Sequenced Reactions with Samarium(II) Iodide. Sequential Intermolecular Carbonyl Addition/Intramolecular Nucleophilic Acyl Substitution for the Preparation of Seven-, Eight-, and Nine-Membered Carbocycles

Article abstract of DOI:10.1021/jo980119e

Samarium(II) iodide has been employed to promote a tandem intermolecular carbonyl addition/ intramolecular nucleophilic acyl substitution sequence, generating seven-through nine-membered monocyclic, bicyclic, and tricyclic ring systems with good yields an

Full text of DOI:10.1021/jo980119e

4366
J . Org. Chem. 1998, 63, 4366-4373
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. Sequ en tia l
In ter m olecu la r Ca r bon yl Ad d ition /In tr a m olecu la r Nu cleop h ilic
Acyl Su bstitu tion for th e P r ep a r a tion of Seven -, Eigh t-, a n d
Nin e-Mem ber ed Ca r bocycles
Gary A. Molander* and Cristina Alonso-Alija
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received J anuary 22, 1998
Samarium(II) iodide has been employed to promote a tandem intermolecular carbonyl addition/
intramolecular nucleophilic acyl substitution sequence, generating seven- through nine-membered
monocyclic, bicyclic, and tricyclic ring systems with good yields and high diastereoselectivities.
This tandem reaction consists of an intermolecular reaction followed by an intramolecular ring
expansion that results in a formal [m + n] cycloaddition, starting from extremely simple, readily
available substrates. The regioselectivity and stereoselectivity of the process arise from a tuning
of the reducing power of samarium(II) iodide with nickel(II) iodide in the first step and irradiation
with visible light in the second. By using this method, a variety of structural motifs have been
assembled rapidly in good yields.
Sch em e 1
Medium-sized carbocycles are structural units present
in a wide range of natural products, existing either as
isolated rings or forming part of bicyclic or tricyclic
frameworks.1 The synthesis of these structures is often
quite challenging, mainly because the application of
carbon-carbon bond-forming reactions to macrocycle
synthesis is not always straightforward. Entropic fac-
tors, together with transannular interactions that inhibit
cyclization, conspire to make the construction of medium-
sized rings difficult.2 As evidence of this, the number of
general methods for preparing medium-sized carbocycles
by cyclization or cycloaddition (annulation) reactions from
acyclic precursors is relatively small.1a,3
We have previously demonstrated that SmI2 in the
presence of catalytic Fe(III) promotes the intramolecular
nucleophilic acyl substitution of haloalkyl-substituted
carboxylic acid derivatives.4 In particular, we have
reported a powerful method for obtaining medium-sized
ring systems from appropriate haloalkyl-substituted lac-
tones through a ring expansion employing this process.4a
In the present contribution we outline a novel way of
obtaining medium ring hydroxy ketones by a more
efficient, sequenced process. The reducing power of
samarium(II) iodide (SmI2) can be tuned by using a
variety of solvents and additives or by a change in the
reaction conditions. The chemoselectivity of this reduc-
tant is therefore highly adjustable.5 Moreover, excellent
diastereoselectivities are associated with many SmI2-
promoted reactions. These characteristics have made
SmI2 an excellent reagent for promoting sequential
organic reactions.5d,6 We reasoned that the intermolecu-
lar reaction between a chloroiodoalkane and a keto ester
would yield a chloroalkyl-substituted lactone via an
initial carbonyl addition reaction (Scheme 1). Preferen-
tial reactivity of the iodide over the chloride would be
necessary to lead the process along a regioselective
pathway. High selectivity for reaction at aldehydes or
ketones in preference to the ester would be required.7
Upon initial carbonyl addition, the formation of a lactone
would be critical for the success of the annulation. This
lactone would serve as a template, providing structural
constraints to permit the medium-sized ring to be gener-
ated by a ring expansion process through what would
formally be a five- or six-membered transition structure.
Thus, reaction of the chloroalkyl-substituted lactone via
an intramolecular nucleophilic acyl substitution would
afford the desired carbocyclic hydroxy ketone.
(1) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757 and
references therein. (b) Oishi, T.; Ohtsuka, Y. In Studies in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989;
Vol. 3, p 73 and references therein. (c) Rigby, J . H. In Studies in
Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amster-
dam, 1993; Vol. 12, p 233.
(2) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(3) Molander, G. A. Acc. Chem. Res. In press.
(6) (a) Molander, G. A.; Harris, C. R. Tetrahedron. In press. (b)
Molander, G. A.; Kenny, C. J . Org. Chem. 1991, 56, 1439. (c) Molander,
G. A.; McKie, J . A. J . Org. Chem. 1992, 57, 3132. (d) Molander, G. A.;
Harris, C. R. J . Am. Chem. Soc. 1996, 118, 4059. (e) Molander, G. A.;
del Pozo Losada, C. J . Org. Chem. 1997, 62, 2935. (f) Molander, G. A.;
Alonso-Alija, C. Tetrahedron 1997, 53, 8067.
(7) (a) Kagan, H. B.; Machrouhi, F.; Hamann, B. Synlett 1996, 633.
(b) Csuk, R.; Hu, S.; Abdou, M.; Kratky, C. Tetrahedron 1991, 47, 7037.
(c) Molander, G. A.; McKie, J . A. J . Org. Chem. 1991, 56, 4112.
(4) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216.
(b) Molander, G. A.; Shakya, S. R. J . Org. Chem. 1994, 59, 3445.
(5) For general reviews, see: (a) Soderquist, J . A. Aldrichimica Acta
1991, 24, 15. (b) Molander, G. A. Chem. Rev. 1992, 92, 29. (c) Molander,
G. A. In Organic Reactions; Paquette, L. A., Ed.; J ohn Wiley & Sons:
New York, 1994; Vol. 46, p 211. (d) Molander, G. A.; Harris, C. R. Chem.
Rev. 1996, 96, 307.
S0022-3263(98)00119-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/30/1998

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 63, No. 13, 1998 4367
Sch em e 2
Irradiation with visible light has been reported to
enhance the reducing ability of SmI2, enabling the
efficient reduction of organic chlorides.11 This procedure
proved to be very useful in the present study. Irradiation
of lactone 3 with visible light in the presence of SmI2
promoted the reduction of the chloride, and subsequent
nucleophilic acyl substitution ensued to provide the
desired hydroxy ketone. In this way, the method for the
efficient one-pot synthesis of cyclic hydroxy ketones via
a sequenced annulation process was established. Addi-
tion of the keto ester to a solution of SmI2 containing 2%
of NiI2, followed by the dropwise addition of a THF
solution of the chloroiodoalkane and subsequent irradia-
tion of the reaction mixture with visible light for 3 h,
afforded the desired hydroxy ketone 4a in equilibrium
with its hemiacetal. The desired product could be
isolated after aqueous workup in good yield and with
total diastereoselectivity. The advantages of the use of
light as a promoter of SmI2 reactions over using HMPA
are obvious in terms of cost, safety, and cleanliness of
the reactions.
There were some potential pitfalls associated with the
proposed process and some obvious restrictions as well.
For example, 1,2-dihaloalkanes could not be utilized
because of the certainty of rapid â-elimination upon
reaction with SmI2,5c and cyclopropane formation from
iodochloropropanes would have to be avoided.8 It was
anticipated that only five- and six-membered lactones
would be formed efficiently after the initial carbonyl
addition. In the final step of the overall process, the
intramolecular nucleophilic acyl substitution was ex-
pected to take place in good yields only when a five- or
six-membered transition structure was involved.
The scope of the reaction with regard to the keto ester
partners was next examined. The synthesis of several
4-keto esters was accomplished by alkylation of the
appropriate ester or lactone with 3-bromo-2-methylpro-
pene and subsequent ozonolysis (eqs 1 and 2). Alterna-
Interestingly, the reactions described in this paper
have been successfully sequenced in the reverse order
previously (i.e., nucleophilic acyl substitution followed by
carbonyl addition).9 The domino reaction developed
herein establishes a formal [m + n] annulation between
a dihaloalkane and a keto ester, generating seven-, eight-,
and even nine-membered rings in an efficient manner.
Resu lts a n d Discu ssion
The desired process was initially tested by treating
commercially available ethyl 2-oxocyclohexaneacetate
(1a ) and 1-chloro-3-iodopropane (2) with SmI2 (Scheme
2). The intermediate chloroalkyl-substituted lactone 3
was smoothly formed within minutes and could be
isolated in high yield and stereoselectivity when a
catalytic amount of NiI2 (2%) was used in the reaction.7a
The second step of the sequenced process did not take
place directly under these reaction conditions. An ad-
justment of the reaction conditions was required in order
to promote the reduction of the terminal chloride. Ad-
dition of an excess of hexamethylphosphoramide (HM-
PA)10 to the reaction mixture provided the desired bicyclic
hydroxy ketone 4a with excellent diasteroselectivity,
although the yields were moderate even after 12 h of
reaction. Large amounts of the intermediate lactone 3
remained unreacted. Using HMPA as a cosolvent from
the beginning of the reaction led only to complex mixtures
because under these conditions the necessary chemose-
lectivity of the SmI2 was lost.
tively, the alkylation of a ketone with ethyl bromoacetate
led to complementary 4-keto esters. The keto ester 7 was
synthesized by a Diels-Alder cycloaddition reaction (eq
3).12 Ether 8 was generated by alkylation of ethyl
glycolate with 3-bromo-2-methylpropene followed by ozo-
nolysis (eq 4). Several 1,5-keto esters were easily pre-
pared via Michael addition reactions.13
Application of the standard experimental procedure
developed to the reaction between 1-chloro-3-iodopropane
(8) (a) Connor, D. S.; Wilson, E. R. Tetrahedron Lett. 1967, 4925.
(b) Semmler, K.; Szeimies, G.; Belzner, J . J . Am. Chem. Soc. 1985,
107, 6410. (c) Bailey, W. F.; Gagnier, R. P. Tetrahedron Lett. 1982, 23,
5123. (d) Wiberg, K. B.; Lampman, G. M. Tetrahedron Lett. 1963, 2173.
(e) House, H. O.; Lord, R. C.; Rao, H. S. J . Org. Chem. 1956, 21, 1487.
(f) Wiberg, K. B.; William, V. Z. J . Org. Chem. 1970, 35, 369.
(9) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1995, 117, 3705.
(10) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485.
(11) (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.
(12) For preparation of the dienophile, see: McMurry, J . E.; Blaszc-
zak, L. C. J . Org. Chem. 1974, 39, 2217.

4368 J . Org. Chem., Vol. 63, No. 13, 1998
Molander and Alonso-Alija
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 betw een Keto Ester s a n d
1-Ch lor o-3-iod op r op a n e (2)
a
b
Simple addition of the organosamarium to the carbonyl without formation of the lactone. Characterized after acylation. c A single
diastereomer was detected. Yield after acylation of the crude product with acetic anhydride/pyridine/DMAP. e Yield when using 2 equiv
d
of dihaloalkane and 8 equiv of SmI2. f Complex mixture obtained. Stereochemistry not assigned.
g
and several of these 4-keto ester and 5-keto ester
substrates afforded the expected cyclic hydroxy ketones,
for the most part isolated as hemiacetals (Table 1).
Simple seven- and eight-membered carbocycles were
efficiently formed from both keto esters and the corre-
sponding aldehydes. As anticipated, the size of the
intermediate lactone was limited to five or six members,
with no formation of a seven-membered lactone evident
when the dihaloalkane was reacted with a 6-keto ester
(entry 3). Substitution R to the ketone was not well
tolerated (entries 10 and 16). In these cases, simple
reduction of the carbonyl group was a competing reaction.
On the contrary, substitution R to the ester group
appeared to present few problems (entries 13 and 15).
R,â-Unsaturated ketones 19 and 2014 (entries 11 and 12)
afforded only complex mixtures in the first step of the
reaction, and the synthesis of oxygen heterocycles also
failed in the chlorolactone formation step (entry 17). Keto
lactones (entry 14) turned out to be suitable substrates
for the reaction, although the nucleophilic acyl substitu-
tion step was much slower than that in other cases.
Bicyclo[5.3.0], -[6.3.0], -[5.4.0], and -[6.4.0] ring systems
were obtained in good yield and with complete diaste-
reoselectivity. Single-crystal X-ray analysis of compound
12b confirmed the expected trans fusion between the two
carbocyclic rings resulting from attack of the organosa-
marium species trans to the side chain on the cyclic keto
ester in the first step of the reaction.
The synthesis of several different 1-chloro-3-iodoal-
kanes was carried out starting from R,â-unsaturated
ketones (Scheme 3). Addition of hydrogen chloride to the
conjugated double bond afforded the corresponding 3-chlo-
ro ketones, which were immediately reduced to the
corresponding alcohols 25 and 27 with lithium aluminum
hydride. Conversion of the resultant hydroxy group into
an iodide provided an efficient way of synthesizing the
1-chloro-3-iodoalkanes 26 and 28.
(13) (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974,
1223. (b) Stork, G.; Brizzolara, A.; Landesman, H.; Smuszkovicz, J .;
Terrell, R. J . Am. Chem. Soc. 1963, 85, 207.
An alternative route utilized for the preparation of
1-chloro-3-iodoalkanes is shown in Scheme 4. The diol
29 was monotosylated in good yield, and the resulting
(14) Ziegler, F. E.; Piwinski, J . J . J . Am. Chem. Soc. 1982, 104, 7181.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 63, No. 13, 1998 4369
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 5-Oxoh exa n oa te
(9b) a n d Sever a l Dih a lo Com p ou n d s
a
b
The major compound isolated was δ-caprolactone. Ethyl 4-oxopentanoate (9a ) was used as the keto ester. c The major compound
d
isolated was 5-cyclohexyl-δ-caprolactone. Yield after methylation of the crude product with methyl orthoformate/PTSA in methanol.
Stereochemistry not determined. e A nonreproducible mixture of the ten-membered ring and 5-pentyl-δ-caprolactone was isolated. f 5-
g
h
Hexyl-δ-caprolactone was the only compound isolated. Reaction with n-butyl 4-oxobutyrate (13). The major diastereomer was
characterized as the acylated compound (acetic anhydride/DMAP).
Sch em e 3
This was converted into the chloroiodoalkane 32, a
suitable substrate for the SmI2-induced reaction.
The reaction between ethyl 5-oxopentanoate (9b) and
several of these 1,3-dihaloalkanes was tested as shown
in Table 2. Secondary iodides reacted efficiently under
the standard reaction conditions, and the cyclization was
completed in good yield (entry 1). However, the reduction
of secondary chlorides with SmI2 and visible light took
place very slowly. In these cases, the only isolated
products were the result of simple reduction of the
chloride to the alkane prior to the cyclization (entry 6).
2-Substituted-1,3-dihalo compounds reacted rather inef-
ficiently. One substituent in this position provided the
desired product, although in modest yield (entry 2).
Presumably, the chloroiodoalkane was partially con-
sumed via the formation of cyclopropane side products.
This effect was much more dramatic in 2,2-disubstituted
compounds such as 35,16 wherein the Barbier reaction
did not take place and the only isolated product was the
δ-caprolactone. The latter was generated as a result of
simple reduction and lactonization of the keto ester 9b
(entry 3). The reaction of compound 32 allowed the
isolation of the bicyclo[6.3.0] product, albeit in moderate
yield (entry 7). The diallylic dichloride 36 was suf-
ficiently activated to afford the desired products without
Sch em e 4
(15) Falorni, M.; Lardicci, L.; Giacomelli, G. J . Org. Chem. 1986,
51, 5291.
(16) (a) Castro, B.; Selve, C. Bull. Soc. Chim. Fr. 1974, 3004. (b)
Castro, B.; Selve, C. Bull. Soc. Chim. Fr. 1974, 3009.
tosylate 30 was subsequently heated at reflux with
lithium chloride in DMF to obtain the chloro alcohol 31.15

4370 J . Org. Chem., Vol. 63, No. 13, 1998
Molander and Alonso-Alija
Sch em e 5
tween a cyclic keto ester and a cyclic 1-chloro-4-iodoal-
kane (eqs 5 and 6). The reaction takes place to provide
the desired carbotricyclics in moderate yield. Both ring
fusions in the molecules are effectively set: one ring
fusion is trans because of the diastereoselectivity of the
initial carbonyl addition reaction and the stereochemistry
of the second is fixed by the dihalide starting material.
Only the relative stereochemistry between the two sets
of stereocenters remains variable. For compound 47, the
relative stereochemistry of the major isomer was deter-
mined by single-crystal X-ray diffraction techniques. The
net outcome of the SmI2-sequenced, one-pot method
provides an extremely simple way of constructing the
5:8:5 ring system that comprises the framework of several
complex naturally occurring structures.20
the need for irradiation (entries 4 and 5). The isolation
of these products in their hemiacetal forms prevented the
isomerization of the double bond which has been observed
in related reactions reported previously.4a,9
While establishing the practical limits of the reaction,
we observed an unexpected annulation utilizing 1,4-
dihaloalkane 39a as a substrate. This one-pot process
allowed the efficient synthesis of a nine-membered ring
(entry 8). It is noteworthy that the ring expansion step
must take place through a seven-membered transition
structure in the attack of the organosamarium onto the
lactone moiety. This example is not an isolated case, as
the reaction of compound 13 with 1-chloro-4-iodobutane
(39a ) afforded the corresponding 4-acetoxycyclooctanone
41 in a comparable yield after acylation of the crude
material (entry 11).
The scope of this unexpected cyclization with respect
to the chain length of the dihalide substrates was briefly
explored. Unfortunately, it was determined to be limited
to 1,3- and 1,4-dihalides. For example, the reaction of
9b with 1-chloro-5-iodopentane gave irreproducible mix-
tures of the desired ten-membered ring and simple
dehalogenated lactone (entry 9), and 1-chloro-6-iodohex-
ane showed only dehalogenation of the intermediate
chlorolactone in the reaction with 9b (entry 10).
The synthesis of some novel 1-chloro-4-iodoalkanes was
accomplished as depicted in Scheme 5. Ring opening of
the cyclic cis-lactones 42a 17 and 42b17a,e with neat thionyl
chloride and further addition of ethanol provided the
3-chloroesters 43 in a convenient one-pot reaction.18
These compounds were reduced with lithium aluminum
hydride at low temperature to afford the 4-chloro alcohols
44. Finally, conversion of the hydroxy group into an
iodide provided the requisite 1,4-chloroiodoalkanes 45.19
The cyclic 1,4-dihalide 45b reacted with the keto ester
9b to afford the desired bicyclic keto alcohol, although
in moderate yield as displayed in entry 12. Approxi-
mately 10% of the simple dehalogenated lactone was also
formed in this case.
Con clu sion s
The SmI2-promoted carbonyl addition/nucleophilic acyl
substitution sequence provides an efficient method for
synthesizing seven- to nine-membered monocyclic, bicy-
clic, and tricyclic hydroxy ketones by intermolecular
reactions between readily available keto esters and
dihaloalkanes. Irradiation with visible light enhances
the reducing power of SmI2 and is of vital importance
for completing this sequence. Noteworthy is the facile
synthesis of the 5:8:5 ring system in a one-pot process
utilizing this new method.
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 purchased form Cerac Inc., Milwaukee, WI,
and was stored under an inert atmosphere. Nickel(II) iodide
(NiI2) and iodine were purchased from Aldrich Chemicals.
Hexamethylphosphoramide (HMPA) was purchased from Al-
drich Chemicals and was distilled from CaH2 at 0.04 mmHg
and stored over 4 Å molecular sieves under Ar. Standard
benchtop techniques were employed for handling air-sensitive
reagents,21 and all the reactions were carried out under Ar.
In light of these results, we investigated the synthesis
of tricyclic frameworks via the sequenced reaction be-
(17) (a) Clive, D. L. J .; Manning, H. W.; Boivin, T. L. B.; Postema,
M. H. D. J . Org. Chem. 1993, 58, 6857. (b) Svendsen, A.; Boll, P. M.
Tetrahedron 1973, 29, 4251. (c) Wilkening, D.; Mundy, P. Synth.
Commun. 1984, 14, 227. (d) Owen, L. N.; Peto, A. G. J . Chem. Soc.
1955, 2383. (e) Bailey, D. M.; J ohnson, R. E. J . Org. Chem. 1970, 35,
3574.
(18) Molander, G. A.; Harris, C. R. J . Org. Chem. 1997, 62, 2944.
(19) (a) Garegg, J . P.; Samuelsson, B. J . Chem. Soc., Chem. Com-
mun. 1979, 978. (b) Garegg, J . P.; Samuelsson, B. J . Chem Soc., Perkin
Trans. 1 1980, 2866.
(20) Wender, P. A.; Nuss, J . M.; Smith, D. B.; Sua´rez-Sobrino, A.;
Vågberg, J .; Decosta, D.; Bordner, J . J . Org. Chem. 1997, 62, 4908
and references therein.
(21) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 63, No. 13, 1998 4371
(1R *,3S *,8R *)-1-Ac e t o x y -12-o x a t r ic y c lo [6.3.1.03,8]-
d od eca n e (4a ′). 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. THF (30 mL) was added to a
mixture of samarium metal (519 mg, 3.45 mmol) and iodine
(761 mg, 3.00 mmol). The brown slurry was stirred for 2 h at
room temperature, while its color changed to yellow, green,
and dark blue. NiI2 (20 mg, 0.06 mmol) was added, and the
mixture was cooled to 0 °C. After the solution was stirred for
5 min, 92 mg (0.50 mmol) of ethyl 2-cyclohexanoneacetate (1)
was added, followed immediately by the dropwise addition of
112 mg (0.55 mmol) of 1-chloro-3-iodopropane (2) in 5 mL of
THF over 30 min. When the addition of the substrates was
complete, the reaction mixture was irradiated with visible light
(250 W krypton lamp) for 3 h, while the temperature was
maintained below 25 °C. The resultant mixture was quenched
with a saturated aqueous solution of Rochelle’s salt.22 A 10%
aqueous solution of potassium carbonate was added, the
mixture was extracted several times with diethyl ether, and
the organic materials were washed with brine and dried over
anhydrous magnesium sulfate. Flash chromatography with
25% ethyl acetate:hexanes and Kugelrohr distillation afforded
64 mg (70% yield) of (1R*,7S*)-7-hydroxybicyclo[5.4.0]undecan-
3-one (4a ) as a single diastereomer (determined by GC),
isolated as a hemiacetal:hydroxy ketone mixture. Further
treatment of the product with an excess of acetic anhydride
and pyridine in dichloromethane in the presence of a catalytic
amount of DMAP23 allowed the isolation of the title compound:
mp 64-65 °C; 1H NMR (500 MHz, CDCl3) δ 2.69 (dd, J ) 13.5,
8.0 Hz, 1H), 2.14 (m, 1H), 2.02 (s, 3H), 1.92 (m, 1H), 1.81-
1.63 (m, 4H), 1.59-1.25 (m, 8H), 1.19 (m, 1H), 1.07 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 168.8, 109.2, 81.4, 43.3, 39.1,
36.6, 33.7, 32.9, 32.3, 23.2, 21.7, 20.4, 18.9; IR (neat) 2933,
1738 cm-1; LRMS (EI+) m/z 224 (2.7), 206 (3.0), 182 (56), 164
(72), 154 (40), 136 (52), 122 (50), 111 (80), 94 (76), 79 (22), 67
(26), 55 (40), 43 (100). Anal. Calcd for C13H20O3: C, 69.61;
H, 8.99. Found: C, 70.02; H, 9.14.
(1R*,6S*)-1-(3-Ch lor op r op yl)-9-oxa bicyclo[4.3.0]n on a n -
8-on e (3). The procedure described above for the synthesis
of 4a was followed, except that the reaction was quenched
immediately after the addition of the substrates. Flash
chromatography over silica gel with 15% ethyl acetate:hexanes
and Kugelrohr distillation afforded 98 mg (91% yield) of the
title compound 3 as a single diastereomer: 1H NMR (500 MHz,
CDCl3) δ 3.57-3.45 (m, 2H), 2.53 (dd, J ) 17.0, 8.0 Hz, 1H),
2.42 (dd, J ) 17.0, 9.0 Hz, 1H), 2.30 (m, 1H), 1.90-1.72 (m,
5H), 1.68-1.61 (m, 2H), 1.59-1.51 (m, 2H), 1.46-1.40 (m, 2H),
1.33-1.26 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 176.3, 86.3,
45.1, 39.0, 34.8, 34.4, 32.0, 26.5, 25.9, 21.6, 20.6; IR (neat) 2937,
1770 cm-1; LRMS (EI+) m/z 218 (4.0), 216 (12), 175 (11), 173
(33), 139 (100), 111 (54), 67 (29), 55 (65), 41 (87). Anal. Calcd
for C11H17ClO2: C, 60.97; H, 7.91. Found: C, 61.34; H, 8.05.
75.4, 35.4, 34.5, 31.6, 20.6; IR (neat) 3390, 2934, 1202 cm-1
LRMS (EI+) m/z 156 (39), 128 (69), 110 (31), 95 (26), 82 (53),
71 (80), 69 (100), 56 (37), 43 (72). Anal. Calcd for C9H16O2:
C, 69.19; H, 10.32. Found: C, 69.58; H, 10.45.
;
(1R *,3R *,7S *)-1-H yd r oxy-11-oxa t r icyclo[5.3.1.03,7]-
u n d eca n e (4b). Following the general procedure described
for the preparation of 4a , 85 mg (0.50 mmol) of ethyl 2-oxo-
cyclopentaneacetate (1b)9 and 112 mg (0.55 mmol) of 1-chloro-
3-iodopropane (2) provided 49 mg (58% yield) of the title
compound 4b after flash chromatography with 25% ethyl
acetate:hexanes as a single diastereomer as determined by
GC: 1H NMR (500 MHz, CDCl3) δ 2.96 (bs, 1H), 2.31 (dd, J )
12.5, 9.0 Hz, 1H), 2.17 (m, 1H), 1.98-1.20 (m, 13H); 13C NMR
(125 MHz, CDCl3) δ 106.0, 92.9, 44.9, 44.5, 37.2, 35.5, 34.9,
32.7, 25.6, 20.1; IR (neat) 3386, 2946, 1103 cm-1; LRMS (EI+)
m/z 168 (18), 150 (8.0), 140 (10), 108 (56), 97 (19), 94 (19), 81
(83), 80 (100), 67 (27), 55 (35), 41 (39). Anal. Calcd for
C
10H16O2: C, 71.39; H, 9.59. Found: C, 71.08; H, 9.64.
(1R *,4R *,8S *)-1-H yd r oxy-12-oxa t r icyclo[6.3.1.04,8]-
d od eca n e (12a ). Following the general procedure described
for the preparation of 4a , 85 mg (0.50 mmol) of methyl 3-(2-
oxocyclopentyl)propionate (11a )13a and 112 mg (0.55 mmol) of
1-chloro-3-iodopropane (2) provided 48 mg (52% yield) of the
title compound 12a after flash chromatography with 25% ethyl
acetate:hexanes as a single diastereomer as determined by GC:
1H NMR (500 MHz, CDCl3) δ 2.50 (bs, 1H), 1.96-1.86 (m, 2H),
1.84-1.35 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 95.7, 84.7,
41.7, 40.4, 36.9, 33.6, 32.2, 32.1, 24.1, 22.2, 19.9; IR (neat) 3390,
2943 cm-1; LRMS (EI+) m/z 182 (29), 154 (33), 136 (71), 122
(42), 108 (29), 94 (100), 79 (58), 67 (76), 55 (39), 41 (82). Anal.
Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.24; H,
10.09.
(1R *,4R *,9S *)-1-H yd r oxy-13-oxa t r icyclo[7.3.1.04,9]-
tr id eca n e (12b). Following the general procedure described
for the preparation of 4, 92 mg (0.50 mmol) of methyl 3-(2-
oxocyclohexyl)propionate (11b)13b and 112 mg (0.55 mmol) of
1-chloro-3-iodopropane (2) provided 65 mg (66% yield) of the
title compound 12b after flash chromatography with 17% ethyl
acetate:hexanes as a single diastereomer as determined by GC:
1
mp 117-118 °C; H NMR (500 MHz, CDCl3) δ 2.70 (bs, 1H),
2.37 (m, 1H), 2.12 (m, 1H), 1.87 (m, 1H), 1.82-1.51 (m, 8H),
1.50-1.19 (m, 7H), 1.18-1.08 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 95.7, 75.9, 40.5, 37.6, 36.3, 36.1, 31.8, 28.7, 27.5, 25.7,
21.2, 21.1; IR (neat) 3418, 2931, 985 cm-1; LRMS (EI+) m/z
196 (41), 168 (56), 150 (46), 108 (98), 98 (59), 81 (72), 67 (53),
55 (58), 41 (100). Anal. Calcd for C12H20O2: C, 73.43; H, 10.27.
Found: C, 73.82; H, 10.41.
4-Acetoxycycloh ep ta n on e (14). The preparation of this
compound was accomplished by following the general proce-
dure described for the preparation of 4a , except that 79 mg
(0.50 mmol) of n-butyl 4-oxobutyrate (13) and 112 mg (0.55
mmol) of 1-chloro-3-iodopropane (2) were added simulta-
neously as a solution in 5 mL of THF. Acylation of the crude
material in dichloromethane with an excess of acetic anhydride
and pyridine and a catalytic amount of DMAP provided 51 mg
(60% yield) of the title compound 14 after flash chromatogra-
phy with 25% ethyl acetate:hexanes: 1H NMR (500 MHz,
CDCl3) δ 4.93 (m, 1H), 2.58 (m, 1H), 2.46 (m, 2H), 2.39 (m,
1H), 2.00 (s, 3H), 1.92-1.82 (m, 4H), 1.80-1.73 (m, 1H), 1.67-
1.58 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 213.3, 170.1, 73.2,
43.4, 37.6, 34.7, 28.8, 21.2, 18.8; IR (neat) 2944, 1732, 1704,
1244 cm-1; LRMS (EI+) m/z 155 (0.1), 152 (0.2), 128 (4.8), 110
(44), 100 (15), 82 (35), 68 (26), 55 (30), 43 (100). Anal. Calcd
for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.19; H, 8.33.
5-Tr id ecyl-9-oxa bicyclo[3.3.1]n on a n -1-ol (16). Follow-
ing the general procedure described for the preparation of 4a ,
156 mg (0.50 mmol) of methyl 5-oxooctadecanoate (15) and 112
mg (0.55 mmol) of 1-chloro-3-iodopropane (2) provided 104 mg
(64% yield) of the title compound 16 after flash chromatogra-
phy with 17% ethyl acetate:hexanes: mp 70-71 °C; 1H NMR
(500 MHz, CDCl3) δ 2.70 (bs, 1H), 2.10 (m, 2H), 1.94 (m, 2H),
1.76-1.68 (m, 2H), 1.66-1.45 (m, 8H), 1.42-1.22 (m, 22H),
0.90 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 95.1,
77.2, 45.1, 35.9, 32.5, 31.9, 30.3, 29.7-29.6 (6), 29.3, 23.1, 22.7,
20.5, 14.1; IR (neat) 3335, 2918, 977 cm-1; LRMS (EI+) m/z
(1R*,5S*)-5-Meth yl-8-oxa bicyclo[3.2.1]octa n -1-ol (10a ).
Following the general procedure described above, 72 mg (0.50
mmol) of ethyl 4-oxopentanoate (9a ) and 112 mg (0.55 mmol)
of 1-chloro-3-iodopropane (2) provided 55 mg (78% yield) of the
title compound 10a after flash chromatography with 30% ethyl
acetate:hexanes: mp 71-72 °C; 1H NMR (500 MHz, CDCl3) δ
3.80 (bs, 1H), 2.05-1.98 (m, 1H), 1.81-1.58 (m, 7H), 1.45-
1.29 (m, 2H), 1.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 104.8,
81.1, 36.1, 36.0, 35.7, 34.3, 26.7, 19.4; IR (neat) 3385, 2945,
1101 cm-1; LRMS (EI+) m/z 142 (12), 114 (24), 99 (66), 71 (83),
55 (62), 43 (100). Anal. Calcd for C8H14O2: C, 67.57; H, 9.92.
Found: C, 67.17; H, 9.93.
5-Meth yl-9-oxa bicyclo[3.3.1]n on a n -1-ol (10b). Follow-
ing the general procedure described for the preparation of 4a ,
79 mg (0.50 mmol) of ethyl 5-oxohexanoate (9b) and 112 mg
(0.55 mmol) of 1-chloro-3-iodopropane (2) provided 58 mg (74%
yield) of the title compound 10b after flash chromatography
with 30% ethyl acetate:hexanes: mp 73-74 °C; 1H NMR (500
MHz, CDCl3) δ 3.58 (s, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.66-
1.45 (m, 8H), 1.18 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 95.4,
(22) Schwaebe, M.; Little, R. D. J . Org. Chem. 1996, 61, 3240.
(23) Ho¨fle, G.; Steglich, W. Synthesis 1972, 619.

4372 J . Org. Chem., Vol. 63, No. 13, 1998
Molander and Alonso-Alija
324 (6.5), 296 (7.5), 156 (44), 128 (100), 110 (21), 95 (28), 83
(32), 69 (48), 55 (56), 41 (76). Anal. Calcd for C21H40O2: C,
77.72; H, 12.42. Found: C, 77.66; H, 12.67.
1196 cm-1; LRMS (EI+) m/z 170 (9.0), 142 (22), 128 (60), 113
(27), 95 (34), 85 (43), 71 (100), 55 (29), 43 (80). Anal. Calcd
for C10H18O2: C, 70.55; H, 10.66. Found: C, 70.18; H, 10.71.
(1R*,3R*/S*,5S*)-3,5-Dim eth yl-9-oxabicyclo[3.3.1]n on an -
1-ol (34). Following the general procedure described for the
preparation of 4a , 79 mg (0.50 mmol) of ethyl 5-oxohexanoate
(9b) and 120 mg (0.55 mmol) of 1-chloro-3-iodo-2-methylpro-
pane (28b) provided 32 mg (38% yield) of the title compound
34 after flash chromatography with 25% ethyl acetate:hexanes,
as a 1:1 diastereomeric mixture, as determined by GC: 1H
NMR (500 MHz, CDCl3) δ 2.85 (two bs, 2H), 2.36 (m, 1H), 2.07
(m, 1H), 1.96 (m, 1H), 1.89 (m, 1H), 1.84-1.25 (m, 14H), 1.22
(s, 3H), 1.21 (s, 3H), 1.14-0.94 (m, 4H), 0.89 (d, J ) 6.5 Hz,
3H), 0.85 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
96.1, 95.6, 75.4, 73.5, 44.7, 44.2, 42.3, 40.4, 38.0, 36.5, 35.2,
34.3, 31.7, 31.3, 26.9, 24.0, 23.8, 20.6, 20.4, 18.1; IR (neat) 3355,
2955 cm-1; LRMS (EI+) m/z 170 (13), 142 (11), 128 (27), 113
(16), 83 (70), 69 (47), 55 (27), 43 (100). Anal. Calcd for
(1R*,5S*)-5-Isopr opyl-8-oxabicyclo[3.2.1]octan -1-ol (18).
Following the general procedure outlined for the preparation
of 4a [except that 4.0 mmol of SmI2 was prepared from 661
mg (4.4 mmol) of Sm and 1.015 g (4.0 mmol) of I2], 86 mg (0.50
mmol) of ethyl 5-methyl-4-oxohexanoate (17) and 204 mg (1.00
mmol) of 1-chloro-3-iodopropane (2) provided 37 mg (44% yield)
of the title compound 18 after flash chromatography with 20%
ethyl acetate:hexanes: mp 66-67 °C; 1H NMR (500 MHz,
CDCl3) δ 2.70 (bs, 1H), 2.03 (m, 1H), 1.85-1.53 (m, 8H), 1.40-
1.33 (m, 2H), 0.91 (d, J ) 7.0 Hz, 3H), 0.86 (d, J ) 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 104.7, 86.4, 36.5, 36.1, 35.7,
31.0, 29.4, 19.1, 17.6, 17.0; IR (neat) 3386, 2959 cm-1; LRMS
(EI+) m/z 170 (29), 142 (43), 127 (81), 99 (92), 83 (62), 71 (100),
55 (43), 41 (76). Anal. Calcd for C10H18O2: C, 70.55; H, 10.66.
Found: C, 70.39; H, 10.84.
(1R *,5S *)-7-P e n t a m e t h y le n e -5-m e t h y l-7,11-o x a b i-
cyclo[3.2.1]octa n -1-ol (22). Following the general procedure
described for the preparation of 4a , 99 mg (0.50 mmol) of
methyl 1-(2-oxopropyl)cyclohexanecarboxylate (21) and 112 mg
(0.55 mmol) of 1-chloro-3-iodopropane (2) provided 84 mg (80%
yield) of the title compound 22 after flash chromatography with
20% ethyl acetate:hexanes: mp 108-109 °C; 1H NMR (500
MHz, CDCl3) δ 2.79 (bs, 1H), 1.80 (m, 1H), 1.77-1.02 (m, 17H),
1.25 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 105.1, 77.3, 47.0,
43.8, 35.4, 32.3, 31.7, 30.3, 28.0, 25.9, 24.3, 21.8, 18.9; IR (neat)
3401, 2934 cm-1; LRMS (EI+) m/z 210 (16), 123 (100), 107 (10),
96 (40), 81 (89), 67 (51), 55 (36), 43 (60). Anal. Calcd for
C
10H18O2: C, 70.55; H, 10.66. Found: C, 70.41; H, 10.43.
(1 R *,5 S *)-5 -M e t h y l -3 -m e t h y l e n e -9 -o x a b i c y c l o -
[3.3.1]n on a n -1-ol (37a ). The same general procedure was
used as for the preparation of 4a , except that the mixture was
stirred at 0 °C for 3 h without being irradiated with light. By
following this procedure, 79 mg (0.50 mmol) of ethyl 5-oxo-
hexanoate (9b) and 69 mg (0.55 mmol) of 3-chloro-2-chloro-
methyl-1-propene (36) provided 45 mg (54% yield) of the title
compound 37a after flash chromatography with 30% ethyl
acetate:hexanes: mp 102-103 °C; 1H NMR (500 MHz, CDCl3)
δ 4.72 (m, 2H), 2.86 (bs, 1H), 2.58 (d, J ) 14.0 Hz, 1H), 2.38-
2.20 (m, 4H), 1.87 (m, 1H), 1.60-1.43 (m, 4H), 1.25 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 144.3, 109.0, 96.0, 75.6, 44.7,
C
13H22O2: C, 74.24; H, 10.54. Found: C, 74.07; H, 10.60.
(1R*,5S*,7R*/S*)-7-(4-H yd r oxyb u t yl)-5-m et h yl-8-oxa -
43.7, 36.5, 35.6, 30.8, 19.6; IR (neat) 3340, 2973, 1107 cm-1
;
bicyclo[3.2.1]octa n -1-ol (23). Following the general proce-
dure described for the preparation of 4a (except that the
irradiation time was 6 h), 85 mg (0.50 mmol) of 2-(2-oxopropyl)-
ꢀ-caprolactone (5) and 112 mg (0.55 mmol) of 1-chloro-3-
iodopropane (2) provided 48 mg (45% yield) of the title
compound 23 as an 8:1 diastereomeric mixture epimeric at C-7
(stereochemistry unassigned) after flash chromatography with
neat ethyl acetate. The title compound was isolated as a
hemiacetal:dihydroxy ketone mixture: 1H NMR (500 MHz,
CDCl3) (major diastereomer, hemiacetal) δ 3.63 (m, 2H), 2.30
(bs, 2H), 2.01-1.87 (m, 2H), 1.75-1.25 (m, 12H), 1.25 (s, 3H),
1.12 (m, 1H); 13C NMR (125 MHz, CDCl3) (major diastereomer,
hemiacetal) δ 104.4, 78.7, 62.5, 44.1, 42.4, 36.3, 35.3, 32.6, 31.1,
27.1, 23.4, 18.8; IR (neat) 3390, 2936, 1770 cm-1; HRMS calcd
for C12H22O3 214.1569, found 214.1588; LRMS (EI+) m/z 214
(3.6), 196 (11), 168 (13), 142 (31), 109 (49), 95 (31), 81 (49), 71
(64), 55 (64), 43 (100).
LRMS (EI+) m/z 168 (37), 153 (26), 125 (24), 113 (37), 93 (43),
85 (40), 67 (26), 55 (29), 43 (100). Anal. Calcd for C10H16O2:
C, 71.39; H, 9.59. Found: C, 71.63; H, 9.61.
(1 R *,5 S *)-5 -M e t h y l -6 -m e t h y l e n e -8 -o x a b i c y c l o -
[3.2.1]octa n -1-ol (37b). The same general procedure was
used as for the preparation of 4a , except that the mixture was
stirred at 0 °C for 3 h without being irradiated with light. By
following this procedure, 72 mg (0.50 mmol) of ethyl 4-oxo-
pentanoate (9a ) and 69 mg (0.55 mmol) of 3-chloro-2-chloro-
methyl-1-propene (36) provided 35 mg (46% yield) of the title
compound 37b after flash chromatography with 30% ethyl
acetate:hexanes: mp 89-90 °C; 1H NMR (500 MHz, CDCl3) δ
4.83 (m, 2H), 3.36 (s, 1H), 2.40 (s, 2H), 2.19 (d, J ) 13.5 Hz,
1H), 2.01 (d, J ) 13.5 Hz, 1H), 1.99-1.94 (m, 1H), 1.75-1.59
(m, 3H), 1.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.2,
112.2, 105.0, 80.5, 46.2, 46.0, 36.5, 34.8, 26.2; IR (neat) 3305
cm-1; LRMS (EI+) m/z 154 (10), 139 (7.5), 125 (7.0), 109 (24),
99 (96), 93 (16), 79 (16), 71 (24), 55 (24), 43 (100). Anal. Calcd
for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.39; H, 9.30.
1 -M e t h o x y -8 -m e t h y l -1 2 -o x a t r i c y c l o [6 .3 .1 .0 3 , 7 ]-
d od eca n e (38). Following the general procedure described
for the preparation of 4a , 79 mg (0.50 mmol) of ethyl 5-oxo-
hexanoate (9b) and 134 mg (0.55 mmol) of 2-chloromethyl-1-
iodocyclopentane (32) were reacted with SmI2. The crude
product was stirred overnight at room temperature with 265
mg (2.5 mmol) of methyl orthoformate and a catalytic amount
of TsOH in 10 mL of dry methanol to afford 38 mg (36%) of
the title compound 38 after flash chromatography with 5%
ethyl acetate:hexanes, as a 1:1 mixture of diastereomers (out
of the four possible, stereochemistry unassigned): 1H NMR (500
MHz, CDCl3) δ 3.33 (s, 3H), 3.29 (s, 3H), 2.10 (dd, J ) 14.0,
(1R *,5S *)-5-M e t h y l-7,7-d i m e t h o x y -8-o x a b i c y c lo -
[3.2.1]oct a n -1-ol (24). Following the general procedure
outlined for the preparation of 4a , 95 mg (0.50 mmol) of methyl
2,2-dimethoxy-4-oxopentanoate (6) and 112 mg (0.55 mmol)
of 1-chloro-3-iodopropane (2) provided 52 mg (51% yield) of the
title compound 24, after flash chromatography with 25% ethyl
acetate:hexanes: 1H NMR (500 MHz, CDCl3) δ 4.27 (s, 1H),
3.28 (s, 3H), 3.24 (s, 3H), 2.05-1.91 (m, 2H), 1.81 (m, 1H),
1.75-1.66 (m, 3H), 1.49 (m, 1H), 1.36 (m, 1H), 1.24 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 106.0, 102.7, 76.2, 50.6, 48.5,
43.1, 35.3, 30.0, 27.5, 18.5; IR (neat) 3540, 2966, 2840 cm-1
;
LRMS (EI+) m/z 202 (1.7), 187 (5.8), 139 (10), 129 (48), 115
(100), 85 (13), 43 (41). Anal. Calcd for C10H18O4: C, 59.39;
H, 8.97. Found: C, 59.28; H, 9.10.
(1R*,4R*/S*,5S*)-4,5-Dim eth yl-9-oxabicyclo[3.3.1]n on an -
1-ol (33). Following the general procedure described for the
preparation of 4a , 79 mg (0.50 mmol) of ethyl 5-oxohexanoate
(9b) and 120 mg (0.55 mmol) of 1-chloro-3-iodobutane (28a )
provided 53 mg (62% yield) of the title compound 33 after flash
chromatography with 25% ethyl acetate:hexanes, as a 1:1
diastereomeric mixture, as determined by GC: 1H NMR (500
MHz, CDCl3) δ 3.02 (bs, 1H), 2.86 (bs, 1H), 2.28 (m, 1H), 2.10-
1.26 (m, 21H), 1.17 (s, 3H), 1.13 (s, 3H), 1.02 (d, J ) 7.0 Hz,
3H), 0.88 (d, J ) 6.5 Hz, 3H),; 13C NMR (75 MHz, CDCl3) δ
95.4, 95.0, 78.4, 38.6, 36.9, 35.8, 35.7, 35.4, 34.3, 31.9, 29.9
(2), 29.5, 28.6, 28.2, 20.7, 20.5, 17.2, 16.8; IR (neat) 3398, 2936,
5.0 Hz, 1H), 1.92-0.90 (m, 31H), 1.19 (s, 3H), 1.14 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 98.8, 98.6, 76.0, 74.3, 54.4, 48.6,
48.3, 48.2, 40.3, 38.9, 38.7, 37.2, 37.1, 34.6, 31.4 (2), 29.9, 28.6,
28.3, 26.8, 25.7, 24.8, 22.5, 21.5, 20.0, 17.3; IR (neat) 2953,
1076 cm-1; LRMS (EI+) m/z 210 (24), 182 (16), 168 (13), 150
(25), 139 (25), 122 (22), 109 (100), 93 (49), 81 (63), 67 (59), 55
(35), 43 (66). Anal. Calcd for C13H22O2: C, 74.24; H, 10.54.
Found: C, 74.40; H, 10.66.
(1R*,6S*)-6-Meth yl-10-oxa bicyclo[4.3.1]d eca n -1-ol (40).
Following the general procedure described for the preparation
of 4a , 79 mg (0.50 mmol) of ethyl 5-oxohexanoate (9b) and 120
mg (0.55 mmol) of 1-chloro-3-iodobutane (39a ) provided 55 mg

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 63, No. 13, 1998 4373
(65% yield) of the title compound 40, after flash chromatog-
raphy with 30% ethyl acetate:hexanes: mp 66-67 °C; 1H NMR
(500 MHz, CDCl3) δ 2.55 (bs, 1H), 2.06 (m, 1H), 1.94-1.68 (m,
6H), 1.59-1.32 (m, 6H), 1.24 (m, 1H), 1.15 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 97.9, 74.8, 36.1, 35.0, 34.2, 33.3, 30.2, 19.2,
18.9, 18.5; IR (neat) 3296, 2940 cm-1; LRMS (EI+) m/z 170
(11), 141 (38), 128 (38), 113 (22), 95 (25), 82 (100), 69 (62), 55
(46), 43 (53). Anal. Calcd for C10H18O2: C, 70.55; H, 10.66.
Found: C, 70.76; H, 10.76.
4-Acetoxycycloocta n on e (41). The preparation of this
compound was accomplished by following the general proce-
dure described for the synthesis of 4a , except that 79 mg (0.50
mmol) of n-butyl 4-oxobutyrate (13) and 120 mg (0.55 mmol)
of 1-chloro-3-iodobutane (39a ) were added simultaneously as
a solution in 5 mL of THF. Acylation of the crude material in
dichloromethane with an excess of acetic anhydride and
pyridine and a catalytic amount of DMAP provided 41 mg (45%
yield) of the title compound 41, after flash chromatography
with 17% ethyl acetate:hexanes: 1H NMR (500 MHz, CDCl3)
δ 4.82 (m, 1H), 2.49-2.40 (m, 3H), 2.38-2.31 (m, 1H), 2.19-
2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.98 (s, 3H), 1.85-1.77 (m,
2H), 1.69-1.45 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 216.4,
170.2, 73.2, 40.5, 38.9, 30.2, 28.1, 27.9, 22.4, 21.2; IR (neat)
2940, 1738, 1732, 1246 cm-1; LRMS (EI+) m/z 185 (0.1), 142
(7.0), 124 (66), 113 (15), 95 (42), 80 (58), 67 (38), 55 (42), 43
(100). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75. Found:
C, 64.92; H, 8.62.
(1R */S *,3R *,8S *,10R */S *)-1-Ac e t o x y -10-m e t h y l-14-
oxa tr icyclo[8.3.1.03,8]tetr a d eca n e (46′). Following the gen-
eral procedure described for the preparation of 4a , 79 mg (0.50
mmol) of ethyl 5-oxohexanoate (9b) and 150 mg (0.55 mmol)
of cis-1-chloromethyl-2-iodomethylcyclohexane (45b) provided
54 mg (48% yield) of the corresponding bicyclic compound 46
as a 3:1 mixture of diastereomers, as a hemiacetal:hydroxy
ketone mixture. The product was acylated with an excess of
acetic anhydride and DMAP in dichloromethane, and the title
compound 46′ was isolated after flash chromatography with
10% ethyl acetate:hexanes. Major diastereomer: 1H NMR (500
MHz, CDCl3) δ 2.42 (m, 1H), 2.21-2.03 (s, 3H), 2.02 (s, 3H),
1.90-1.65 (m, 3H), 1.60-1.26 (m, 10H), 1.24-1.13 (m, 2H),
1.23 (s, 3H), 1.06 (dd, J ) 14.5, 2.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 169.2, 106.8, 75.3, 39.5, 37.3, 34.9, 33.0, 31.0,
30.6, 30.4, 28.9, 28.5, 22.7, 21.6 (2), 18.1; IR (neat) 2932, 1731
cm-1; HRMS calcd for C14H24O2 (M - C2H2O)+ 224.1776, found
224.1756; LRMS (EI+) m/z 224 (3.8), 206 (18), 189 (8.6), 163
(11), 135 (13), 111 (29), 96 (37), 81 (48), 67 (28), 55 (39), 43
(100).
minor diastereomer (due to the two relative ring fusions) in a
4:1 ratio. Further flash chromatography with 20% ethyl
acetate:hexanes afforded the title compound 47: 1H NMR (500
MHz, CDCl3) δ 2.72 (bs, 1H), 2.60-2.49 (m, 2H), 2.23 (m, 1H),
2.09 (m, 1H), 1.96 (m, 1H), 1.89-1.33 (m, 14H), 1.31-1.22 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 106.1, 92.5, 46.1, 45.0, 44.7,
42.0, 40.9, 39.7, 36.0, 34.9, 34.6, 34.2, 23.8, 22.8; IR (neat) 2923
cm-1; HRMS calcd for C14H22O2 222.1620, found 222.1620;
LRMS (EI+) m/z 222 (11), 205 (8.8), 162 (22), 122 (35), 107
(27), 95 (41), 81 (82), 67 (77), 55 (54), 41 (100).
(1R *,3S */R *,8R */S *,10S *,12S *)-10-Me t h oxy-17-oxa -
tetr a cyclo[8.6.1.01,12.03,8]h ep ta d eca n e (48). Following the
general procedure described for the preparation of 4a , 92 mg
(0.50 mmol) of ethyl 2-cyclohexanoneacetate (1a ) and 150 mg
(0.55 mmol) of cis-1-chloromethyl-2-iodomethylcyclohexane
(45b) were reacted with SmI2. The crude product was stirred
overnight at room temperature with 265 mg (2.5 mmol) of
methyl orthoformate and a catalytic amount of TsOH in 10
mL of dry methanol to afford 50 mg (40% yield) of the title
compound 48 as a 1:1 mixture of diastereomers. Higher Rf
diastereomer: 1H NMR (500 MHz, CDCl3) δ 3.33 (s, 3H), 2.37
(dd, J ) 13.5, 6.5 Hz, 1H), 2.30 (dd, J ) 13.5, 10.0 Hz, 1H),
1.99-1.84 (m, 3H), 1.75-1.02 (m, 20H); 13C NMR (125 MHz,
CDCl3) δ 108.6, 82.8, 49.2, 47.7, 44.0, 40.9, 39.7, 37.5, 37.2,
34.8, 32.5, 29.7, 28.9, 26.3, 24.7, 22.3, 21.6; IR (neat) 2923,
2860 cm-1; LRMS (EI+) m/z 264 (12), 232 (6.5), 207 (7.8), 190
(14), 168 (32), 153 (100), 121 (74), 95 (53), 81 (42), 67 (40), 55
(39), 41 (40). Anal. Calcd for C17H28O2: C, 77.22; H, 10.67.
Found: C, 77.49; H, 10.83. Lower Rf diastereomer: 1H NMR
(500 MHz, CDCl3) δ 3.29 (s, 3H), 2.32-2.20 (m, 3H), 2.04 (m,
1H), 1.91-1.76 (m, 3H), 1.72-1.08 (m, 18H); 13C NMR (125
MHz, CDCl3) δ 108.5, 81.3, 49.2, 44.6, 42.9, 42.5, 40.1, 37.2,
36.8, 35.4, 32.1, 29.6, 29.5, 28.0, 24.9, 21.9, 21.6; IR (neat) 2926,
2852 cm-1; HRMS calcd for C17H28O2 264.2089, found 264.2092
LRMS (EI+) m/z 264 (7.6), 232 (6.3), 190 (12), 168 (27), 166
(29), 153 (100), 121 (74), 95 (71), 81 (49), 67 (56), 55 (55), 41
(62).
Ack n ow led gm en t. C. Alonso-Alija is indebted to the
Fundacio´n Ramo´n Areces (Spain) for a Postdoctoral
Fellowship. We gratefully acknowledge the National
Institutes of Health (GM35249) for their generous
support. We also thank Dr. Bruce C. Noll for performing
the X-ray crystal structure determinations.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterizations for compounds 5-8, 28, 31, 32, and
43-45 (53 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 R *,3 S *,7 R *,9 S *,1 1 S *)-9 -H y d r o x y -15 -o x a t e t r a -
cyclo[7.5.1.01,11.03,7]p en ta d eca n e (47). Following the gen-
eral procedure described for the preparation of 4a , 85 mg (0.50
mmol) of ethyl 2-oxocyclopentaneacetate (1b) and 150 mg (0.55
mmol) of cis-1-chloromethyl-2-iodomethylcyclopentane (45a )
provided 53 mg (48% yield) of the title compound 47 and its
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