Samarium(II) iodide-mediated reductive annulations of ketones bearing a distal vinyl epoxide moiety

Article abstract of DOI:10.1021/jo960335s

Samarium(II) iodide in the presence of hexamethylphosphoramide (HMPA) efficiently promotes the intramolecular coupling of ketones with distal epoxy olefins. The reaction appears to proceed by a mechanism wherein a ketyl couples with the unsaturated epoxide. Subsequent fragmentation of the epoxide ring in compounds 1a-k yields carbocycles 2a-k with an allyl alcohol side chain in good yields, and often with high diastereoselectivity. When tetramethylguanidine was used as an additive instead of HMPA, the desired carbocycle was obtained in good yield, but the diastereoselectivity was diminished. A palladium(0)-catalyzed SmI₂ reaction provided the expected product in modest yield, but the sense of diastereoselectivity was reversed. In the latter case, a different reaction mechanism may be involved. Thus, formation of an allylsamarium species may be invoked, with nucleophilic carbonyl addition leading to the observed facial selectivity.

Full text of DOI:10.1021/jo960335s

J . Org. Chem. 1996, 61, 5885-5894
5885
Sa m a r iu m (II) Iod id e-Med ia ted Red u ctive An n u la tion s of Keton es
Bea r in g a Dista l Vin yl Ep oxid e Moiety
Gary A. Molander* and Sagar R. Shakya
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received February 20, 1996X
Samarium(II) iodide in the presence of hexamethylphosphoramide (HMPA) efficiently promotes
the intramolecular coupling of ketones with distal epoxy olefins. The reaction appears to proceed
by a mechanism wherein a ketyl couples with the unsaturated epoxide. Subsequent fragmentation
of the epoxide ring in compounds 1a -k yields carbocycles 2a -k with an allyl alcohol side chain in
good yields, and often with high diastereoselectivity. When tetramethylguanidine was used as an
additive instead of HMPA, the desired carbocycle was obtained in good yield, but the diastereo-
selectivity was diminished. A palladium(0)-catalyzed SmI2 reaction provided the expected product
in modest yield, but the sense of diastereoselectivity was reversed. In the latter case, a different
reaction mechanism may be involved. Thus, formation of an allylsamarium species may be invoked,
with nucleophilic carbonyl addition leading to the observed facial selectivity.
In tr od u ction
using samarium(II) iodide as a reductant.4 The oxophi-
licity of samarium ions permits the addition of chelating
additives such as HMPA,5 thereby increasing the steric
bulk around the ketyl oxygen. As a result, cyclizations
under these conditions provide inherently higher dia-
stereoselectivities when compared to methods employing
ketyl formation via electrochemical,6 photochemical,7 and
other chemical8 reductants.
Earlier observations have revealed that a number of
allylically functionalized units, including allyl alcohols,
can successfully couple with ketones under SmI2-HMPA-
promoted reductive coupling conditions (eq 1).9 Although
Intramolecular radical cyclizations leading to the
formation of carbocycles or heterocycles have been ex-
tensively utilized in a large number of important syn-
thetic applications.1 Compared to simple radical cycliza-
tions, the cyclizations of ketyls are relatively new and
have many advantages. One of the most appealing
features of ketyl-olefin cyclizations is the diastereose-
lective introduction of a hydroxyl group at the newly
formed carbon-carbon bond of the cyclic products. Our
earlier work2 and results from other laboratories3 have
unveiled useful aspects of ketyl-olefin coupling reactions
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
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allylstannanes,10 allyl sulfides, and allyl sulfones11 have
been used in similar reactions, olefins bearing an epoxide
terminus have not been studied until recently. Vinyl-
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Chem. Soc., Chem. Commun. 1988, 1669. (c) Ujikawa, O.; Inanaga,
J .; Yamaguchi, M. Tetrahedron Lett. 1989, 30, 2873. For the X-ray
crystal structure of the SmI2(HMPA)4 complex, see: (d) Hou, Z.;
Wakatsuki, Y. J . Chem. Soc., Chem. Commun. 1994, 1205. For the
X-ray crystal structure of SmI2(ketyl)(L)4, see: (e) Hou, Z.; Miyano,
T.; Yamazaki, H.; Wakatsuki, Y. J . Am. Chem. Soc. 1995, 117, 4421.
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Org. Chem. 1988, 53, 2287. (d) Kariv-Miller, E.; Mahachi, T. J . J . Org.
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J . J . Org. Chem. 1989, 54, 4022.
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Lett. 1988, 29, 6113.
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2369. (b) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
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Boulder, CO, 1994. (b) Inanaga, J .; Ujikawa, O.; Yamaguchi, M.
Tetrahedron Lett. 1991, 32, 1737. (c) Molander, G. A.; McKie, J . A. J .
Org. Chem. 1994, 59, 3186.
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(11) (a) Kan, T.; Nara, S.; Ito, S.; Matsuda, F.; Shirahama, H. J .
Org. Chem. 1994, 59, 5111. (b) Kan, T.; Hosokawa, S.; Nara, S.;
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59, 5532.
S0022-3263(96)00335-0 CCC: $12.00 © 1996 American Chemical Society

5886 J . Org. Chem., Vol. 61, No. 17, 1996
Molander and Shakya
Sch em e 1a
substituted epoxides would appear to be excellent sub-
strates for the reaction because they can be readily
reduced by SmI2 and because the epoxide moiety can
12
be opened under both radical and anionic â-elimination
processes.13 Furthermore, in contrast to the above-
mentioned leaving groups, the functionality remains
appended to the product in the epoxide ring-opening
process. Thus, successful coupling of ketones with vinyl
epoxides would provide access to functionalized car-
bocycles having an allyl alcohol side chain,14 a structural
pattern found in many biologically active compounds.15
In a recent study, the intermolecular coupling of
ketones with a variety of vinyl epoxides was com-
municated (eq 2).16 In that contribution, it was postu-
a
Key: (a) R′PPh3+I- (R′ ) 5-hexenyl or 6-heptenyl), 2PhLi‚LiBr,
THF, -78 °C (for 3a ) or NaNH2, THF, -78 °C (for 3c and 3e); (b)
10% aqueous HCl, THF; (c) TsCl, pyridine, -25 to -20 °C; (d) 10
mol % PdCl2, 1.1 equiv of CuCl, O2, DMF/H2O (7:1).
Sch em e 2a
lated that the process transpired exclusively via an
allylsamarium species that subsequently added to the
ketone. Herein we report the results of our initial studies
on intramolecular reactions and stereochemical studies
that suggest that a ketyl-olefin coupling reaction may
be involved in the intramolecular version of the reaction
(eq 3).
a
Key: (a) HO(CH2)3PPh3+I-; n-BuLi, TMSCl, THF, -78 °C; (b)
2 mol % PhSSPh, hexane, hν; (c) Ph3P, I2, imidazole, CH3CN; (d)
TBDMSO(CH2)3PPh3+I-, n-BuLi, THF, -78 °C; (e) TBAF, THF.
careful, strategic sequencing of the reactions leading to
their synthesis. In all cases, the epoxide moiety was
assembled in the last step (eq 4). We incorporated
Resu lts a n d Discu ssion
The substrates required for the study (1a -k ) were
readily obtained in several steps utilizing standard
procedures. The sensitivity of the requisite unsaturated
epoxides toward both acids and strong bases demanded
enantiopure (2R)-bis-O-methylethylideneglyceraldehyde
into the synthesis of many of the substrates simply for
the sake of convenience. For example, 1a ,c,e were
constructed from the glyceraldehyde derivative utilizing
a Wittig reaction in the initial step, which led to 3
(Scheme 1). Deprotection of the acetal, followed by
selective conversion of the primary alcohol to the tosylate,
provided 5, which was subjected to a Wacker oxidation
to afford ketones 6. Treatment with base at low tem-
peratures, as indicated in eq 4, led to the desired
substrates.
For alkyl ketones wherein a Wacker oxidation could
not be utilized, an alkylative coupling strategy was
pursued. The alkylating agents were synthesized from
the acetonide of glyceraldehyde (Scheme 2), and these
were subsequently coupled to the appropriate ketone
dimethylhydrazones to afford the desired intermediates
(Scheme 3). Acidic workup, selective conversion to the
tosylate, and ring closure as in eq 4 provided 1b,d ,h -k .
Compounds 1f,g required a more customized approach.
These substrates were synthesized by chloromethylation
of the butenyl-substituted cycloalkenones, followed by a
Wacker oxidation (Scheme 4), with epoxide ring forma-
tion as described previously (eq 4) completing the syn-
thesis.
(12) Molander, G. A.; La Belle, B. E.; Hahn, G. J . Org. Chem. 1986,
51, 5259.
(13) Anionic cleavage of oxiranyl carbanions: (a) Crandall, J . K.;
Crawley, L. C. Org. Synth. 1974, 53, 17. (b) Molander, G. A.; Hahn,
G. J . Org. Chem. 1986, 51, 2596. Free radical cleavage of oxiranyl
radicals: (c) Ziegler, F. E.; Petersen, A. K. J . Org. Chem. 1994, 59,
2707. (d) Pasto, D. J .; Cottard, F.; Picconato, C. J . Org. Chem. 1994,
59, 7172 and references therein. For SmI2-mediated reduction of
oxiranyl bromides, see: (e) Hasegawa, E.; Takahashi, M.; Horaguchi,
T. Tetrahedron Lett. 1995, 36, 5215.
(14) For the use of related alkynyloxiranes in radical reactions,
see: (a) Suzuki, A.; Miyaura, N.; Itoh, M. Synthesis 1973, 305. (b)
Dulce´re, J .-P.; Dumez, E.; Faure, R. J . Chem. Soc., Chem. Commun.
1995, 897. (c) Aurrecoechea, J . M.; Iztueta, E. Tetrahedron Lett. 1995,
36, 2501.
(15) (a) Amemiya, S.; Kojima, K.; Sakai, K. Chem. Pharm. Bull.
1984, 32, 913. (b) Lin, C. H. Chem. Ind. 1976, 994. (c) Ohno, H.;
Morikawa, Y.; Hirata, F. J . Biochem. 1978, 84, 1485. (d) Yasuda, H.;
Fukaya, C.; Okano, K.; Yokoyama, K. Chem. Abstr. 1994, 110, 57180
Eur. Pat. Appl. EP 270,124 (J une 8, 1988).
(16) Aurrecoechea, J . M.; Iztueta, E. Tetrahedron Lett. 1995, 36,
7129.
(17) The lithio species was obtained by tin-lithium exchange of the
corresponding tributyltin derivative.
(18) Eis, M. J .; Wroebel, J . E.; Ganem, B. J . Am. Chem. Soc. 1984,
106, 3693.
(19) Determined by 19F NMR of the mono-MTPA esters of 2a ,c.
Dull, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(20) Marshall, J . A. Chem. Rev. 1989, 89, 1503.

SmI2-Mediated Reductive Annulations
J . Org. Chem., Vol. 61, No. 17, 1996 5887
Sch em e 3a
Ta ble 1. Ketyl Cou p lin g Rea ction s of Vin yl Ep oxid es
P r om oted by Sa m a r iu m (II) Iod id e
a
Key: (a) n-BuLi or LDA, 8 or 11, then aqueous HCl, MeOH;
(b) TsCl, pyridine, -25 to -20 °C.
Sch em e 4a
a
Key: (a) 1.3 equiv of ClCH2I, 1.3 equiv of n-BuLi, THF, -78
°C; (b) 10 mol % PdCl2, 1.1 equiv of CuCl, O2, DMF/H2O (7:1).
With the substrates in hand, studies were initiated on
the SmI2-promoted cyclization reactions (Table 1). The
initial experiments with 1a ,c provided rather interesting
results. As indicated in entries 1 and 3 of Table 1, only
one diastereomer was obtained. The trans relationship
between the hydroxyl group and the allyl alcohol side
chain was established by comparison of the 1H NMR
spectrum of an authentic sample prepared by an unam-
biguous synthetic route. Thus, methylcyclopentene oxide
was treated with the (3E)-lithio species of the TBDMS
ether of 2-propen-1-ol17 in the presence of BF3‚OEt2.18 The
major adduct from this reaction was treated with TBAF
in THF to provide the comparison sample. Furthermore,
2a ,c were found to differ only in their handedness and
enantiomeric enrichment. Thus, double bond geometry
has a slight influence on the enantiotopic facial selectivity
of the addition. Unfortunately, the asymmetric induction
was very low (2a ,c were generated with <10% ee),19 and
the absolute stereochemistry of the products was, there-
fore, not determined. These results indicate that the
stereogenicity of the epoxide has very little influence on
the facial bias of addition, in contrast to the stereoselec-
tive reactions of vinyl epoxides with cuprates.20 The
conversion with partial enantiomeric enrichment sug-
gests that some portion of the reaction probably proceeds
via a ketyl-olefin coupling pathway. Conversion via an
allylsamarium species would most likely result in racemic
material; furthermore, there is some evidence to suggest
that the opposite diastereomer would probably be gener-
ated (vide infra).
The generality of the intramolecular coupling reaction
was examined utilizing the diverse substrates displayed
in Table 1. In the case of more highly hindered ketone
substrates, competing reactions led to a number of side
products. For example, reductive ring opening of the
vinyl epoxide terminus of 1b competed with the desired
reductive cyclization, and thus several acyclic compounds
could be isolated. In an attempt to improve this situa-
tion, two different reductive coupling protocols were
tested with substrate 1d . The best yield of the cyclic
product 2d was realized when HMPA was replaced by
tetramethylguanidine (TMG).21 Unfortunately, in this
case, a 1:1 mixture of diastereomers was obtained,
perhaps owing to the decreased steric bulk of the com-
a
b
Characterized as the mono-TBDMS ether. 19 equiv of TMG
was used. c By GLC analysis.
plexed ketyl when using this additive. Compound 1d was
also subjected to a palladium-catalyzed SmI2 reaction.22
This reaction provided only a modest yield (41%) of the
cyclized product, but interestingly, the sense of diaste-
reoselectivity was reversed (4:1 in favor of the minor
diastereomer from the HMPA reaction). The cis stere-
ochemistry of the final product was established by an
X-ray crystal structure determination. The results of this
experiment indicate a dramatic change in the mechanism
of the reaction. The palladium-catalyzed reaction is
believed to proceed via initial formation of a π-allyl
palladium complex, which undergoes reductive trans-
metalation to provide an allylsamarium species. Subse-
quent carbonyl addition through this allylsamarium
species would afford the observed product. Again, in
contrast to these palladium-catalyzed SmI2 reactions, the
(22) The reaction was performed using 5 mol % of the Pd(0) catalyst
generated in situ from Pd(OAc)2 and Ph3P. A solution of the epoxide
was slowly added to a mixture of the Pd(0) catalyst and SmI2 at -30
°C over 1 h. For examples of Pd(0)-catalyzed SmI2 reactions, see: (a)
Fukuzawa, S.; Fujinami, T.; Sakai, S. Chem. Lett. 1990, 927. (b)
Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
1195. (c) Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 601. (d) Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Tetrahedron
Lett. 1986, 27, 5237.
(21) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A.
Tetrahedron Lett. 1995, 36, 949.

5888 J . Org. Chem., Vol. 61, No. 17, 1996
Molander and Shakya
Sch em e 5
SmI2-HMPA-promoted reactions may well proceed via
a ketyl-olefin pathway. Ketyl-olefin coupling reactions
mediated by SmI2 are known to lead to products enriched
in the trans isomers.2,9a
diffractometry. In conformationally more flexible sys-
tems, the diastereomeric purity is again diminished.
Thus, a 10:1 mixture of diastereomers is generated when
a cycloheptanone substrate is utilized (Table 1, entry 8),
and a mixture of at least three diastereomers was
isolated from a cyclooctanone precursor (Table 1, entry
11).
In this vein, it is interesting to note the analogy
between the SmI2-promoted reactions of vinyl epoxides
with carbonyl substrates and analogous reactions involv-
ing allyl sulfones and sulfides.11 In the latter, the
mixture of regioisomers observed in the intermolecular
reactions provides sufficient evidence that a significant
fraction of the process occurs via an allylsamarium
species. In the intramolecular reactions, the results are
much more ambiguous. A single regioisomer is generated
in the examples reported, but this result is expected
regardless of whether an allylsamarium intermediate is
involved or the process occurs via the ketyl. However,
the sense and magnitude of diastereoselection varies
dramatically in the various substrates examined to date.
A possible explanation may involve the reversible nature
of the reaction of SmI2 with ketones.23 In intermolecular
coupling reactions, SmI2 can reversibly reduce the ketone
to a ketyl, but ketyl coupling with the olefinic substrate
is a relatively slow bimolecular process. This may
provide ample time for competitive reduction of the allylic
substrate to an allylsamarium species by the SmI2, with
subsequent addition of the resulting allylsamarium spe-
cies to the ketone, leading to the observed product. In
the intramolecular version of the reactions, any ketyl
formed can be rapidly trapped by addition to the acti-
vated alkene. Consequently, a greater proportion of the
reaction may proceed via the ketyl coupling process
(Scheme 5).
Further synthetic studies revealed that the cyclization
reaction is generally restricted to five-membered ring
formation. As indicated in entry 5, of Table 1, the
corresponding six-exo annulation/fragmentation reaction
provides a low yield of the expected cyclic product.
Significant amounts of uncyclized material were obtained
as side products.
Substrates 1f,g provided further confirmation that the
stereochemistry of the epoxide stereogenic center does
not dramatically influence facial selectivity in the carbon-
carbon bond-forming event. Starting with a mixture of
diastereomers of 1f or 1g, only one isomer of 2f or 2g
was obtained in excellent yield. The formation of a single
diastereomer in these reactions must be due to the
topographical bias of the conformationally fixed cyclic
olefin.
Con clu sion s
A versatile new method for the construction of car-
bocycles has been demonstrated. The reductive coupling
reaction of ketones with vinyl epoxides, mediated by
SmI2-HMPA, leads to highly functionalized diols in high
yields. Evidence has been presented that suggests that
the reaction proceeds via an initial radical cyclization
route, although reaction through an allylsamarium spe-
cies cannot be ruled out at this stage. Reaction with
SmI2-catalytic Pd(0), on the other hand, presumably
transpires via allylsamarium species, with nucleophilic
carbonyl addition completing the process.
Exp er im en ta l Section
Details concerning the preparation of the SmI2-HMPA
solution are provided in the experimental sections of our
earlier publications.2,24 KOt-Bu was sublimed and handled
under argon using Schlenk techniques. A suspension of
NaNH2 in toluene was purchased from Aldrich. The solvent
was removed in vacuo, and the NaNH2 was handled under
argon. PdCl2, CuCl, and DMF were used as received. TsCl
was recrystallized before use. Pyridine was distilled from
KOH and stored over 4 Å molecular sieves. Chloroiodomethane
(Aldrich) was distilled prior to use. n-BuLi was titrated using
diphenylacetic acid.
(2S,3E)-1,2-Bis-O-m eth yleth ylid en e-3,8-n on a d ien e-1,2-
d iol (3a ). Freshly prepared phenyllithium25 (0.95 M, 5.26 mL,
5.0 mmol) was added to a suspension of 5-hexenyltri-
phenylphosphonium iodide26 (2.36 g, 5.0 mmol). After being
stirred for 1 h at rt, the clear solution of ylide was cooled to
-78 °C. A solution of (2R)-2,3-bis-O-methylethylideneglycer-
aldehyde27 (0.715 g, 5.50 mmol) in 5 mL of THF was added
dropwise to the ylide solution at -78 °C. The reaction mixture
was stirred at -30 °C for 30 min, and an additional equivalent
of phenyllithium was added to it.28 After the mixture was
stirred for 30 min at 25 °C and 15 min at -78 °C, t-BuOH
(0.37 g, 5.0 mmol) and KOt-Bu (0.672 g, 6.0 mmol) were
sequentially added to it. The mixture was warmed to rt and
stirred for 1.5 h. Aqueous workup gave a crude product, which
was taken up in pentane. The pentane layer was decanted
(24) Molander, G. A. Org. React. 1994, 46, 211.
(25) Preparation: Gilman, H.; Morton, J . W. In Organic Reactions;
J . Wiley & Sons: New York, 1954; Vol. 8, p 286.
(26) Prepared from 5-hexenol (Aldrich) by treatment with (a) Ph3P,
I2, imidazole, CH3CN. Lange, G. L.; Gottardo, C. Synth. Commun.
1990, 20, 1473. (b) Ph3P, CH3NO2, heated at reflux.
(27) Schmid, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6.
(28) Schlosser, M.; Tuong, H. B.; Schaub, B. Tetrahedron Lett. 1985,
26, 311.
Finally, high diastereoselectivity was observed in the
synthesis of the bicyclo[3.3.0]alkanols and bicyclo[4.3.0]-
alkanols 2i and 2j, respectively. The relative stereo-
chemistry of 2i was established by single-crystal X-ray
(23) Curran, D. P.; Fevig, T. L.; J asperse, C. P.; Totleben, M. J .
Synlett 1992, 943.

SmI2-Mediated Reductive Annulations
J . Org. Chem., Vol. 61, No. 17, 1996 5889
and concentrated to give an oil, which was purified by flash
silica gel columm chromatography to provide 0.492 g (50%) of
the desired product 3a (98% E by GLC): Kugelrohr distilled
ot 80-90 °C/1.0 mmHg; Rf 0.18 (1:20 ether/pentane); 1H NMR
(400 MHz, CDCl3) δ 1.36 (s, 3H), 1.40 (s, 3 H), 1.42-1.53 (m,
2H), 2.00-2.08 (m, 4H), 3.53 (t, J ) 8.0 Hz, 1H), 4.04 (dd, J )
6.0, 8.1 Hz, 1H), 4.44 (m, 1H), 4.92-5.01 (m, 2H), 5.38-5.45
(m, 1H), 5.72-5.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.9,
26.7, 28.0, 31.6, 33.1, 69.4, 77.3, 109.0, 114.6, 127.5, 135.5,
138.4.
0.208 g (86%) of the diol 4e: Kugelrohr distilled ot 130-140
°C/1.5 mmHg; Rf 0.22 (1:1 hexanes/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 1.36-1.43 (m, 4H), 1.90-2.12 (m, 6H),
3.48 (dd, J ) 8.0, 11.1 Hz, 1H), 3.57 (dd, J ) 3.7, 11.1 Hz,
1H), 4.51-4.56 (m, 1H), 4.91-5.00 (m, 2H), 5.33-5.38 (m, 1H),
5.55-5.61 (m, 1H), 5.72-5.83 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 27.7, 28.4, 29.0, 33.5, 66.4, 68.6, 114.5, 127.9, 134.5,
138.7.
(2S,3E)-1-[(4-Meth ylben zen esu lfon yl)oxy]-3,8-n on adien -
2-ol (5a ). Diol 4a (0.350 g, 2.24 mmol) in 3 mL of dry pyridine
was treated with TsCl (0.427 g, 2.24 mmol) in 2 mL of pyridine
at -25 to -20 °C for 2 d.31 Aqueous workup using CH2Cl2
afforded the crude tosylate, which was purified by flash silica
gel column chromatography to give 0.498 g (72%) of the desired
tosylate 5a : Rf 0.33 (3:1 hexanes/ethyl acetate); 1H NMR (400
MHz, CDCl3) δ 1.39-1.46 (m, 2H), 1.98-2.06 (m, 5H), 2.43 (s,
3H), 3.87 (dd, J ) 7.7, 10.1 Hz, 1H), 4.02 (dd, J ) 3.3, 10.1
Hz, 1H), 4.32-4.33 (br m, 1H), 4.92-4.99 (m, 2H), 5.33 (dd, J
) 6.5, 15.4 Hz, 1H), 5.72-5.79 (m, 2H), 7.34 (d, J ) 8.0 Hz,
2H), 7.78 (d, J ) 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
21.6, 27.9, 31.6, 33.0, 70.2, 73.3, 114.7, 126.5, 127.9, 129.9,
132.7, 135.0, 138.3, 145.0.
(2S,3Z)-1,2-Bis-O-m eth yleth ylid en e-3,8-n on a d ien e-1,2-
d iol (3c). A mixture of 5-hexenyltriphenylphosphonium iodide
(12.0 g, 25.42 mmol) and NaNH2 (0.992 g, 25.42 mmol) in 80
mL of THF was stirred for 4 h to afford a reddish-orange
solution.29 Argon was bubbled through this solution to remove
residual ammonia. A solution of freshly distilled (2R)-2,3-bis-
O-methylethylideneglyceraldehyde (3.97 g, 30.51 mmol) in 20
mL of THF was added dropwise to the ylide solution at -78
°C and stirred for 2 h. The cooling bath was removed, and
the reaction mixture was stirred for an additional 16 h.
Pentane was added to bring the final volume of the reaction
mixture to 400 mL; the mixture was then filtered and the
filtrate concentrated. Flash silica gel column chromatography
yielded 2.92 g (59%) of 3c (>97% Z by GLC): Rf 0.33 (1:20
ether/pentane); 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 3H), 1.47
(s, 3H), 1.51-1.60 (m, 2H), 2.07-2.22 (m, 4H), 3.56 (t, J ) 8.1
Hz, 1H), 4.10 (dd, J ) 6.1, 8.1 Hz, 1H), 4.84-4.92 (m, 1H),
5.00-5.09 (m, 2H), 5.43-5.50 (m, 1H), 5.63-5.69 (m, 1H),
5.79-5.88 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.7,
27.0, 28.7, 33.1, 69.4, 71.9, 109.0, 114.8, 127.4, 134.6, 138.3.
(2S,3Z)-1,2-Bis-O-m eth yleth ylid en e-3,9-d eca d ien e-1,2-
d iol (3e). A mixture of 6-heptenyltriphenylphosphonium
iodide30 (1.70 g, 3.50 mmol) and NaNH2 (0.141 g, 3.61 mmol)
in 10 mL of THF was stirred for 4 h to afford a reddish-orange
solution. As described in the preparation of 3c, this mixture
was treated with a solution of freshly distilled (2R)-2,3-bis-O-
methylethylideneglyceraldehyde (0.550 g, 4.23 mmol) in 10 mL
of THF. The usual workup and purification of the crude
product by flash silica gel column chromatography yielded
0.298 g (41%) of 3e: Rf 0.34 (1:20 ether/pentane); 1H NMR
(400 MHz, CDCl3) δ 1.32-1.40 (m with two overlapping s at
1.38 and 1.40, 10H), 1.95-2.11 (m, 4H), 3.49 (t, J ) 8.0 Hz,
1H), 4.37 (dd, J ) 6.1, 8.0 Hz, 1H), 4.82 (q, J ) 8.0 Hz, 1H),
4.91-5.00 (m, 2H), 5.38 (dd, J ) 8.8, 10.9 Hz, 1H), 5.58-5.64
(m, 1H), 5.72-5.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.0,
26.8, 27.5, 28.3, 29.0, 33.5, 69.4, 71.9, 109.0, 114.4, 127.2, 134.9,
138.7.
(2S,3E)-3,8-Non a d ien e-1,2-d iol (4a ). A solution of 3a
(0.470 g, 2.40 mmol) in 12 mL of THF/10% aqueous HCl (4:1)
was stirred for 18 h at ambient temperature. The reaction
mixture was quenched with anhydrous K2CO3, filtered, and
concentrated. Kugelrohr distillation of the crude product gave
the desired diol 4a (0.355 g, 95%): Kugelrohr distilled ot 120
°C/1.0 mmHg; 1H NMR (300 MHz, CDCl3) δ 1.41-1.51 (m, 2H),
1.95-2.29 (m, 6H), 3.42-3.51 (m, 1H), 3.58-3.65 (m, 1H), 4.18
(br s, 1H), 4.91-5.02 (m, 2H), 5.40-5.48 (m, 1H), 5.70-5.84
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 28.1, 31.6, 33.1, 66.6,
73.1, 114.7, 128.6, 133.8, 138.5.
(2S,3Z)-3,8-Non a d ien e-1,2-d iol (4c). A solution of 3c
(2.473 g, 12.62 mmol) was hydrolyzed as described for 3a to
provide 1.899 g (96%) of the diol 4c: Kugelrohr distilled ot
120 °C/0.1 mmHg; 1H NMR (400 MHz, CDCl3) δ 1.42-1.50
(m, 2H), 1.96 (br s, 2H), 2.02-2.16 (m, 4H), 3.48 (dd, J ) 8.0,
11.1 Hz, 1H), 3.56 (dd, J ) 3.7, 11.1 Hz, 1H), 4.53 (dt, J ) 3.7,
8.5 Hz, 1H), 4.93-5.02 (m, 2H), 5.38 (dd, J ) 8.8, 10.8 Hz,
1H), 5.54-5.61 (m, 1H), 5.72-5.82 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 27.2, 28.6, 33.1, 66.3, 68.6, 114.8, 128.1, 134.1, 138.4.
(2S,3Z)-3,9-Deca d ien e-1,2-d iol (4e). Compound 3e (0.298
g, 1.419 mmol) was hydrolyzed as described for 3a to provide
(2S,3Z)-1-[(4-Meth ylben zen esu lfon yl)oxy]-3,8-n on adien -
2-ol (5c). Diol 4c (1.87 g, 12.0 mmol) was treated with TsCl
(2.286 g, 11.99 mmol) as described for 5a to give 2.63 g (71%)
1
of tosylate 5c: Rf 0.33 (1:3 ethyl acetate/hexanes); H NMR
(300 MHz, CDCl3) δ 1.38-1.47 (m, 2H), 1.94-2.10 (m, 5H),
2.43 (s, 3H), 3.88 (dd, J ) 7.8, 10.2 Hz, 1H), 3.96 (dd, J ) 3.4,
10.2 Hz, 1H), 4.62-4.69 (m, 1H), 4.92-5.02 (m, 2H), 5.23-
5.30 (m, 1H), 5.53-5.62 (m, 1H), 5.68-5.82 (m, 1H), 7.33 (d,
J ) 8.0 Hz, 2H), 7.79 (d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 21.6, 27.2, 28.4, 33.0, 66.0, 73.0, 114.9, 126.2, 128.0,
129.9, 132.7, 135.4, 138.2, 145.1.
(2S,3Z)-1-[(4-Meth ylben zen esu lfon yl)oxy]-3,9-decadien -
2-ol (5e). Diol 4e (0.197 g, 1.16 mmol) was treated with TsCl
(0.221 g, 1.16 mmol) as described for 5a to give 0.280 g (75%)
of the desired tosylate 5e: Rf 0.44 (3:1 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.33-1.39 (m, 4H), 1.95-2.02
(m, 5H), 2.44 (s, 3H), 3.88 (dd, J ) 8.0, 10.3 Hz, 1H), 3.96 (dd,
J ) 3.4, 10.3 Hz, 1H), 4.67 (dt, J ) 3.5, 8.1 Hz, 1H), 4.92-
5.00 (m, 2H), 5.25 (t, J ) 10.9 Hz, 1H), 5.55-5.61 (m, 1H),
5.71-5.81 (m, 1H), 7.34 (d, J ) 8.1 Hz, 2H), 7.79 (d, J ) 8.3
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 27.8, 28.4, 28.8,
33.5, 66.0, 73.0, 114.5, 125.9, 128.0, 129.9, 132.7, 135.7, 138.6,
145.0.
(8S,6E)-8-Hyd r oxy-9-[(4-m eth ylben zen esu lfon yl)oxy]-
6-n on en -2-on e (6a ). A suspension of PdCl2 (0.0246 g, 0.139
mmol) and CuCl (0.1516 g, 1.53 mmol) in 4 mL of a mixture
of DMF/H2O (7:1) was stirred under oxygen (using an oxygen-
filled balloon) for 1 h.32 The precursor 5a (0.454 g, 1.46 mmol)
in 4 mL of DMF was added to this catalyst mixture, and the
mixture was stirred under oxygen for an additional 20 h.
Aqueous workup was followed by purification of the crude
product by flash silica gel column chromatography to yield
0.354 g (74%) of 6a : Rf 0.33 (1:1 hexanes/ethyl acetate); 1H
NMR (400 MHz, CDCl3) δ 1.59-1.66 (m, 2H), 1.98-2.04 (m,
3H), 2.11 (s, 3H), 2.40 (t, J ) 7.3 Hz, 2H), 2.44 (s, 3H), 3.87
(dd, J ) 7.4, 10.1 Hz, 1H), 4.00 (dd, J ) 3.5, 10.2 Hz, 1H),
4.30-4.34 (br m, 1H), 5.35 (dd, J ) 6.4, 15.5 Hz, 1H), 5.69-
5.77 (m, 1H), 7.34 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.3 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 22.6, 29.9, 31.4, 42.7,
70.1, 73.2, 127.2, 127.9, 129.9, 132.6, 134.2, 145.0, 208.8.
(8S,6Z)-8-Hyd r oxy-9-[(4-m eth ylben zen esu lfon yl)oxy]-
6-n on en -2-on e (6c). The toluenesulfonate 5c (2.60 g, 8.39
mmol) was oxidized as described for 6a to give 1.90 g (70%) of
1
ketone 6c: Rf 0.33 (1:1 hexanes/ethyl acetate); H NMR (300
MHz, CDCl3) δ 1.57-1.68 (m, 2H), 1.98-2.11 (m, 3H), 2.12 (s,
3H), 2.41 (t, J ) 7.1 Hz, 2H), 2.43 (s, 3H), 3.89 (dd, J ) 7.3,
10.2 Hz, 1H), 3.94 (dd, J ) 3.9, 10.2 Hz, 1H), 4.60-4.67 (m,
1H), 5.27-5.34 (m, 1H), 5.50-5.59 (m, 1H), 7.34 (d, J ) 8.6
Hz, 2H), 7.78 (d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
(29) Schaub, B.; Blaser, G.; Schlosser, M. Tetrahedron Lett. 1985,
26, 307.
(30) Prepared from 6-heptenoic acid (Aldrich) in three steps: (a)
LiAlH4, THF, 0 °C. Lo´pez-Tudanca, P. L.; J ones, K.; Brownbridge, P.
Tetrahedron Lett. 1991, 32, 2261. (b) Ph3P, I2, imidazole, CH3CN. (c)
Ph3P, CH3NO2, heated at reflux.
(31) For selective monotosylation of a primary alcohol in the
presence a secondary alcohol, see: Gerlach, H.; Oertle, K.; Thalmann,
A. Helv. Chim. Acta 1976, 59, 755.
(32) Tsuji, J .; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9.

5890 J . Org. Chem., Vol. 61, No. 17, 1996
Molander and Shakya
δ 21.6, 23.1, 27.0, 29.8, 42.5, 65.7, 72.9, 127.1, 127.9, 129.9,
132.6, 134.5, 145.1, 209.0.
to a mixture of 7 (2.00 g, 11.6 mmol), Ph3P (3.66 g, 13.9 mmol),
and imidazole (1.186 g, 17.44 mmol) in 20 mL of CH3CN at 0
°C. The reaction mixture was stirred for 4 h at 25 °C. After
removal of CH3CN, ether was added to the residue, and the
insoluble Ph3PO was removed by filtration. Purification of the
crude product by silica gel column chromatography gave 2.76
g (84%) of 8: Rf 0.32 (8:1 hexanes/ethyl acetate); 1H NMR (400
MHz, CDCl3) δ 1.37 (s, 3H), 1.41 (s, 3H), 2.56-2.64 (m, 2H),
3.09-3.18 (m, 2H), 3.55-3.59 (m, 1H), 4.6-4.09 (m, 1H), 4.46
(q, J ) 7.4 Hz, 0.9H), 4.74-4.80 (m, 0.1H), 5.50-5.57 (m, 1H),
5.68-5.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 4.2, 4.6, 25.8,
25.9, 26.66, 26.71, 31.6, 36.1, 69.3, 69.4, 71.8, 109.3, 129.8,
130.2, 132.5, 133.0.
(2S,3Z)-1,2-Bis-O-m et h ylet h ylid en e-6-iod o-3-h exen e-
1,2-d iol (11). Alcohol 10 (0.432 g, 2.51 mmol) was converted
by the method described for 8 to 0.681 g (96%) of iodide 11:
Rf 0.32 (8:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3)
δ 1.37 (s, 3H), 1.40 (s, 3H), 2.64-2.76 (m, 2H), 3.04-3.22 (m,
2H), 3.54 (t, J ) 8.0 Hz, 1H), 4.08 (dd, J ) 6.1, 8.1 Hz, 1H),
4.73-4.80 (m, 1H), 5.50-5.60 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 4.5, 25.9, 26.7, 31.6, 69.4, 71.8, 109.3, 129.8, 132.5.
(10S,8E)-10,11-Dih yd r oxy-2-m et h yl-8-u n d ecen -4-on e
(12b). A solution of lithium diisopropylamide [LDA, prepared
from diisopropylamine (0.339 g, 3.35 mmol) and n-BuLi (2.4
mL, 1.38 M, 3.3 mmol) in 10 mL of THF] was slowly added to
a solution of the N,N-dimethylhydrazone of 4-methylpentan-
2-one (0.468 g, 3.30 mmol) in 10 mL of THF at -78 °C. The
reaction mixture was warmed to 0 °C and stirred for 20 min.
A solution of iodide 8 (0.846 g, 3.00 mmol) in 5 mL of THF
was added to the solution of the anion at 0 °C.35 The resultant
reaction mixture was stirred for 5 h at 0-25 °C, concentrated
in vacuo, and treated with 10 mL of a 1:1 mixture of aqueous
HCl (10%) and methanol for 18 h. The water layer was
saturated with K2CO3 and extracted with EtOAc. The crude
product was purified by silica gel flash column chromatography
to provide 0.538 g (84%) of 12b: Rf 0.3 (1:4 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 0.87 (s, 3H), 0.89 (s,
3H), 1.64 (p, J ) 7.3 Hz, 2H), 1.97-2.17 (m, 5H), 2.24-2.27
(overlapping 2 d, J ) 6.9 Hz, 2H), 2.36 (t, J ) 7.3 Hz, 2H),
3.47 (dd, J ) 7.3, 11.0 Hz, 1H, overlapping with m from minor
isomer), 3.62 (dd, J ) 11.2, 3.7 Hz, 1H), 4.15-4.21 (m, 1H, m
for minor isomer is observed near 4.45 ppm), 5.45 (dd, J )
6.6, 15.6 Hz, 1H), 5.68-5.77 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.6, 22.9, 23.4, 24.6, 27.1, 31.6, 42.3, 42.4, 51.75,
51.85, 66.3, 66.5, 68.3, 73.0, 129.0, 129.3, 132.9, 133.3, 211.0.
(5S ,3E )-2-(5,6-Dih yd r oxy-3-h e xe n yl)cycloh e p t a n -1-
on e (12h ). The N,N-dimethylhydrazone of cycloheptanone
(0.473 g, 3.07 mmol) was treated with n-BuLi (2.23 mL, 1.38
M, 3.08 mmol) at -78 °C for 40 min. The anion solution was
reacted with iodide 8 as described for 12b to yield 0.427 g (62%)
of 12h : Rf 0.25 (1:3 hexanes/ethyl acetate); 1H NMR (300 MHz,
CDCl3) δ 1.23-1.41 (m, 4H), 1.44-1.63 (m, 1H), 1.70-1.80 (m,
5H), 2.01 (q, J ) 7.5 Hz, 2H), 2.17 (s with overlapping m, 2H),
2.37-2.52 (m, 3H), 3.46 (dd, J ) 7.3, 11.2 Hz, 1H, overlapping
with m from minor isomer), 3.60 (dd, J ) 3.7, 11.0 Hz, 1H),
4.14-4.19 (m, 0.8H), 4.47-4.50 (m, 0.2H), 5.38-5.51 (m, 1H),
5.66-5.76 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 24.4, 28.4,
29.4, 29.9, 31.3, 31.45, 31.47, 42.78, 42.80, 51.4, 66.5, 72.95,
72.98, 129.1, 133.1, 133.2, 216.4.
(9S,7Z)-9-Hyd r oxy-10-[(4-m eth ylben zen esu lfon yl)oxy]-
7-d ecen -2-on e (6e). The monotosylate 5e (0.270 g, 0.833
mmol) was oxidized as described for 6a to yield 0.134 g (47%)
of the desired ketone 6e: Rf 0.25 (1.5:1 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.29-1.36 (m, 2H), 1.50-1.57
(m, 2H), 1.95-2.11 (m with an overlapping s at 2.11, 6H), 2.42
(t with an overlapping s at 2.43, 5H), 3.88 (dd, J ) 9.5, 7.7
Hz, 1H), 3.95 (dd, J ) 2.0, 10.3 Hz, 1H), 4.63-4.67 (m, 1H),
5.26 (t, J ) 9.6 Hz, 1H), 5.23-5.59 (m, 1H), 7.34 (d, J ) 7.9
Hz, 2H), 7.78 (d, J ) 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.6, 23.1, 27.6, 28.7, 29.9, 43.3, 65.9, 73.0, 126.4, 127.9,
129.9, 132.7, 135.0, 145.0, 209.0.
(2S ,3E )-1,2-Bis-O-m e t h yle t h ylid e n e -3-h e xe n e -1,2,6-
tr iol (7). n-BuLi (139.55 mL, 1.38 M, 192.58 mmol) was added
dropwise to a suspension of (3-hydroxypropyl)triphenylphos-
phonium iodide33 (43.14 g, 96.29 mmol) in 150 mL of THF at
-78 °C. The reaction mixture was gradually warmed to -10
°C over 3 h. TMSCl (10.443 g, 96.125 mmol) was added to
the mixture at -78 °C. After 1 h, (2R)-2,3-bis-O-methyleth-
ylideneglyceraldehyde (13.77 g, 105.92 mmol) was added to
the ylide solution, and the resultant mixture was stirred for
18 h without further cooling. The crude product obtained after
aqueous workup was stirred with 24 g of silica gel in 120 mL
of MeOH for 0.5 h. Removal of the silica gel, followed by
purification of the concentrated residue by silica gel flash
column chromatography, afforded 5.86 g (35%) of 7 (E/Z ≈ 1:1)
as an oil.
The E-enriched 7 was obtained by irradiation of a solution
of a 1:1 (E/Z) mixture of 7 (5.86 g, 34.1 mmol) and 2 mol % of
diphenyl disulfide (0.149 g, 0.682 mmol) in 341 mL of hexane
in a Pyrex flask for 6 h, to provide 2.00 g (34%) of 7 (E/Z ≈ 9:1
1
by H NMR): Kugelrohr distilled ot 120 °C/1 mmHg; Rf 0.25
(1:1 hexanes/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 1.37
(s, 3H), 1.41 (s, 3H, contains 2 s at 1.43 and 1.46 due to minor
isomer of OH, 1H), 2.32 (q, J ) 6.2 Hz, 2H, overlapping with
m from minor isomer), 3.56 (t, J ) 7.7 Hz, 1H), 3.67 (t, J )
6.4 Hz, 2H), 4.04-4.09 (m, 1H), 4.46 (q, J ) 7.5 Hz, 0.9H),
4.83 (q, J ) 6.4 Hz, 0.1H), 5.52-5.82 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 25.86, 25.89, 26.66, 26.72, 31.2, 35.6, 61.6, 63.0,
69.37, 69.39, 71.7, 109.16, 109.2, 130.04, 130.26, 131.0, 131.5.
(2S ,3Z)-1,2-Bis-O-m e t h yle t h ylid e n e -3-h e xe n e -1,2,6-
tr iol (10). n-BuLi (16.5 mL, 1.38 M, 22.78 mmol) was added
to a suspension of {[(tert-butyldimethylsilyl)oxy]propyl}-
triphenylphosphonium iodide34 (12.80 g, 22.78 mmol) in 150
mL of THF at -78 °C. The reaction mixture was warmed to
rt and stirred for 30 min to give an orange solution. A solution
of (2R)-2,3-bis-O-methylethylideneglyceraldehyde (4.50 g, 34.610
mmol) in 10 mL of THF was added to the ylide solution at
-78 °C, and the mixture was stirred for 3 h at -78 to 25 °C.
Aqueous workup and purification of the crude product by flash
silica gel column chromatography yielded 4.71 g (72%) of the
tert-butyldimethylsilyl ether 9.
Tetrabutylammonium fluoride (TBAF) in THF (19.76 mL,
1 M, 19.76 mmol) was added to the tert-butyldimethylsilyl
ether 9 (4.71 g, 16.5 mmol) in 20 mL of wet THF, and the
reaction mixture was stirred for 5 h at 25 °C. After removal
of THF, the residue was subjected to aqueous workup using
saturated NH4Cl and EtOAc. The crude product was purified
by silica gel column chromatography to provide 2.10 g (74%)
of 10: Kugelrohr distilled ot 100-110 °C/1 mmHg; Rf 0.25 (1:1
(5S ,3Z)-2-(5,6-Dih yd r oxy-3-h e xe n yl)cyclop e n t a n -1-
on e (12i). The hydrazone of cyclopentanone (0.658 g, 5.222
mmol) was coupled with iodide 11 (1.473 g, 5.222 mmol), and
the crude product was hydrolyzed as described for 12b to yield
0.54 g (52%) of diol 12i: Rf 0.24 (1:4 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.30-1.59 (m, 2H), 1.72-1.86
(m, 2H), 1.96-2.45 (m, 9H), 3.45-3.59 (m, 2H), 4.51-4.56 (m,
1H), 5.36-5.43 (m, 1H), 5.51-5.59 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 20.6, 25.6, 25.7, 29.5, 29.6, 29.7, 38.14, 38.17,
48.0, 48.4, 66.27, 66.31, 68.3, 68.5, 128.9, 129.0, 133.16, 133.24,
215.7, 216.1.
1
hexanes/ethyl acetate); H NMR (400 MHz, CDCl3) δ 1.37 (s,
3H), 1.41 (s, 3H), 1.60 (s, 1H), 2.33-1.46 (m, 2H), 3.54 (t, J )
8.0 Hz, 1H), 3.65 (t, J ) 6.3 Hz, 2H), 4.07 (t, J ) 6.1 Hz, 1H),
4.83 (q, J ) 6.2 Hz, 1H), 5.59 (dd, J ) 11.2, 8.3 Hz, 1H), 5.67
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.9, 26.7, 31.2, 61.6,
69.4, 71.7, 109.2, 130.0, 131.0.
(2S,3E)-1,2-Bis-O-m et h ylet h ylid en e-6-iod o-3-h exen e-
1,2-d iol (8). Iodine (3.54 g, 13.9 mmol) was added in portions
(5S ,3Z)-2-(5,6-Dih yd r oxy-3-h e xe n yl)c yc loh e xa n -1-
on e (12j). Iodide 11 (0.524 g, 1.858 mmol) and the hydrazone
of cyclohexanone (0.26 g, 1.857 mmol) were coupled and
(33) Prepared from 3-iodopropanol and Ph3P. Maryanoff, B. E.;
Reitz, A. B.; Duhl-Emswiler, B. A. J . Am. Chem. Soc. 1985, 107, 217.
(34) Prepared from the TBDMS ether of 3-iodopropanol and Ph3P
in nitromethane. When ethanol was used as a solvent, desilylation
occurred during the reaction.
(35) Corey, E. J .; Enders, D. Tetrahedron Lett. 1976, 3.

SmI2-Mediated Reductive Annulations
J . Org. Chem., Vol. 61, No. 17, 1996 5891
hydrolyzed as described for 12b to provide 0.220 g (56%) of
12j: Rf 0.22 (4:1 ethyl acetate/hexanes); H NMR (300 MHz,
2H), 4.68-4.70 (m, 1H), 5.27-5.33 (m, 1H), 5.52-5.59 (m, 1H),
7.34 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 7.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 20.6, 21.6, 25.7, 25.8, 29.3, 29.4, 29.5, 29.7,
38.08, 38.10, 48.0, 48.3, 65.7, 65.9, 72.9, 73.0, 126.8, 127.0,
127.93, 127.94, 129.9, 132.6, 134.70, 134.72, 145.01, 145.04,
216.3, 216.6.
(5S,3Z)-2-{5-H yd r oxy-6-[(4-m et h ylb en zen esu lfon yl)-
oxy]-3-h exen yl}cycloh exa n -1-on e (13j). Diol 12j (0.209 g,
0.986 mmol) was treated with TsCl (0.188 g, 0.986 mmol) in
pyridine as described for 5a to give 0.26 g (71%) of 13j: Rf 0.2
(1:1.5 hexanes/ether); 1H NMR (400 MHz, CDCl3) δ 1.22-1.34
(m, 1H), 1.37-1.40 (m, 1H), 1.54 (s, 1H), 1.62-1.67 (m, 2H),
1.79-1.87 (m, 2H), 2.02-2.05 (m, 4H), 2.20-2.38 (m, 3H), 2.43
(s, 3H), 3.86-3.97 (m, 2H), 4.61-4.68 (m, 1H), 5.25-5.31 (m,
1H), 5.52-5.60 (m, 1H), 7.34 (d, J ) 8.0 Hz, 2H), 7.78 (d, J )
8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 24.6, 24.8,
25.5, 25.6, 27.9, 28.0, 29.2, 29.3, 34.0, 41.8, 42.0, 49.6, 49.9,
65.6, 65.7, 72.9, 73.0, 126.6, 126.7, 127.9, 129.9, 132.6, 134.98,
135.08, 144.94, 144.96, 213.3, 213.6.
(5S,3Z)-2-{5-H yd r oxy-6-[(4-m et h ylb en zen esu lfon yl)-
oxy]-3-h exen yl}cycloocta n -1-on e (13k ). Diol 12k (0.100 g,
0.417 mmol) was treated with TsCl (0.0795 g, 0.417 mmol) in
pyridine as described for 5a to give 0.110 g (67%) of 13k : Rf
0.48 (1.5:1 hexanes/ethyl acetate); 1H NMR (400 MHz, CDCl3)
δ 1.21-1.46 (m, 5H), 1.53-2.03 (m, 9.5H), 2.19-2.53 (m with
overlapping s at 2.51, 6H), 2.98 (d, J ) 3.7 Hz, 0.5 H), 3.86-
3.95 (m, 2H), 4.56-4.64 (m, 1H), 5.23-5.34 (m, 1H), 5.44-
5.54 (m, 1H), 7.33 (d, J ) 8.0 Hz, 2H), 7.78 (d, J ) 8.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 24.6, 25.3, 25.5, 25.6,
25.7, 25.9, 26.3, 26.7, 27.0, 31.7, 31.8, 32.0, 32.3, 40.7, 41.7,
50.1, 65.1, 65.5, 72.7, 72.8, 126.8, 127.4, 127.8, 129.76, 129.77,
132.51, 132.53, 134.1, 134.4, 144.8, 144.9, 216.8, 217.4.
4-(3-Bu ten yl)-1-(ch lor om eth yl)-2-cyclopen ten -1-ol (14f).
n-BuLi (1.12 mL, 1.4 M, 1.57 mmol) was added to a solution
of 4-(3-butenyl)-2-cyclopentenone36 (0.164 g, 1.21 mmol) and
chloroiodomethane (0.277 g, 1.57 mmol) in 5 mL of THF at
-78 °C.37 The reaction mixture was stirred for 8.5 h at -78
°C and quenched with saturated aqueous NH4Cl solution.
Aqueous workup and purification of the crude product by flash
silica gel column chromatography gave 0.145 g (65%) of 14f
as a mixture of diastereomers, contaminated with traces of
starting enone: Rf 0.2-0.25 (8:1 hexanes/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ 1.33-1.65 (m, 3H), 2.02-2.20 (m,
2H), 2.31-2.39 (m, 2H), 2.61-2.69 (m, 1H), 3.55 (d, J ) 10.8
Hz, 0.8H), 3.60 (d, J ) 10.7 Hz, 0.8H), 3.64 (s, 0.4H), 4.91-
5.04 (m, 2H), 5.67-5.82 (m, 2H), 5.83-5.97 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 31.7, 32.0, 34.6, 35.0, 42.4, 42.5, 43.7, 52.5,
53.1, 84.6, 84.8, 114.7, 114.8, 132.0, 132.6, 138.2, 138.3, 139.5,
140.6.
1
CDCl3) δ 1.19-1.48 (m, 2H), 1.56-1.89 (m, 4H), 1.94-2.18 (m,
4H), 2.22-2.50 (m, 4H), 2.74-2.84 (br t, 1H), 3.43-3.54 (m,
2H), 4.49 (br s, 1H), 5.33-5.40 (m, 1H), 5.48-5.59 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 24.5, 24.7, 25.4, 27.89, 27.90,
29.3, 29.4, 33.93, 33.99, 41.8, 41.9, 49.7, 49.9, 66.2, 68.32, 68.34,
128.7, 128.8, 133.0, 133.1, 213.9, 214.1.
(5S,3Z)-2-(5,6-Dih yd r oxy-3-h exen yl)cyclooct a n -1-on e
(12k ). The hydrazone of cyclooctanone (0.34 g, 2.02 mmol)
and iodide 11 were coupled and hydrolyzed as described for
12h to afford 0.11 g (23%) of 12k : Rf 0.28 (1:1 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 1.20-2.58 (m, 19H),
3.46-3.58 (m, 2H), 4.18-4.52 (m, 1H), 5.32-5.55 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 24.6, 25.4, 25.58, 25.63, 25.9, 26.1,
26.8, 27.0, 32.1, 32.2, 32.3, 32.5, 40.9, 41.7, 50.15, 50.20, 66.1,
66.2, 68.0, 68.3, 128.9, 129.2, 132.7, 132.9, 221.0, 221.4.
(10S,8E)-10-Hyd r oxy-2-m eth yl-11-[(4-m eth ylben zen e-
su lfon yl)oxy]-8-u n d ecen -4-on e (13b). Diol 12b (0.520 g,
2.43 mmol) was treated with TsCl (0.463 g, 2.43 mmol) as
described for 5a to give 0.605 g (68%) of 13b: Rf 0.29 (2:1
1
hexanes/ethyl acetate); H NMR (400 MHz, CDCl3) δ 0.87 (s,
3H), 0.89 (s, 3H), 1.61 (p, J ) 7.3 Hz, 2H), 2.00 (q, J ) 7.2 Hz,
2H), 2.05-2.15 (m, 2H), 2.24 (d, J ) 6.9 Hz, 2H, overlapping
with d from minor isomer), 2.34 (t, J ) 7.3 Hz, 2H, overlapping
with t from minor isomer), 2.44 (s, 3H), 3.86 (dd, J ) 7.6, 10.2
Hz, 1H, overlapping with m from minor isomer), 4.01 (dd, J )
3.1, 10.1 Hz, 1H), 4.32 (m, 0.8H), 4.64 (m, 0.2H), 5.34 (dd, J )
3.4, 15.5 Hz, 1H, overlapping with peaks from minor isomer),
5.51-5.58 (m, 0.2H), 5.70-5.77 (m, 0.8H), 7.34 (d, J ) 8.0 Hz,
2H), 7.78 (d, J ) 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
21.6, 22.5, 22.6, 23.1, 24.53, 24.55, 27.1, 31.5, 42.2, 42.3, 51.7,
51.8, 65.7, 70.1, 72.9, 73.2, 127.0, 127.1, 127.9, 129.9, 132.6,
134.3, 134.6, 145.0, 210.7.
(10S,8Z)-10-Hyd r oxy-2-m eth yl-11-[(4-m eth ylben zen e-
su lfon yl)oxy]-8-u n d ecen -4-on e (13d ). A solution of iodide
11 (8.20 g, 29.1 mmol) in 15 mL of THF was added to a solution
of the anion derived from the N,N-dimethylhydrazone of
4-methylpentanone (4.54 g, 32.0 mmol) in 30 mL of THF at 0
°C. The reaction mixture was worked up and purified as
described in the case of 12b to provide 5.2 g (84%) of diol 12d ,
contaminated with an inseparable impurity, which was re-
moved by careful column chromatography after the tosylation
step described below.
Diol 12d (5.20 g, 24.3 mmol) was treated with TsCl (4.633
g, 24.30 mmol) in 10 mL of pyridine as described for 5a to
give 5.89 g (66%) of 13d : Rf 0.25 (1:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 0.88 (d, J ) 6.6 Hz, 6H), 1.56-
1.66 (m, 2H), 1.99-2.15 (m, 3H), 2.24-2.26 (m with overlap-
ping d, J ) 6.6 Hz, 3H), 2.36 (t, J ) 7.3 Hz, 2H), 2.43 (s, 3H),
3.89 (dd, J ) 7.6, 10.3 Hz, 1H), 3.96 (dd, J ) 3.9, 10.2 Hz,
1H), 4.61-4.67 (m, 1H), 5.26-5.33 (m, 1H), 5.50-5.59 (m, 1H),
7.34 (d, J ) 8.5 Hz, 2H), 7.80 (d, J ) 8.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.6, 22.5, 23.1, 24.5, 27.1, 42.2, 51.7, 65.7,
72.9, 127.0, 127.9, 129.9, 132.6, 134.6, 145.0, 210.9.
4-(3-Bu ten yl)-1-(ch lor om eth yl)-2-cycloh exen -1-ol (14g).
n-BuLi (3.59 mL, 1.38 M, 4.95 mmol) was added to a solution
of 4-(3-butenyl)-2-cyclohexenone38 (0.576 g, 3.84 mmol) and
chloroiodomethane (0.874 g, 4.95 mmol) in 10 mL of THF at
-78 °C. According to the procedure described for 14f, 0.66 g
(86%) of 14g was obtained as a mixture of diastereomers: Rf
1
(5S,3E)-2-{5-H yd r oxy-6-[(4-m et h ylb en zen esu lfon yl)-
oxy]-3-h exen yl}-cycloh ep ta n -1-on e (13h ). Diol 12h (0.42
g, 1.86 mmol) was treated with TsCl (0.354 g, 1.86 mmol) as
described for 5a to yield 0.458 g (65%) of 13h : Rf 0.3 (1:2
0.27 (3:1 hexanes/ether); H NMR (400 MHz, CDCl3) δ 1.20-
1.92 (m, 6H), 1.99-2.20 (m, 4H), 3.52-3.59 (m, 2H), 4.93-
5.03 (m, 2H), 5.56-5.84 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 24.8, 25.6, 31.0, 31.1, 31.9, 32.9, 34.3, 34.5, 34.7, 35.3, 53.1,
54.3, 69.1, 70.0, 114.7, 114.8, 127.7, 128.5, 136.5, 137.5, 138.3,
138.4.
1
hexanes/ether); H NMR (400 MHz, CDCl3) δ 1.27-1.36 (m,
4H), 1.56-1.59 (m, 1H), 1.70-1.82 (m, 6H), 1.98 (q, J ) 7.2
Hz, 2H), 2.44 (s with overlapping m, 6H), 3.86 (dd, J ) 7.6,
10.2 Hz, 1H, overlapping with m from minor isomer), 3.99 (dd,
J ) 4.4, 10.1 Hz, 1H), 4.31 (m, 0.8H), 4.60 (m, 0.2H), 5.33 (dd,
J ) 6.5, 15.5 Hz, 1H, overlapping with m from minor isomer),
5.69-5.76 (m, 1H), 7.34 (d, J ) 8.0 Hz, 2H), 7.78 (d, J ) 8.3
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 24.4, 28.5, 29.4,
29.9, 31.26, 31.30, 42.9, 51.3, 70.2, 73.2, 126.8, 128.0, 129.9,
132.7, 134.7, 145.0, 216.0.
4-(3-Oxobu tyl)-1-(ch lor om eth yl)-2-cyclopen ten -1-ol (15f).
Chlorohydrin 14f (0.1444 g, 0.776 mmol) was oxidized as
described for 6a to yield 0.104 g (66%) of 15f (10% of impure
product was also obtained): Rf 0.24 (1:2 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.49-1.60 (m, 1H), 1.62-1.82
(m, 2H), 2.13 (s, 3H), 2.32 (dd, J ) 7.9, 13.8 Hz, 1H), 2.43-
2.47 (m, 3H), 2.62-2.69 (m plus a m for the minor diastere-
omer at 2.9 ppm, 1H), 3.57 (d, J ) 10.9 Hz, 0.45H), 3.59 (d, J
) 11.3 Hz, 0.45H), 3.63 (s, 0.1H), 5.70 (dd, J ) 2.2, 5.6 Hz,
0.9H), 5.74 (dd, J ) 2.4, 5.6 Hz, 0.1H), 5.86 (dd, J ) 2.0, 5.7
(5S,3Z)-2-{5-H yd r oxy-6-[(4-m et h ylb en zen esu lfon yl)-
oxy]-3-h exen yl}-cyclop en ta n -1-on e (13i). Diol 12i (0.469
g, 2.37 mmol) was treated with TsCl (0.452 g, 2.37 mmol) in
pyridine as described for 5a to give 0.65 g (78%) of 13i: Rf
(36) Snowden, R. L. Tetrahedron Lett. 1981, 22, 97.
(37) Matteson, D. S.; Sadhu, K. M. Tetrahedron Lett. 1986, 27, 795.
(38) Schinzer, D.; Solyom, S.; Becker, M. Tetrahedron Lett. 1985,
26, 1831.
1
0.25 (1:1 hexanes/ethyl acetate); H NMR (400 MHz, CDCl3)
δ 1.28-1.37 (m, 1H), 1.45-1.53 (m, 1H), 1.55 (s, 0.5 H), 1.73-
1.83 (m, 2H), 1.96-2.30 (m, 7.5H), 2.44 (s, 3H), 3.86-3.97 (m,

5892 J . Org. Chem., Vol. 61, No. 17, 1996
Molander and Shakya
Hz, 0.9H), 5.92 (dd, J ) 2.0, 5.6 Hz, 0.1H); 13C NMR (100 MHz,
CDCl3) δ 29.0, 29.2, 29.9, 41.2, 41.6, 42.0, 42.2, 43.5, 43.6, 52.4,
52.9, 84.5, 84.8, 132.6, 133.2, 138.7, 139.8, 208.5, 208.7.
4-(3-Oxobu tyl)-1-(ch lor om eth yl)-2-cycloh exen -1-ol (15g).
Chlorohydrin 14g (0.64 g, 3.19 mmol) was oxidized as de-
scribed for 6a to give 0.474 g (69%) of 15g: Rf 0.3 (2:1 hexanes/
ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 1.19-1.28 (m, 1H),
1.42-1.74 (m, 4H), 1.83-1.91 (m, 1H), 1.98-2.04 (m, 1H), 2.14
(s, 3H), 2.22 (s, 1H), 2.44-2.50 (m, 2H), 3.51-3.58 (m, 2H),
5.61-5.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.5, 25.5,
28.6, 28.9, 30.0, 31.7, 32.8, 34.6, 35.2, 40.7, 40.9, 53.0, 54.2,
68.9, 69.8, 128.3, 129.1, 135.6, 136.7, 208.5, 208.6.
6-(3-Oxobu tyl)-1-oxaspir o[2.5]-4-octen e (1g). Compound
15g (0.1082 g, 0.5 mmol) was treated with KOt-Bu (0.056 g,
0.5 mmol) as described for 1a to yield 0.073 g (81%) of 1g: 1H
NMR (400 MHz, C6D6) δ 1.10-1.18 (m, 1H), 1.28-1.48 (m, 4H),
1.51-1.76 (m with overlapping s at 1.61 and 1.62 ppm, 4H),
1.83-1.89 (m, 3H), 2.44 and 2.46 (s, 2H), 5.17-5.22 (m, 1H),
5.64 (dd, J ) 3.0, 10.1 Hz, 1H); 13C NMR (100 MHz, C6D6) δ
27.0, 27.8, 28.99, 29.03, 29.3, 29.5, 30.3, 34.5, 34.8, 40.2, 40.6,
54.3, 54.4, 55.0, 55.7, 128.8, 129.8, 137.9, 139.0, 205.7.
(5S,3E)-2-(5,6-Ep oxy-3-h exen yl)cycloh epta n -1-on e (1h ).
Tosylate 13h (0.273 g, 0.718 mmol) was treated with KOt-Bu
(0.0804 g, 0.718 mmol) in THF as described for 1a to provide
0.122 g (82%) of 1h : 1H NMR (400 MHz, C6D6) δ 0.93-1.12
(m, 3H), 1.15-1.30 (m, 2H), 1.38-1.59 (m, 4H), 1.74-1.92 (m,
3H), 1.96-2.27 (m, 4H), 2.48-2.54 (m, 1H), 3.00-3.04 (m,
0.8H), 3.38-3.42 (m, 0.2H), 4.96-5.08 (m, 1H), 5.45-5.70 (m,
1H), with m from minor isomer; 13C NMR (100 MHz, C6D6) δ
24.8, 29.1, 29.9, 30.7, 31.9, 32.0, 43.2, 43.3, 48.5, 51.5, 51.6,
52.3, 129.5, 129.6, 135.9, 136.0, 213.5.
(5S,3E)-2-(5,6-Ep oxy-3-h exen yl)cyclop en ta n -1-on e (1i).
Tosylate 13i (0.242 g, 0.69 mmol) was treated with KOt-Bu
(0.077 g, 0.69 mmol) in THF as described for 1a to give 0.100
g (81%) of 1i: 1H NMR (300 MHz, C6D6) δ 0.86-0.96 (m, 1H),
1.07-1.19 (m, 2H), 1.34-1.44 (m, 1H), 1.56-2.15 (m, 7H),
2.15-2.27 (m, 1H), 2.51-2.55 (m, 1H), 3.37-3.46 (m, 1H), 5.00
(t, J ) 10.0 Hz, 1H), 5.46 (m, 1H); 13C NMR (75 MHz, C6D6) δ
20.61, 20.63, 25.5, 25.8, 29.4, 29.6, 29.8, 29.9, 37.69, 37.71,
47.53, 47.58, 47.85, 47.92, 47.94, 47.96, 128.87, 128.9, 135.55,
135.57, 218.4.
(5S,3E)-2-(5,6-Ep oxy-3-h exen yl)cycloh exa n -1-on e (1j).
Tosylate 13j (0.460 g, 1.26 mmol) was treated with KOt-Bu
(0.140 g, 1.26 mmol) as described for 1a to provide 0.222 g
(91%) of 1j: 1H NMR (400 MHz, C6D6) δ 0.95-1.38 (m, 5H),
1.50-1.66 (m, 2H), 1.78-2.28 (m, 7H), 2.54 (dd, J ) 5.2, 9.4
Hz, 1H), 3.45-3.48 (m, 1H), 4.99-5.04 (m, 1H), 5.50-5.57 (m,
1H); 13C NMR (75 MHz, C6D6) δ 25.4, 25.5, 25.7, 26.1, 28.2,
28.4, 30.1, 30.3, 34.2, 34.8, 42.3, 42.5, 48.0, 48.3, 48.4, 49.86,
49.91, 129.1, 129.2, 136.3, 136.4, 210.8, 211.0.
(5S,3E)-2-(5,6-Ep oxy-3-h exen yl)cycloocta n -1-on e (1k ).
Tosylate 13k (0.100 g, 0.254 mmol) was treated with KOt-Bu
(0.0284 g, 0.254 mmol) in THF as described for 1a to provide
0.046 g (82%) of 1k : 1H NMR (400 MHz, C6D6) δ 1.12-1.54
(m, 10H), 1.68-2.39 (m, 8H), 2.51-2.55 (m, 1H), 3.34-3.39
(m, 1H), 4.95-5.00 (m, 1H), 5.43-5.50 (m, 1H); 13C NMR (100
MHz, C6D6) δ 25.3, 26.17, 26.22, 26.9, 28.0, 28.2, 32.8, 33.0,
33.3, 34.0, 34.1, 42.5, 43.2, 47.9, 48.0, 48.4, 49.7, 50.0, 129.13,
129.15, 135.9, 136.1, 217.5, 217.7.
Gen er a l Meth od of Ep oxid e P r ep a r a tion . Base-washed
glassware was used as a precaution in all cases. The use of
silica gel chromatography and deuteriochloroform as an NMR
solvent was avoided.
(8S,6E)-8,9-Ep oxy-6-n on en -2-on e (1a ). The tosylate 6a
(0.310 g, 0.951 mmol) in 5 mL of THF was added to a solution
of KOt-Bu39 (0.1065 g, 0.951 mmol) in 5 mL of THF at -78
°C. After being stirred for 0.25-0.5 h, the reaction mixture
was diluted with 40 mL of pentane, filtered, and concentrated.
The crude epoxide was again dissolved in pentane, and the
insoluble material was filtered to provide 0.142 g (97%) of 1a :
1H NMR of crude product (400 MHz, C6D6) δ 1.43-1.48 (m,
2H), 1.59 (s, 3H), 1.73-1.82 (m, 6H), 2.24 (dd, J ) 2.5, 5.4 Hz,
1H), 2.49 (dd, J ) 4.0, 5.4 Hz, 1H), 2.98-3.02 (m, 1H), 4.96-
5.02 (m, 1H), 5.52-5.60 (m, 1H).
(10S,8E)-10,11-E p oxy-2-m et h yl-8-u n d ecen -4-on e (1b).
The tosylate 13b (0.188 g, 0.511 mmol) was converted, by the
method described for 1a , to 0.074 g (74%) of 1b: 1H NMR (300
MHz, C6D6) δ 0.79 (s, 3H), 0.81 (s, 3H), 1.46-1.57 (m, 2H),
1.78-2.05 (m, 6H), 2.05-2.14 (m, 1H), 2.24 (dd, J ) 2.7, 5.6
Hz, 1H), 2.48-2.52 (m, 1H), 2.99-3.04 (m, 0.8H), 3.36-3.40
(m, 0.2H), 4.98-5.07 (m, 1H), 5.55-5.64 (m, 1H); 13C NMR
(100 MHz, C6D6) δ 22.6, 23.0, 23.5, 24.5, 27.1, 31.9, 41.9, 42.1,
47.6, 48.0, 48.1, 51.6, 51.9, 129.0, 129.4, 135.3, 135.4, 208.1.
(8S,6Z)-8,9-Ep oxy-6-n on en -2-on e (1c). The precursor
tosylate 6c (0.452 g, 1.39 mmol) was converted, by the method
described for 1a , to 0.175 g (82%) of 1c: 1H NMR (300 MHz,
C6D6) δ 1.37-1.59 (m, 2H), 1.62 (s, 3H), 1.82-1.97 (m, 4H),
2.23 (dd, J ) 2.7, 5.6 Hz, 1H), 2.51 (dd, J ) 4.1, 5.4 Hz, 1H),
3.29-3.34 (m, 1H), 4.94-5.00 (m, 1H), 5.34-5.41 (m, 1H); 13
C
NMR (100 MHz, C6D6) δ 23.5, 26.9, 29.4, 42.0, 47.5, 48.0, 129.0,
135.4, 205.9.
(10S,8Z)-10,11-E p oxy-2-m et h yl-8-u n d ecen -4-on e (1d ).
Tosylate 13d (0.50 g, 1.36 mmol) was converted, by the method
described for 1a , to 0.260 g (98%) of 1d : 1H NMR (400 MHz,
C6D6) δ 0.80-0.83 (overlapping d, J ) 6.7 Hz, 6H), 1.46-1.59
(m, 2H), 1.87 (d, J ) 7.5 Hz, 2H), 1.92-2.02 (m with
overlapping t, J ) 7.3 Hz, 4H), 2.09-2.15 (m, 1H), 2.25 (dd, J
) 2.5, 5.5 Hz, 1H), 2.52 (dd, J ) 4.0, 5.4 Hz, 1H), 3.34-3.37
(m, 1H), 4.99 (dd, J ) 9.2, 10.9 Hz, 1H), 5.44 (dt, J ) 7.6, 11.0
Hz, 1H); 13C NMR (100 MHz, C6D6) δ 23.0, 23.9, 24.8, 27.4,
42.3, 48.0, 48.4, 52.0, 129.4, 135.8, 208.6.
(9S,7Z)-9,10-Ep oxy-7-d ecen -2-on e (1e). The tosylate 6e
(0.114 g, 0.335 mmol) was treated with KOt-Bu (0.0376 g,
0.335 mmol) in THF as described for 1a to yield 0.056 g (99%)
of 1e: 1H NMR (400 MHz, CDCl3) δ 1.35-1.44 (m, 2H), 1.53-
1.64 (m, 2H), 2.12 (s, 3H), 2.15-2.39 (m, 2H), 2.43 (t, J ) 7.4
Hz, 2H), 2.63 (dd, J ) 2.7, 5.3 Hz, 1H), 2.96 (dd, J ) 4.2, 5.0
Hz, 1H), 3.55-3.59 (m, 1H), 5.00 (dd, J ) 9.2, 10.5 Hz, 1H),
5.66-5.70 (m, 1H); 13C NMR (100 MHz, C6D6) δ 23.3, 27.5,
29.13, 29.22, 42.9, 47.6, 47.9, 128.5, 135.8, 206.1.
6-(3-Oxob u t yl)-1-oxa sp ir o[2.4]-4-h ep t en e (1f). Com-
pound 15f (0.093 g, 0.46 mmol) was treated with KOt-Bu (0.051
g, 0.46 mmol) in THF as described for 1a to provide 0.047 g
(62%) of 1f: 1H NMR (400 MHz, C6D6) δ 1.41 (dd, J ) 4.2,
14.3 Hz, 1H), 1.48-1.65 (m with overlapping s at 1.62 ppm,
5H), 1.88-2.62 (m, 3H), 2.46 (s, 1H), 2.60-2.65 (m, 2H), 5.28
(dd, J ) 1.9, 5.6 Hz, 1H), 5.68 (dd, J ) 1.3, 5.7 Hz, 1H); 13C
NMR (75 MHz, C6D6) δ 29.5, 29.7, 30.1, 35.2, 35.9, 40.6, 41.4,
43.3, 43.6, 52.8, 53.2, 68.0, 68.3, 132.0, 132.2, 141.7, 142.4,
206.6.
Gen er a l Meth od of An n u la tion . [1R*,2S*,(1E)]-2-(3-
Hyd r oxy-1-p r op en yl)-1-m eth ylcyclop en ta n -1-ol (2a ). A
solution of epoxide 1a (0.140 g, 0.909 mmol) in 40 mL of THF
was added dropwise to a solution of freshly prepared SmI2
[obtained from Sm (0.375 g, 2.50 mmol) and CH2I2 (0.535 g,
1.999 mmol)] in 20 mL of THF and HMPA (2.812 g, 17.26
mmol) over 1 h by a syringe pump. After being stirred for an
additional 15-30 min at rt, the reaction mixture was quenched
with 5 mL of saturated K2CO3. The resulting slurry was
extracted repeatedly with EtOAc. The organic phase was
decanted from the flask to another receiver, and the combined
organic extracts were dried with anhydrous MgSO4 and
concentrated. Purification of the crude product by flash silica
gel column chromatography gave 0.081 g (57%) of 2a : Kugel-
rohr distilled ot 100-120 °C/1.0 mmHg; Rf 0.2 (1:8 hexanes/
ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 1.13 (s, 3H), 1.40-
1.89 (m, 8H), 1.92-2.02 (m, 1H), 2.36-2.45 (m, 1H), 4.10 (d,
J ) 6.6 Hz, 2H), 5.57 (dd, J ) 7.3, 15.4 Hz, 1H), 5.68 (dt, J )
5.4, 15.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.4, 23.4, 29.3,
40.2, 53.8, 63.4, 80.9, 130.5, 132.8; IR (neat) 3356 cm-1; HRMS
calcd for C9H14O (M - H2O)+ 138.1045, found 138.1058; LRMS
(EI) m/z 156 (0.1), 138 (33), 123 (11), 95 (35), 80 (100); CI+
using NH3 gave M+ ion peak at 156; [R]20 -41.9° (c ) 0.7,
D
CHCl3).
[1R*,2R*,(2E)]-2-{3-[(ter t-Bu t yld im et h ylsilyl)oxy]-1-
p r op en yl}-1-(2-m eth yl)p r op ylcyclop en ta n -1-ol (2b). The
epoxide 1b (0.090 g, 0.459 mmol) was treated with a solution
of SmI2-HMPA in THF as described for 2a to give 0.050 g
(55%) of impure annulated product. 1H NMR of the crude
(39) Use of KOt-Bu in the preparation of vinyl epoxides: Tanis, S.
P.; McMills, M. C.; Herrinton, P. M. J . Org. Chem. 1985, 50, 5887.

SmI2-Mediated Reductive Annulations
J . Org. Chem., Vol. 61, No. 17, 1996 5893
product indicated the presence of 10% of the open-chain diol
and a 3:1 mixture of diastereomeric cyclic diols (3:1 determined
by GLC and isolation). To facilitate separation, this impure
fraction (0.050 g, ∼0.252 mmol) was treated with TBDMSCl
(0.047 g, 0.303 mmol) and imidazole (0.0258 g, 0.379 mmol)
in 2 mL of CH2Cl2. Aqueous workup, followed by purification
of the crude product by silica gel flash column chromatography,
provided 0.017 g (22%) of the impure minor diastereomer and
0.044 g (56%) of 2b: Kugelrohr distilled ot 135-140 °C/l
mmHg; Rf 0.19 (12:1 hexanes/ethyl acetate); 1H NMR (400
MHz, CDCl3) δ 0.05 (s, 6H), 0.89 (s, 9H), 0.94 (apparent t due
to overlapping d, J ) 6.4 Hz, 6H), 1.25 (s, 1H), 1.32 (d, J )
6.0 Hz, 2H), 1.40-1.49 (m, 1H), 1.60-1.86 (m, 5H), 1.97-2.06
(m, 1H), 2.37-2.42 (m, 1H), 4.12 (d, J ) 4.1 Hz, 2H), 5.43-
5.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ -5.1, 18.4, 21.1,
24.5, 24.7, 24.8, 25.9, 29.6, 37.1, 45.4, 55.1, 63.8, 84.3, 130.0,
131.3; IR (neat) 3451 cm-1; HRMS calcd for C18H35O2Si (M -
H)+ 311.2406, found 311.2404; LRMS (EI) m/z 311 (9), 295 (37),
255 (10), 180 (99), 163 (65).
acetate); 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 3H), 1.30-1.37
(m, 1H), 1.44-1.51 (m, 3H), 1.88 (s, 1H), 1.98-2.15 (m, 2H),
2.63 (dd, J ) 8.9, 16.7 Hz, 1H), 2.91-2.95 (m, 2H), 4.10 (s,
2H), 5.38 (d, J ) 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
25.1, 32.6, 39.0, 39.6, 41.6, 62.0, 63.4, 81.7, 124.8, 145.8; IR
(CDCl3) 3316 cm-1; HRMS calcd for C10H14O (M - H2O)+
150.1045, found 150.1017; LRMS (EI) m/z 150 (20), 135 (6),
119 (6), 107 (14), 92 (100); CI+ using NH3 gave M+ ion peak at
168.
(1R*,6S*,9S*)-3-(Hydr oxym eth yl)-9-m eth ylbicyclo[4.3.0]-
2-n on en -9-ol (2g). The epoxide 1g (0.070 g, 0.389 mmol) in
20 mL of THF was added to a solution of SmI2-HMPA in THF
over 3 h. Usual workup and purification of the crude product
by flash silica gel column chromatography provided 0.055 g
(78%) of 2g: Kugelrohr distilled ot 150-160 °C/1 mmHg; Rf
1
0.3 (1:4 hexanes/ethyl acetate); H NMR (300 MHz, CDCl3) δ
1.25 (s, 3H), 1.31-1.55 (m, 4H), 1.58-1.71 (m, 3H), 1.87-2.03
(m, 3H), 2.31-2.33 (m, 1H), 2.47-2.59 (m, 1H), 4.01 (s, 2H),
5.63 (t, J ) 1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.6,
25.4, 26.0, 27.3, 34.8, 39.8, 50.4, 67.4, 81.9, 121.9, 139.3; IR
(neat) 3345 cm-1; LRMS (EI) m/z 164 (5), 122 (8), 106 (100),
91 (22); CI+ using NH3 gave a peak at 182 (M+). Anal. Calcd
for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.40; H, 9.98.
[1S*,7R*,10R*,(1E)]-10-(3-Hyd r oxy-1-p r op en yl)bicyclo-
[5.3.0]d eca n -1-ol (2h ). A solution of epoxide 1h (0.120 g,
0.577 mmol) in 25 mL of THF was added to a solution of SmI2-
HMPA in THF over 3 h by a syringe pump as described for
2a . Usual workup and purification of the crude product by
flash silica gel column chromatography provided 0.075 g (62%)
of 2h [8 mg (∼7%) of a minor diastereomer was obtained as
an impure fraction and was not characterized; these isolated
amounts are in agreement with a 1:10 diastereomeric ratio
determined by GC]: Kugelrohr distilled ot 160 °C/1 mmHg;
Rf 0.2 (1:1 hexanes/ethyl acetate); 1H NMR (400 MHz, CDCl3)
δ 1.22-1.65 (m, 12H), 1.77-1.81 (m, 2H), 1.93-2.09 (m, 3H),
2.41 (m, 1H), 4.12 (d, J ) 13.3 Hz, 2H), 5.48-5.71 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 22.9, 29.0, 30.0, 30.8, 32.0, 33.9,
[1S*,2R*,(1E)]-2-(3-H yd r oxy-1-p r op en yl)-1-m et h ylcy-
clop en ta n -1-ol (2c). Epoxide 1c (0.015 g, 0.0974 mmol) was
added over a period of 0.5 h to a solution of SmI2-HMPA in
THF as described for 2a . Purification of the crude product by
flash silica gel column chromatography gave 0.011 g (72%) of
2c: Kugelrohr distilled ot 100-120 °C/1.0 mmHg; Rf 0.25
(ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 1.13 (s, 3H),
1.45-1.49 (m, 1H), 1.51-1.78, (m, 6H), 1.92-1.96 (m, 1H),
2.36-2.44 (m, 1H), 4.10 (d, J ) 5.3 Hz, 2H), 5.57 (dd, J ) 8.3,
15.4 Hz, 1H), 5.68 (dt, J ) 4.4, 15.4 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 20.6, 23.7, 29.5, 40.3, 53.9, 63.6, 81.0, 130.4,
132.8; IR (neat) 3300 cm-1; HRMS calcd for C9H14O (M -
H2O)+ 138.1045, found 138.1062; LRMS (EI) m/z 138 (15), 95
(24), 80 (100), 67 (24), 55 (18); CI+ using NH3 gave M+ ion
peak at 156; [R]20 +21.4° (c ) 0.7, CHCl3).
D
(1E)-2-(3-H yd r oxy-1-p r op en yl)-1-(2-m et h ylp r op yl)cy-
clop en ta n -1-ol (2d ). A solution of epoxide 1d (0.084 g, 0.429
mmol) in 20 mL of THF was added to a mixture of SmI2
solution in THF (9.43 mL, 0.1 M, 0.943 mmol) and tetra-
methylguanidine (TMG, 0.956 g, 8.30 mmol) at rt over 2.3 h
by a syringe pump. A standard workup after stirring the
reaction mixture for 15 min and purification of the product
by silica gel flash column chromatography afforded 0.06 g
(71%) of a 1:1 mixture of diastereomers of 2d : Rf 0.35 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 0.85-
0.97 (m, 6H), 1.08 (s, 0.5H), 1.22-1.87 (m, 10H), 1.96-2.06
(m, 0.5H), 2.14-2.21 (m, 0.5H), 2.41 (q, J ) 7.8 Hz, 0.5H),
4.09-4.13 (m, 2H), 5.51 (dd, J ) 8.5, 15.1 Hz, 0.5H), 5.63 (dt,
J ) 15.4, 5.6 Hz, 0.5H), 5.69-5.76 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.8, 21.4, 24.4, 24.55, 24.61, 24.8, 29.0, 29.4, 36.8,
38.1, 44.8, 48.3, 52.9, 55.1, 63.3, 63.4, 83.2, 84.1, 129.9, 131.3,
36.1, 52.4, 57.8, 63.6, 85.8, 129.9, 132.7; IR (CDCl3) 3346 cm-1
;
LRMS (EI) m/z 210 (0.1), 192 (25), 161 (4), 149 (6), 112 (100);
CI+ using NH3 gave a peak at 210 (M+). Anal. Calcd for
C13H22O2: C, 74.24; H, 10.54. Found: C, 74.66; H, 10.98.
[1R*,2S*,5S*,(1E)]-2-(3-H yd r oxy-1-p r op en yl)b icyclo-
[3.3.0]octa n -1-ol (2i). A solution of epoxide 1i (0.099 g, 0.55
mmol) in 30 mL of THF was added to a solution of SmI2-
HMPA in THF over 5 h as described for 2a . The usual workup
and purification of the crude product by silica gel flash column
chromatography afforded 0.078 g (78%) of 2i: mp 95-96 °C;
Rf 0.21 (1:1 hexanes/ethyl acetate); 1H NMR (400 MHz, CDCl3)
δ 1.03-1.12 (m, 1H), 1.23-1.76 (m, 9H), 1.83-1.94 (m, 1H),
2.06-2.21 (m, 2H), 2.43-2.49 (m, 1H), 4.11 (s, 2H), 5.67-5.77
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.8, 30.0, 30.1, 34.8,
131.5, 133.0; IR (CH2Cl2) 3354 cm-1; HRMS calcd for C12H20
O
37.3, 50.8, 54.1, 63.5, 92.8, 130.3, 132.2; IR (CDCl3) 3385 cm-1
;
(M - H2O)+ 180.1514, found 180.1518; LRMS (EI) m/z 197 (2),
HRMS calcd for C11H16O (M - H2O)+ 164.1204, found 164.1224;
LRMS (EI) m/z 164 (12), 97 (19), 84 (100), 67 (15), 55 (18); CI+
using NH3 gave a peak at 182 (M+).40
180 (62), 165 (46), 137 (48), 123 (62).40
[1S*,2R*,(1E)]-2-(3-H yd r oxy-1-p r op en yl)-1-m et h ylcy-
cloh exa n -1-ol (2e). The epoxide 1e (0.071 g, 0.423 mmol)
was treated with a solution of SmI2-HMPA in THF as
described for 2a to afford 0.012 g (17%) of 2e: Rf 0.14 (1:4
[1R*,6S*,9S*,(1E)]-9-(3-H yd r oxy-1-p r op en yl)b icyclo-
[4.3.0]n on a n -1-ol (2j). A solution of epoxide 1j (0.220 g, 1.13
mmol) in 57 mL of THF was added to a solution of SmI2-
HMPA in THF over 5 h as described for 2a . Usual workup
and purification of the crude product provided 0.170 g (76%)
of 2j: mp 110-111 °C; Rf 0.24 (1:1.5 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.29-1.37 (m, 4H), 1.40-1.52
(m, 6H), 1.50-1.70 (m, 3H), 1.81-1.97 (m, 2H), 2.42 (q, J )
9.3 Hz, 1H), 4.10 (t, J ) 5.4 Hz, 2H), 5.62 (dd, J ) 7.0, 15.4
Hz, 1H), 5.68 (dt, J ) 15.4, 5.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.2, 20.9, 23.5, 24.0, 26.0, 28.9, 44.0, 54.6, 63.6, 79.2,
130.9, 132.3; IR (CDCl3) 3378 cm-1; LRMS (EI) m/z 178 (14),
98 (100), 83 (19), 70 (22), 55 (17); CI+ using NH3 gave a peak
at 196 (M+). Anal. Calcd for C12H20O2: C, 73.43; H, 10.27.
Found: C, 73.15; H, 10.42.
1
hexanes/ethyl acetate); H NMR (400 MHz, CDCl3) δ 1.09 (s,
3H), 1.19-1.42 (m, 5H), 1.65-1.78 (m, 5H), 2.03-2.06 (br m,
1H), 4.11 (d, J ) 4.3 Hz, 2H), 5.63-5.74 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.9, 23.7, 25.1, 29.6, 40.5, 51.4, 63.6, 72.3,
131.1, 132.8; IR (neat) 3358 cm-1; HRMS calcd for C10H16
O
(M - H2O)+ 152.1201, found 152.1199; LRMS (EI) m/z 169
(0.2), 152 (5), 109 (25), 94 (15), 79 (57); CI+ using NH3 gave
M+ ion peak at 170.
(1R*,5S*,8S*)-3-(Hydr oxym eth yl)-8-m eth ylbicyclo[3.3.0]-
2-octen -8-ol (2f). A solution of epoxide 1f (0.047 g, 0.283
mmol) in 15 mL of THF was added dropwise to a solution of
SmI2-HMPA in THF over 3 h. The reaction mixture was
worked up and purified as described for 2a to yield 0.034 g
(72%) of 2f: mp 125-126 °C; Rf 0.34 (1:1.5 hexanes/ethyl
[1R*,8S*,11S*,(1E)]-11-{3-[(ter t-Bu tyldim eth ylsilyl)oxy]-
1-p r op en yl}bicyclo[6.3.0]u n d eca n -1-ol (2k ). A solution of
epoxide 1k (0.040 g, 0.180 mmol) in 10 mL of THF was added
dropwise to a solution of SmI2-HMPA over 1 h as described
for 2a . Usual workup and purification of the crude product
by silica gel flash column chromatography gave 0.037 g of
(40) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

5894 J . Org. Chem., Vol. 61, No. 17, 1996
Molander and Shakya
impure product, which was silylated as described for 2b. TLC
showed the presence of six spots, four of which after silica gel
flash column chromatography appeared to have the features
Ack n ow led gm en t. We thank Dr. Bruce Noll for
performing the X-ray crystallographic analyses, the
National Institutes of Health (NIH) for their generous
support of our research program, and the National
Science Foundation for financial support to acquire the
X-ray crystallographic equipment through Grant
CHE9505926.
1
of the desired product on the basis of the H NMR spectra of
partially separated fractions. These four fractions when
combined gave 0.050 g (83% overall yield) of 2k . GLC analysis
of 2k gave only three peaks (1.5:1.2:1): Rf 0.2-0.35 (25:1
1
hexanes/ethyl acetate); H NMR (400 MHz, CDCl3) δ 0.05 (s,
6H), 0.88 (s, 9H), 1.22-2.03 (m, 17.5H), 2.12-2.41 (m, 1.5H),
4.07-4.20 (m, 2H), 5.32-5.65 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ -5.12, -5.08, 18.4, 21.2, 21.6, 23.6, 23.7, 25.55, 25.65,
25.74, 25.94, 26.5, 26.88, 26.91, 27.4, 27.8, 28.0, 28.9, 29.2,
30.37, 30.45, 31.2, 32.0, 33.3, 34.4, 34.5, 34.6, 36.7, 43.2, 49.8,
50.1, 52.6, 57.9, 58.2, 63.76, 63.80, 64.1, 81.5, 82.3, 83.8, 84.8,
129.1, 129.7, 130.1, 130.2, 131.6, 132.2, 132.6, 132.8; IR (neat)
3454 cm-1; HRMS calcd for C20H37O2Si (M - 1)+ 337.2563,
found 337.2563; LRMS (EI) m/z 337 (0.1), 320 (0.8), 281 (4),
263 (4), 206 (35).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds synthesized (107 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O960335S