Sequenced reactions with samarium(II) iodide. Sequential intramolecular Barbier cyclization/Grob fragmentation for the synthesis of medium-sized carbocycles

Article abstract of DOI:10.1021/jo001513r

Samarium(II) iodide was used to access eight-, nine-, and ten-membered carbocycles via a domino reaction composed of a cyclization/fragmentation process. 2-(Iodoalkyl)-, 2-(iodomethyl)allyl-, and 2-(2-iodomethyl)benzyl-2-methyl-3-(methanesulfonyloxy)cycloalkanones were subjected to Barbier-type reductive coupling conditions. Intermediate cycloalkanedione derivatives were also treated under similar conditions, providing bicyclic hydroxy ketones with complete diastereoselectivity and high yields. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.

Full text of DOI:10.1021/jo001513r

J . Org. Chem. 2001, 66, 4511-4516
4511
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. Sequ en tia l
In tr a m olecu la r Ba r bier Cycliza tion /Gr ob F r a gm en ta tion for th e
Syn th esis of Med iu m -Sized Ca r bocycles
Gary A. Molander,* Yvan Le Hue´rou, and Giles A. Brown
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received October 23, 2000
Samarium(II) iodide was used to access eight-, nine-, and ten-membered carbocycles via a domino
reaction composed of a cyclization/fragmentation process. 2-(Iodoalkyl)-, 2-(iodomethyl)allyl-, and
2-(2-iodomethyl)benzyl-2-methyl-3-(methanesulfonyloxy)cycloalkanones were subjected to Barbier-
type reductive coupling conditions. Intermediate cycloalkanedione derivatives were also treated
under similar conditions, providing bicyclic hydroxy ketones with complete diastereoselectivity and
high yields. This method represents a general and efficient approach to a variety of highly
functionalized, stereodefined carbocycles.
In tr od u ction
reaction has been widely applied to the synthesis of
natural products, but the diversity and complexity of the
molecules isolated from plants and other organisms
dictates the need for further development.6 This is
especially true when it comes to the synthesis of the
bicyclic precursor required for the fragmentation.
The formation of medium-sized rings remains chal-
lenging because of well-known entropic and enthalpic
factors.1 To circumvent these, numerous methods involv-
ing ring expansion or fragmentation have been used to
access such frameworks.2 For example, oxy-Cope rear-
rangements,3 Wharton/Grob fragmentations,4 and sa-
marium(II) iodide sequenced reactions5 have been suc-
cessfully applied. Among these methods, the Grob
fragmentations possess several attractive features. First,
they are stereospecific with regard to the stereochemistry
of the leaving group. Consequently, both cis and trans
cyclic olefins are accessible from diastereomeric starting
materials. Second, the stereochemistry at the alkoxide
plays no role in the stereoselectivity of the fragmentation.
Finally, the fragmentation proceeds under fairly mild
conditions with excellent yields. For these reasons, the
An elegant way of solving this problem is to perform a
domino reaction during which the bicyclic system is first
formed and then fragmented to yield a carbocycle.
Sequential protocols that are related to this approach
have been developed using stannyl radicals to initiate
the ring expansion/fragmentation. Unfortunately, the
species formed in these cases are often capable of
alternative reactions (hydrogen abstraction in particular)
that lower the yield of fragmented products.7 More
recently, stannyl anion8 or indium metal9 have proven
to be useful agents to perform the ring expansion/Grob
fragmentation of functionalized cycloalkanones, but they
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10.1021/jo001513r CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/24/2001

4512 J . Org. Chem., Vol. 66, No. 13, 2001
Molander et al.
Sch em e 1
Sch em e 3
Sch em e 2
their “W” geometry and steric hindrance at the carbon
site.13 As a consequence, both conditions employed (Cs2-
CO3/DMF and NaH/DMF) yielded mixtures of C- and
O-alkylated products, the C-/O- ratio depending on the
reactivity of the electrophile. From this mixture the
desired C-alkylated products were isolated.
Conversion of the resultant C-alkylated chloro- or
bromo-substituted diones into the corresponding iodides
under Finkelstein conditions then provided a series of
iodo diones. Only 2-(2-chloroethyl)-2-methylcyclohexane-
1,3-dione could not be converted to the corresponding
iodide, the latter being too unstable.
At this point, it appeared prudent to submit our
intermediate cycloalkanedione derivatives to a SmI2-
promoted intramolecular reductive coupling reaction.
This early investigation was undertaken to confirm that
the Barbier coupling could be realized and to probe the
possibility of fragmentation of the samarium alkoxide
intermediates by a retro aldol process (Scheme 3). Thus,
diones 1 were added to a solution of SmI2 containing 2%
of NiI2 as a catalyst at or below 0 °C (Table 1).14 The first
attempt (entry 1) proved to be disappointing because a
complex mixture was isolated even when the reaction was
carried out under irradiation with visible light.15 It
appeared that none of the conditions used enabled the
effective reductive coupling of the chloride to the ketone,
and only competitive reduction of the carbonyls or other
undesired reactions predominated.11 Fortunately, the
next attempts (entries 2 and 4) were more successful, and
2-(3-iodopropyl)-2-methylcycloalkane-1,3-diones 1b and
1d could be effectively transformed to the corresponding
bicyclic hydroxy ketones 2b and 2d with complete cis
diastereoselectivity at the ring junction. As expected, the
higher homologues (entries 3, 5, and 6) proved to be more
difficult (1c and 1e) or impossible (1f ) to cyclize owing
to entropic considerations. The formation of cyclized
products 2c and 2e could be observed in 62% and 30%
have only been involved in the synthesis of eight-
membered rings from cycloalkanone derivatives.
We report in this contribution an intramolecular Bar-
bier-type coupling/fragmentation protocol mediated by
samarium(II) iodide (Scheme 1). This mild reductive
coupling agent appears especially suited to the desired
sequence for the following reasons: several sequential
reactions involving SmI2-promoted coupling followed by
elimination or fragmentation have been reported.5b The
intramolecular Barbier reaction can occur between the
iodoalkyl chain and the ketone of the cycloalkanones,
generating a bicyclic alkoxide that can then undergo
fragmentation. During the latter process, the stereo-
chemistry at the alkoxide center will have no effect on
the stereochemistry of the fragmented product because
of the characteristics of the Grob fragmentation. As a
consequence, even if the annulation is not completely
diastereoselective, only one unsaturated isomer will be
isolated depending on the configuration of the side chain/
leaving group system. We also felt confident that two of
the potential problems in such an approach (i.e., reduc-
tion or elimination of the leaving group prior to the
cyclization) could be avoided. Although SmI2 reacts with
sulfonates under reductive coupling conditions, it does
so at rates that are much slower than primary iodides.10
Finally, SmI2-promoted processes are essentially neutral
so that the leaving group is not expected to be eliminated
prior to the reductive cyclization. The major restriction
of the method concerns the length of the iodoalkyl chain.
All these elements were integrated in our protocol. The
following results describe an efficient method for the
synthesis of functionalized, stereodefined, eight-, nine-,
and ten-membered rings.
(11) (a) Molander, G. A.; Etter, J . B. J . Org. Chem. 1986, 51, 1778-
1786. (b) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem. Soc.
1987, 109, 453-463.
Resu lts a n d Discu ssion
(12) (a) Bedekar, A. B.; Watanabe, T.; Kiyoshi, T.; Fuji, K. Synthesis
1995, 1069-1070. (b) Schick, H.; Scwarz, H.; Finger, A. Tetrahedron
1982, 38, 1279-1283. (c) Rajamannar, T.; Palani, N.; Balasubrama-
nian, K. K. Synth. Commun. 1993, 23, 3095-3108. (d) Fujiwara, M.;
Hitomi, K.; Baba, A.; Matsuda, H. Chem. Lett. 1994, 875-876.
(13) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo
Park, 1972; pp 520-532.
(14) Kagan, H. B.; Machrouhi, F.; Hamann, B. Synlett 1996, 633.
(15) (a) Ogawa, A.; Ohya, S.; Hirao, T. Chem. Lett. 1997, 275. (b)
Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao, T. J .
Am. Chem. Soc. 1997, 119, 2745. (c) Skene, W. G.; Scaino, J . C.; Cozens,
F. L. J . Org. Chem. 1996, 61, 7918.
The substrates were prepared according to the general
route shown in Scheme 2. The first step involved the
alkylation of 2-methylcycloalkane-1,3-diones with suit-
able dihalides. Although many methods have been re-
ported for such reactions,12 2-methylcycloalkane-1,3-
diones are especially prone to O-alkylation because of
(10) (a) Molander, G. A. Chem. Rev. 1992, 92, 29. (b) Molander, G.
A. Org. React. 1994, 46, 211.

Sm(II)-Mediated Synthesis of Medium-Sized Carbocycles
J . Org. Chem., Vol. 66, No. 13, 2001 4513
Ta ble 1. Cycliza tion of Su bstitu ted 2-Meth ylcycloa lk a n e-1,3-d ion es w ith Sm I2/Ca t. NiI2
a
b
Complex mixtures were observed. 2c and 2e could be observed by NMR along with 3a and 3b but could not be separated.
Complex mixture.
c
Sch em e 4
configuration was assigned on the basis of single-crystal
X-ray analysis. As in the preceding examples, none of the
conditions tested enabled the fragmentation.
The next reactions involved trans- and cis-2-(4-iodobut-
2-enyl)-2-methylcyclohexane-1,3-diones. Complex mix-
tures were observed when the trans isomer 6a was
subjected to reductive conditions but the cis isomer 6b
yielded the desired fragmented compound as its hydrated
bis-hemiacetal. Unfortunately, none of the conditions
tested (irradiation, low temperatures, or exchange to the
less reactive bromide) could increase the low yield
observed. Substrate 6b reacts with allylic inversion,
generating a strained 6-4 bicyclic ring system that is
prone to fragmentation. The 5-5, 5-6, and 6-6 bicyclic
systems, formed by substrates 1b-1e, 4a , 4b, 8a , and 8b,
are too stable to allow the expansion process. These
results are consistent with literature precedent.8,9 Through
a similar sequence, Li et al. had previously shown that
4-bromobut-2-enyl-â-keto esters yielded ring-expanded
products when treated with indium in water. In that
study, both olefin isomers of the substrate allylic halide
could be utilized in the process.9
yields; however, these compounds were inseparable from
the reduced â-hydroxy ketone products 3a and 3b (Scheme
4).11b Substrate 1f gave only a complex mixture of
products. At this point it is interesting to note that at
room temperature or even under reflux, none of the
samarium alkoxide intermediates led to fragmentation.
The highly reactive 2-(2-iodomethyl)benzyl-2-methyl-
cycloalkane-1,3-diones (entries 7 and 8) turned out to be
excellent substrates for the cyclization because both 4a
and 4b were converted to the tricyclic hydroxy ketones
5 without irradiation and in short reaction times. In these
two cases the inherent reactivity of the benzylic halide
in concert with the conformational bias imposed by the
aromatic ring proved to be an excellent combination for
the formation of the six-membered ring. Furthermore,
the reaction was completely diastereoselective. The cis
Finally, reactive 2-(2-iodomethyl)allyl-2-methylcycloal-
kane-1,3-diones (entries 11 and 12) were smoothly cy-
clized, yielding the cis-fused systems 9 with excellent
yield and complete diastereoselectivity. The reductive

4514 J . Org. Chem., Vol. 66, No. 13, 2001
Ta ble 2. Rin g Exp a n sion s Med ia ted by Sa m a r iu m (II) Iod id e
Molander et al.
a
b
c
The mesylate was reduced before the chloride. Complex mixture. The fragmented nine membered ring 21 could be obtained in
88% yield by treating 17 with 1 equiv of NaOMe in methanol heated at reflux (see Scheme 5).
coupling of cyclic diketones bearing iodoalkyl, -allyl, or
-benzyl side chains therefore constitutes an effective
method to access a variety of diastereomerically pure
polycyclic hydroxy ketones affording an alternative to the
existing methods.16
In light of these results, we felt confident that in the
presence of a leaving group, the substrates would un-
dergo fragmentation because the cyclization had occurred
with good yields in most of the cases. The requisite
2-substituted-2-methyl-3-(methanesulfonyloxy)cycloal-
kanones were therefore prepared by reduction of the
corresponding cycloalkanediones.
ties (Scheme 2). Using NaBH4 in MeOH/H2O, the diones
could be reduced with good yields, affording the corre-
sponding ketols with cis/trans selectivities varying from
2/1 to 9/1. The use of EuCl3‚6H2O as a chelating agent
proved to increase the diastereoselectivity slightly.17b,18
In the case of butenyl halides, the reduction of the dione
did not yield the expected ketol but rather a mixture of
diastereomeric vinyl ethers 12 and 13 resulting from an
intramolecular SN2′ displacement of the halide (eq 1).19
This undesired reaction could not be avoided by using
different hydrides (DIBALH, LiBHEt3), exchanging the
halogen from iodine to bromine, or by performing the
reaction at low temperature.
Both chemical and yeast-mediated reduction protocols
have been described to access ketols from cyclic diones.17
We focused on a sodium borohydride reduction, hydrides
being known to yield ketols with good diastereoselectivi-
(16) (a) Kinoshita, A.; Mori, M. Chem. Lett. 1994, 1475-1478. (b)
Helquist, P.; Carey, J . T. Tetrahedron Lett. 1988, 29, 1243-1246. (c)
Watanabe, T.; Sakai, M.; Miyaura, N.; Susuki, A. J . Chem. Soc., Chem.
Commun. 1994, 467. (d) Schinzer, D.; Panke, G. J . Org. Chem. 1994,
61, 4496-4497. (e) Ahiko, T.-A.; Ishiyama, T.; Miyaura, N. Chem. Lett.
1997, 811.
(17) (a) Renouf, P.; Poirier, J .-P.; Duhamel, P. J . Chem. Soc., Perkin
Trans. 1 1997, 1739-1745. (b) Renouf, P.; Poirier, J .-P.; Duhamel, P.
J . Org. Chem. 1999, 64, 2513-2515. (c) Brooks, D. W.; Mazdiyasni,
H.; Chakrabarti, S. Tetrahedron Lett. 1984, 25, 1241-1244. (d) Brooks,
D. W.; Mazdiyasni, H.; Grothaus, P. G. J . Org. Chem. 1987, 52, 3223-
3232. (e) Fuhshuku, K.-I.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi,
H.; Ohba, S.; Sugai, T. J . Org. Chem. 2000, 65, 129-135. (f) Mori, K.;
Fujiwhara, M. Tetrahedron 1988, 44, 343-354.
After mesylation under standard conditions (MsCl,
Et3N, CH2Cl2, -78 °C, 3 h), the diastereomers were
(18) Krief, A.; Surleraux, D. Synlett 1991, 273-275.
(19) Wang, T.; Chen, J .; Zhao, K. J . Org. Chem. 1995, 60, 2668-
2669.

Sm(II)-Mediated Synthesis of Medium-Sized Carbocycles
J . Org. Chem., Vol. 66, No. 13, 2001 4515
Sch em e 5
was observed. This result attests to the mild nature of
these cyclization/fragmentation processes, which appar-
ently occur under near-neutral reaction conditions.
Con clu sion
A samarium(II) iodide-promoted sequential cyclization/
fragmentation protocol was developed that provides an
efficient approach to the synthesis of functionalized,
stereodefined medium-sized carbocycles. This method
involves the reduction under Barbier-type conditions of
substituted keto mesylates bearing iodoalkyl, -allyl, or
-benzyl side chains. The reaction proceeds in a stereose-
lective manner with high yields under mild conditions.
The cyclization of cycloalkanediones under similar condi-
tions was also observed, yielding functionalized polycyclic
hydroxy ketones in high yields with complete diastereo-
selectivity.
separated by recrystallization, and their configuration
was confirmed by NOE experiments. Only the cis isomers
could be isolated diastereomerically pure. The cis keto
mesylates were treated with samarium(II) iodide in THF
in the presence of 2% NiI2. The reactivity of these
substrates proved to be consistent with the reactivity of
the parent diones. Furthermore, the intermediate orga-
nosamarium species underwent fragmentation at room
temperature (Table 2). Finally, the isolated yields were
similar to those observed for the previous cyclizations
(Table 1), suggesting that the fragmentations are quan-
titative and irreversible. The ring expansion also proved
to be stereoselective because the isolated olefins showed
the expected cis geometry. The configurations were
assigned on the basis of NOE experiments and by
comparison with literature data.4f As observed during the
preliminary study, the chloroalkyl substrate 14a (entry
1) did not yield the desired eight-membered ring. How-
ever, eight-, nine-, and ten-membered cycloenones could
be readily generated from substrates 14b, 14c, and 14d ,
respectively (entries 2-5).
Surprisingly, 16a (entry 7) could not be fragmented
under standard conditions. The only isolated product was
the intermediate hydroxy mesylate 17. Heating the
reaction mixture at reflux yielded degraded products. Use
of either LiBr or HMPA as alternative additives for the
SmI2 reaction also failed to induce fragmentation. How-
ever, 17 was easily fragmented to 21 by treatment with
sodium methoxide in methanol heated at reflux (Scheme
5). At this point, it is not clear why the samarium
alkoxide of 16 did not fragment. Even if it does not easily
satisfy the antiperiplanar orientation required for syn-
chronous fragmentation because of conformational fac-
tors, this barrier should also apply to several of the other
intermediates in the study that do undergo fragmenta-
tion at room temperature. The nature of the alkoxide-
metal species must play an important role as demon-
strated by the results displayed in Scheme 5. The bond
between the oxophilic samarium(III) and the alkoxide
appears to be too strong to allow further reaction
compared to the more ionic bond engaged between
sodium and oxygen. However, even if the nine-membered
ring cannot be directly accessed during the sequential
process, it can still be obtained in two steps with an
overall yield of 73%. The homolog, 16b, cyclizes and
readily fragments to provide cyclodecenone 18 in excel-
lent yield (entry 8).
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H and 13C NMR were recorded at
500 and 125 MHz for proton and carbon, respectively. CDCl3
was employed as the solvent unless stated otherwise, and
residual CHCl3 was applied as an internal standard (δ ) 7.24
1
ppm) for H spectra while the CDCl3 signal served as internal
standard (δ ) 77.0 ppm) for 13C spectra. Standard flash
chromatography procedures were followed using 32-63 µm
silica gel.20 Tetrahydrofuran (THF) was distilled immediately
prior to use from sodium benzophenone ketyl under Ar.
Samarium metal was purchased from Aldrich (99.9%, 40
mesh). CH2I2 was purchased from Aldrich, distilled under Ar,
and stored over copper granules. NiI2 powder was purchased
from Aldrich (99.999%). Standard benchtop techniques were
employed for handling air-sensitive reagents,21 and all air-
sensitive reactions were carried out under N2.
Gen er a l P r oced u r e for th e Alk yla tion of 2-Meth ylcy-
cloa lk a n e-1,3-d ion es w ith Dih a loa lk a n es. 2-(2-Ch lor oet-
h yl)-2-m eth ylcycloh exa n e-1,3-d ion e (1a ). To a solution of
2-methylcyclohexane-1,3-dione (12.6 g, 100 mmol) in 150 mL
of dry DMF was added anhydrous Cs2CO3 (35.8 g, 110 mmol)
at room temperature. The suspension was stirred for 10 min,
and 1-bromo-2-chloroethane (43 g, 300 mmol) was added at
once. The resulting yellow suspension was stirred for 14 h at
room temperature and then quenched with 150 mL of brine.
The mixture was extracted several times with EtOAc, and the
organic extracts were washed with water and dried with
MgSO4. Flash chromatography (50% EtOAc/petroleum ether)
yielded 1.72 g (9%) of the title compound and 9 g (48%) of 3-(2-
chloroethoxy)-2-methylcyclohex-2-enone as colorless oils. 1a :
1H NMR (CDCl3, 500 MHz) δ 3.36 (t, J ) 7.3 Hz, 2H), 2.65-
2.55 (m, 4H), 2.27 (t, J ) 7.4 Hz, 2H), 1.98-1.87 (m, 2H), 1.08
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 209.5, 63.2, 40.3, 37.7,
37.3, 23.1, 17.5; IR (film) νmax 1726, 1697, 1457, 1317 cm-1
;
HRMS (CI+) calc for (M - H)+ C9H12ClO2 187.0525, found
187.0527. 3-(2-Ch lor oeth oxy)-2-m eth ylcycloh ex-2-en on e:
1H NMR (CDCl3, 500 MHz) δ 4.17 (t, J ) 5.6 Hz, 2H), 3.67 (t,
J ) 5.6 Hz, 2H), 2.50-2.45 (m, 2H), 2.27 (t, J ) 6.8 Hz, 2H),
1.95-1.88 (m, 2H), 1.64 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
198.7, 169.9, 116.0, 67.3, 42.2, 36.1, 25.4, 20.8, 7.3; IR (film)
νmax 2949, 1620, 1355, 1234 cm-1; HRMS (CI+) calc for (M)+
C9H13ClO2 188.0604, found 188.0594.
Gen er a l P r oced u r e for Alk yla tion of 2-Meth ylcycloa l-
k a n e-1,3-d ion es w ith Bis(ben zylic) a n d Bis(a llylic) Di-
h alides. 2-(2-Br om om eth yl)ben zyl-2-m eth ylcyclopen tan e-
1,3-d ion e. To a suspension of hexanes washed NaH (1.76 g,
66 mmol) in 70 mL of anhydrous DMF at 0 °C was slowly
added a solution of 2-methyl-1,3-cylopentanedione (4.5 g, 40
mmol) in 70 mL of anhydrous DMF. The resulting solution
Finally, substrate 19 can be smoothly converted to
cyclononadienone 20 in exceptional yield (entry 9). Of
particular note here is the fact that no isomerization of
the exomethylidene to the conjugated endocyclic isomer
(20) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(21) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.

4516 J . Org. Chem., Vol. 66, No. 13, 2001
Molander et al.
was stirred for 1 h at room temperature and then added over
2 h to a solution of R,R′-dibromo-o-xylene in 70 mL of
anhydrous DMF. The reaction mixture was stirred for an
additional 48 h and then cooled to 0 °C before being hydrolyzed
with 200 mL of ice. The organic materials were extracted with
Et2O, and the organic phase was washed with brine and dried
over MgSO4. Flash chromatography (50% EtOAc/petroleum
ether) yielded 2.3 g (19%) of the title compound and 1.3 g (11%)
of 3-(2-bromomethylbenzyloxy)-2-methylcyclohex-2-enone as
colorless crystals. 2-(2-Br om om eth yl)ben zyl-2-m eth ylcy-
2H), 2.33-2.25 (m, 1H), 2.22-2.17 (m, 2H), 2.08-1.95 (m, 2H),
1.76-1.70 (m, 1H), 1.23 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
209.8, 85.9, 52.8, 39.6, 38.9, 37.1, 35.7, 27.0, 19.9, 19.3; IR (film)
ν
max 1712, 1350, 1174 cm-1; HRMS (CI+) calc for (MH)+ C10H18
-
ClO4S 269.0614, found 269.0627.
Gen er a l P r oced u r e for th e Sequ en ced Rea ction s Us-
in g Sa m a r iu m (II) Iod id e. Samarium metal (420 mg, 2.8
mmol) was added under a flow of N2 to an oven-dried flask.
20 mL of THF were added, the suspension was cooled between
-10 °C and 0 °C, and CH2I2 (699 mg, 2.6 mmol) was added.
The mixture was stirred at room temperature for 2 h, and NiI2
(2% mol) was added. After stirring 5 min, the deep-blue
solution was cooled to the requisite temperature, and the
substrate (1 mmol) in 10 mL of THF was added over 5 min.
The reaction was irradiated or not with visible light (250 W
krypton lamp) while keeping the temperature at the previously
mentioned level. After the starting material was consumed
(TLC or GC analysis), the reaction mixture was warmed to
room temperature and stirred for 1 h. The resultant solution
was quenched with a saturated aqueous solution of Rochelle’s
salt and extracted several times with Et2O. The organic
extracts were washed with brine and dried over MgSO4. The
products were purified by flash chromatography unless stated
otherwise.
3R-Hydr oxy-6R-m eth ylh exah ydr open talen -1-on e (2b).16b
Prepared from 1b (279 mg, 1 mmol) according to the general
procedure described above (under irradiation, -30 °C for 3 h)
to afford, after flash chromatography (50% EtOAc/petroleum
ether), 2b (144 mg, 94%) as a colorless gel:1H NMR (CDCl3,
500 MHz) δ 2.51-2.42 (m, 1H), 2.34-2.24 (m, 1H), 2.13-2.04
(m, 1H), 1.98-1.72 (m, 5H), 1.63-1.42 (m, 3H), 1.10 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 222.0, 87.4, 58.6, 40.1, 36.2, 35.9,
32.8, 22.2, 16.3; IR (film) νmax 3452, 1731 cm-1; HRMS (CI+)
calc for (MH)+ C9H15O2 155.1072, found 155.1073.
(Z)-10-Meth yl-5,7,8,11-tetr a h yd r oben zocyclon on en -6-
on e (21). 17 (60 mg, 0.2 mmol) was added to a solution of
NaOMe (11 mg, 0.2 mmol) in 3 mL of MeOH and heated to
reflux for 1 h. The MeOH was evaporated, and 3 mL of water
were added. The aqueous phase was extracted with EtOAc,
and the combined organic phases were washed with brine and
dried over MgSO4. After evaporation of the solvent, the
resulting solid was recrystallized (Et2O/petroleum ether) to
yield 21 (34 mg, 88%) as colorless crystals: mp 118-120 °C;
1H NMR (CDCl3, 500 MHz) δ 7.19-7.11 (m, 4H), 5.23 (t, J )
8.5 Hz, 1H), 3.76 (s, 2H), 3.39 (s, 2H), 2.76-2.67 (m, 2H), 2.62-
2.55 (m, 2H), 1.57 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 210.0,
138.2, 136.5, 134.0, 132.5, 130.8, 127.0, 126.9, 122.6, 45.8, 44.0,
37.0, 24.1, 22.9; IR (film) νmax 2959, 1704, 1470 cm-1; HRMS
(CI+) calcd for (M)+ C14H16O 200.120115, found 200.120287.
1
clop en ta n e-1,3-d ion e: mp 86-88 °C; H NMR (CDCl3, 500
MHz) δ 7.35-7.30 (m, 1H), 7.25-7.19 (m, 2H), 7.10-7.05 (m,
1H), 4.68 (s, 0.6H), 4.60 (s, 1.4H), 3.19 (m, 2H), 2.69-2.57 (m,
2H), 2.23-2.14 (m, 2H), 1.28 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 217.3, 136.5, 136.3, 135.0, 131.1, 130.9, 130.4, 130.2,
129.92, 128.88, 127.9, 127.8, 58.1, 28.0, 44.2, 37.7, 37.5, 35.7,
31.9, 21.0, 20.8; IR (film) νmax 2969, 1762, 1722, 1449 cm-1
;
HRMS (CI+) calc for (MH)+ C14H16BrO2 295.0333, found
295.0329. 3-(2-Br om om eth yl)ben zyloxy-2-m eth ylcycloh ex-
1
2-en on e: mp 94 °C; H NMR (CDCl3, 500 MHz) δ 7.41-7.32
(m, 4H), 5.37 (s, 2H), 4.66 (s, 2H), 2.71-2.67 (m, 2H), 2.46-
2.40 (m, 2H), 1.65 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 205.2,
183.1, 135.3, 134.5, 130.6, 129.3, 129.2, 128.7, 117.1, 68.4, 43.6,
33.5, 25.2, 6.1; IR (film) νmax 2920, 1632, 1339 cm-1; HRMS
(CI+) calcd for (MH)+ C14H16BrO2 295.0333, found 295.0344.
Gen er a l P r oced u r e for th e F in k elstein Rea ction . 2-(3-
Iod op r op yl)-2-m eth ylcycloh exa n e-1,3-d ion e (1d ). To the
chloride precursor (4 g, 20 mmol) in 150 mL of acetone was
added 30 g (0.2 mol) of NaI. The solution was heated at reflux
for 12 h and cooled to room temperature, and 200 mL of water
was added. The aqueous phase was extracted with Et2O, and
the combined organic phases were washed with 10% aqueous
Na2S2O3 and brine and dried over MgSO4. Purification by flash
chromatography (50% EtOAc/petroleum ether) afforded 5.2 g
(88%) of 1d as a yellow oil:1H NMR (CDCl3, 500 MHz) δ 3.07
(dd, J ) 1.3, 6.7 Hz, 2H), 2.65-2.51 (m, 4H), 1.98-1.82 (m,
4H), 1.62-1.57 (m, 2H), 1.21 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 209.7, 64.9, 37.8, 37.1, 28.6, 20.2, 17.6, 5.8; IR (film)
νmax 1725, 1693, 1456 cm-1; HRMS (CI+) calcd for (MH)+
C10H15CIO2 295.0195, found 295.0187.
Gen er a l P r oced u r e for Red u ction a n d Mesyla tion of
t h e 1,3-Dion es. Met h a n esu lfon ic Acid , (Z)-(2R*,3R*)-2-
(2-Ch lor oeth yl)-2-m eth yl-3-oxocycloh exyl Ester (14a ). To
the dione 1a in 30 mL of THF at room temperature was added
dropwise 2.5 mL of a 0.5 M solution of aqueous NaBH4. The
solution was stirred for 1 h at room temperature, 60 mL of
water were added, and the pH was adjusted to 2 with a 0.5 M
aqueous HCl solution. The aqueous phase was extracted with
Et2O, and the combined organic phases were washed with
brine and dried over MgSO4. The crude mixture (60/40 cis/
trans) was purified by flash chromatography (30% EtOAc/
petroleum ether) to yield 756 mg (79%) of the alcohol as a
colorless liquid. To 1.65 g (8.7 mmol) of the alcohol in 140 mL
of CH2Cl2 and 1.8 g (18 mmol) of Et3N at -78 °C were added
1.5 g (13 mmol) of MsCl. The solution was stirred for 2 h at
the same temperature and hydrolyzed with 150 mL of brine.
The aqueous phase was extracted with Et2O, and the combined
organic phases were washed with brine and dried over MgSO4.
Purification by flash chromatography (30% EtOAc/petroleum
ether) and recrystallization (Et2O/EtOAc/petroleum ether)
yielded 1.70 g (73%) of 14a as colorless crystals: mp 84-86
°C; 1H NMR (CDCl3, 500 MHz) δ 4.71 (t, J ) 4.8 Hz, 1H), 3.55-
3.47 (m, 1H), 3.44-3.38 (m, 1H), 3.02 (s, 3H), 2.49-2.38 (m,
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM 35249) and Merck
& Co. for their generous support. We also thank Dr.
Patrick J . Caroll for performing the X-ray crystal
structure determinations.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, 1H and 13C NMR spectra for all compounds, and X-ray
structural data for 5a and 5b. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O001513R