Sequenced Reactions with Samarium(II) Iodide. Domino Epoxide Ring-Opening/Ketyl Olefin Coupling Reactions

Article abstract of DOI:10.1021/jo970022c

A new sequential reductive coupling process promoted by samarium(II) iodide is described. Cascade epoxide ring opening and ketyl radical olefin cyclization leads to a variety of cis-1,3-cyclopentanediols and cis-1,3-cyclohexanediols in good yields and with high diastereoselectivity.

Full text of DOI:10.1021/jo970022c

J . Org. Chem. 1997, 62, 2935-2943
2935
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. Dom in o Ep oxid e
Rin g-Op en in g/Ketyl Olefin Cou p lin g Rea ction s
Gary A. Molander* and Carlos del Pozo Losada
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received J anuary 2, 1997X
A new sequential reductive coupling process promoted by samarium(II) iodide is described. Cascade
epoxide ring opening and ketyl radical olefin cyclization leads to a variety of cis-1,3-cyclopentanediols
and cis-1,3-cyclohexanediols in good yields and with high diastereoselectivity.
Sch em e 1
In tr od u ction
The development of novel synthetic methods for carbon-
carbon bond formation is an important goal in organic
synthesis. The significance of this goal is enhanced when
the new methods lead to annulated products. It has been
shown that samarium(II) iodide efficiently promotes a
variety of regio- and stereoselective reductive coupling
reactions, providing access to a wide range of car-
bocycles.1 Here we report the synthetic utility of samari-
um(II) iodide in a novel sequential transformation re-
sulting in the formation of stereodefined cis-1,3-cyclo-
pentanediols and cis-1,3-cyclohexanediols.
Previously, we reported a preparation of â-hydroxy
ketones (aldols) that proceeded via reduction of R,â-epoxy
ketones with samarium(II) iodide (Scheme 1). By em-
ploying the Sharpless asymmetric epoxidation for the
preparation of the substrates, enantiomerically enriched,
highly functionalized aldols could be obtained.2
phoramide) is necessary to effect these cyclizations when
an unactivated olefin serves as the ketyl radical acceptor.
In the reductive cyclization of substrates bearing unac-
tivated (terminal) olefins, additives such as HMPA have
been postulated to increase the steric bulk about the ketyl
oxygen.3 Under these conditions, higher diastereoselec-
tivities are achieved at the newly formed stereocenters
compared to other methods that create the ketyl radical
(e.g., by electrochemical,5 photochemical6 or other chemi-
cal7 methods).
Our earlier work3 and results reported from other
laboratories4 have demonstrated that samarium(II) io-
dide also promotes intramolecular ketyl olefin cyclization
processes (eqs 1 and 2). These reactions occur with high
Further studies demonstrated that unsaturated â-di-
carbonyl systems cyclize efficiently with complete dias-
tereoselectivity (eq 3). Presumably, this process is
controlled by chelation of the oxophilic Sm(III) species
with the ketyl oxygen and the ester carbonyl of the
substrate.8
Herein we describe a novel combination of these SmI2-
promoted processes; i.e., a sequential epoxide ring-
opening linked to a ketyl olefin cyclization. This protocol
utilizes R,â-epoxy ketones bearing remote olefins as
diastereoselectivity about the newly formed carbon-
carbon bonds. The presence of HMPA (hexamethylphos-
(5) (a) Shono, T.; Nishiguchi, I.; Ohmiza, H.; Mitani, M. J . Am.
Chem. Soc. 1978, 100, 545. (b) Fox, D. P.; Little, R. D.; Baizer, M. H.
J . Org. Chem. 1985, 50, 2202. (c) Little, R. D.; Fox, D. P.; Hifte, L. V.;
Dannecker, R.; Sowell, G.; Wolin, R. L.; Moens, L.; Baizer, M. M. J .
Org. Chem. 1988, 53, 2287. (d) Kariv-Miller, E.; Mahachi, T. J . J . Org.
Chem. 1986, 51, 1041. (e) Kariv-Miller, E; Maeda, H.; Lombardo, F. J .
J . Org. Chem. 1989, 54, 4022.
(6) (a) Belotti, D.; Cossy, J .; Pete, J . P.; Portella, C. Tetrahedron
Lett. 1985, 26, 4591. (b) Belotti, D.; Cossy, J .; Pete, J . P.; Portella, C.
J . Org. Chem. 1986, 51, 4196. (c) Cossy, J .; Belotti, D. Tetrahedron
Lett. 1988, 29, 6113.
(7) (a) Sowinski, A. F.; Whitesides, G. M. J . Org. Chem. 1979, 44,
2369. (b) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
(8) (a) Molander, G. A.; Kenny, C. Tetrahedron Lett. 1987, 28, 4367.
(b) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236. (c)
Shive, J .-S.; Lin, C.-C., Fang, J . M. Tetrahedron Lett. 1993, 34, 335.
(d) Kise, N.; Suzumoto, T.; Shono, T. J . Org. Chem. 1994, 59, 1407. (e)
Kawatsura, M.; Matsuda, F.; Shirahama, H. J . Org. Chem. 1994, 59,
6900.
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) For general reviews see: (a) Soderquist, J . A. Aldrichim. Acta
1991, 24, 15. (b) Molander, G. A. Chem. Rev. 1992, 92, 29. (c)
Brandukova, N. E.; Vygodskii, Y. S.; Vinogradova, S. V. Russ. Chem.
Rev. 1994, 63, 345. (d) Molander, G. A. In Organic Reactions; Paquette,
L. A., Ed.; J ohn Wiley & Sons: New York, 1994; Vol. 46, p 211. (e)
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(2) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 2596.
(3) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1992, 57, 3132.
(b) Molander, G. A.; McKie, J . A. J . Org. Chem. 1994, 59, 3186. (c)
Molander, G. A.; McKie, J . A. J . Org. Chem. 1995, 60, 872.
(4) (a) Enholm, E. J .; Trivellas, A. Tetrahedron Lett. 1989, 30, 1063.
(b) Fukuzawa, S.-I.; Iida, M.; Fujinami, T.; Sakai, S. J . Chem. Soc.,
Chem. Commun. 1987, 920. (c) Kito, M.; Sakai, T.; Yamada, K.;
Matsuda, F.; Shirahama, H. Synlett 1992, 158. (d) Curran, D. P.; Fevig,
T. L.; J asperse, C. P.; Totleben, M. J . Synlett 1992, 943. (e) Baldwin,
J . E., Turner, S. C. M.; Moloney, M. G. Tetrahedron 1994, 50, 9425.
S0022-3263(97)00022-4 CCC: $14.00 © 1997 American Chemical Society

2936 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and del Pozo Losada
Sch em e 2
Ta ble 1. Sequ en tia l Cycliza tion s of r,â-Ep oxy Keton es 4
To Yield Cycloh exa n ed iols 5 a n d 6, Ald ols 7,
a n d Op en -Ch a in 1,3-Diols 8
substrates, with the stereochemistry of the process being
controlled by chelation effects.9
%
%
reaction
times
(min)
Resu lts a n d Discu ssion
% yield 5 + 6 yield yield
entry substrate
R
(ratio 5:6)a
7
8
In order to probe the scope of the samarium(II) iodide-
promoted epoxide ring-opening/ketyl olefin cyclization, a
series of olefinic R,â-epoxy ketones was prepared. Com-
pounds 4a -e were assembled through Darzens conden-
sation10 of Weinreb amide 1 with ketone 2 to afford the
epoxy amide 3 as a mixture of diastereomers at the
methyl-bearing stereocenter. This was followed by treat-
ment with an organomagnesium or organolithium re-
agent11 to afford compounds 4a -e in good yields (Scheme
2).12
1
2
3
4
5
4a
4b
4c
4d
4e
Me
Et
i-Pr
t-Bu
Ph
88 (12:1)
86 (10:1)
72 (10:1)
10 (7:1)
15
20
20
60
20
47
16b
45b
a
The ratios of diastereomers were determined by fused silica
b
capillary GC analysis of crude reaction mixtures. This reaction
was carried out at -78 °C. At 0 °C the reaction afforded a mixture
of products.
in the ketyl olefin cyclization step. The diastereomeric
ratios were 10:1 or greater in all of these cases. The yield
of cyclization products drops off dramatically in the
reductive cyclization of substrate 4d (R ) t-Bu) with only
a modest yield of the diol product (10%) being formed.
Presumably, the increase in steric congestion adjacent
to the reacting center supresses the efficiency of the
cyclization. The initial aldol product is simply further
reduced to the acyclic diol 8d . For the phenyl ketone 4e,
reduction with samarium(II) iodide leads only to the
hydroxy ketone 7e in low yield and the corresponding
acyclic diol 8e. In this case, the stable ketyl-radical
anion intermediate is simply protonated and reduced to
afford the major product.
Optimal reaction conditions for the epoxide ring-
opening/ketyl olefin cyclization of compounds 4a -e were
found to involve the slow addition of a methanol/THF (1:
30) solution of the R,â-epoxy ketones 4 to a THF/HMPA
(1:4) solution of SmI2 (6 equiv)13 at 0 °C (eq 4). These
reactions generally required 15 min to 1 h to proceed to
completion, after which the reaction mixtures were
quenched with Rochelle’s salt.14 An extractive workup
and flash chromatography provided the desired cis-1,3-
cyclohexanediols (Table 1).
The exclusive formation of cis-diols (5a -d , 6a -d ) is
believed to be the direct result of a samarium(III) chelate
in the carbon-carbon bond-forming process (Scheme 3).3c
Chelation of the ketyl oxygen and the â-hydroxy group
with samarium(III) in the cyclization step enforces the
cis-1,3-diol stereochemistry. The second stereocenter
formed in the ketyl olefin cyclization, the methyl-bearing
stereocenter, is also formed with high diastereoselectiv-
ity. Stereochemical control at this center has been
ascribed to favorable secondary orbital overlap interac-
tions between the developing methylene radical and the
adjacent alkyl substituent in the transition state.5d,6a,15
Electrostatic interactions may also contribute to the
formation of this product. Both the ketyl oxygen and the
developing methylene radical centers carry partial nega-
tive charge. As a consequence, the trans relationship is
adopted to avoid unfavorable electronic interactions.
Compound 5c formed crystals suitable for single-
crystal X-ray analysis, and the three-dimensional struc-
ture of this compound was confirmed by this technique.
Cyclic diols 5a , 5b, 6a , and 6b required structural
assignment using spectroscopic techniques. The high-
dilution (0.02 M in CCl4) IR spectra of compounds 5a ,
5b, 6a , and 6b revealed two hydroxyl resonances. This
is indicative of a structure possessing intramolecular
For substrates 4a , 4b, and 4c (R ) Me, Et, i-Pr),
reductive cyclization proceeded smoothly to afford cis-
1,3-cyclohexanediols 5a -c and 6a -c, respectively. Re-
ductive opening of the R,â-epoxy ketones and subsequent
ketyl olefin cyclization provided the respective diols as a
mixture of two diastereomers. The mixture results from
imperfect diastereoselectivity at the stereocenter formed
(9) Several different examples of samarium(II) iodide-promoted
sequential reactions have recently been described: (a) Molander, G.
A.; Kenny, C. J . Org. Chem. 1991, 56, 1439. (b) Molander, G. A.; Harris,
C. R. J . Am. Chem. Soc. 1995, 117, 3705. (c) Molander, G. A.; Harris,
C. R. J . Am. Chem. Soc. 1996, 118, 4059.
(10) Borch, R. F. Tetrahedron Lett. 1972, 13, 3761.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(12) RLi was used only when R ) t-Bu. The reaction performed with
the corresponding Grignard reagent failed.
(13) The use of less than 6 equiv of samarium(II) iodide in this
process resulted in the recovery of some starting material.
(14) Rochelle’s salt is a 10% solution of sodium potassium tartrate
tetrahydrate in water. The use of this solution in the workup of
samarium(II) iodide-promoted reactions was first described by:
Schwaebe, M.; Little, R. D. J . Org. Chem. 1996, 61, 3240.
(15) (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073. (b) Giese, B.
Angew. Chem., Int. Ed. Engl. 1983, 22, 253.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2937
Sch em e 3
Ta ble 2. Sequ en tia l Cycliza tion s of r,â-Ep oxy Keton es 9
To Yield Cycloh exa n ed iols 10 a n d 11 a n d Op en -Ch a in
1,3-Diols 12
hydrogen bonding between two hydroxyls and was taken
as evidence for the cis-1,3-diol stereochemistry. Another
experiment that provided useful stereochemical informa-
tion was pyridine-d5/CDCl3 difference 1H NMR.16 On the
basis of the magnitude of pyridine-d5 deshielding (com-
pared to CDCl3 frequencies), the stereochemistry of the
C-4 methyl group relative to the C-3 hydroxyl functional-
ity could be determined. For example, the pyridine-d5
1H NMR resonance frequency for the C-4 methyl in 5b
is downfield 0.05 ppm with respect to its resonance
frequency in CDCl3. For 6b the deshielding is 0.18 ppm.
These results suggest a trans relationship between the
C-3 hydroxyl and the C-4 methyl in 5b and a cis
relationship in 6b.
A straightforward mechanism for these sequential
reactions can be envisioned to occur through a series of
electron-transfer reactions. Single-electron reduction of
the ketone by SmI2 first generates a ketyl intermediate,
inducing epoxide ring opening. Protonation and further
reduction in the protic media affords the aldol intermedi-
ate. Subsequently, the ketone of the aldol is reduced by
a third equivalent of SmI2, providing the corresponding
ketyl intermediate. Irreversible addition of the Sm(III)-
chelated hydroxy-ketyl to the olefin and reduction/pro-
tonation of the resulting primary radical afford the
carbocyclic products (Scheme 3).
%
% yield 10 + 11
(ratio 10:11)a
yield
12
entry
substrate
R1
R2
1
2
3
9a
9b
9c
H
i-Pr
Et
H
H
Me
74 (3:1)
40 (3:1)
mixtureb
26
b
a
Ratios of diastereomers were determined by fused silica
b
capillary GC analysis of crude reaction mixtures. This reaction
led to an inseparable mixture.
reocenter decreased markedly. Cyclization of 9a provided
10a and 11a in a 3:1 ratio, respectively. Cyclization of
9b also afforded a 3:1 ratio of products 10b and 11b.
Cyclization of 9c led to a mixture of six products,
including both cyclized and uncyclized diols.
To explore more thoroughly the effects of substrate
substitution on the diastereomeric ratio of products, the
R,â-epoxy ketones 9 were synthesized. Substrate 9a was
prepared by Darzens condensation of 4-pentenal and
acetamide 1 with subsequent treatment with methyl-
magnesium bromide. The preparation of 9b was carried
out by reaction of N,O-dimethylhydroxylamine hydro-
chloride, 4-pentenoic acid, and trimethylamine-borane
complex in boiling xylenes.17 This afforded the unsatur-
ated Weinreb amide. Addition of isopropylmagnesium
bromide, followed by Darzens condensation with aceta-
mide 1 and exposure to methylmagnesium bromide,
provided the desired product. The last compound in this
series, compound 9c, was obtained by alkylation of
3-pentanone with allyl bromide. Subsequent Darzens
condensation with 1 and reaction with methylmagnesium
bromide afforded 9c.
Exposure of substrates 9a -c to samarium(II) iodide
led once again to a mixture of diastereomeric 1,3-
cyclohexanediols (Table 2) and the acyclic diols from
reduction of the ketyl (except in the case of the R,â-epoxy
ketone 9a ). As with the previously observed cyclization
adducts, cis-1,3-cyclohexanediols were obtained. How-
ever, diastereoselectivity at the C-4 methyl-bearing ste-
With these data hand, it became apparent that, in
general, an increase in the steric requirements of the
starting materials resulted in lower diastereoselectivities
in the final products. For such substrates, side reactions
producing uncyclized reduction products also became
more important. More difficult to explain is the case of
9a , wherein steric hindrance is seemingly less, but only
a 3:1 mixture of diastereomers was obtained.
The extension of this protocol to the synthesis of
5-membered rings was examined next. Substrates 13a-e
were prepared once again through Darzens condensation
of the Weinreb amide 1, this time using 4-penten-2-one.
Subsequent treatment with the appropriate organo-
lithium or Grignard reagent provided the desired prod-
ucts. Exposure of the substrates 13a-e to the samarium-
(II)-promoted epoxide ring-opening/ketyl olefin cyclization
conditions resulted in smooth conversion to the corre-
sponding cis-1,3-cyclopentanediols (eq 6, Table 3). In-
terestingly, cyclization of compounds 13a -c proceeded
with very high diastereoselection, producing essentially
a single diastereomer in each case (compounds 14a -c,
respectively). The cyclization of 13d proceeded in good
(16) Trapani, G.; Reho, A.; Latrofa, A. Synthesis 1983, 1013.
(17) Demarco, P. V.; Farkas, E.; Doddrell, D.; Mylari, B. L.; Wenkert,
E. J . Am. Chem. Soc. 1968, 90, 5480.

2938 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and del Pozo Losada
Sch em e 4a
a
Key: (a) O3/Me2S/NaHCO3, MeOH/CH2Cl2/-78 °C; (b) (EtO)2P(O)CH2R, base/THF/0 °C; (c) LiN(SiMe3)2, THF/0 °C f rt, 1; (d) MeMgBr/
THF, 0 °C/30 min.
Ta ble 3. Sequ en tia l Cycliza tion s of r,â-Ep oxy
Keton es 13 To Yield Cyclop en ta n ed iols 14 a n d 15,
Ald ols 16, a n d Op en -Ch a in 1,3-Diols 17
activated olefins. Substrates 18a and 18b (n ) 1) were
readily prepared through ozonolysis of 5-penten-2-one,
followed by a Horner-Emmons reaction18 with the ap-
propriate phosphonate. Darzens condensation with the
amide 1 and treatment with methylmagnesium bromide
afforded 18a and 18b (Scheme 4). This method failed to
provide 18c. However, 18c could be obtained via ozo-
nolysis of 13a and subsequent Horner-Emmons conden-
sation with triethyl phosphonoacetate (eq 7).
%
%
reaction
times
(min)
% yield 14 + 15 yield yield
entry substrate
R
(ratio 14:15)a
16
17
1
2
3
4
5
13a
13b
13c
13d
13e
Me
Et
i-Pr
t-Bu
Ph
61 (>100:1)
65 (100:1)
66 (50:1)
81 (2:1)
10
15
20
30
15
53b
24b
a
Ratios of diastereomers were determined by fused silica
b
capillary GC analysis of crude reaction mixtures. This reaction
was carried out at -78 °C. At 0 °C the reaction afforded a mixture
of products.
Ta ble 4. Sequ en tia l Cycliza tion s of r,â-Ep oxy Keton es
With an ethyl ester activating the radical acceptor,
substrates 18b and 18c underwent the epoxide ring-
opening/ketyl olefin cyclization with samarium(II) iodide
at -78 °C to provide essentially one diastereomer (eq 8,
Table 4). However, when a phenyl substituent was used
18 To Yield Cycloh exa n ed iols 19 a n d 20
% yield 19 + 20
entry substrate
R1
Ph
R2
T (°C)
n
(ratio 19:20)a
1
2
3
4
5
6
18a
18b
18c
18a
18a
18a
Me
-78
-78
-78
rt
1
1
0
1
1
1
82 (2.55:1)
85 (>50:1)
81 (>50:1)
79 (1:1.6)
76 (1:1)
CO2Et Me
CO2Et i-Pr
Ph
Ph
Ph
Me
Me
Me
0
-20
78 (1.5:1)
a
Ratios of diastereomers were determined by fused silica
capillary GC analysis of crude reaction mixtures.
as the activating group (18a ), control over the methyl-
bearing stereocenter was lost. It is known that the rate
of addition of free radicals to alkenes is greatly affected
by substituents on the alkene,15d increasing up to 4 orders
of magnitude when an electron-withdrawing group is
positioned â to the carbon of the olefin undergoing radical
attack. These electron-withdrawing substituents de-
crease the SOMO energy of the radical and thereby favor
interactions between the SOMO of the radical and the
HOMO of the olefin.19 Esters are better activating groups
than the phenyl group, and the lower temperatures that
can be used with the former substituent could explain
why the ester functionality showed higher stereochemical
control. In fact, when the reaction of 18c was performed
at 0 °C (or at rt) in the absence of HMPA, four different
products were detected by TLC.
yield but suffered from low diastereoselectivity. As in
the previous case (i.e., compound 4e), the phenyl ketone-
containing substrate 13e did not cyclize, instead provid-
ing the aldol product 16e and acyclic diol 17e.
The stereochemistry of the compounds 14d and 15d
was confirmed by use of the previously described tech-
niques. High-dilution IR spectra (0.02 M in CCl4) of the
products 14d and 15d showed two hydroxyl absorbances,
indicating a cis diol configuration. The pyridine-d5/CDCl3
difference proton NMR study revealed a 0.09 ppm shift
for 14d and a 0.245 ppm change for 15d , indicative of a
trans and cis relationship, respectively. The stereochem-
istry of the other cyclization products was assigned by
comparison of their proton NMR’s to compounds 14d and
15d .
Kinetic resolution of a racemic allylic alcohol using the
Sharpless asymmetric epoxidation reaction could provide
enantiomerically enriched R,â-epoxy ketones for an asym-
metric preparation of cis-1,3-cyclohexanediols and cis-1,3-
cyclopentanediols. Compound 21 was prepared by a
route involving initial condensation of diethyl (cyanom-
(18) March, J . Advanced Organic Chemistry, 3rd ed.; Wiley-
Interscience: New York, 1985 and references therein.
(19) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
The third phase of our study was to investigate the
reductive cyclization of R,â-epoxy ketones possessing

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2939
Sch em e 5a
a
Key: (a) t-BuOOH/Ti(Oi-Pr)4, L-(+)-DIPT, CH2Cl2/-20 °C/12 h; (b) Swern oxidation; (c) 6 SmI2/HMPA, THF/MeOH/0 °C.
mmol) in 20 mL of THF at 0 °C was added dropwise methyl-
magnesium bromide (4.28 mL of a 1.4 M solution in THF, 6.0
mmol), and the reaction mixture was stirred for an additional
30 min period at 0 °C. Then, TLC revealed the complete
comsumption of the starting material, and the reaction
mixture was quenched with saturated aqueous NH4Cl. Aque-
ous workup followed by flash chromatography (20% ethyl
ether/hexanes) afforded 0.75 g (4.85 mmol) of 4a in 97% yield:
1H NMR (400 MHz, CDCl3) δ 1.23 (s, 1.62H), 1.39 (s, 1.38H),
1.52-1.65 (m, 2H), 1.76-1.83 (m, 1H), 2.04-2.22 (m, 1H), 2.18
(s, 1.62H), 2.21 (s, 1.38H), 3.35 (s, 0.46H), 3.37 (s, 0.54H), 4.90-
5.05 (m, 2H), 5.64-5.83 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 16.22, 22.06, 28.07, 28.39, 29.32, 29.64, 31.58, 37.41, 63.14,
63.72, 64.82, 65.79, 115.52, 137.18, 137.24, 204.30; IR (neat)
3077.9, 2976.2, 1721.5, 1453.2, 1406.6, 1185.1 cm-1; HRMS
calcd for C9H14O2 (M + H)+ 155.1072, found 155.1031; LRMS
(EI) m/ z 139 (14), 111 (32), 99 (82), 81 (31), 71 (74), 55 (59),
43 (100).
ethyl)phosphonate with 5-hexen-2-one (Scheme 5). The
Wittig adduct was reduced with DIBAH, and subsequent
addition of methylmagnesium bromide afforded 21. The
resulting allylic alcohol was subjected to Sharpless ep-
oxidation conditions,20 affording the nonracemic chiral
epoxide 22. Unfortunately, the kinetic resolution of rac-
21 afforded epoxide 22 in low enantiomeric excess (ee )
18%). Swern oxidation of 22 provided access to nonra-
cemic 23. Reaction with samarium(II) iodide resulted in
a mixture of diastereomeric 1,3-cyclohexanediols 24. The
enantiomeric excess of each isomer of 24 was determined
to be 16% based on chiral-GC analysis. This result
indicates that, as expected, the overall process transpires
with retention of the configuration at the position â to
the ketone carbonyl.
4,5-Ep oxy-5-m eth yl-8-n on en -3-on e (4b) was prepared
from 3 according to the general procedure for the preparation
of 4a by reaction with ethylmagnesium bromide (3.0 mL of a
2.0 M solution in THF, 6.0 mmol) to afford 4b in 78% yield
after flash chromatography with 20% ethyl ether/hexanes: 1H
NMR (400 MHz, CDCl3) δ 1.05 (t, J ) 7.41 Hz, 3H), 1.20 (s,
1.68H), 1.39 (s, 1.32H), 1.49-1.81 (m, 2H), 1.98-2.23 (m, 2H),
2.49-2.60 (m, 2H), 3.37 (s, 0.44H), 3.39 (s, 0.56H), 4.90-5.07
(m, 2H), 5.62-5.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 7.18,
16.15, 22.00, 29.29, 29.66, 31.45, 34.12, 34.42, 37.37, 64.36,
65.32, 115.38, 115.44, 137.19, 137.27, 206.68; IR (neat) 3077.8,
2977.2, 2938.3, 1722.5, 1409.7, 1381.4 cm-1; HRMS calcd for
C10H16O2 (M + H)+ 169.1228, found 169.1183; LRMS (EI) m/ z
153 (12), 113 (79), 97 (18), 81 (36), 71 (73), 57 (100), 43 (72).
4,5-E p oxy-2,5-d im et h yl-8-n on en -3-on e (4c) was pre-
pared from 3 according to the general procedure for the
preparation of 4a by reaction with isopropylmagnesium bro-
mide (3.0 mL of a 2.0 M solution in THF, 6.0 mmol) to afford
4c in 81% yield after flash chromatography with 20% ethyl
ether/hexanes: 1H NMR (400 MHz, CDCl3) δ 1.01-1.06 (m,
6H), 1.13 (s, 1.56H), 1.35 (s, 1.44H), 1.44-1.48 (m, 1H), 1.57-
1.76 (m, 1H), 1.96-2.16 (m, 2H), 2.70-2.80 (m, 1H), 3.40 (s,
0.48H), 3.43 (s, 0.52H), 4.85-5.00 (m, 2H), 5.60-5.77 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 15.92, 16.86, 17.02, 17.54, 17.60,
21.75, 29.06, 29.44, 31.11, 37.17, 38.62, 63.22, 63.42, 63.59,
64.42, 115.08, 115.22, 137.11, 208.88, 209.06; IR (neat) 2971.3,
2932.6, 1718.5, 1465.9, 1405.3, 1383.8 cm-1; HRMS calcd for
C11H18O2 (M + H)+ 183.1385, found 184.1423; LRMS (EI) m/ z
127 (29), 111 (12), 85 (14), 71 (75), 55 (25), 43 (100).
Con clu sion s
The samarium(II) iodide-promoted epoxide ring-open-
ing/ketyl olefin cyclization sequence efficiently converts
a variety of R,â-epoxy ketones to cis-1,3-cyclopentanediols
and cis-1,3-cyclohexanediols. In addition, the relative
stereochemistry can be controlled at three stereocenters
in the cyclization product. In all cases, complete selectiv-
ity for cis-1,3-diols was achieved. As expected, the
diastereoselectivity at the second newly formed stereo-
center was substrate dependent.
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 from Cerac Inc., Milwaukee, WI,
and was weighed and stored under an inert atmosphere.
CH2I2 was purchased from Aldrich Chemicals and was distilled
prior to use and stored under argon over copper turnings.
HMPA was purchased from either Aldrich or Sigma Chemicals
and was distilled from either Na(0) or CaH2 at 0.04 mmHg
and stored over 4 Å molecular sieves under Ar. Standard
benchtop techniques were employed for handling air-sensitive
reagents, and all reactions were carried out under argon.
3,4-Ep oxy-4-m eth yl-7-octen -2-on e (4a ). Gen er a l P r o-
ced u r e for th e P r ep a r a tion of r,â-Ep oxy Keton es 4. To
a stirred solution of N-chloro-N-methylacetamide (2.75 g, 20.0
mmol) in 20 mL of THF at -78 °C was added dropwise lithium
bis(trimethylsilyl)amide (22 mL of a 1.0 M solution in THF,
22.0 mmol). After the addition, the reaction mixture was
stirred for an additional 20 min at -78 °C. After this period
of stirring, a solution of 5-hexen-2-one (2) (1.96 g, 20.0 mmol)
in 30 mL of THF was added slowly dropwise, and when the
addition was complete, the reaction mixture was warmed to
room temperature with continued stirring overnight. The
reaction mixture was then quenched with saturated aqueous
NH4Cl after TLC analysis revealed the complete comsumption
of the starting material. Aqueous workup followed by flash
chromatography (50% EtOAc/hexanes) afforded 3.66 g (18.4
mmol) of 3 in 92% yield. To a stirred solution of 3 (0.99 g, 5.0
4,5-Ep oxy-2,2,5-tr im eth yl-8-n on en -3-on e (4d ) was pre-
pared from 3 according to the general procedure for the
preparation of 4a by reaction with tert-butyllithium (3.53 mL
of a 1.7 M solution in pentane, 6.0 mmol) to afford 4d in 71%
yield after flash chromatography with 20% ethyl ether/
hexanes: 1H NMR (400 MHz, CDCl3) δ 1.28 (s, 1.5H), 1.29 (s,
9H), 1.42 (s, 1.5H), 1.50-1.58 (m, 1H), 1.68-1.82 (m, 1H),
2.01-2.25 (m, 2H), 3.69 (s, 0.5H), 3.72 (s, 0.5H), 4.91-5.06
(m, 2H), 5.68-5.85 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 15.67,
21.61, 26.03, 28.95, 29.46, 30.49, 37.09, 43.38, 43.43, 61.68,
62.94, 63.46, 63.80, 115.05, 115.23, 137.28, 137.38, 208.90,
208.98; IR (neat) 2967.7, 2933.2, 1712.4, 1478.1, 1398.6 cm-1
;
HRMS calcd for C12H20O2 (M + H)+ 197.1542, found 197.1539;
LRMS (EI) m/ z 141 (19), 111 (11), 99 (21), 85 (14), 71 (36), 57
(100).
(20) (a) Martin, S. V.; Woodard, S. S.; Katsuki, T.; Yamada, Y.;
Ikeda, M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237. (b)
Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J . Am. Chem. Soc. 1991,
113, 106.
1,2-Ep oxy-2-m eth yl-5-h exen yl p h en yl k eton e (4e) was
prepared from 3 according to the general procedure for the
preparation of 4a by reaction with phenylmagnesium bromide

2940 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and del Pozo Losada
(2.0 mL of a 3.0 M solution in ethyl ether, 6.0 mmol) to afford
4e in 99% yield after flash chromatography with 20% ethyl
ether/hexanes: 1H NMR (400 MHz, CDCl3) δ 1.22 (s, 1.5H),
1.51-1.60 (m, 1H), 1.55 (s, 1.5H), 1.85-1.91 (m, 1H), 1.97-
2.07 (m, 0.5H), 2.10-2.19 (m, 0.5H), 2.20-2.29 (m, 1H), 4.04
(s, 0.5H), 4.06 (s, 0.5H), 4.80-4.91 (m, 1H), 5.00-5.10 (m, 1H),
5.54-5.65 (m, 0.5H), 5.80-5.90 (m, 0.5H), 7.19-7.60 (m, 3.5H),
7.93-7.98 (m, 1.5H); 13C NMR (100 MHz, CDCl3) δ 16.41,
21.76, 29.12, 29.60, 31.58, 37.09, 63.51, 63.58, 63.99, 64.65,
115.26, 115.55, 127.16, 127.26, 128.24, 128.76, 128.84, 133.85,
135.76, 137.29, 137.40, 193.98, 194.25; IR (neat) 3066.3,
2975.6, 2928.6, 1690.5, 1449.8, 1228.3 cm-1; HRMS calcd for
C14H16O2 (M - H)+ 215.1072, found 215.1084; LRMS (EI) m/ z
201 (10), 154 (64), 105 (100), 89 (35), 77 (77).
saturated aqueous NH4Cl. Aqueous workup followed by flash
chromatography (10% ethyl ether/hexanes) afforded 0.74 g
(5.86 mmol) of 4-methyl-7-hepten-3-one in a 30% yield. 9c was
prepared from this ketone according to the general procedure
for the preparation of 4a in an 23% (two steps): 1H NMR (400
MHz, CDCl3) δ 0.76-0.83 (m, 4.92H), 1.01 (d, J ) 6.76 Hz,
1.08H), 1.45-1.58 (m, 1H), 1.64-2.03 (m, 3.36H), 2.19 (s,
1.08H), 2.20 (s, 1.92H), 2.31-2.39 (m, 0.64H), 3.42 (s, 0.64H),
3.47 (s, 0.36H), 4.92-5.03 (m, 2H), 5.47-5.58 (m, 0.36H), 5.68-
5.79 (m, 0.64H); 13C NMR (100 MHz, CDCl3) δ 7.66, 7.88, 15.63,
16.05, 20.72, 20.95, 28.37, 28.63, 35.70, 36.29, 37.12, 38.04,
62.26, 63.08, 69.50, 69.67, 116.26, 116.59, 136.13, 136.51,
204.84, 204.95; IR (neat) 2924.7, 1717.7, 1457.9, 1356.2, 1186.2
cm-1; HRMS calcd for C11H18O2 (M + H)+ 183.1385, found
183.1374; LRMS (EI) m/ z 153 (55), 139 (50), 113 (100), 99 (87),
81 (67), 69 (95), 57 (92).
3,4-Ep oxy-7-octen -2-on e (9a ). A solution of 4-penten-1-
ol (1.72 g, 20 mmol) in 60 mL of CH2Cl2 was treated with Et3N
(8.09 g, 80 mmol), cooled to 0 °C, treated with a solution of
pyridine‚SO3 complex (9.55 g, 60 mmol) in 60 mL of DMSO,
and stirred for 1 h at 0 °C. The reaction mixture was then
quenched with aqueous saturated NaHCO3. The aqueous
layer was extracted with Et2O (3 × 50 mL), and the combined
organic extracts were washed with 1 M Na2HPO4 solution (100
3,4-Ep oxy-4-m eth yl-6-h ep ten -2-on e (13a ) was prepared
from 4-penten-2-ol according to the procedure for the prepara-
tion of 9a to afford 13a in 21% overall yield: 1H NMR (400
MHz, CDCl3) δ 1.20 (s, 1.29H), 1.36 (s, 1.71H), 2.16 (s, 1.29H),
2.19 (s, 1.71H), 2.15-2.40 (m, 2H), 3.37 (s, 0.43H), 3.38 (s,
0.57H), 5.00-5.12 (m, 2H), 5.60-5.75 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 16.50, 22.02, 28.02, 28.39, 37.10, 42.27, 62.77,
63.18, 63.86, 65.17, 118.68, 119.10, 132.10, 132.39, 203.82,
.
mL), 5 M CuSO4 5H2O solution (100 mL), and brine (100 mL),
respectively. The organic layer was dried (MgSO4), concen-
trated in vacuo, and used without further purification (because
the aldehyde formed was very volatile). 9a was prepared from
this aldehyde according to the general procedure for the
preparation of 4a in an 28% overall yield: 1H NMR (400 MHz,
CDCl3) δ 1.48-1.73 (m, 2H), 2.01 (s, 0.78H), 2.21 (s, 2.22H),
2.10-2.25 (m, 2H), 3.02-3.08 (m, 0.26H), 3.14-3.21 (m,
0.74H), 3.52 (s, 0.26H), 3.54 (s, 0.74H), 4.94-5.04 (m, 2H),
5.68-5.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.75, 28.35,
29.26, 29.90, 30.38, 31.03, 57.55, 58.03, 58.82, 59.90, 115.84,
115.90, 136.80, 204.14, 205.87; IR (neat) 3078.0, 2978.8,
1722.2, 1421.4, 1356.0, 1180.4 cm-1; HRMS calcd for C8H12O2
(M - H)+ 139.0759, found 139.0743; LRMS (EI) m/ z 107 (11),
97 (62), 85 (70), 67 (63), 57 (65), 43 (100).
204.41; IR (neat) 2917.3, 2848.8, 1720.3, 1260.2, 1018.8 cm-1
;
HRMS calcd for C8H12O2 (M + H)+ 141.0916, found 141.0892;
LRMS (EI) m/ z 99 (21), 83 (5), 67 (6), 53 (7), 43 (100).
4,5-Ep oxy-5-m eth yl-7-octen -3-on e (13b) was prepared
from 4-penten-2-ol according to the procedure for the prepara-
tion of 9a to afford 13b in 23% overall yield: 1H NMR (400
MHz, CDCl3) δ 0.98 (t, J ) 7.27 Hz, 3H), 1.13 (s, 1.38H), 1.32
(s, 1.62H), 2.08-2.55 (m, 4H), 3.36 (s, 1H), 4.95-5.08 (m, 2H),
5.57-5.72 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 7.11, 16.35,
21.93, 34.10, 34.43, 36.95, 42.25, 62.67, 63.06, 63.39, 64.65,
118.48, 118.98, 132.16, 132.53, 206.23, 206.67; IR (neat)
3097.7, 2978.8, 2938.3, 1720.7, 1380.5 cm-1; HRMS calcd for
C9H14O2 (M + H)+ 155.1072, found 155.1090; LRMS (EI) m/ z
113 (57), 97 (36), 83 (11), 69 (13), 57 (100), 43 (71).
3,4-E p oxy-4-isop r op yl-7-oct en -2-on e (9b ). Me3N.BH3
complex (1.46 g, 20 mmol) was added to a solution of 4-pen-
tenoic acid (2.0 g, 20 mmol) and N,O-dimethylhydroxylamine
hydrochloride (1.95 g, 20 mmol) in 100 mL of xylenes, and the
resultant solution was heated at reflux at 137-144 °C for 8
h. The mixture was then cooled to room temperature and
shaken with aqueous 10% NaHCO3 (2 × 25 mL). Aqueous
workup followed by flash chromatography (50% ethyl ether/
hexanes) afforded 2.14 g (15.0 mmol) of N-methoxy-N-methyl-
4-pentenamide in 75% yield. To a solution of this amide in
30 mL of THF was added isopropylmagnesium bromide (9 mL
of a 2.0 M solution in THF, 18 mmol), and the reaction mixture
was stirred for 30 min at 0 °C. After this period of time, the
reaction mixture was quenched with saturated aqueous NH4-
Cl. Aqueous workup followed by flash chromatography (10%
ethyl ether/hexanes) afforded 0.59 g (4.85 mmol) of 2-methyl-
6-hepten-3-one in a 31% yield. 9b was prepared from this
ketone according to the general procedure for the preparation
of 4a in a 44% yield (two steps): 1H NMR (400 MHz, CDCl3)
δ 0.87 (d, J ) 7.08 Hz, 2.1H), 0.88 (d, J ) 6.91 Hz, 0.9H), 0.98
(d, J ) 6.87 Hz, 0.9H), 1.04 (d, J ) 6.89 Hz, 2.1H), 1.49-1.64
(m, 2H), 1.76-1.81 (m, 1H), 1.86-2.05 (m, 2H), 2.19 (s, 2.1H),
2.22 (s, 0.9H), 3.41 (s, 0.3H), 3.50 (s, 0.7H), 4.90-5.04 (m, 2H),
5.69-5.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 17.14, 17.77,
18.68, 18.76, 26.75, 27.75, 28.37, 29.45, 30.95, 31.16, 62.57,
63.83, 69.13, 69.22, 115.16, 125.30, 128.23, 129.04, 137.48,
137.72, 204.78, 205.03; IR (neat) 2923.9, 2852.4, 1725.7,
1462.8, 1377.7, 1274.2 cm-1; HRMS calcd for C11H18O2 (M +
H)+ 183.1385, found 183.1381; LRMS (EI) m/ z 183 (6), 139
(90), 127 (36), 99 (58), 81 (38), 69 (37), 55 (52), 43 (100).
3,4-Ep oxy-4-eth yl-5-m eth yl-7-octen -2-on e (9c). To a
stirred solution of 22 mmol of LDA at -78 °C was added
dropwise a solution of 3-pentanone (1.73 g, 20 mmol) in 20
mL of THF. After the addition of the substrate was complete,
the reaction mixture was stirred for an additional 20 min
period at -78 °C. Then, allyl bromide (2.42 g, 20 mmol) in 20
mL of THF was added slowly dropwise. The reaction mixture
was warmed to room temperature with continued stirring for
3 h. After this period, the reaction mixture was quenched with
4,5-Ep oxy-2,5-d im eth yl-7-octen -3-on e (13c) was pre-
pared from 4-penten-2-ol according to the procedure for the
preparation of 9a to afford 13c in 22% overall yield: 1H NMR
(400 MHz, CDCl3) δ 1.02-1.08 (m, 6H), 1.13 (s, 1.80H), 1.37
(s, 1.20H), 2.11-2.42 (m, 2H), 2.70-2.80 (m, 1H), 3.45 (s,
0.4H), 3.46 (s, 0.6H), 5.00-5.12 (m, 2H), 5.61-5.80 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 16.31, 16.82, 17.17, 17.69, 21.88,
22.62, 31.56, 36.78, 38.86, 42.37, 62.73, 63.04, 63.40, 63.96,
118.62, 119.06, 132.20, 132.60, 208.97; IR (neat) 2972.5,
2933.8, 1716.3, 1467.3, 1384.0, 1001.3 cm-1; HRMS calcd for
C10H16O2 168.1150, found 168.1142; LRMS (EI) m/ z 127 (18),
97 (28), 85 (17), 71 (32), 43 (100).
4,5-Ep oxy-2,2,5-tr im eth yl-7-octen -3-on e (13d ) was pre-
pared from 4-penten-2-ol according to the procedure for the
preparation of 9a to afford 13d in 17% overall yield: 1H NMR
(400 MHz, CDCl3) δ 1.07 (s, 1.65H), 1.08 (s, 4.95H), 1.10 (s,
4.05H), 1.33 (s, 1.35H), 2.10-2.12 (m, 1H), 2.28-2.42 (m, 1H),
3.64 (s, 0.55H), 3.68 (s, 0.45H), 4.93-5.09 (m, 2H), 5.48-5.62
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 15.92, 21.67, 26.02,
26.04, 36.20, 42.32, 43.42, 43.47, 60.95, 62.13, 63.15, 63.52,
118.67, 119.11, 132.19, 132.75, 208.93, 209.04; IR (neat)
2966.3, 2916.4, 1712.0, 1478.2, 1398.6, 1065.0 cm-1; HRMS
calcd for C11H18O2 (M + H)+ 183.1385, found 183.1407; LRMS
(EI) m/ z 141 (27), 99 (28), 83 (10), 69 (9), 57 (100).
1,2-Ep oxy-2-m eth yl-4-p en ten yl p h en yl k eton e (13e)
was prepared from 4-penten-2-ol according to the procedure
for the preparation of 9a to afford 13e in 29% overall yield:
1H NMR (400 MHz, CDCl3) δ 1.18 (s, 1.35H), 1.50 (s, 1.65H),
2.11-2.29 (m, 1.10H), 2.40-2.58 (m, 0.90H), 4.04 (s, 0.55H),
4.05 (s, 0.45H), 4.89-4.94 (m, 1.10H), 5.16-5.22 (m, 0.90H),
5.53-5.61 (m, 0.55H), 5.79-5.84 (m, 0.45H), 7.41-7.46 (m, 2H),
7.53-7.57 (m, 1H), 7.90-7.93 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 16.56, 21.64, 37.21, 42.16, 62.68, 63.20, 63.47, 64.13,
118.89, 119.33, 128.18, 128.20, 128.83, 128.85, 132.26, 132.36,
133.85, 135.75, 193.94, 194.15; IR (neat) 2979.9, 1693.6,
1641.6, 1597.6, 1449.6, 1383.2 cm-1; HRMS calcd for C13H14O2
(M + H)+ 203.1072, found 203.1077; LRMS (EI) m/ z 185 (16),
161 (68), 105 (100), 77 (65), 43 (65).

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2941
E t h yl 6,7-E p oxy-6-m et h yl-8-oxo-2-n on en oa t e (18b ).
Ozone was bubbled through a solution of 5-hexen-2-one (1.96
g, 20 mmol) and NaHCO3 (3.36 g, 40 mmol) in 40 mL of 50%
MeOH/CH2Cl2 at -78 °C until a blue color persisted. Then,
Me2S was added (12.42 g, 200 mmol), and the reaction mixture
was stirred and warmed to room temperature. The resultant
crude reaction mixture was diluted with brine (50 mL),
extracted with ether, dried over MgSO4, and concentrated in
vacuo. This crude was used in the next step without further
purification. To a suspension of NaH (0.53 g, 22 mmol) in 20
mL of THF at 0 °C was added slowly dropwise a solution of
triethyl phosphonoacetate (4.48 g, 20 mmol) in 20 mL of THF
and the mixture stirred for 20-30 min at 0 °C after the
addition was finished. Then, a solution of the keto aldehyde
(obtained in the ozonolysis) in 30 mL of THF was added
dropwise. When the addition of the substrate was complete,
the reaction mixture was stirred for an additional 2 h at 0 °C.
The reaction mixture was then quenched with saturated
aqueous NH4Cl. Aqueous workup followed by flash chroma-
tography (50% ethyl ether/hexanes) afforded 2.04 g (12 mmol)
of ethyl 6-oxo-2-heptenoate in a 60% yield as a 97:3 mixture
of the trans and cis diastereomers, respectively. 18a was
prepared from this keto ester according to the general proce-
dure for the preparation of 4a , in 35% yield after flash
chromatography with 33% ethyl ether/hexanes: 1H NMR (400
MHz, CDCl3) δ 1.21-1.25 (m, 3H), 1.22 (s, 1.5H), 1.39 (s, 1.5H),
1.59-1.83 (m, 2H), 2.17 (s, 1.5H), 2.20 (s, 1.5H), 2.22-2.34
(m, 2H), 3.36 (s, 0.5H), 3.37 (s, 0.5H), 4.09-4.16 (m, 2H), 5.75-
5.83 (m, 1H), 6.76-6.93 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.24, 16.19, 21.20, 27.59, 28.00, 28.07, 28.43, 30.64, 36.41,
60.31, 62.65, 63.20, 64.57, 65.64, 122.29, 146.86, 146.97,
166.25, 203.88, 203.93; IR (neat) 2981.8, 1719.5, 1694.6,
1270.9, 1186.7, 1043.1 cm-1; HRMS calcd for C12H18O4 (M +
H)+ 227.1283, found 227.1263; LRMS (EI) m/ z 127 (10), 114
(19), 99 (24), 81 (18), 71 (17), 55 (19), 43 (100).
3,4-Ep oxy-4-m eth yl-8-p h en yl-7-octen -2-on e (18a ) was
prepared following the procedure described above for the
preparation of 18a by ozonolysis of 5-hexen-2-one, and sub-
sequent Horner-Emmons reaction with the keto aldehyde
using diethyl phosphonoacetate to afford after flash choro-
matography (20% ethyl ether/hexanes) 0.70 g of the Wittig
adduct (3.3 mmol) in a 20% yield. Following the procedure
described for the synthesis of 4a , 18b was obtained in a 62%
yield (two steps): 1H NMR (400 MHz, CDCl3) δ 1.28 (s, 1.71H),
1.44 (s, 1.29H), 1.66-1.89 (m, 2H), 2.20-2.38 (m, 2H), 2.15
(s, 1.71H), 2.18 (s, 1.29H), 3.38 (s, 0.43H), 3.42 (s, 0.57H), 6.06-
6.21 (m, 1H), 6.35-6.39 (m, 1H), 7.18-7.20 (m, 1H), 7.24-
7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 16.14, 22.04, 27.98,
28.37, 28.57, 28.89, 31.84, 37.76, 63.04, 63.61, 64.74, 65.64,
125.89, 127.10, 127.13, 128.45, 128.49, 128.71, 128.77, 130.73,
130.79, 137.17, 204.17; IR (neat) 2952.2, 1718.3, 1654.5,
1436.7, 1275.7, 1199.7 cm-1; HRMS calcd for C15H18O2 (M +
H)+ 213.1127, found 213.1137; LRMS (EI) m/ z 137 (10), 109
(12), 99 (43), 81 (14), 68 (16), 53 (10), 43 (100).
Eth yl 5,6-Ep oxy-5,8-d im eth yl-8-oxo-2-octen oa te (18c)
was prepared according to the procedure for the preparation
of ethyl 2-oxo-6-heptenoate described in the synthesis of 18a
by ozonolysis of 13c and further Horner-Emmons reaction
with triethyl phosphonoacetate at -78 °C in a 38% yield (two
steps). 18c was obtained as the trans diastereomer: 1H NMR
(400 MHz, CDCl3) δ 1.05-1.11 (m, 6H), 1.20 (s, 3H), 1.34 (t, J
) 7.13 Hz, 3H), 2.45-2.60 (m, 2H), 2.72-2.83 (m, 1H), 3.47
(s, 1H), 4.13-4.19 (q, J ) 7.13 Hz, 2H), 5.88-5.93 (m, 1H),
6.76-6.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.23, 16.64,
16.80, 17.78, 31.59, 38.88, 40.50, 60.52, 62.62, 125.33, 141.56,
165.84, 208.59; IR (neat) 2972.8, 2935.0, 1719.9, 1657.5,
1270.3, 1199.8 cm-1; HRMS calcd for C14H20O4 240.1362, found
240.1360; LRMS (EI) m/ z 169 (13), 127 (48), 95 (40), 85 (47),
71 (54), 55 (34), 43 (100).
5,8-Dim eth yl-1,6-n on a d ien -7-ol (21). To a suspension of
t-BuOK (2.61 g, 22 mmol) in 20 mL of THF at 0 °C was added
dropwise a solution of diethyl (cyanomethyl)phosphonate (3.54
g, 20 mmol) in 20 mL of THF. After the addition was complete,
the reaction mixture was stirred for 20-30 min at 0 °C. Then,
a solution of 5-hexen-2-one (1.96 g, 20 mmol) in 20 mL of THF
was added slowly dropwise, and after the addition was
complete, stirring was continued for 3 h. The reaction mixture
was quenched with saturated aqueous NH4Cl. Aqueous
workup and concentration in vacuo afforded a crude mixture
that was used without further purification. This crude
mixture was disolved in 30 mL of THF and treated at 0 °C
with DIBAH (22 mL of a 1.0 M solution in hexanes, 22 mmol).
The reaction mixture was stirred for 1 h at 0 °C and quenched
with water. Aqueous workup followed by flash chromatogra-
phy (20% ethyl ether/hexanes) afforded 1.88 g (11.2 mmol) of
the R,â-unsaturated aldehyde in 56% yield as a mixture 2:1
of the trans:cis diastereomers. The treatment of a solution of
this mixture in 20 mL of THF at 0 °C with isopropylmagne-
sium bromide (6.72 mL of a 2.0 M solution in THF, 13.44
mmol), continued stirring for 1 h at 0 °C, quenching with
saturated aqueous NH4Cl, and aqueous workup afforded the
allylic alcohol 21 as a mixture 2:1 of the trans:cis diastereo-
mers. After several flash chromatographies (10% ethyl ether/
hexanes), the trans isomer was separated in a 99% purity and
used in the Sharpless epoxidation: 1H NMR (400 MHz, CDCl3)
δ 0.83 (d, J ) 6.88 Hz, 3H), 0.92 (d, J ) 6.62 Hz, 3H), 1.65 (s,
3H), 1.60-1.71 (m, 1H), 2.09 (m, 3H), 2.11-2.20 (m, 2H), 4.01-
4.06 (m, 1H), 4.90-5.01 (m, 2H), 5.17-5.20 (m, 1H), 5.71-
5.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 16.74, 18.09, 18.39,
32.08, 34.46, 39.04, 73.62, 114.66, 126.54, 138.30, 138.56; IR
(neat) 3374.1, 2956.7, 2927.0, 1465.7, 1381.9, 1008.2 cm-1
.
P r ep a r a tion of th e Sm I2 Solu tion . Samarium metal
(0.827 g, 5.5 mmol) was added under a flow of argon to an
oven-dried, round-bottomed flask containing a magnetic stir-
ring bar and a septum inlet. To the samarium was added 20
mL of THF followed by CH2I2 (1.473 g, 5.0 mmol). The mixture
was stirred at room temperature for 2 h. The resulting deep
blue solution was used directly to effect the following sequen-
tial reactions.
Gen er a l P r oced u r e for th e Sm I2-P r om oted Sequ en tia l
Rea ction s of r,â-Ep oxy Keton es. To the SmI2 (5.0 mmol)
in THF was added HMPA (4.93 g, 27.5 mmol), and Ar was
bubbled through the solution for 10 min. A solution of the
R,â-epoxy ketone (0.83 mmol), and MeOH (1 mL) in 30 mL of
THF was added over 1 h. After the starting material was
consumed, aqueous workup followed by flash chromatography
and/or Kugelrohr distillation afforded the title compounds. For
the cases in Table 4, no HMPA was added to the samarium
solution.
1,3,4-Tr im eth yl-1,3-cycloh exa n ed iol (5a , 6a ) was pre-
pared from 4a according to the general procedure described
above to afford after flash chromatography (75% ethyl ether/
hexanes) 0.115 g (0.73 mmol) of a 12:1 mixture of diastereo-
mers 5a :6a in 88% yield. 5a (major): 1H NMR (400 MHz,
CDCl3) δ 0.88 (d, J ) 7.23 Hz, 3H), 1.11 (s, 3H), 1.15 (s, 3H),
1.21-1.28 (m, 1H), 1.39-1.54 (m, 4H), 1.69-1.73 (m, 1H),
2.15-2.24 (m, 1H), 3.40-3.70 (br s, 2H); 13C NMR (100 MHz,
CDCl3) δ 15.88, 24.33, 28.74, 31.10, 32.60, 38.67, 43.41, 71.15,
74.34; IR (neat) 3328.5, 2965.7, 2929.9, 1457.9, 1175.0 cm-1
;
HRMS calcd for C9H18O2 158.1307, found 158.1301; LRMS (EI)
m/ z 140 (10), 125 (15), 101 (47,), 83 (18,), 43 (100). Anal. Calcd
for C9H18O2: C, 68.31; H, 11.46. Found: C, 68.09; H, 11.55.
6a (minor): 1H NMR (400 MHz, CDCl3) δ 0.91 (d, J ) 6.59
Hz, 3H), 1.11 (s, 3H), 1.16 (s, 3H), 1.18-1.40 (m, 4H), 1.55-
1.70 (m, 2H), 1.72-1.76 (m, 1H), 2.80-3.30 (br s, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.82, 26.40, 28.40, 31.08, 39.07, 39.98,
49.49, 71.56, 72.64; IR (neat) 3346.4, 2931.8, 1457.6, 1367.8,
1119.3, 1033.3 cm-1; HRMS calcd for C9H18O2 158.1307, found
158.1295; LRMS (EI) m/ z 141 (10), 123 (14), 101 (33), 82 (17),
43 (100). Anal. Calcd for C9H18O2: C, 68.31; H, 11.46.
Found: C, 69.74; H, 11.65.
3-Eth yl-1,4-d im eth yl-1,3-cycloh exa n ed iol (5b, 6b) was
prepared from 4a according to the general procedure described
above to afford after flash chromatography (75% ethyl ether/
hexanes) 0.122 g (0.71 mmol) of a 10:1 mixture of diastereo-
mers 5b:6b in 86% yield. 5b (major): 1H NMR (400 MHz,
CDCl3) δ 0.83 (d, J ) 7.27 Hz, 3H), 0.85 (t, J ) 7.45 Hz, 3H),
1.13 (s, 3H), 1.20-1.26 (m, 1H), 1.30-1.41 (m, 3H), 1.43-1.52
(m, 3H), 1.75-1.79 (m, 1H), 2.11-2.19 (m, 1H), 3.20-4.30 (br
s, 2H); 13C NMR (100 MHz, CDCl3) δ 5.99, 15.37, 24.26, 31.09,
32.87, 33.15, 35.55, 42.48, 71.01, 75.83; IR (neat) 3332.7,
2926.7, 1456.8, 1173.8 cm-1; HRMS calcd for C10H20O2 172.1463,

2942 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and del Pozo Losada
found 172.1468; LRMS (EI) m/ z 154 (10), 143 (8), 125 (45),
115 (55), 57 (100), 43 (47). Anal. Calcd for C10H20O2: C, 69.72;
H, 11.70. Found: C, 69.53; H, 11.77. 6b (minor): 1H NMR
(400 MHz, CDCl3) δ 0.82 (t, J ) 7.54 Hz, 3H), 0.86 (d, J )
6.48 Hz, 3H), 0.89-1.30 (m, 1H), 1.17 (s, 3H), 1.28-1.47 (m,
5H), 1.50-1.72 (m, 3H), 2.80-3.20 (br s, 2H); 13C NMR (100
MHz, CDCl3) δ 8.16, 14.40, 26.28, 31.25, 33.10, 37.06, 39.00,
45.19, 71.48, 74.96; IR (neat) 3370.8, 2927.9, 1696.0, 1458.4,
1172.2 cm-1; HRMS calcd for C10H20O2 172.1463, found
172.1458; LRMS (EI) m/ z 154 (18), 137 (24), 125 (81), 115 (73),
96 (48), 81 (48), 57 (100). Anal. Calcd for C10H20O2: C, 69.72;
H, 11.70. Found: C, 70.87; H, 11.01.
3-Isop r op yl-1,4-d im eth yl-1,3-cycloh exa n ed iol (5c, 6c)
was prepared from 4a according to the general procedure
described above to afford after flash chromatography (75%
ethyl ether/hexanes) 0.112 g (0.60 mmol) of a 10:1 mixture of
diastereomers 5c:6c in 72% yield. 5c (major): 1H NMR (400
MHz, CDCl3) δ 0.81-0.88 (m, 9H), 1.14 (s, 3H), 1.19-1.24 (m,
2H), 1.40-1.46 (m, 2H), 1.48-1.55 (m, 1H), 1.68-1.72 (m, 1H),
1.82-1.86 (m, 1H), 2.11-2.20 (m, 1H), 3.08 (br s, 1H), 4.04
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 15.02, 15.11, 16.07,
24.57, 31.23, 32.71, 33.34, 34.87, 40.14, 65.79, 70.83, 76.99;
IR (neat) 3260.4, 2960.6, 2919.4, 1474.7, 1449.1 cm-1; HRMS
calcd for C11H22O2 186.1620, found 186.1617; LRMS (EI) m/ z
168 (10), 143 (28), 125 (100), 97 (30), 71 (72), 43 (53). Anal.
Calcd for C11H22O2: C, 70.92; H, 11.90. Found: C, 71.16; H,
12.12. 6c (minor): 1H NMR (400 MHz, CDCl3) δ 0.79 (d, J )
7.57 Hz, 3H), 0.84 (d, J ) 6.49 Hz, 3H), 0.92 (d, J ) 7.57 Hz,
3H), 1.02-1.13 (m, 1H), 1.18 (s, 3H), 1.21-1.45 (m, 2H), 1.48-
1.84 (m, 5H), 2.74 (br s, 1H), 3.03 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 14.03, 16.44, 17.40, 26.52, 31.47, 34.45, 36.08,
38.98, 39.09, 71.37, 76.87; IR (neat) 3335.5, 2960.3, 2929.6,
2873.8, 1461.7, 1373.7 cm-1; HRMS calcd for C11H22O2 (M -
CH3) 171.1385, found 171.1397, (M - H2O) 168.1515, found
168.1514; LRMS (EI) m/ z 168 (12), 143 (52), 125 (90), 97 (63),
85 (54), 71 (91), 43 (100). Anal. Calcd for C11H22O2: C, 70.92;
H, 11.90. Found: C, 71.19; H, 12.00.
3-ter t-Bu tyl-1,4-d im eth yl-1,3-cycloh exa n ed iol (5d , 6d )
was prepared from 4a according to the general procedure
described above to afford after flash chromatography (75%
ethyl ether/hexanes) 0.017 g (0.083 mmol) of a 7:1 mixture of
diastereomers 5d :6d in 10% yield. 5d (major): 1H NMR (400
MHz, CDCl3) δ 0.95 (s, 9H), 1.04 (d, J ) 7.17 Hz, 3H), 1.19 (s,
3H), 1.20-1.24 (m, 1H), 1.41-1.68 (m, 4H), 1.91-1.97 (m, 1H),
2.23-2.34 (m, 1H), 2.62 (br s, 1H), 3.99 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 18.18, 25.97, 27.31, 31.49, 33.06, 36.30,
36.36, 38.37, 71.21, 79.78; IR (neat) 3473.3, 2967.9, 2930.5,
1397.7, 1377.4, 1159.8 cm-1; HRMS calcd for C12H24O2 (M -
H2O) 182.1671, found 182.1652, (M - CH3) 185.1542, found
185.1534; LRMS (EI) m/ z 182 (4), 143 (27), 125 (94), 83 (29),
57 (86), 41 (100). Anal. Calcd for C12H24O2: C, 71.95; H, 12.07.
Found: C, 71.92; H, 12.44.
ether 0.073 g (0.51 mmol) of a >100:1 mixture of diastereomers
14a :15a in 61% yield. 14a (major): 1H NMR (400 MHz,
CDCl3) δ 0.88 (d, J ) 6.88 Hz, 3H), 1.19 (s, 3H), 1.30 (s, 3H),
1.17-1.24 (m, 1H), 1.33-1.40 (m, 1H), 1.70-1.81 (m, 2H),
2.19-2.23 (m, 1H), 2.60-2.90 (br s, 2H); 13C NMR (100 MHz,
CDCl3) δ 18.24, 23.68, 28.35, 44.97, 50.25, 53.38, 78.68, 82.59;
IR (neat) 3363.1, 2963.9, 2929.5, 1457.8, 1376.8, 1245.3 cm-1
;
HRMS calcd for C8H16O2 (M - H2O) 126.1045, found 126.1053;
LRMS (EI) m/ z 126 (8), 111 (35), 101 (13), 83 (42), 71 (57), 55
(50), 43 (100). Anal. Calcd for C8H16O2: C, 66.63; H, 11.18.
Found: C, 63.79; H, 11.64.
3-Eth yl-1,4-d im eth yl-1,3-cyclop en ta n ed iol (14b, 15b)
was prepared from 13b according to the general procedure
described above to afford after flash chromatography with
ethyl ether 0.085 g (0.54 mmol) of a 100:1 mixture of diaster-
eomers 14b:15b in 65% yield. 14b (major): 1H NMR (400
MHz, CDCl3) δ 0.83 (d, J ) 7.13 Hz, 3H), 0.91 (t, J ) 7.43 Hz,
3H), 1.29 (s, 3H), 1.34-1.40 (m, 1H), 1.42-1.58 (m, 2H), 1.61-
1.65 (m, 1H), 1.72-1.76 (m, 1H), 2.14-2.20 (m, 1H), 2.22-
2.30 (m, 1H), 2.40-2.90 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 8.13, 18.40, 28.60, 28.95, 44.22, 50.19, 50.41, 78.57, 85.35;
IR (neat) 3372.4, 2963.2, 2929.9, 1458.5, 375.8, 1149.1 cm-1
;
HRMS calcd for C9H18O2 (M - H2O) 140.1201, found 140.1187;
LRMS (EI) m/ z 140 (10), 125 (18), 111 (41), 97 (25), 83 (40),
71 (35), 57 (100). Anal. Calcd for C9H18O2: C, 68.31; H, 11.46.
Found: C, 67.52; H, 11.90.
3-Isopr opyl-1,4-dim eth yl-1,3-cyclopen tan ediol (14c, 15c)
was prepared from 13c according to the general procedure
described above to afford after flash chromatography with
ethyl ether 0.094 g (0.55 mmol) of a 50:1 mixture of diaster-
eomers 14c:15c in 66% yield. 14c (major): 1H NMR (400 MHz,
CDCl3) δ 0.82 (d, J ) 7.33 Hz, 3H), 0.87 (d, J ) 6.85 Hz, 3H),
0.89 (d, J ) 6.92 Hz, 3H), 1.31 (s, 3H), 1.47-1.52 (m, 1H),
1.63-1.67 (m, 1H), 1.68-1.72 (m, 1H), 1.77-1.81 (m, 1H),
2.09-2.15 (m, 1H), 2.35-2.41 (m, 1H), 2.80 (br s, 2H); 13C NMR
(100 MHz, CDCl3) δ 16.28, 17.73, 19.34, 29.60, 31.49, 43.53,
49.36, 50.41, 78.70, 88.15; IR (neat) 3382.2, 2966.6, 2934.2,
1377.5, 1244.1, 1151.2 cm-1; HRMS calcd for C10H20O2 172.1463,
found 172.1467; LRMS (EI) m/ z 154 (28), 129 (46), 111 (55),
83.43, 69 (60), 55 (50), 43 (100). Anal. Calcd for C10H20O2:
C, 69.72; H, 11.70. Found: C, 69.72; H, 12.01.
3-ter t-Bu tyl-1,4-dim eth yl-1,3-cyclopen tan ediol (14d, 15d)
was prepared from 13d according to the general procedure
described above to afford after flash chromatography with
ethyl ether 0.125 g (0.67 mmol) of a 2:1 mixture of diastere-
omers 14d :15d in 81% yield. 14d (major): 1H NMR (400 MHz,
CDCl3) δ 0.93 (s, 9H), 1.06 (d, J ) 7.01 Hz, 3H), 1.27 (s, 3H),
1.52-1.58 (m, 1H), 1.69-1.73 (m, 1H), 1.81-1.85 (m, 1H),
1.94-2.00 (m, 1H), 2.27-2.35 (m, 1H), 2.50-3.00 (br s, 2H);
13C NMR (100 MHz, CDCl3) δ 17.69, 26.00, 27.80, 37.12, 37.42,
49.60, 50.23, 78.71, 87.63; IR (neat) 3380.9, 2958.8, 2874.5,
1395.8, 1375.5, 1128.1 cm-1; HRMS calcd for C11H22O2 (M -
CH3) 171.1385, found 171.1396, (M - H2O) 168.1514, found
168.1510; LRMS (EI) m/ z 143 (10), 129 (37), 111 (77), 95 (11),
83 (32), 69 (60), 57 (100). Anal. Calcd for C11H22O2: C, 70.92;
H, 11.90. Found: C, 71.24; H, 11.96. 15d (minor): 1H NMR
(400 MHz, CDCl3) δ 0.99 (s, 9H), 1.00 (d, J ) 7.01 Hz, 3H),
1.83 (s, 3H), 1.45-1.49 (m, 1H), 1.68-1.71 (m, 1H), 1.93-1.96
(m, 1H), 2.18-2.25 (m, 1H), 2.38-2.44 (m, 1H), 2.60-2.90 (br
s, 2H); 13C NMR (100 MHz, CDCl3) δ 21.80, 26.59, 29.99, 36.62,
45.22, 45.44, 51.78, 77.60, 90.07; IR (neat) 3310.5, 2962.7,
2952.4, 1483.3, 1373.9, 1263.0 cm-1; HRMS calcd for C11H22O2
(M - CH3) 171.1385, found 171.1376, (M - H2O) 168.1514,
found 168.1501; LRMS (EI) m/ z 129 (16), 111 (28), 95 (8), 83
(22), 69 (37), 57 (94), 43 (100). Anal. Calcd for C11H22O2: C,
70.92; H, 11.90. Found: C, 70.58; H, 12.01.
3,4-Dim eth yl-1,3-cycloh exa n ed iol (10a , 11a ) was pre-
pared from 9a according to the general procedure described
above to afford after flash chromatography with ethyl ether
0.088 g (0.61 mmol) of a 3:1 mixture of diastereomers 10a :
11a in 74% yield.3c
1-Isopr opyl-3,4-dim eth yl-1,3-cycloh exan ediol (10b, 11b)
was prepared from 9b according to the general procedure
described above to afford after flash chromatography (75%
ethyl ether/hexanes) 0.060 g (0.33 mmol) of a 3:1 mixture of
diastereomers 10b:11b in 40% yield. 10b (major): 1H NMR
(400 MHz, CDCl3) δ 0.88 (d, J ) 7.18 Hz, 3H), 0.89 (d, J )
6.83 Hz, 6H), 1.12 (s, 3H), 1.23-1.31 (m, 2H), 1.37-1.40 (m,
1H), 1.46-1.55 (m, 3H), 1.71-1.75 (m, 1H), 2.18-2.25 (m, 1H),
2.80-3.50 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 15.92,
16.62, 16.73, 24.12, 27.53, 28.92, 38.54, 38.63, 38.95, 74.12,
75.31; IR (neat) 3324.0, 2960.4, 2877.7, 1455.9, 1380.8, 1168.9
cm-1; HRMS calcd for C11H22O2 (M - H2O) 168.1514, found
168.1507, (M - CH3) 171.1385, found 171.1407; LRMS (EI)
m/ z 168 (7), 143 (45), 125 (48), 83 (58), 69 (61), 55 (42), 43
(100). Anal. Calcd for C11H22O2: C, 70.92; H, 11.70. Found:
C, 71.30; H, 12.30.
4-Ben zyl-2,3-d im eth yl-1,3-cycloh exa n ed iol (19a , 20a )
was prepared from 18a according to the general procedure
described above to afford after flash chromatography (66%
ethyl ether/hexanes) 0.136 g (0.63 mmol) of a 2.55:1 mixture
of diastereomers 19a :20a in 82% yield. 19a (major): 1H NMR
(400 MHz, CDCl3) δ 1.22 (s, 3H), 1.27 (s, 3H), 1.16-1.24 (m,
1H), 1.41-1.45 (m, 1H), 1.50-1.55 (m, 2H), 1.63-1.67 (m, 1H),
1.86-1.98 (m, 2H), 2.28-2.35 (m, 1H), 2.72-2.77 (m, 1H), 3.50
(br s, 1H), 3.70 (br s, 1H), 7.12-7.19 (m, 3H), 7.24-7.29 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 18.69, 28.89, 31.21, 32.67,
1,3,4-Tr im eth yl-1,3-cyclop en ta n ed iol (14a , 15a ) was
prepared from 13a according to the general procedure de-
scribed above to afford after flash chromatography with ethyl

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2943
34.68, 44.28, 45.99, 71.28, 74.08, 125.95, 128.42, 128.90,
141.00; IR (neat) 3330.6, 2964.5, 2935.4, 1453.6, 1374.0, 1191.3
cm-1; HRMS calcd for C15H22O2 (M - H2O) 1216.1514, found
216.1522; LRMS (EI) m/ z 216 (31), 198 (20), 158 (42), 118 (68),
101 (50), 91 (70), 43 (100). Anal. Calcd for C15H22O2: C, 76.88;
H, 9.46. Found: C, 74.99; H, 9.63. 20a (minor): 1H NMR (400
MHz, CDCl3) δ 1.17 (s, 3H), 1.23 (s, 3H), 1.18-1.35 (m, 3H),
1.41-1.47 (m, 2H), 1.53-1.59 (m, 1H), 1.77-1.81 (m, 1H),
2.33-2.40 (m, 1H), 2.70 (br s, 1H), 3.03-3.07 (m, 1H), 3.50
(br s, 1H), 7.14-7.18 (m, 3H), 7.24-7.28 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 22.55, 28.56, 31.17, 35.68, 38.73, 47.39,
49.87, 71.57, 72.65, 125.64, 128.19, 129.24, 141.65; IR (neat)
3337.0, 2928.0, 1452.6, 1185.8 cm-1; HRMS calcd for C15H22O2
(M - H2O) 216.1514, found 216.1528; LRMS (EI) m/ z 216 (39),
198 (16), 158 (40), 118 (62), 91 (80), 43 (100). Anal. Calcd for
C15H22O2: C, 76.88; H, 9.46. Found: C, 75.76; H, 9.63.
Eth yl (1R*,3R*,4S*)-1,3-dim eth yl-4-(car boxylatom eth yl)-
1,3-cycloh exa n ed iol (19b, 20b) was prepared from 18b
according to the general procedure described above to afford
after flash chromatography (66% ethyl ether/hexanes) 0.163
g (0.71 mmol) of a 50:1 mixture of diastereomers 19b:20b in
85% yield. 19b (major): 1H NMR (400 MHz, CDCl3) δ 1.14
(s, 3H), 1.18 (s, 3H), 1.24 (t, J ) 7.18 Hz, 3H), 1.32-1.55 (m,
1H), 1.58-1.63 (m, 5H), 2.15-2.23 (m, 2H), 2.25-2.35 (m, 1H),
3.10-3.60 (br s, 2H), 4.12 (q, J ) 7.10 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 14.22, 21.39, 28.24, 30.95, 32.86, 35.08, 40.76,
44.06, 60.59, 70.99, 73.42, 173.08; IR (neat) 3357.7, 2968.8,
2932.7, 1732.3, 1290.8, 1184.1 cm-1; HRMS calcd for C12H22O4
(M - H2O) 212.1412, found 212.1414; LRMS (EI) m/ z 167 (10),
151 (6), 115 (14), 101 (42), 43 (100). Anal. Calcd for
C12H22O4: C, 62.58; H, 9.63. Found: C, 61.85; H, 10.03.
Eth yl (1R*,3S*,4S*)-1-m eth yl-3-isop r op yl-4-(ca r boxyl-
a tom eth yl)-1,3-cycloh exa n ed iol (19c, 20c) was prepared
from 18c according to the general procedure described above
to afford after flash chromatography (66% ethyl ether/hexanes)
0.163 g (0.67 mmol) of a 50:1 mixture of diastereomers 19c:
20c in 81% yield. 19c (major): 1H NMR (400 MHz, CDCl3) δ
0.90-0.93 (m, 6H), 1.23 (t, J ) 7.31 Hz, 3H), 1.33 (s, 3H), 1.57-
1.64 (m, 3H), 1.83-1.94 (m, 2H), 2.32-2.38 (m, 1H), 2.41-
2.46 (m, 1H), 2.51-2.57 (m, 2H), 3.09 (br s, 1H), 4.08-4.13
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.23, 16.34, 17.82,
29.42, 31.84, 37.76, 45.87, 47.56, 49.86, 60.59, 78.53, 87.04,
172.70; IR (neat) 3422.4, 2967.2, 1734.1, 1372.5, 1257.2, 1160.7
cm-1; HRMS calcd for C13H24O4 (M - H2O) 226.1569, found
226.1552, (M - CH3) 229.1440, found 229.1431; LRMS (EI)
m/ z 226 (17), 209 (38), 183 (41), 137 (52), 109 (50), 71 (56), 43
(100). Anal. Calcd for C13H24O4: C, 63.91; H, 9.90. Found:
C, 63.20; H, 10.36.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 35249) for their generous support
of this work. Additional support from the Ministerio
de Educacion y Ciencia of Spain for a Postdoctoral
Fellowsip to C.d.P.L. is gratefully acknowledged. Fi-
nally, we thank Dr. Bruce Noll for performing the X-ray
crystallographic structure determinations.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra of synthesized compounds (70 pages).
This material is contained in libraries on microfiche, im-
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J O970022C