal. Calcd for C11 : C,
16 3
H O m/z
114 (12), 111 (10), 109 (12), 96 (28), 81 (100), 79 (35), 67 (26), 55
(3). Anal. Calcd for C10
H
16
O
2
: C, 71.39; H, 9.59. Found: C,
16 3
H O
71.19; H, 9.65.
6
7.32; H, 8.22. Found: C, 67.26; H, 8.25.
P r ep a r a tion of Com p ou n d 26.22 To a solution of 2 (2.3 g,
1.6 mmol, 1.0 equiv) in dry THF (20 mL) were added imidazole
Redu ctive Cyclization by Na/NH . Com pou n ds 10. Small
3
pieces of sodium (0.3 g, 12.0 mmol, 6.0 equiv) were added to
liquid ammonia at -78 °C (150 mL). After 15 min, a solution
of â-hydroxy ester (2.0 mmol, 1.0 equiv) in THF (5 mL) was
added dropwise. The reaction mixture was warmed to -33 °C
and stirred in refluxing ammonia for 10 min. The excess of Na
was then destroyed by addition of ammonium chloride, and the
ammonia was evaporated under a stream of nitrogen (fume
1
(2.0 g, 29.0 mmol, 2.5 equiv) and tert-butyldimethylsilyl chloride
(2.1 g, 14.0 mmol, 1.2 equiv). After 12 h at room temperature,
the reaction mixture was diluted with a saturated aqueous
solution of NH Cl and extracted with Et O. The ethereal
extracts were washed with water and dried over MgSO
Removal of the solvent in vacuo gave the desired product (()-
1SR,2SR)-methyl 2-(tert-butyldimethylsiloxy)-1-(but-3-enyl)cy-
clopentane-1-carboxylate (27) as a colorless oil (3.4 g, 94%
yield): R 0.36 (PE/AcOEt 98/2); IR 1730, 1640, 1260, 835, 725
4
2
4
.
hood). Et
ized by a solution of HCl (10%). The residue was extracted with
Et O. The organic layers were dried over MgSO and filtered,
2
O was added, and the reaction mixture was neutral-
(
2
4
and the solvent was removed in vacuo. The crude oil was
purified by crystallization in pentane or by flash chromatogra-
phy.
f
-
1 1
cm ; H NMR δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.49-
1
3
.81 (m, 6H), 1.83-2.01 (m, 3H), 2.11-2.24 (m, 1H), 3.65 (s, 3H),
.98 (m, 1H), 4.89-4.98 (m, 2H), 5.78-5.85 (m, 1H); 1 C NMR
3
(()-(1SR,2RS,5SR,6RS)-2-Met h yl-sp ir o[4.4]n on a n e-1,6-
d iol (10):
f
R 0.10 (PE/AcOEt 50/50); purification by crystal-
δ -5.2 (q), -4.7 (q), 17.8 (s), 20.7 (t), 25.6 (q), 29.8 (t), 31.9 (t),
3.9 (t), 51.4 (q), 58.7 (s), 77.4 (d), 113.9 (t), 138.5 (d), 176.8 (s);
EI MS C17 Si m/z (relative intensity) 297 (M - CH , 1), 256
20), 255 (M - t-Bu, 100), 223 (20), 185 (5), 121 (14), 89 (76), 75
83), 73 (78), 59 (42), 57 (36); Anal. Calcd for C17 Si: C,
5.33; H, 10.32. Found: C, 65.37; H, 10.27.
A solution of Dibal-H in hexane (12.8 mL, 12.8 mmol, 4.0
equiv) was added dropwise to a solution of ester 27 (1.0 g, 3.2
mmol, 1.0 equiv) in CH Cl (20 mL) at -78 °C. After 1 h at
room temperature, the solution was diluted with CH Cl (60 mL)
-
1
lization in pentane; mp 132-133 °C; yield 95%; IR 3310 cm
;
3
1
H NMR δ 1.05 (d, 3H, J ) 6.6 Hz), 1.12-1.25 (m, 1H), 1.26-
H
32
O
3
3
1
.38 (m, 1H), 1.39-1.70 (m, 5H), 1.72-2.09 (m, 6H), 3.45 (d, 1H,
(
(
6
1
3
J ) 5.1 Hz), 4.20 (dd, 1H, J ) 9.6, 7.7 Hz); C NMR δ 18.7 (q),
9.1 (t), 28.1 (t), 29.9 (t), 30.9 (t), 35.0 (t), 43.8 (d), 54.8 (s), 75.3
d), 87.3 (d); EI MS C10 m/z (relative intensity) 152 (M -
O, 8), 137 (28), 134 (44), 119 (44), 108 (59), 97 (32), 94 (42),
32 3
H O
1
(
H
9
18 2
H O
2
3 (65), 81 (100), 79 (56), 67 (48), 57 (51), 55 (58), 53 (38). Anal.
2
2
Calcd for C10 : C, 70.55; H, 10.66. Found: C, 70.41; H,
18 2
H O
2
2
1
0.54.
and poured into a solution of ice/water (20 mL). The aqueous
layer was acidified with a solution of HCl 10%, and the resulting
solution was extracted with CH
layers were washed with brine, dried over MgSO
trated. The crude material was purified by flash chromatogra-
Syn th esis of com p ou n d s 19, 20 a n d 32. (()-(2RS,5SR)-
2
-m eth ylsp ir o[4-4]n on a n e-1,6-d ion e (19). To a stirred sus-
2
Cl
2
.
The combined organic
, and concen-
pension of PCC (0.4 g, 2.0 mmol, 2.0 equiv) and molecular sieves
4
4
Å (0.4 g) in dry CH
of 10 (0.2 g, 1.0 mmol, 1.0 equiv) in CH
min, Et O (10 mL) was added, and the reaction mixture was
filtered through florisil. The filtrate was concentrated in vacuo
to give a colorless oil (0.31 g, 94% yield). 0.34 (PE/AcOEt
0/10); IR 1740, 1720 cm ; H NMR δ 1.09 (d, 1H, J ) 7.3 Hz),
2
Cl
2
(3 mL) was added dropwise a solution
2
2
Cl (1 mL). After 30
phy and provided (()-(1RS,2SR)-2-(tert-butyldimethylsiloxy)-1-
2
(but-3-enyl)cyclopentanemethanol (28) as a yellow oil (0.73 g,
8
7
1
f
0% yield): R 0.25 (PE/AcOEt 60/10); IR 3380, 1640, 1260, 840,
R
f
-1 1
70 cm ; H NMR δ 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 1.19-
-
1 1
9
1
.78 (m, 7H), 1.79-1.95 (m, 2H), 1.95-2.17 (m, 2H), 3.39 (d, 1H,
1
3
.37-1.56 (m, 1H), 1.63-1.98 (m, 3H), 2.08-2.48 (m, 7H);
C
J ) 10.8 Hz), 3.53 (d, 1H, J ) 10.8 Hz), 4.00 (t, 1H, J ) 6.6 Hz),
4
NMR δ -5.2 (q), -4.2 (q), 17.8 (s), 19.7 (t), 25.7 (q), 28.2 (t),
NMR δ -13.9 (q), 19.6 (s), 28.5 (s), 32.1 (s), 34.8 (s), 38.2 (s),
4.6 (t), 64.1 (q), 217.1 (q), 217.4 (q); EI MS C10 m/z
relative intensity) 166 (M , 56), 151 (4), 148 (5), 123 (12), 111
.91-4.95 (m, 1H), 5.01-5.04 (m, 1H), 5.81-5.85 (m, 1H); 13
C
4
14 2
H O
•
+
(
(
(
2
1
CH
(
8.5 (t), 29.8 (t), 32.9 (t), 49.1 (s), 67.9 (t), 79.0 (d), 113.7 (t),
39.7 (d); EI MS C16 Si m/z (relative intensity) 253 (M -
OH, 1), 227 (M - t-Bu, 19), 209 (3), 185 (100), 171 (7), 135
30), 107 (14), 93 (35), 75 (98). Anal. Calcd For C16 Si: C,
7.55; H, 11.34. Found: C, 67.76; H, 11.30.
To a stirred suspension of PCC (0.4 g, 1.6 mmol, 1.5 equiv)
and molecular sieves 4 Å (0.3 g) in dry CH Cl (2 mL) was added
dropwise a solution of 28 (0.3 g, 1.1 mmol, 1.0 equiv) in CH Cl
1 mL). After 30 min, Et O (10 mL) was added, and the reaction
39), 110 (100), 109 (18), 97 (35), 95 (22), 68 (37), 67 (39), 55
32 2
H O
34), 53 (28); HRMS calcd for C10
14 2
H O 166.0994, found 166.0995.
2
Compound 19 was also obtained by the same reaction from
compound 11.
32 2
H O
6
(
()-(1SR,2RS,5SR,6RS)-1,6-d im et h oxy-2-m et h ylsp ir o-
[
4-4]n on a n e (20). To a stirred suspension of NaH (0.3 g, 3.0
2
2
mmol, 1.5 equiv) in THF (13 mL) at 0 °C was added dropwise a
solution of 15 (0.4 g, 2.0 mmol, 1.0 equiv) in THF (2 mL). The
solution was stirred at room temperature for 1 h, and io-
domethane (0.4 mL, 6.0 mmol) was added. After 2 h at room
2
2
(
2
mixture was filtered through Florisil. The filtrate was concen-
trated in vacuo to give (()-(1SR,2SR)-2-(tert-butyldimethylsi-
loxy)-1-(but-3-enyl)cyclopentanemethanal (29) as a colorless oil
temperature, an aqueous saturated solution of NH
were added. The organic layer was washed with water and dried
over MgSO . The solvent was removed in vacuo, and a yellow
oil was obtained (0.36 g, 90%). R 0.85 (PE/AcOEt 80/20); IR
4 2
Cl and Et O
(0.3 g, 98% yield), which was used directly in the next step; R
f
4
-
1 1
0
.40 (PE/AcOEt 90/10); IR 1725, 1640, 1260, 840, 770 cm ; H
f
NMR δ 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 1.44-1.82 (m,
7
5
-1 1
1
1
460 cm ; H NMR δ 1.10 (d, 3H, J ) 7.0 Hz), 1.30-1.42 (m,
H), 1.82-2.06 (m, 3H), 4.26 (dd, 1H, J ) 4.8, 4.4 Hz), 4.93-
H), 1.45-1.72 (m, 5H), 1.76-2.06 (m, 5H), 2.83 (d, 1H, J ) 6.3
.05 (m, 2H), 5.75-5.90 (m, 1H), 9.51 (s, 1H); 13C NMR δ -5.1
13
Hz), 3.31 (s, 3H), 3.39 (s, 3H), 3.69 (dd, 1H, J ) 5.2, 5.9 Hz);
C
(
q), -4.5 (q), 17.8 (s), 20.8 (t), 25.6 (q), 28.2 (t), 29.1 (t), 29.2 (t),
NMR δ 20.4 (q), 20.6 (t), 29.6 (t), 30.7 (t), 31.0 (t), 36.8 (t), 39.9
3
4.2 (t), 62.3 (s), 74.9 (d), 114.4 (t), 138.4 (d), 205.2 (s); EI MS
Si m/z (relative intensity) 265 (1), 241 (1), 225 (M -
t-Bu, 11), 207 (1), 183 (100), 171 (36), 157 (4), 141 (8), 133 (18),
29 (9), 115 (13), 105 (10), 91 (29), 75 (79), 73 (59); HRMS calcd
for C12 Si (M - C ) 225.1310, found 225.1310.
(
d), 56.2 (s), 56.9 (q), 58.6 (q), 83.8 (d), 95.4 (d); EI MS C12H O
22 2
C
16
H
30
O
2
•+
m/z (relative intensity) 198 (M , 1), 166 (7), 151 (12), 134 (100),
25 (14), 119 (23), 108 (89), 93 (36), 85 (23), 72 (14), 71 (41).
Anal. Calcd for C12 : C, 72.68; H, 11.18. Found: C, 72.51;
1
1
22 2
H O
H
21
O
2
4 9
H
H, 11.46. Compound 20 was also obtained by treating 10 with
NaH (2.5 equiv) and MeI (4.0 equiv).
P r ep a r a tion of com p ou n d 32. To a stirred suspension of
To a solution of 29 (0.30 g, 1.06 mmol, 1.00 equiv) in THF (10
mL) was added a solution of TBAF (1.6 mL, 1.0 M in THF, 1.6
mmol, 1.5 equiv). After 1 h at room temperature, the reaction
mixture was diluted with Et
and dried over magnesium sulfate. Evaporation of the solvent
LiAlH
was added dropwise a solution of 30 (0.7 g, 3.0 mmol, 1.0 equiv)
in Et O (10 mL). After 1 h at room temperature, the mixture
4 2
(0.7 g, 18.0 mmol, 6.0 equiv) in Et O (40 mL) at 0 °C
2
O, washed with water and brine,
2

3
146 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
was heated under reflux for 2 h. After being cooled at 0 °C, the
solution was quenched with water (0.7 mL) and an aqueous
solution of NaOH (15%) (0.7 mL), which was followed by addition
of water (2 mL). The white suspension was filtered on Celite.
The filtrate was concentrated in vacuo to give (()-(1RS,2SR)-
1.25 (m, 1H), 1.45-1.88 (m, 8H), 1.89-2.13 (m, 4H), 2.46-2.49
(m, 1H), 3.73 (d, 1H, J ) 10.8 Hz), 3.78 (m, 1H), 3.92 (d, 1H, J
) 10.8 Hz), 5.01 (d, 1H, J ) 10.3 Hz), 5.04-5.09 (m, 1H), 5.53
(s, 1H), 5.85-5.90 (m, 1H), 7.34-7.45 (m, 3H), 7.53-7.57 (m,
2H); 13C NMR δ 19.8 (t), 21.0 (t), 26.6 (t), 27.1 (t), 29.1 (t), 29.9
(t), 32.8 (t), 38.6 (s), 78.3 (t), 82.8 (d), 101.8 (d), 114.5 (t), 126.2
2
-hydroxy-1-(but-3-enyl)cycloheptanemethanol (31) as a colorless
-
1
oil (0.56 g, 94% yield): R
f
0.28 (PE/AcOEt 80/20); IR 1640 cm
;
26 2
(d), 128.2 (d), 128.7 (d), 138.7 (d), 138.9 (s); EI MS C19H O m/z
1
•+
H NMR δ 1.20-2.23 (m, 14H), 2.97 (s, 2H), 3.32 (d, 1H, J )
1.4 Hz), 3.71 (d, 1H, J ) 9.2 Hz), 3.78 (d, 1H, J ) 11.4 Hz),
.96-4.98 (m, 1H), 5.01-5.06 (m, 1H), 5.88-5.94 (m, 1H); 13
NMR δ 21.9 (t), 25.2 (t), 27.8 (t), 29.6 (t), 31.4 (t), 33.8 (t), 34.0
t), 42.9 (s), 67.3 (t), 80.4 (d), 114.0 (t), 139.3 (d); EI MS C12
m/z (relative intensity) 199 (M + 1, 3), 168 (2), 149 (9), 133 (14),
21 (13), 109 (17), 107 (17), 95 (36), 94 (37), 81 (100), 67 (54), 55
58). Anal. Calcd for C12 : C, 72.68; H, 11.18. Found: C,
(relative intensity) 286 (M , 6), 285 (7), 268 (5), 202 (2), 180
(4), 162 (17), 149 (7), 147 (7), 135 (11), 133 (9), 121 (19), 107 (7),
105 (89), 81 (100), 79 (64), 77 (70), 67 (82), 55 (71). Anal. Calcd
1
4
C
for C19
26 2
H O : C, 79.68; H, 9.15. Found: C, 79.63; H, 8.95.
(
22 2
H O
Ack n ow led gm en t. We thanks the Minist e` re de la
Recherche et de l’Enseignement Sup e´ rieur for financial
support (B.G.) and J .-E. Devos (STOE-Oxford Cryosys-
tems-INSTO) for single crystal X-ray diffraction studies.
1
(
22 2
H O
7
2.64; H, 11.00.
A mixture of 31 (0.4 g, 2.0 mmol, 1.0 equiv), benzaldehyde
0.3 mL, 3.0 mmol, 1.5 equiv), and PPTS (0.05 g, 0.20 mmol,
(
0
2
.10 equiv) in dry toluene (20 mL) was heated under reflux for
h in a Dean Stark apparatus. After being cooled at room
Su p p or tin g In for m a tion Ava ila ble: The characteriza-
tion data of 2, 3, 9, 11-18, 25, and 30, the H NMR spectra of
, 15′, 29, and 30, ORTEP drawing for 10, and details of the
data acquisition (12 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1
temperature, the solution was neutralized with NaHCO
g, 1.00 mmol), diluted in Et O, and washed with water. The
organic layer was dried over MgSO and concentrated in vacuo
and the residue was purified by flash chromatography to provide
the ketal (()-(2RS,4aRS,9aSR)-4a-(but-3-enyl)-2-phenyl-4,-
4
3
(0.08
1
2
4
a,5,6,7,8,9,9a-octahydrocyclohepta-1,3-dioxine (32) (0.34 g, 60%
yield): R
f
0.25 (PE/AcOEt 98/2); IR 1640 cm-1; 1H NMR δ 1.22-
J O972339I