Sequenced Reactions with Samarium(II) Iodide. A Complementary Annulation Process Providing Access to Seven-, Eight-, and Nine-Membered Carbocycles

Article abstract of DOI:10.1021/jo990216n

Samarium(II) iodide promotes an efficient one-pot annulation reaction between ω-iodo esters and 2-(ω-chloroalkyl)cycloalkanones. An initial intermolecular carbonyl addition reaction between the iodo ester and the ketone generates a lactone intermediate. The lactone undergoes a subsequent nucleophilic acyl substitution reaction with an organosamarium derived from the chloride. Nickel-(II) iodide is an efficient catalyst for the first step of the process, and light is utilized to promote the second step. Seven-, eight-, and nine-membered rings can be accessed by this sequential dianionic process. This annulative approach to carbocycles is complementary to previously reported procedures.

Full text of DOI:10.1021/jo990216n

J . Org. Chem. 1999, 64, 4119-4123
4119
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. A Com p lem en ta r y
An n u la tion P r ocess P r ovid in g Access to Seven -, Eigh t-, a n d
Nin e-Mem ber ed Ca r bocycles
Gary A. Molander*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Fouzia Machrouhi
Laboratoire de Synthe`se Asyme´trique, Associe´ au CNRS, Institut de Chimie Mole´culaire d’Orsay,
Universite´ Paris-Sud, 91405 Orsay, France
Received February 4, 1999
Samarium(II) iodide promotes an efficient one-pot annulation reaction between ω-iodo esters and
2-(ω-chloroalkyl)cycloalkanones. An initial intermolecular carbonyl addition reaction between the
iodo ester and the ketone generates a lactone intermediate. The lactone undergoes a subsequent
nucleophilic acyl substitution reaction with an organosamarium derived from the chloride. Nickel-
(II) iodide is an efficient catalyst for the first step of the process, and light is utilized to promote
the second step. Seven-, eight-, and nine-membered rings can be accessed by this sequential dianionic
process. This annulative approach to carbocycles is complementary to previously reported
procedures.
In tr od u ction
philic acyl substitution reaction, which provided access
to medium-ring compounds via a one-step ring expansion
(eq 1).7 This strategy was employed as one component of
more efficient, two-step domino annulations. In one of
these sequential processes, (ω-chloroalkyl) ketones were
coupled with R,â-unsaturated esters to provide a one-pot
synthesis of six- through eight-membered hydroxycy-
cloalkanones (eq 2).8 An intermolecular ketyl-olefin
coupling reaction, generating a lactone, was followed by
a nucleophilic acyl substitution reaction to complete the
annulation process. An important feature of this trans-
formation was the utilization of light to activate the SmI2
in the last stage of the two-step process.6 Consequently,
the rapid ketyl-olefin coupling could be carried out
selectively, with light facilitating reduction of the chloride
to an organosamarium species, thereby permitting the
final carbon-carbon bond-forming event. Formation of
a lactone is a key step in bringing these domino processes
to a successful conclusion, because they provide a rigid
template upon which the nucleophilic acyl substitution
reaction can be accomplished through five-, six-, or even
seven-membered transition structures.7,9
Since the first publication on the use of samarium(II)
iodide (SmI2) in organic synthesis,1 literally hundreds of
reports have appeared on the use of this reagent in
selective organic synthesis.2 Although many of the early
investigations focused on single transformations, it sub-
sequently became evident that SmI2 was an ideal reduc-
tive coupling agent for sequential processes as well.3 In
addition to its ability to promote a wide array of useful
organic reactions (both radical and anionic processes), one
of the unique advantages one has in utilizing SmI2 is the
ability to manipulate its reactivity through solvent ef-
fects,4 by the addition of catalysts,1,5 and even through
irradiation of reaction mixtures.6 This feature greatly
facilitates the sequencing of reactions because the re-
ductant can be selectively tuned for each individual step
of a multistep process.
Two reports emanating from our laboratories have
taken advantage of the singular characteristics of SmI2
to provide annulative routes to medium-sized carbocycles.
Both of these investigations had their genesis in the
development of a SmI2-promoted intramolecular nucleo-
(1) Girard, P.; Namy, J .-L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(2) (a) Soderquist, J . A. Aldrichimica Acta 1991, 24, 15. (b) Molan-
der, G. A. Chem. Rev. 1992, 92, 29. (c) Sasaki, M.; Collin, J .; Kagan,
K. B. New J . Chem. 1992, 16, 89. (d) Molander, G. A. Org. React. 1994,
46, 211.
(3) (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (b)
Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321.
(4) (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485. (b) Ruder, S. M. Tetrahedron Lett. 1992, 33, 2621. (c) Hasegawa,
E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008. (d) Namy, J .-L.;
Colombo, M.; Kagan, H. B. Tetrahedron Lett. 1994, 35, 1723. (e) Cabri,
W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron
Lett. 1995, 36, 949. (f) Hamann, B.; Namy, J .-L.; Kagan, H. B.
Tetrahedron 1996, 45, 14225.
(5) (a) Machrouhi, F.; Hamann, B.; Namy, J .-L.; Kagan, H. B. Synlett
1996, 633. (b) Molander, G. A.; McKie, J . A. J . Org. Chem. 1991, 57,
3132.
(6) (a) Skene, W. G.; Scaiano, J . C.; Cozens, F. L. J . Org. Chem. 1996,
61, 7918. (b) Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.;
Hirao, T. J . Am. Chem. Soc. 1997, 119, 2745. (c) Ogawa, A.; Ohya, S.;
Hirao, T. Chem. Lett. 1997, 275.
In the second annulative process developed, R,ω-
chloroiodoalkanes reacted with keto esters in the pres-
ence of SmI2 to afford seven- through nine-membered
10.1021/jo990216n CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/13/1999

4120 J . Org. Chem., Vol. 64, No. 11, 1999
Machrouhi
Sch em e 1
carbocycles (eq 3). The dihaloalkanes serve as dianionic
synthons in the overall transformation, reacting sequen-
tially with the dielectrophilic dicarbonyl substrates.
Nickel(II) iodide was utilized as a catalyst in this
reaction5a to promote the selective intermolecular Bar-
bier-type reaction between the iodide and the ketone of
the keto ester, generating a lactone. The second step of
the two-step transformation, an intramolecular nucleo-
philic acyl substitution reaction, was again promoted by
light.6 The combination of the NiI2 catalyst and light not
only permits high selectivity in the two-step transforma-
tion, but also alleviates the necessity to employ toxic
HMPA as a promoter to enhance the reductive capability
of SmI2.4a
to the corresponding organosamariums in THF,1,2d,10 it
has been demonstrated that visible light activates SmI2,6,8,9
facilitating this process. Thus, the lactone would undergo
a subsequent nucleophilic acyl substitution reaction with
an organosamarium derived from the chloride, providing
the desired product.7-9 Herein we describe our successful
efforts to develop this process as a useful annulation
strategy for the synthesis of seven-, eight-, and nine-
membered hydroxycycloalkanones.
Resu lts a n d Discu ssion
To explore the scope and limitation of the proposed
annulation, ethyl 3-iodopropanoate was chosen as the
first dipolar synthon, with several 2-(ω-chloroalkyl)-
cycloalkanones utilized as partners for the annulation.
Six different 2-(ω-chloroalkyl)cycloalkanones were syn-
thesized and, employing the protocol outlined above,
paired with the halo ester in the annulation process
(Table 1). In the cyclopentanone series, those 2-(ω-
chloroalkyl)cycloalkanones that would allow conversion
through a six- or seven-membered transition structure
for the nucleophilic acyl substitution reaction (substrates
2 and 3, entries 1 and 2, Table 1) provided good yields of
the desired products. As expected, the higher homologues
(4 and 5) were not able to cyclize for entropic reasons. In
these cases, the products isolated were the lactones
derived from an intermolecular Barbier reaction followed
by simple reduction of the chloride. Appropriately func-
tionalized cyclohexanones (entries 5 and 6, Table 1)
reacted analogously to the cyclopentanones. Thus reason-
able yields of the seven- and eight-membered annulated
products were achieved.
The stereochemistry of the annulation products is
determined in the initial carbonyl addition reaction.
Stereochemical assignments in the current systems are
based upon previous annulation reactions on analogous
substrates in which the stereochemically determinant
step is the same (i.e., SmI2-promoted intermolecular
carbonyl addition to an R-substituted cycloalkanone).9
Single-crystal X-ray structure determinations were uti-
lized to assign stereochemistry in the previous effort.
Utilizing 2-(ω-chloroalkyl)cycloalkanones known to
function well in the annulation process, three reactions
were performed employing ethyl 4-iodobutanoate as the
dipolar synthon (Table 2). Whereas the intermediate for
the iodopropanoate is a readily formed butyrolactone, use
of the iodobutanoate required formation of a valerolac-
A third complementary annulation process was envi-
sioned that would provide access to similar carbocycles
from a different set of starting materials. Thus, it seemed
that ω-iodo esters and 2-(ω-chloroalkyl)cycloalkanones
would react in the presence of SmI2 to provide medium-
membered hydroxycycloalkanones (Scheme 1). Selectivity
was assured in the generation of an organosamarium
species by reduction of the iodide in the presence of the
chloride.1,2d,10 Utilizing NiI2 as a catalyst,5a an intermo-
lecular Barbier reaction was expected between the iodide
of the ester and the ketone of the cycloalkanone, forming
the requisite lactone. The ketone was anticipated to react
selectively with the organometallic in preference to the
ester,1,9,11 even though the latter would be an intramo-
lecular process. Based upon substantial precedent, high
diastereoselectivity in this reaction was virtually guar-
anteed.9 Although chlorides are only reluctantly reduced
(7) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216.
(b) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1995, 117, 3705.
(c) Molander, G. A.; Harris, C. R. J . Org. Chem. 1998, 63, 4374.
(8) Molander, G. A.; Sono, M. Tetrahedron 1998, 54, 9289.
(9) Molander, G. A.; Alonso-Alija, C. J . Org. Chem. 1998, 63, 4366.
(10) Ogawa, A.; Nanke, T.; Takami, N.; Sumino, Y.; Ryu, I.; Sonoda,
N. Chem. Lett. 1994, 379.
(11) (a) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem.
Soc. 1987 109, 453. (b) Otsuba, K.; Kawamura, K.; Inanaga, J .;
Yamaguchi, M. Chem. Lett. 1987, 1487. (c) Csuk, R.; Hu, Z.; Abdou,
M.; Kratky, C. Tetrahedron 1991, 47, 7037.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 64, No. 11, 1999 4121
Ta ble 1. Sequ en tia l Sm I2-P r om oted Ca r bon yl Ad d ition /
Nu cleop h ilic Acyl Su bstitu tion Rea ction s Betw een Eth yl
3-Iod op r op a n oa te (1) a n d Ch lor ok eton e Su bstr a tes
in this annulation. Attempts at utilizing ethyl 6-iodohex-
anoate, for example, led to none of annulation product
(eq 4). The lack of annulation product in this case has
been ascribed to intramolecular nucleophilic acyl substi-
tution of the iodo ester itself, providing cyclohexanone
and byproducts resulting therefrom.
Con clu sion s
A SmI2-promoted annulation process has been devel-
oped that is complementary to two previously reported
procedures for the construction of medium-membered
carbocycles. Substrates for this reaction are readily
available ω-iodo esters and 2-(ω-chloroalkyl)cycloal-
kanones. The reaction brings these two dipolar synthons
together in an intermolecular Barbier-type process, which
results in the formation of lactone intermediates. A
subsequent intramolecular nucleophilic acyl substitution
reaction completes the process. Seven-, eight-, and even
nine-membered rings constituting a variety of substitu-
tion patterns can thus be readily accessed in high yields
and with excellent diastereoselectivities. The difficulties
normally associated with the construction of medium-
sized rings12 makes this a valuable approach to these
structural motifs.
Exp er im en ta l Section
Rea gen ts. Tetrahydrofuran (THF) was distilled immedi-
ately prior to use from benzophenone ketyl under Ar. Sa-
marium metal was stored under an inert atmosphere. Nickel-
(II) iodide (NiI2) and iodine were purchased from Aldrich
Chemicals. Hexamethylphosphoramide (HMPA) was pur-
chased from Aldrich Chemicals and was distilled from CaH2
at 10-2 mmHg and stored over 4 Å molecular sieves under Ar.
Standard benchtop techniques were employed for handling air-
sensitive reagents,13 and all of the reactions were carried out
under Ar.
P r ep a r a tion of th e Sm I2 Solu tion . Samarium metal (519
mg, 3 mmol) was added under a flow of argon to an oven-dried,
two-necked Schlenk flask containing a magnetic stirring bar
and a septum inlet. Iodine (761 mg, 3 mmol) was added to a
vigorously stirred suspension of samarium metal in THF (30
mL). The mixture was stirred vigorously for 2 h at room
temperature. The resultant deep blue-green solution was used
directly to effect the sequential reactions.
Gen er a l P r oced u r e for th e Syn th esis of Hyd r oxy
Cycloa lk a n on es. To the SmI2 (3 mmol) in THF at room
temperature was added NiI2 (1 mol %). After stirring for 5 min,
a solution of the halo ketone (0.5 mmol) and iodo ester (0.5
mmol) in 5 mL of THF was added in a Barbier-type procedure.
The mixture was stirred for 90 min. After the starting material
was consumed and the intermediate lactone was formed (TLC
analysis), the reaction mixture was irradiated with visible light
(250 W krypton lamp) for 8 h, while the temperature was
maintained below 25 °C. The resultant mixture was quenched
with a saturated aqueous solution of Rochelle’s salt.14 The
mixture was extracted several times with diethyl ether, and
tone. Rapid formation of a lactone was assumed to be
crucial for the success of the process, as unfavorable
entropic factors were anticipated to prevent intramolecu-
lar nucleophilic acyl substitution on the ethyl ester.
Because the organosamariums generated would have a
limited lifetime in the presence of the various electro-
philes present in the reaction mixture, the overall success
of the endeavor seemed incumbent on the ability of the
substrates to rapidly form the required lactone. In the
event, all of the substrates led to quite good yields of the
annulated products. Even a nine-membered ring could
be accessed (entry 2, Table 2), which again required
transformation through a seven-membered transition
structure. Although we have no explanation for the
success in this reaction manifold, we note that similar
results had been achieved in our earlier study.9
(12) Molander, G. A. Acc. Chem. Res. 1998, 31, 603 and references
cited therein.
(13) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.
The ethyl 4-iodobutanoate synthon represents the
practical limit of halo ester substrates that can be utilized
(14) Schwaebe, M.; Little, R. D. J . Org. Chem. 1996, 61, 3240.

4122 J . Org. Chem., Vol. 64, No. 11, 1999
Machrouhi
Ta ble 2. Sequ en tia l Sm I2-P r om oted Ca r bon yl Ad d ition /Nu cleop h ilic Acyl Su bstitu tion Betw een Eth yl 4-Iod obu ta n oa te
(8) a n d Ch lor ok eton e Su bstr a tes
the organic extracts were washed with brine and dried over
anhydrous magnesium sulfate. The products were purifed by
silica gel flash chromatography.
1765, 1664, 1013 cm-1; LRMS (EI+) m/z 210 (52), 110 (100),
43 (25). Anal. Calcd for C13H22O2: C, 74.23; H, 10.55. Found:
C, 74.25; H, 10.70.
1-Hyd r oxy-11-oxa tr icyclo[6.2.1.04,8]u n d eca n e (11)8 was
prepared from 2 (81.25 mg, 0.5 mmol) and ethyl 3-iodopro-
panoate (1, 114 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (30% ethyl acetate:hexanes), 11 (59.7 mg, 71% yield) as a
single diastereomer as determined by GC: 1H NMR (300 MHz,
CDCl3) δ 3.87 (bs, 1H), 1.98-2.14 (m, 2H), 1.43-1.94 (m, 13H);
13C NMR (75 MHz, CDCl3) δ 106.4, 91.9, 43.0, 34.8, 33.4, 32.6,
30.9, 28.1, 21.6, 21.1; IR (neat) 3394, 1735, 1097 cm-1; LRMS
(EI+) m/z 169 (33), 81 (100), 40 (81). Anal. Calcd for C10H16O2:
C, 71.39; H, 9.58. Found: C, 71.27; H, 9.58.
1-Hyd r oxy-12-oxa tr icyclo[7.2.1.04,9]d od eca n e (15)8 was
prepared from 6 (80.25 mg, 0.5 mmol) and ethyl 3-iodopro-
panoate (1, 114 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (30% ethyl acetate:hexanes), 15 (69.25 mg, 75% yield) as
1
a single diastereomer as determined by GC: mp 104 °C; H
NMR (300 MHz, CDCl3) δ 3.85 (bs, 1H), 1.40-2.07 (m, 11H),
1.12-1.35 (m, 4H), 0.90-1.05 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 104.3, 83.5, 42.6, 37.5, 36.7, 35.5, 29.9, 29.5, 26.7,
25.7, 23.4; IR (neat) 3372, 1435, 1332, 1116, 1015 cm-1; LRMS
(EI+) m/z 182 (81), 136 (54), 134 (100), 43 (30). Anal. Calcd for
1-Hyd r oxy-12-oxa tr icyclo[7.2.1.05,9]d od eca n e (12)8 was
prepared from 3 (88.25 mg, 0.5 mmol) and ethyl 3-iodopro-
panoate (1, 114 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (30% ethyl acetate: hexanes), 12 (56.5 mg, 62% yield) as
a single diastereomer as determined by GC: 1H NMR (300
MHz, CDCl3) δ 3.52 (bs, 1H), 1.27-2.22 (m, 17H); 13C NMR
(75 MHz, CDCl3) δ 107.6, 91.2, 51.4, 40.6, 38.9, 35.4, 34.0, 31.3,
24.8, 24.2; IR (neat) 3390, 1458, 1071 cm-1; LRMS (EI+) m/z
182 (59), 94 (100), 43 (58). Anal. Calcd for C11H18O2: C, 72.48;
H, 9.96. Found: C, 72.68; H, 9.96.
6-Bu t yl-1-oxa t r icyclo[4.4]n on a n -2-on e (13) was pre-
pared from 4 (95.25 mg, 0.5 mmol) and ethyl 3-iodopropanoate
(1, 114 mg, 0.5 mmol) according to the general procedure
described above to afford, after flash chromatography (25%
ethyl acetate:hexanes), 13 (66.2 mg, 68% yield) as a single
diastereomer as determined by GC: 1H NMR (300 MHz,
CDCl3) δ 2.58-2.68 (m, 2H), 1.15-2.30 (m, 15H), 0.95 (t, J )
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 95.4, 49.2,
39.8, 30.4, 29.8, 29.7, 27.7, 22.9, 21.2, 14.1; IR (neat) 1770,
1163, 1017 cm-1; LRMS (EI+) m/z 196 (43), 110 (100), 43 (39).
Anal. Calcd for C12H20O2: C, 73.41; H, 10.28. Found: C, 73.39;
H, 10.25.
C
11H18O2: C, 72.48; H, 9.96. Found: C, 72.68; H, 9.96.
1-Hyd r oxy-13-oxa tr icyclo[8.2.1.05,10]tr id eca n e (16)8 was
prepared from 7 (87.03 mg, 0.5 mmol) and ethyl 3-iodopro-
panoate (1, 114 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (15% ethyl acetate:hexanes), 16 (42.10 mg, 43% yield) as
a single diastereomer as determined by GC: mp 72 °C; 1H
NMR (300 MHz, CDCl3) δ 3.08 (bs, 1H), 1.13-2.20 (m, 19H);
13C NMR (75 MHz, CDCl3) δ 107.8, 84.2, 44.7, 42.4, 40.4, 40.3,
36.2, 30.5, 28.7, 25.8, 23.2, 18.9; IR (neat) 3390, 1453, 1335,
1115, 1011 cm-1; LRMS (EI+) m/z 197 (76), 196 (64), 108 (100),
43 (37). Anal. Calcd for C12H20O2: C, 73.41; H, 10.28. Found:
C, 73.53; H, 10.37.
1-Hyd r oxy-12-oxa tr icyclo[6.3.1.04,8]d od eca n e (17) was
prepared from 2 (81.25 mg, 0.5 mmol) and ethyl 4-iodobu-
tanoate (8, 121 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (30% ethyl acetate:hexanes), 17 (65.54 mg, 71% yield) as
a single diastereomer as determined by GC: 1H NMR (300
MHz, CDCl3) δ 2.47 (bs, 1H), 1.98-1.82 (m, 2H), 1.80-1.30
(m, 15H); 13C NMR (75 MHz, CDCl3) δ 96.4, 84.2, 42.1, 40.4,
36.7, 33.7, 33.4, 32.8, 32.0, 24.5, 22.5, 20.3; IR (neat) 3390,
1451, 1335, 1116 cm-1; LRMS (EI+) m/z 182 (30), 96 (57), 94
(100), 43 (43). Anal. Calcd for C11H18O2: C, 72.49; H, 9.95.
Found: C, 72.28; H, 10.07.
6-P en tyl-1-oxa tr icyclo[4.4]n on a n -2-on e (14) was pre-
pared from 5 (102.25 mg, 0.5 mmol) and ethyl 3-iodopro-
panoate (1, 114 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (25% ethyl acetate:hexanes), 14 (85.6 mg, 81% yield) as a
single diastereomer as determined by GC: 1H NMR (300 MHz,
CDCl3) δ 2.50-2.64 (m, 2H), 1.18-2.25 (m, 17H), 0.90 (t, J )
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.2, 95.8, 49.1,
39.4, 32.1, 29.8, 29.7, 29.4, 28.2, 28.0, 22.5, 21.3, 14.1; IR (neat)
13-Oxa tr icyclo[7.3.1.01,5]tr id eca n -9-ol (18) was prepared
from 3 (88.25 mg, 0.5 mmol) and ethyl 4-iodobutanoate (8, 121
mg, 0.5 mmol) according to the general procedure described
above to afford, after flash chromatography (15% ethyl acetate:
hexanes), 18 (78.33 mg, 80% yield) as a single diastereomer
1
as determined by GC: mp 76 °C; H NMR (300 MHz, CDCl3)
δ 2.97 (bs, 1H), 1.28-1.15 (m, 19H); 13C NMR (75 MHz, CDCl3)

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 64, No. 11, 1999 4123
δ 98.7, 85.8, 45.7, 43.2, 40.8, 40.5, 37.0, 31.1, 30.0, 27.3, 23.5,
19.2; IR (neat) 3390, 1440, 1312, 1116 cm-1; LRMS (EI+) m/z
196 (89), 108 (100), 43 (58). Anal. Calcd for C12H20O2: C, 73.41;
H, 10.28. Found: C, 73.27; H, 10.15.
Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C, 73.52; H,
10.23.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM35249), the Universite´ Paris-Sud,
and the CNRS for their generous support. We also thank
the Ministry of Education and Research (France) for a
fellowship (to F. Machrouhi).
1-Hyd r oxy-13-oxa tr icyclo[7.3.1.04,9]tr id eca n e (19) was
prepared from 6 (80.25 mg, 0.5 mmol) and ethyl 4-iodobu-
tanoate (8, 121 mg, 0.5 mmol) according to the general
procedure described above to afford, after flash chromatogra-
phy (15% ethyl acetate:hexanes), 19 (66.0 mg, 67% yield) as a
single diastereomer as determined by GC: mp 117 °C; 1H NMR
(300 MHz, CDCl3) δ 2.65 (bs, 1H), 2.37-2.33 (m, 1H), 2.13-
2.10 (m, 1H), 1.87-1.85 (m, 1H), 1.81-1.59 (m, 8H), 1.45-
1.18 (m, 7H), 1.15-0.99 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
100.9, 75.7, 43.5, 37.5, 36.2, 36.0, 32.6, 31.7, 28.5, 27.5, 25.8,
21.3, 21.2; IR (neat) 3398, 1448, 1312, 1107, 1010 cm-1; LRMS
(EI+) m/z 196 (43), 167 (64), 108 (100), 81 (72), 43 (83). Anal.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details for the synthesis of all of the substrates used
in this research. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O990216N