Sequential Ketyl-Olefin Coupling/β-Elimination Reactions Mediated by Samarium(II) Iodide

Article abstract of DOI:10.1021/jo971889d

Samarium(II) iodide (SmI₂) has been employed in an intramolecular sequential ketyl-olefin coupling/β-elimination reaction. The overall process results in the net addition of an alkenyl species to a ketone carbonyl. This novel protocol for the intramolecular delivery of an alkenyl moiety avoids the basic reaction conditions typical of nucleophilic additions that are mediated by alkenylmagnesium halides and alkenyllithium reagents. A high degree of stereocontrol is imparted in the SmI₂-mediated process as a result of the excellent facial selectivity conveyed in the initial ketyl-olefin coupling reaction. The relative asymmetric induction engendered in these addition reactions is complementary to more traditional nucleophilic addition reactions in that the alkenyl group is directed to the carbonyl center by an attached tether.

Full text of DOI:10.1021/jo971889d

812
J . Org. Chem. 1998, 63, 812-816
Sequ en tia l Ketyl-Olefin Cou p lin g/â-Elim in a tion Rea ction s
Med ia ted by Sa m a r iu m (II) Iod id e
Gary A. Molander* and Christina R. Harris
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received October 13, 1997
Samarium(II) iodide (SmI2) has been employed in an intramolecular sequential ketyl-olefin
coupling/â-elimination reaction. The overall process results in the net addition of an alkenyl species
to a ketone carbonyl. This novel protocol for the intramolecular delivery of an alkenyl moiety avoids
the basic reaction conditions typical of nucleophilic additions that are mediated by alkenylmag-
nesium halides and alkenyllithium reagents. A high degree of stereocontrol is imparted in the
SmI2-mediated process as a result of the excellent facial selectivity conveyed in the initial ketyl-
olefin coupling reaction. The relative asymmetric induction engendered in these addition reactions
is complementary to more traditional nucleophilic addition reactions in that the alkenyl group is
directed to the carbonyl center by an attached tether.
In tr od u ction
During the course of a previous investigation a novel
radical-based protocol was discovered that resulted in the
net addition of an alkenyl moiety to a carbonyl group.
As outlined in Scheme 1, the SmI2-promoted cyclization
of the keto enol ether was anticipated to afford the
oxabicyclo[3.3.0]octane. Instead, the reaction provided
2-(hydroxymethyl)-1-ethenylcyclopentan-1-ol in high yield
and high diastereoselectivity even in the presence of an
added proton source. The overall conversion thus in-
volved a ketyl-olefin coupling between the ketone and
the enol ether (Scheme 1). The organosamarium that
was generated after ketyl-olefin coupling and subse-
quent reduction suffered â-elimination (instead of un-
dergoing protonation) to generate the observed 2-(hy-
droxymethyl)-1-ethenylcyclopentan-1-ol. The observed
stereocontrol in these ring-forming reactions has been
extensively investigated previously and results from a
cis-fused stereochemistry generated at the ring junction
upon radical cyclization onto a preexisting five-, six-, or
seven-membered ring.9
Realizing that this novel protocol represented an
alternative method to perform a net carbonyl addition
reaction with an alkenyl unit, we sought to explore the
scope and limitations of this internal alkenyl delivery
process. There were several perceived advantages to
pursuing this line of research. For example, the system
developed would provide a novel pathway for the directed
addition of an alkenyl group to a carbonyl moiety (eq 1).
The SmI2-mediated procedure was anticipated to allow
excellent stereocontrol in the net delivery of the alkenyl
species because the stereochemistry of the product would
be established in a preliminary 5-exo or 6-exo ketyl-
olefin coupling reaction.9c Notably, the introduction of
the alkenyl species would be directed by a tether to the
reaction center. This stereochemical outcome would be
The nucleophilic addition of organometallics such as
alkenylmagnesium halides and alkenyllithium reagents
to carbonyl compounds represents a powerful tool in
synthetic organic chemistry.1 However, nucleophilic
addition reactions of these unsaturated organometallics
are at times problematic. For example, the preparation
of these organometallic species often requires special
reaction conditions.2 Additionally, the diastereoselectiv-
ity in the nucleophilic addition reaction is often low.
Furthermore, because of the ability of these organome-
tallic agents to function both as nucleophiles and as
bases, enolate formation often competes with the nucleo-
philic addition reaction.3 Some improvement in the yield
of carbonyl addition of these alkenylmetallics has been
3
realized by the use of Lewis acids such as CeCl3 or the
use of ultrasound techniques.4 Additional modifications
of these reagents involving the use of covalent chiral
reagents1 and organocuprates5 have been introduced to
provide increased stereocontrol and enhanced yield in the
carbonyl addition reactions.
Other organometallic reagents have also been devel-
oped that are quite successful.6 Thus, anhydrous chro-
mium(II) chloride, in the presence of catalytic Ni(II), is
able to reduce alkenyl halides and alkenyl triflates to
provide an alkenylchromium species that participates in
carbonyl additions. Initially described by Nozaki and co-
workers7 and later expanded upon by Kishi and co-
workers,8 the alkenylchromium reagents are particularly
useful for the addition of alkenyl units to carbonyl
compounds, especially aldehydes.
(1) O’Neill, B. T. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: New York, 1991; Vol. 1, pp 397-458.
(2) (a) Newman, H. Tetrahedron Lett. 1971, 4571. (b) J acob P., III.;
Brown, H. C. J . Org. Chem. 1977, 42, 579.
(3) (a) Thies, R. W.; Daruwala, K. P. J . Org. Chem. 1987, 52, 3798.
(b) Cowan, D. O.; Mosher, H. S. J . Org. Chem. 1962, 27, 1.
(4) Luche, J .-L.; Damianco, J .-C. J . Am. Chem. Soc. 1980, 102, 7926.
(5) (a) Grootaert, W. M.; De Clercq, P. J . Tetrahedron Lett. 1982,
23, 3291. (b) Whitesides, G. M.; Casey, C. P.; Krieger, J . K. J . Am.
Chem. Soc. 1971, 93, 1379. (c) Patterson, J . W., J r.; Fried, J . H. J .
Org. Chem. 1974, 39, 2506.
(6) Saccomano, N. A. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: New York, 1991; Vol. 1, pp 193-201 and
references therein.
(7) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Takai, K.; Tagashira, M.; Kurada,
T.; Shima, K. O.; Utimoto, K.; Nozaki, H. J . Am. Chem. Soc. 1986,
108, 6048.
(8) (a) J in, H.; Uenishi, J .-i.; Christ, W. J .; Kishi, Y. J . Am. Chem.
Soc. 1986, 108, 5644.
(9) (a) Molander, G. A.; Shakya, S. R. J . Org. Chem. 1996, 61, 5885.
(b) Molander, G. A.; McKie, J . A. J . Org. Chem. 1995, 60, 872. (c)
Molander, G. A.; McKie, J . A. J . Org. Chem. 1992, 57, 3132.
S0022-3263(97)01889-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Sequential Ketyl-Olefin Coupling/â-Elimination Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 813
Ta ble 1. Sequ en tia l Ketyl-Olefin Cou p lin g/â-Elim in a tion
Sch em e 1
Rea ction s Med ia ted by Sm I2
complementary to alkenylmetallic carbonyl addition re-
actions.10 Additionally, the SmI2-mediated protocol would
not suffer the consequences of a strongly basic reaction
mixture and hence substrate enolization would not be
problematic as with magnesium- and lithium-based or-
ganometallics.
Resu lts a n d Discu ssion
Initially, a series of keto-enol ether substrates was
prepared to investigate the potential of this novel alkenyl
addition protocol. Substrates 3a -c (entries 1 and 2,
Table 1) were prepared in two steps from commercially
available starting materials by alkylation of the ap-
propriate â-keto ester 1 with 2-chloroethyl vinyl ether
and catalytic NaI in DMF solvent.11 Subsequent decar-
boxylation of the â-keto ester 2 with LiI afforded the
desired vinyl ether 3 in good yield (Scheme 2).12
The keto enol ether 6 (entry 3, Table 1) was prepared
by acid-catalyzed conjugate addition of allyl alcohol to
methyl vinyl ketone to afford allyl ether 5. Isomerization
of 5 to the enol ether 6 was accomplished with Wilkin-
son’s catalyst, ClRh(PPh3)3 (Scheme 3).13 The isomer-
ization with Wilkinson’s catalyst generally afforded a
1-2:1 mixture of E and Z olefins, respectively.
Attempts to prepare the remainder of the desired
substrates (entries 4-6, Table 1) via this short protocol
were thwarted because the acid-catalyzed conjugate
addition reaction of allyl alcohol would proceed only with
monosubstituted enones. The requisite substrates 10a -c
in entry 4, Table 1, were thus prepared from the readily
available keto esters 1a -c as outlined in Scheme 4. In
each instance the keto ester 1 was protected as the
ethylene glycol acetal14 and subsequently ester 7 was
reduced with LiAlH4 in THF.15 The alcohol 8 was
O-alkylated with allyl bromide under standard reaction
conditions16 and then subjected to an acidic aqueous
a
The reaction was performed on a 1-2:1 mixture of diastere-
b
omeric olefin isomers. The ratios refer to olefin diastereoselec-
tivity. c A >20:1 mixture of diastereomeric olefins (1H NMR) was
d
obtained. The ratios refer to diastereoselectivity at the newly
created stereogenic center. e The reaction was performed at rt.
f The reaction was performed at 60 °C.
Sch em e 2
(10) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(11) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1995, 117,
3705.
(12) Bunce, R. A.; Dowdy, E. D.; J ones, P. B.; Holt, E. M. J . Org.
Chem. 1993, 58, 7143.
(13) (a) Gent, P. A.; Gigg, R. J . Chem. Soc., Chem. Commun. 1974,
277. (b) Corey, E. J .; Suggs, J . W. J . Org. Chem. 1973, 38, 3224.
(14) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1996, 118,
4059-4071.
(15) Brown, W. G. Org. React. 1951, 6, 469.
(16) Hart, D. J .; Hong, W.-P.; Hsu, L.-Y. J . Org. Chem. 1987, 52,
4665.
workup which afforded allyl ether 9 directly. The result-
ant allyl ether 9 was isomerized to the enol ether 10 with
Wilkinson’s catalyst, as above, to afford the desired
substrates 10a -c, entry 4.
Substrates 14 in entry 5 were prepared similarly from
the allyl ether generated in two steps from the cycloal-
kane-1,3-diol as outlined in Scheme 5. The cycloalkane-
1,3-diol was monoalkylated with allyl bromide, and the
resultant alcohol 12 was subjected to a Swern oxidation,17

814 J . Org. Chem., Vol. 63, No. 3, 1998
Molander and Harris
Sch em e 3
isomerized to the requisite enol ether 19, entry 6, upon
treatment with Wilkinson’s catalyst.
Thus prepared, these substrates were employed to
examine the intramolecular alkenyl transfer reactions
promoted by SmI2. The results of this study are pre-
sented in Table 1. Optimized reaction conditions for this
cyclization-elimination protocol were determined to
involve the dropwise addition of the enol ether substrate
(0.03-0.05 M in THF) to a solution of SmI2 (5 equiv, 0.12
M in THF) containing 5 equiv of HMPA. In substrates
where the alkenyl group did not contain a substituent
at the terminal position, performing the reaction at
ambient temperature met with success. However, for
substrates in which the alkenyl group was terminally
substituted, optimum yields of the alkenyl transfer
product could be obtained only if the substrate was added
to a solution of SmI2-HMPA in THF heated at 60 °C.
Performing transfer reactions with more highly substi-
tuted alkenyl units at ambient temperatures resulted in
the isolation of products resulting from â-hydride elimi-
nation instead of elimination of the primary alcohol. In
either case, the transfer reactions were found to be
complete immediately upon addition of the starting enol
ether substrates to the SmI2 solution.
Sch em e 4
Sch em e 5
Substrates 3a ,b (entry 1) were converted in fair yield
to afford the desired alkenyl transfer products 4a ,b with
excellent diastereoselectivity when the radical cyclization
event took place upon the preexisting five-membered
cyclopentanone 3a . Cyclization onto the preexisting
seven-membered ring 3b afforded only a 4:1 mixture of
diastereomeric products. The stereochemistry in these
transformations was assigned on the basis of previous
cyclizations employing the all-carbon cyclization ana-
logues.9 The major diastereomers observed in the 5-exo
and 6-exo ketyl-olefin cyclization reactions were those
with the developing radical center trans to the alkoxy
group. The formation of this isomer avoids unfavorable
stereoelectronic interactions in the radical cyclization.19
The anticipated relative asymmetric induction was
further confirmed by independent synthesis of the dias-
tereomer of 4a , (1R*,2R*)-1-ethenyl-2-(2-hydroxyethyl)-
cyclopentan-1-ol, by addition of vinylmagnesium bro-
mide10 to the requisite ketone and subsequent deprotection
as outlined in eq 2.
Sch em e 6
Cyclization of substrate 3c in entry 2 likewise pro-
ceeded in good yield to afford the alkenyl transfer product
4c, albeit with fairly low diastereoselectivity. The ster-
eochemistry of the major diastereomer in this cyclization/
elimination event was not proven rigorously, but was
assigned on the basis of comparison with the all-carbon
cyclization analogue. It was anticipated that a moderate
level of asymmetric induction would be evident in the
alkenyl group transfer as the previously investigated all-
carbon substrate had afforded a 6:1 mixture of diaster-
eomeric products.9b
affording the requisite allyl ether 13. The latter isomer-
ized readily upon treatment with Wilkinson’s catalyst to
provide the requisite enol ethers 14a ,b, entry 5.
Finally, substrate 19 in entry 6 was prepared in several
steps beginning with the Diels-Alder adduct 16 derived
from the reaction of 2,3-dimethyl-1,3-butadiene and
methyl 4-oxo-2(E)-pentenoate and catalytic AlCl3 (Scheme
6).18 The resultant ketone 16 was protected as the
ethylene glycol acetal, and the ester 17 was reduced to
the alcohol with LiAlH4. The alcohol was O-alkylated
with allyl bromide, and the resultant allyl ether 18 was
In general, the yields and diastereoselectivities of these
alkenyl transfer reactions were higher in instances where
the ketyl-olefin reaction transpired via a 5-exo-trig
process. This is clearly evident in entries 3-5, where
the desired alkenyl transfer products (7, 11a -c, 15a )
(17) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b)
Mancuso, A. J .; Huang, S.-L.; Swern, D. J . J . Org. Chem. 1978, 43,
2480.
(18) Angelli, E. C.; Fringnelli, F.; Guo, M.; Minuti, L.; Taticchi, A.;
Wenkert, E. J . Org. Chem. 1988, 53, 859.

Sequential Ketyl-Olefin Coupling/â-Elimination Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 815
Sch em e 7
the more familiar methods of nucleophilic alkenyl addi-
tion to carbonyl compounds. For example, stereochemical
complementarity is observed because of the directed
addition of the alkenyl group to the carbonyl through a
tethered unit. Higher diastereoselectivities often result.
Additionally, more traditional methods often suffer from
enolization of the substrate carbonyl species. The SmI2-
mediated net alkenyl addition protocol developed herein
avoids the strongly basic, nucleophilic reaction conditions
typical of the traditional organometallic alkenyl addition
reactions. Finally, this protocol permits the introduction
of trans-substituted alkenyl groups to carbonyl species
by use of substituted enol ethers in the initial ketyl-
olefin coupling reaction.
We are currently investigating this novel method for
the construction of more elaborate ring systems in
another SmI2-mediated sequential process.
were obtained with excellent diastereoselectivity and in
high yield. The diastereomers in entry 3, performed at
ambient temperature, were a mixture of cis and trans
olefin isomers resulting from incomplete stereocontrol in
the â-elimination step. Entries 4 and 5 depict substrates
exhibiting excellent stereocontrol created by the initial
ketyl-olefin coupling sequence (>100:1 diastereoselec-
tivity at the newly created stereogenic center as deter-
mined by fused silica capillary GC). The diastereoselec-
tivity in the â-elimination step for terminally substituted
olefins in this sequential process was determined to be
temperature dependent. For example, the alkenyl trans-
fer reactions for entries 4 and 5, performed at 60 °C,
showed enhanced diastereoselectivity in the â-elimination
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 stored under an inert atmosphere. CH2I2 was
purchased from Aldrich Chemicals and was distilled prior to
use and stored over copper turnings under an inert atmo-
sphere. Standard benchtop techniques were employed for
handling air-sensitive reagents,20 and all reactions were car-
ried out under argon.
1-E t h en yl-2-(2-h yd r oxyet h yl)cycloh ep t a n -1-ol (4b ).
Gen er a l P r oced u r e for th e Alk en yl Tr a n sfer Rea ction s.
Samarium metal (0.15 g, 1.00 mmol) and CH2I2 (0.24 g, 0.90
mmol) in 15 mL of dry THF were stirred together vigorously
for 2 h. HMPA (1.34 g, 7.50 mmol) was added to the deep
blue-green SmI2 solution to afford a deep violet reaction
mixture. 3b (0.116 g, 0.64 mmol) was added dropwise via
cannula over 1.0 h as a 0.03 M solution in THF to the SmI2-
HMPA-THF solution. TLC analysis of the reaction mixture
after the substrate addition was finished revealed the complete
consumption of the starting keto olefin and formation of a
major, lower Rf product. The reaction mixture was quenched
with saturated aqueous NaHCO3 and subjected to an aqueous
workup. The desired diols 4b (39.2 mg, 0.21 mmol, a 4:1
mixture of diastereomers) were isolated in 71% combined yield
after flash column chromatography with 50% EtOAc/hex-
1
step (>20:1 by H NMR) as compared to diastereomeric
ratios of 5-6:1 for the trans olefin isomer in reactions
performed at ambient temperature. The cyclization
product resulting from the cyclohexanone derivative 14a
in entry 5 afforded excellent 1,3-asymmetric induction
in the alkenyl delivery. Such diastereoselectivities can-
not be readily achieved through traditional carbonyl
addition methods. The sequential cyclization event failed
for the cyclopentanone 14b in entry 5. In this example,
the 5-exo ketyl-olefin cyclization did not proceed and,
instead, the reaction provided an intractable mixture of
products. The major diastereomeric product depicted in
each entry assumes that the ketyl-olefin coupling reac-
tions proceed through transition structures similar to
those previously reported.9
1
anes: (low Rf, minor) H NMR (500 MHz, CDCl3) δ 5.95 (dd,
J ) 10.9, 17.2 Hz, 1H), 5.25 (dd, J ) 0.4, 17.2 Hz, 1H), 5.09
(dd, J ) 1.29, 10.9 Hz, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 2.02
(bs, 2H), 1.81 (m, 2H), 1.70 (m, 1H), 1.69-1.57 (m, 4H), 1.56
(m, 1H), 1.43-1.22 (m, 5H); 13C NMR (125 MHz, CDCl3) δ
142.44, 112.19, 78.21, 61.64, 45.84, 43.40, 36.35, 30.70, 29.95,
29.83, 21.62; IR (neat) 3353.4, 1681.7 cm-1; HRMS calcd for
Finally, the level of asymmetric induction for substrate
19 (entry 6) was investigated. The keto-enol ether 19
in this example cyclized in excellent yield but only fair
diastereoselectivity to afford a 5:1:1:1 mixture of diaster-
eomers inseparable by flash column chromatography. The
derived products in this cyclization-elimination sequence
appear to result from incomplete stereocontrol in both
the 6-exo ketyl-olefin coupling reaction and the â-elim-
ination reaction. By comparison with the previously
investigated all-carbon analogue,9c the major diastere-
omer 20 is expected to be that depicted in Table 1, entry
6. The asymmetric induction anticipated in the sequen-
tial cyclization-elimination process in entry 6 is likely to
proceed as outlined in Scheme 7.9b
C
11H20O2 184.1463, found 184.1471; LRMS (EI+) m/z 184 (10),
167 (53), 149 (100), 137 (62), 123 (22), 109 (41), 97 (40), 83
(98), 70 (62), 55 (83); (high Rf, major) 1H NMR (500 MHz,
CDCl3) δ 5.92 (dd, J ) 17.4, 10.8 Hz, 1H), 5.21 (dd, J ) 17.37,
1.19 Hz, 1H), 5.04 (dd, J ) 10.8, 1.19 Hz, 1H), 3.71 (m, 1H),
3.59 (m, 1H), 1.85 (m, 2H), 1.78 (m, 2H), 1.71-1.62 (m, 5H),
1.57 (m, 1H), 1.48-1.42 (m, 3H), 1.34 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 146.45, 110.89, 77.13, 60.74, 44.49, 41.82, 34.08,
28.83, 28.33, 26.89, 21.35; IR (neat) 3389.9, 1651.7 cm-1
;
HRMS calcd for C11H20O2 184.1463, found 184.1466; LRMS
(EI+) m/z 184 (13), 167 (49), 149 (72), 139 (100), 109 (42), 97
(30), 83 (98), 70 (61), 55 (72).
(1R*,2S*)-1-E t h en yl-2-(2-h yd r oxyet h yl)cyclop en t a n -
1-ol (4a ) was prepared from 3a according to the general
procedure outlined for the preparation of 4b to afford the
desired diol as a single diastereomeric product (TLC and 1H
Con clu sion
The ketyl-olefin cyclization/â-elimination reaction de-
scribed herein provides a novel method for the introduc-
tion of an alkenyl moiety to a carbonyl species in high
yield while maintaining an excellent degree of stereo-
control. The method is complementary in many ways to
(19) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236.
(20) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.

816 J . Org. Chem., Vol. 63, No. 3, 1998
Molander and Harris
NMR) in 50% yield after flash column chromatography with
50% EtOAc/hexanes: 1H NMR (500 MHz, CDCl3) δ 5.98 (dd,
J ) 10.9, 17.3 Hz, 1H), 5.26 (dd, J ) 1.49, 17.3 Hz, 1H), 5.14
(dd, J ) 1.39, 10.92 Hz, 1H), 3.77 (m, 1H), 3.59 (ddd, J ) 10.7,
9.23, 4.37 Hz, 1H), 2.24 (bs, 2H), 1.99 (m, 1H), 1.91 (m, 1H),
1.87-1.75 (m, 3H), 1.62 (m, 2H), 1.44 (m, 1H), 1.35 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 140.39, 112.50, 82.03, 62.76,
75.83, 66.20, 48.32, 41.29, 25.76, 25.37, 23.07, 18.17; IR (neat)
3354.8, 1681.8 cm-1; HRMS calcd for C10H18O2 170.1307, found
170.1293; LRMS (EI+) m/z 170 (20), 152 (59), 137 (92), 97 (30),
84 (41), 69 (100), 41 (82), 27 (49).
(1′E,1R*,2S*)-2-(Hyd r oxym eth yl)-1-(1′-p r op en yl)cyclo-
h ep ta n -1-ol (11b) was prepared from 10b according to the
general procedure outlined for the preparation of 11a to afford
the desired 1,3-diol as a >20:1 mixture of E and Z olefin
isomers (diastereomeric olefins, E isomer major) and >100:1
at the newly created stereogenic center, in 74% combined yield
after an aqueous workup and flash column chromatography
with 45% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.78
(dq, J ) 6.43, 15.3 Hz, 1H), 5.61 (m, 1H), 3.61 (dd, J ) 10.57,
10.71 Hz, 1H), 3.47 (dd, J ) 10.44, 4.81 Hz, 1H), 2.79 (bs, 1H),
2.41 (bs, 1H), 1.96 (m, 1H), 1.81 (m, 3H), 1.72 (dd, J ) 1.34,
6.43 Hz, 3H), 1.64 (m, 2H), 1.56 (m, 2H), 1.39 (m, 1H), 1.25
(m, 1H), 1.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.45,
123.50, 78.46, 66.34, 49.98, 43.66, 30.18, 29.59, 26.10, 21.81,
17.86; IR (neat) 3356.0, 1684.0, 1455.5 cm-1; HRMS calcd for
C11H18O (M - H2O)+ 166.1358, found 166.1346; LRMS (EI+)
m/z 166 (72), 137 (100), 128 (30), 109 (54), 91 (33), 79 (48), 67
(40), 55 (98), 41 (81), 27 (60).
49.31, 39.61, 32.76, 30.33, 20.38; IR (neat) 3389.8, 1643.6 cm-1
;
HRMS calcd for C9H16O2 156.1150, found 156.1128; LRMS
(EI+) m/z 156 (10), 138 (100), 111 (42), 83 (43), 70 (49), 55 (98),
41 (39), 27 (61), 18 (71).
(3R*,4R*)/(3R*,4S*)-3,4-Dim eth yl-5-h exen e-1,4-d iol (4c)
(m a jor /m in or ) was prepared from 3c according to the general
procedure outlined for the preparation of 4b to afford the
desired 1,4-diol as a 2.7:1 mixture of diastereomers inseparable
by chromatography in 77% combined yield after an aqueous
workup and flash column chromatography with 45%
EtOAc/hexanes: (major diastereomer) 1H NMR (500 MHz,
CDCl3) δ 5.91 (dd, J ) 10.8, 17.3 Hz, 1H), 5.22 (d, J ) 17.3
Hz, 1H), 5.10 (dd, J ) 10.8, 1.29 Hz, 1H), 3.75 (m, 1H), 3.60
(m, 1H), 2.03 (bs, 2H), 1.79 (m, 1H), 1.70 (m, 1H), 1.37 (m,
1H), 1.28 (s, 3H), 0.91 (d, J ) 6.95 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 142.38, 112.95, 75.38, 61.30, 40.74, 34.57, 26.49,
15.65; HRMS calcd for C7H13O2 [M - CH3]+ 129.0916, found
129.0900; LRMS (EI+) m/z 129 (10), 111 (100), 71 (95), 55 (32),
43 (98); (minor diastereomer) 1H NMR (500 MHz, CDCl3) δ
5.91 (dd, J ) 10.8, 17.4 Hz, 1H), 5.22 (d, J ) 17.4 Hz, 1H),
5.08 (dd, J ) 10.8, 1.29 Hz, 1H), 3.75 (m, 1H), 3.60 (m, 1H),
2.03 (bs, 2H), 1.79 (m, 1H), 1.70 (m, 1H), 1.42 (m, 1H), 1.23 (s,
3H), 0.91 (d, J ) 6.95 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
145.05, 112.31, 75.28, 61.10, 34.95, 34.54, 23.78, 14.78; IR
(1R*,3R*)-1-(1-P r op en yl)cycloh exa n e-1,3-d iol (15a ) was
prepared from 14a according to the general procedure outlined
for the preparation of 11a to afford the desired 1,3-diol as a
>20:1 mixture of E and Z olefin isomers (diastereomeric
olefins, E isomer major) and >100:1 at the newly created
stereogenic center, in 74% combined yield after an aqueous
workup and flash column chromatography with 45%
EtOAc/hexanes: 1H NMR (500 MHz, CDCl3) δ 5.65 (dq, J )
15.5, 6.16 Hz, 1H), 5.56 (m, 1H), 3.95 (tt, J ) 10.9, 4.37 Hz,
1H), 1.97 (m, 1H), 1.92 (m, 1H), 1.70 (m, 1H), 1.68 (d, J )
6.15 Hz, 3H), 1.64 (m, 1H), 1.52 (m, 1H), 1.41-1.22 (m, 4H),
1.14 (dq, J ) 12.31, 4.47 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 139.12, 122.45, 73.10, 67.50, 46.26, 36.76, 35.04, 19.82, 17.68;
IR (neat) 3389.9, 1651.5 cm-1; LRMS (EI+) m/z 156 (31), 138
(23), 84 (18), 69 (42), 39 (100), 27 (62). Anal. Calcd for
C9H16O2: C, 69.19; H, 10.32. Found: C, 69.00; H, 10.57.
(neat) 3353.9, 1643.8 cm-1
.
(E)-3-Meth yl-4-h exen e-1,3-d iol (7) was prepared from 6
according to the general procedure outlined for the preparation
of 4b to afford the desired 1,3-diol as a 6:1 mixture of E and
Z olefin isomers (E isomer major) in 85% combined yield after
an aqueous workup and flash column chromatography with
45% EtOAc/hexanes: (major diastereomer, lower Rf) 1H NMR
(500 MHz, CDCl3) δ 5.69 (dq, J ) 15.5, 6.45 Hz, 1H), 5.52 (m,
1H), 3.81 (m, 2H), 2.40 (bs, 2H), 1.82 (m, 2H), 1.70 (d, J )
6.45 Hz, 3H), 1.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
137.26, 123.18, 73.94, 60.11, 42.48, 28.99, 17.63; IR (neat)
3344.1 cm-1; HRMS calcd for C7H13O2 (M - H)+ 129.0916,
found 129.0905; LRMS (EI+) m/z 129 (100), 113 (21), 95 (65),
85 (71), 69 (82), 55 (42), 43 (92), 18 (98).
(1′E,1R*,2S*)-2-(Hyd r oxym eth yl)-1-(1′-p r op en yl)cyclo-
p en ta n -1-ol (11a ) was prepared from 10a according to the
general procedure outlined for the preparation of 4b, except
the SmI2-HMPA solution in THF was heated to 60 °C for the
dropwise substrate addition, to afford the desired 1,3-diol, as
a >20:1 mixture of E and Z olefin isomers (E isomer major)
and >100:1 at the newly created stereogenic center, in 92%
combined yield after an aqueous workup and flash column
chromatography with 45% EtOAc/hexanes: 1H NMR (400
MHz, CDCl3) δ 5.78 (dq, J ) 15.5, 6.16, 1H), 5.65 (m, 1H),
3.56 (d, J ) 7.23 Hz, 2H), 2.11 (m, 1H), 1.90 (m, 1H), 1.87-
1.73 (m, 7H), 1.64 (m, 2H), 1.25 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 132.93, 124.21, 82.55, 64.15, 51.88, 39.67, 25.78,
20.88, 17.96; IR (neat) 3353.8, 1671.8 cm-1; HRMS calcd for
C9H14O (M - H2O)+ 138.1045, found 138.1095; LRMS (EI+)
m/z 156 (10), 138 (95), 123 (100), 84 (43), 69 (98), 41 (48).
(1′E,1R*,2S*)-2-(Hyd r oxym eth yl)-1-(1′-p r op en yl)cyclo-
h exa n -1-ol (11c) was prepared from 10c according to the
general procedure outlined for the preparation of 11a to afford
the desired 1,3-diol as a >20:1 mixture of E and Z olefin
isomers (E isomer major) and >100:1 at the newly created
stereogenic center, in 93% combined yield after an aqueous
workup and flash column chromatography with 45%
EtOAc/hexanes: 1H NMR (500 MHz, CDCl3) δ 5.89 (dq, J )
15.5, 5.89 Hz, 1H), 5.83 (m, 1H), 3.63 (t, J ) 10.4 Hz, 1H),
3.46 (dd, J ) 10.7, 3.97 Hz, 1H), 2.64 (bs, 2H), 1.78 (m, 1H),
1.75 (d, J ) 5.16 Hz, 3H), 1.73 (m, 1H), 1.71 (m, 1H), 1.66 (m,
1H), 1.51 (dt, J ) 3.97, 13.0 Hz, 1H), 1.44 (m, 1H), 1.38 (dt, J
) 3.57, 13.0 Hz, 1H), 1.34-1.23 (m, 1H), 0.97 (dq, J ) 16.9,
3.87 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 131.11, 125.28,
(2′R*,4R*,5R*)-1,2-Dim et h yl-4-(h yd r oxym et h yl)-5-(2′-
h yd r oxy-3′-p en ten yl)cycloh exen e (20) was prepared from
19 according to the general procedure outlined for the prepa-
ration of 11a to afford the desired 1,4-diol as a 5:1:1:1 mixture
of diastereomers (at C2′ and C5, each diastereomer a mixture
of cis and trans olefin isomers, trans olefin major) in 74%
combined yield after an aqueous workup and flash column
chromatography with 25% EtOAc/hexanes: 1H NMR (500
MHz, CDCl3) δ 5.68 (m, 0.20H), 5.63 (dq, J ) 15.6, 6.25 Hz,
1H), 5.76-5.54 (m, 0.80H), 3.94 (dd, J ) 11.4, 3.47 Hz, 0.20H),
3.90 (dd, J ) 11.3, 2.68 Hz, 0.80H), 3.42 (dd, J ) 11.4, 3.77
Hz, 0.80H), 3.37 (m, 0.20H), 2.38 (bs, 2H), 2.09 (m, 1H), 1.80
(m, 2H), 1.70 (d, J ) 4.96 Hz, 3H), 1.67-1.59 (m, 3H), 1.57 (s,
3H), 1.55 (s, 3H), 1.29 (s, 3H); (major diastereomer) 13C NMR
(125 MHz, CDCl3) δ 139.24, 125.17, 124.40, 123.19, 75.67,
65.80, 45.95, 38.64, 36.87, 35.41, 21.19, 18.66, 18.48, 17.75;
IR (neat) 3331.6, 1665.7, 1442.8 cm-1; HRMS calcd for
C14H22O2 (M - H2O)+: 206.1671, found 206.1672; LRMS (EI+)
m/z 206 (8), 175 (12), 121 (19), 107 (59), 85 (100), 69 (38), 43
(37).
Ack n ow led gm en t. This work was carried out with
generous support from the National Institutes of Health
(GM 35249).
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details for the preparation of substrates described
herein and 1H and 13C NMR spectral data for all of the
compounds prepared (13 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microform version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O971889D