Stereoselective synthesis of heterocyclic zinc reagents via a nickel-catalyzed radical cyclization

Article abstract of DOI:10.1021/jo960617s

Unsaturated iodo or bromo acetals of type 2 undergo a smooth cyclization mediated by diethylzinc (2 equiv) and Ni(acac)₂ as catalyst (2-5 mol %). These cyclizations proceed via a radical mechanism affording a (tetrahydrofuranylmethyl)zinc halide of type 1, which can be reacted with various electrophiles after a transmetalation with CuCN·2LiCl. High stereoselectivities are usually observed in the ring closures, especially if monocyclic cyclization precursors are used. In these cases, bicyclic products of the endo-configuration are obtained with over 94% diastereoselectivity. The synthetic method has been extended to the preparation of a nitrogen heterocycle and over 98% pure trans-4,5-disubstituted γ-butyrolactones. A short enantioselective synthesis of (-)-methylenolactocine (3) using the radical cyclization and a novel oxidation of α-silyl zinc peroxide as a key step is also described.

Full text of DOI:10.1021/jo960617s

J . Org. Chem. 1996, 61, 5743-5753
5743
Ster eoselective Syn th esis of Heter ocyclic Zin c Rea gen ts via a
Nick el-Ca ta lyzed Ra d ica l Cycliza tion
Andrea Vaupel and Paul Knochel*
Fachbereich Chemie der Philipps-Universita¨t Marburg, Hans-Meerwein-Strasse,
D-35032 Marburg, Germany
Received April 2, 1996X
Unsaturated iodo or bromo acetals of type 2 undergo a smooth cyclization mediated by diethylzinc
(2 equiv) and Ni(acac)2 as catalyst (2-5 mol %). These cyclizations proceed via a radical mechanism
affording a (tetrahydrofuranylmethyl)zinc halide of type 1, which can be reacted with various
electrophiles after a transmetalation with CuCN‚2LiCl. High stereoselectivities are usually observed
in the ring closures, especially if monocyclic cyclization precursors are used. In these cases, bicyclic
products of the endo-configuration are obtained with over 94% diastereoselectivity. The synthetic
method has been extended to the preparation of a nitrogen heterocycle and over 98% pure trans-
4,5-disubstituted γ-butyrolactones. A short enantioselective synthesis of (-)-methylenolactocine
(3) using the radical cyclization and a novel oxidation of R-silyl zinc peroxide as a key step is also
described.
In tr od u ction
5 in the presence of N-iodosuccinimide (NIS) (Scheme 1).9
The resulting unsaturated iodo acetals 6a -c were ob-
tained in 70-85% yield. Cyclic alkenyl ethers like 2,3-
dihydrofuran (4d ) and 2,3-dihydro-2H-pyran (4a ) afford
the cyclic trans-iodo acetals 6d and 6e in, respectively,
61% and 75% yield with the NIS procedure. By using
substituted allylic alcohols like 5b or 5c, substituted
acetals like 6f-h are obtained as 1:1 mixtures of dias-
tereoisomers (Scheme 1). The iodo acetals 6 have a
limited stability and decompose slowly at rt; therefore,
the synthesis of more stable cyclization precursors like
the corresponding bromo acetals 7 was envisioned. Thus,
the treatment of alkenyl ethers with allylic alcohols in
the presence of NBS10 in CH2Cl2 (0 °C to rt) affords the
desired unsaturated bromo acetals 7a -e in good yields
(Scheme 2).
Polyfunctional organozincs are versatile intermediates
that react with various electrophiles in the presence of
the appropriate transition metal catalyst.1 These orga-
nometallics can be prepared by the direct insertion of zinc
to an organic halide2 or by a halogen-zinc exchange
reaction mediated by diethylzinc.3 This second prepara-
tion method could be improved by the addition of transi-
tion metal salts of Cu(I),4 Pd(II),5 or Mn(II).6 These
transition metal catalysts induce radical processes7 that
can be used to prepare substituted cyclopentanes from
acyclic precursors with excellent stereoselectivity.5 Herein,
we wish to report the extension of this reaction to the
stereoselective preparation of tetrahydrofurans of type
1 starting from the unsaturated iodo or bromo acetals 2
(eq 1). Application to a stereoselective synthesis of
disubstituted butyrolactones and to a formal synthesis
of antitumor antibiotic (-)-methylenolactocin (3) will also
be described.1,8
The preparation of unsatured alkyl iodide 8 was
performed by opening cyclohexene oxide11 with the
magnesium amide 9 (THF, rt, 4 h; 69% yield), affording
the intermediate amino alcohol 10, which was converted
to the corresponding cis-alkyl iodide 8 using 2 DCC‚MeI12
(1.8 equiv, THF, 3d, 40 °C, 68% yield). The cyclization
of 5-hexenyl iodides with Et2Zn was best performed with
dichloro (1,1′-bis(diphenylphosphino)ferrocene)palladium-
(II) (PdCl2(dppf))13 as catalyst. We observed less effective
reactions with substrates 6 and 7, but a far better
reaction was achieved with Ni(acac)2 (2 mol %) as
catalyst. Under these conditions, the cyclization of the
iodo acetals 6 is completed within 1 h at rt furnishing
Resu lts
The synthesis of the cyclization precursors was readily
achieved by reacting vinylic ethers 4 with allylic alcohols
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) Knochel, P.; Singer, R. Chem. Rev. 1993, 93, 2117. (b) Knochel,
P. Synlett 1995, 393.
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Antibiot. 1988, 41, 751. (b) de Azevedo, M. B. M.; Murta, M. M.; Greene,
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2120.
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K.; Knochel, P. Tetrahedron Lett. 1993, 34, 3115.
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Tucker, C. E.; Knochel, P. J . Am. Chem. Soc. 1993, 115, 7027. (b)
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Lett. 1993, 34, 7911.
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1994, 35, 1177.
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Chem. Soc. 1983, 105, 3741. (b) Lu¨bbers, T.; Scha¨fer, H. J . Synlett 1992,
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Yavari, I.; Roberts, J . D. J . Org. Chem. 1978, 43, 4689.
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M. Synthesis 1981, 1001. (d) Hayashi, T.; Katsuro, Y.; Kumada, M.
Tetrahedron Lett. 1980, 21, 3915. (e) Hayashi, T.; Konoshi, M.; Yokota,
K.; Kumada, M. Chem. Lett. 1980, 6, 767. (f) Hayashi, T.; Konoshi,
M.; Yokata, K.-I.; Kumada, M. J . Organomet. Chem. 1985, 285, 359.
S0022-3263(96)00617-2 CCC: $12.00 © 1996 American Chemical Society

5744 J . Org. Chem., Vol. 61, No. 17, 1996
Vaupel and Knochel
Ta ble 1. P olyfu n ction a l Tetr a h yd r ofu r a n s 14a -e a n d
16a -i Obta in ed by th e Cycliza tion of th e Un sa tu r a ted
Iod o Aceta ls 6a -h w ith Et2Zn
Sch em e 1
Sch em e 2
a
All yields refer to analytically pure products. b Cis:trans or exo:
endo ratio. c PdCl2(dppf) was used as a catalyst. Mixture of
d
diastereomers at position 2.
ratio as shown by NMR spectroscopy (1H1H NOESY
spectra). This high selectivity can be explained by the
intermediate pseudochair conformation 15 in which the
alkyl substituents at C(1) and C(2) occupy equatorial
positions and the alkoxy substituent at C(3) occupies the
axial position (eq 2). This stereochemistry should be
Sch em e 3
further favored by an anomeric effect and has been
observed for several cyclization reactions involving cyclic
radicals.15 This excellent endo-selectivity is also observed
with cyclic acetals substituted on C(2) like 6f and 6g
(endo:exo > 96:4). As seen from Table 1, the zinc-copper
reagents have been trapped with ethyl (R-bromomethyl)-
(tetrahydrofuranylmethyl)zinc iodides 11, which after
transmetalation with CuCN‚2LiCl (1 equiv) leading to
the zinc-copper reagent 12, were reacted with various
electrophiles to furnish the products 14 (Table 1 and
Scheme 3). In the case of open-chain iodo acetals 6a -c,
a cis:trans ratio of 15:85 was obtained, which can be
rationalized via the transition state conformation 13 in
which all the substituents occupy pseudoequatorial posi-
tions according to the Beckwith model.14 In the case of
cyclic iodo acetals like 6d -e higher stereoselectivities are
observed and the endo-products 16 are obtained in g95:5
(14) (a) Beckwith, A. L. J .; Lawrence, T.; Serelis, A. K. J . Chem.
Soc., Chem. Commun. 1980, 484. (b) Beckwith, A. L. J . Tetrahedron
1981, 37, 3073. (c) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron
1985, 41, 3925. (d) Curran, D. P. In Comprehensive Organic Chemistry;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991;
Chapter 4.4.
(15) (a) Rajanbabu, T. V. Acc. Chem. Res. 1991, 24, 139. (b)
Beckwith, A. L. J .; Phillipon, G.; Serelis, A. K. Tetrahedron Lett. 1981,
22, 2811. (c) Rajanbabu, T. V.; Fukunaga, T. J . Am. Chem. Soc. 1989,
111, 296. (d) Rajanbabu, T. V.; Fukunaga, T.; Reddy, G. S. J . Am.
Chem. Soc. 1989, 111, 1759.

Synthesis of Heterocyclic Zinc Reagents
J . Org. Chem., Vol. 61, No. 17, 1996 5745
Ta ble 2. P olyfu n ction a l Tetr a h yd r ofu r a n s 17a -h
Obta in ed by th e Cycliza tion of Un sa tu r a ted Br om o
Aceta ls 7a -e in th e P r esen ce of Ni(a ca c)2 a s Ca ta lyst
Ta ble 3. tr a n s-4,5-Disu bstitu ted γ-Bu tyr ola cton es 18a -e
Obta in ed by m -CP BA Oxid a tion
a
All yields refer to analytically pure products.
γ-butyrolactones using a solution of m-CPBA18 in CH2-
Cl2 in the presence of BF3‚OEt2 (0.4 equiv) at rt. This
method affords the desired lactones 18 in 70-98% yield
(method A; eq 4). It is also possible to perform a “one-
a
b
All yields refer to analytically pure products. Exo:endo ratio.
pot reaction” starting from the bromo acetals 7b,c. The
zinc reagent resulting from the cyclization procedure was
transmetalated with CuCN‚2LiCl and reacted with an
electrophile. The crude mixture was filtered over a short
column, and after evaporation of the solvent the crude
product was submitted to the oxidation conditions de-
scribed above to afford the lactones 18 in 50-53% overall
yield (method B; Table 3). The relative stereochemistry
acrylate, acid chlorides, and ethyl propiolate in satisfac-
tory yields.16 As mentioned previously, bromo acetals of
type 7 are more stable and more easy to prepare.
Although the compounds 7 do not undergo the nickel-
catalyzed cyclization, we found that a smooth reaction
occurs if dry lithium iodide (25 mol %) is added to the
reaction mixture and if the reaction is performed 40 °C
(eq 3). Under these conditions, a range of unsaturated
1
of the products was established by two-dimensional H-
NMR experiments (1H1H NOESY) on the lactone 18a (see
the Experimental Section). The alkyl iodide 8 was also
submitted to the cyclization conditions using either PdCl2-
(dppf) (3 mol %) or Ni(acac)2 (2 mol %) as a catalyst. In
both cases, a rapid reaction was observed at rt, affording
the intermediate zinc reagent 19 that could be trapped
efficiently with AcOD to provide the endo-product 20 as
the only stereoisomer. Attempts to quench 19 with other
electrophiles were not successful, due to the low reactivity
of the organozinc reagent due to the coordination of zinc
to nitrogen (eq 5). As an application of this synthetic
bromo acetals were cyclized (Table 2) and quenched with
different electrophiles after a transmetalation with CuCN‚-
2LiCl leading to the tetrahydrofurans 17. The role of
lithium iodide may be to generate in situ small amounts
of the corresponding alkyl iodide, which may initiate the
radical reaction. Whereas the relative stereochemistry
of the anomeric carbon is not controlled, a high diaste-
reocontrol is observed between C(4) and C(5), giving the
trans-product in over 98% stereoselectivity (see Table 2).
The monocyclic acetals 17 were oxidized to pure trans-
method, we have developed a formal total synthesis of
(-)-methylenolactocin (3), a molecule of biological interest
for which two total syntheses have already been reported
(16) Vaupel, A.; Knochel, P. Tetrahedron Lett. 1994, 35, 8349.
(17) J ubert, C.; Knochel, P. J . Org. Chem. 1992, 57, 5425.
(18) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
19, 419.

5746 J . Org. Chem., Vol. 61, No. 17, 1996
Vaupel and Knochel
by Greene8b and Zhu.8c,d The target molecule is the
lactone 21, which has been converted in one step to (-)-
methylenolactocin (3).8b This molecule was prepared by
the diethylzinc-mediated cyclization of the unsaturated
bromo acetal 22, which was obtained in optically pure
form from (E)-3-(trimethylsilyl)propenal (23) (eq 6). The
Sch em e 4
aldehyde 23 was prepared from propargylic alcohol in
three steps. Thus, the metalation of propargylic alcohol
with ethylmagnesium bromide and silylation affords after
acidic workup 3-(trimethylsilyl)-2-propyn-1-ol, which was
reduced stereoselectively with sodium bis(2-methoxy-
ethoxy)aluminum hydride (Red-Al) to afford (E)-3-(trim-
ethylsilyl)-2-propen-1-ol (24) in 50-60% overall yield.19
The oxidation of 24 with MnO2 in CH2Cl2 at 35 °C for 12
h provides the aldehyde 23 in 90% yield (eq 7).20 The
of 30 gives the target carboxylic acid 21 (90% yield;
Scheme 4). This crystalline product has a melting point
of 104 °C (lit.25 mp 105-107 °C) and a specific rotation
of [R]D ) -50.5 (c ) 0.41, CHCl3) (lit.25 [R]D ) -54 (c )
0.4, CDCl3)).
In summary, we have developed a new efficient cy-
clization of unsaturated iodo and bromo acetals that
affords substituted tetrahydrofurans and butyrolactones
with good stereoselectivity. This method was applied to
the enantioselective preparation of (-)-methylenolactocin
(3) in four steps starting from (E)-3-(trimethylsilyl)-
propenyl in 30% overall yield and ca. 90% ee.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Unless otherwise indicated, all
reactions were carried out under argon. Solvents (THF,
toluene) were dried and freshly distilled over sodium/ben-
zophenone. Dichloromethane was freshly distilled over CaH2.
Reactions were monitored by gas-liquid-phase chromatogra-
phy (GC) or thin-layer chromatography (TLC) analysis of
hydrolyzed aliquots.
reaction of 23 with dipentylzinc in the presence of Ti(O-
i-Pr)4 and (1R,2R)-1,2-bis(trifluoromethanesulfonamido)-
cyclohexane (25)21 in toluene at -30 °C affords the allylic
alcohol 2620,22 in 70% and 82% ee as determined by
derivatization to the corresponding mandelic ester using
(S)-(+)-O-acetylmandelic acid.23 The treatment of 26
with butyl vinyl ether (4a ) in the presence of NBS in CH2-
Cl2 (0 °C, 1 h) produces the expected cyclization precursor
22 in 88% yield (Scheme 4). The cyclization of 22 in the
presence of diethylzinc (2 equiv), lithium iodide (0.25
equiv), and Ni(acac)2 (5 mol %) affords the intermediate
zinc organometallic 27 via the transition state conforma-
tion 28. The organozinc bromide 27 could be directly
oxidized with oxygen in the presence of TMSCl, leading
to an intermediate zinc peroxide 29 that undergoes an
oxy-Peterson elimination to furnish the trans-aldehyde
30 (100% trans) in 55% overall yield.24 J ones oxidation
Sta r tin g Ma ter ia ls. The following starting materials were
prepared according to literature procedures: ethyl R-(bromom-
ethyl)acrylate,26 N-methyl-N,N ′-dicyclohexylcarbodiimidium
iodide (2 DCC‚MeI),12 dichloro (1,1′-bis(diphenylphosphino)-
ferrocene)palladium(II),13 3-iodo-2-cyclohexen-1-one,27 1-phen-
yl-2-propen-1-ol,28 1-nonen-3-ol,29 4-methyl-1-penten-3-ol,30 N-
iodosuccinimide (NIS),31 (E)-3-(trimethylsilyl)-2-propenal,32
and (1R,2R)-1,2-bis(trifluoromethanesulfonamido)cyclohexane.21a
P r ep a r a tion of Cycliza tion P r ecu r sor s of Typ e 6, 7,
a n d 8. P r ep a r a tion of 2-Bu toxy-1-iod o-3-oxa -5-h exen e
(6a ). The preparation of the alkyl iodide 6a was carried out
according to the literature procedure9 with butyl vinyl ether
(4a ) (2.0 g, 20 mmol, 1 equiv), 2-propen-1-ol (5a ) (1.70 g, 20.0
mmol, 1 equiv), and NIS31 (4.5 g, 20 mmol, 1 equiv). Purifica-
tion by silica gel chromatography (hexanes/ether 9:1) of the
crude product afforded the iodo acetal 6a (4.0 g, 14.5 mmol,
70% yield) as a colorless liquid.
(19) J ones, T. K.; Denmark, S. E. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, p 524.
(20) Ostwald, R.; Chavant, P.-Y.; Stadtmu¨ller, H.; Knochel, P. J . Org.
Chem. 1944, 59, 4143.
(21) (a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett.
1989, 30, 1657. (b) Takahashi, H.; Kawakita, T.; Yoshioka, M.;
Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095. (c) Taka-
hashi, T.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691.
(22) (a) Brieden, W.; Ostwald, R.; Knochel, P. Angew. Chem. 1993,
105, 629. (b) Knochel, P.; Brieden, W.; Eisenberg, C.; Rozema, M. J .
Tetrahedron Lett. 1993, 34, 5881. (c) Eisenberg, C.; Knochel, P. J . Org.
Chem. 1994, 59, 3760. (d) Schwink, L.; Knochel, P. Tetrahedron Lett.
1994, 35, 9007.
(23) Parker, D. J . Chem. Soc., Perkin Trans. 2 1983, 83.
(24) (a) Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36, 231. (b)
Knochel, P.; Xiao, C.; Yeh, M. C. P. Tetrahedron Lett. 1988, 29, 6697.
(c) Knochel, P.; Yeh, M. C. P.; Xiao, C. Organometallics 1989, 8, 2831.
(d) Klement, I.; Lu¨tjens, H.; Knochel, P. Tetrahedron Lett. 1995, 36,
3161.
IR (neat): 2910 (s), 2870 (s), 1110 (vs) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.86 (m, 1H), 5.19 (d, J ) 17.2 Hz, 1H),
(25) Honda, T.; Kimura, N. J . Chem. Soc., Chem. Commun. 1994,
77.
(26) Villieras, J .; Rambaud, M. Synthesis 1982, 924.
(27) Piers, E.; Grierson, J . R.; Lau K. C. Can. J . Chem. 1982, 60,
210.
(28) Brewster, J . H.; Bayer, H. O. J . Org. Chem. 1964, 29, 116.
(29) Smith, J . G.; Drozda, S. E.; Petraglia, S. P.; Quinn, N. R.; Rice,
E., M.; Taylor, B. S.; Viswanathan, M. J . Org. Chem. 1984, 49, 4112.
(30) Midland, M. M.; Koops, R. W. J . Org. Chem. 1990, 55, 5058.
(31) Vankar, Y. D.; Kumaravel, G. Tetrahedron Lett. 1984, 25, 233.
(32) Stadtmu¨ller, H. Ph.D. Thesis, Philipps University, Marburg,
1995.

Synthesis of Heterocyclic Zinc Reagents
J . Org. Chem., Vol. 61, No. 17, 1996 5747
5.10 (d, J ) 10.3 Hz, 1H), 4.58 (t, J ) 5.5 Hz, 1H), 4.05 (dd, J
) 14.3, 5.3 Hz, 1H), 3.54 (m, 1H), 3.43 (m, 2H), 3.15 (d, J )
5.6 Hz, 2H), 1.49 (m, 2H), 1.37 (m, 2H), 0.85 (t, J ) 7.3 Hz,
3H). 13C-NMR (CDCl3, 75 MHz): δ 134.0, 117.2, 101.7, 67.1,
66.2, 31.6, 19.1, 13.6, 5.0. MS (EI): 227 (M+ - C4H9, 12), 211
(20), 87 (78), 41 (100). Anal. Calcd for C9H17IO (283.19): C,
38.16; H, 6.01. Found: C, 38.24; H, 5.93.
affording a 1:1 mixture of diastereomers of the iodo acetal 6f
(5.7 g, 16.6 mmol, 83% yield) as a yellow oil.
IR (neat): 3050 (vs), 2950 (s), 1450 (m), 1440 (m) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 7.30 (m, 5H), 6.02 (ddd, J ) 17.1,
8.1, 5.6 Hz, 1H), 5.32 (m, 2H), 4.53 (d, J ) 5.1 Hz, 1H), 4.13
(m, 1H), 4.02 (m, 1H), 3.55 (m, 1H), 2.41 (m, 1H), 1.98 (m,
2H), 1.76 (m, 1H), 1.57 (m, 1H). 13C-NMR (CDCl3, 75 MHz):
δ 140.7, 138.6, 129.4, 128.3, 127.9, 118.3, 100.0, 79.2, 63.5, 32.4,
29.5, 25.3 (first diastereomer); δ 139.3, 137.3, 128.4, 127.7,
127.5, 115.3, 98.8, 78.8, 63.2, 32.3, 29.1, 25.2 (second diaste-
reomer). MS (EI): 211 (12), 117 (100), 84 (25). Anal. Calcd
for C14H17IO2 (343.25): C, 48.98; H, 4.97. Found: C, 48.80;
H, 4.73.
P r ep a r a tion of 1-Iod o-3-oxa -2-p r op oxy-5-h exen e (6b).
The literature procedure9 was followed with propyl vinyl ether
(4b) (2.10 g, 20 mmol), 2-propen-1-ol (5a ) (1.70 g, 20.0 mmol),
and NIS31 (4.5 g, 20 mmol). Usual workup and purification
by silica gel chromatography (hexanes/ether 9:1) afforded the
iodo acetal 6b (3.90 g, 14.6 mmol, 73% yield) as a colorless
liquid.
P r ep a r a tion of tr a n s-3-Iod o-2-[(3-isop r op yl-2-p r op e-
n yl)oxy]tetr a h yd r ofu r a n (6g). The literature procedure9
was followed with 2,3-dihydrofuran (4e) (2.1 g, 30 mmol, 1.5
equiv), 4-methyl-1-penten-3-ol30 (5c) (2.0 g, 20.0 mmol, 1
equiv), and NIS31 (4.5 g, 20 mmol, 1 equiv). After usual
workup the crude product was purified by bulb-to-bulb distil-
lation (80 °C, 0.1 mmHg), affording a 1:1 mixture of diaster-
omers of the iodo acetal 6g (4.7 g, 15.8 mmol, 79% yield) as a
yellow oil.
IR (neat): 2918 (vs), 1645 (w), 1410 (s) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.91 (m, 1H), 5.23 (d, J ) 17.2 Hz, 1H),
5.19 (d, J ) 10.3 Hz, 1H), 4.62 (t, J ) 5.5 Hz, 1H), 4.12 (dd, J
) 12.7, 5.4 Hz, 1H), 4.06 (dd, 1H, J ) 12.6, 5.4 Hz), 3.55 (m,
1H), 3.51 (m, 1H), 3.22 (d, 2H, J ) 5.5 Hz), 1.60 (sextet, 2H,
J ) 7.4 Hz), 0.93 (t, 3H, J ) 7.4 Hz). 13C-NMR (CDCl3, 75
MHz): δ 134.2, 117.3, 101.3, 68.3, 67.3, 22.9, 10.7, 5.2. MS
(EI): 227 (10), 143 (54), 87 (40), 57 (100). Anal. Calcd for
C8H15IO2 (269.18): C, 35.68; H, 5.57. Found: C, 35.58; H, 5.52.
P r ep a r a t ion of 2-E t h oxy-1-iod o-3-oxa -5-h exen e (6c).
The literature procedure9 was followed with ethyl vinyl ether
(4c) (1.70 g, 24.0 mmol, 1.2 equiv), 2-propen-1-ol (5a ) (1.70 g,
20 mmol, 1 equiv), and NIS31 (4.5 g, 20 mmol, 1 equiv). Usual
workup and purification by silica gel chromatography (hex-
anes/ether 9:1) of the crude product afforded the iodo acetal
6c (4.33 g, 17.0 mmol, 85% yield) as a colorless liquid.
IR (neat): 2950 (vs), 1195 (m), 910 (vs), 810 (vs) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 5.62 (m, 1H), 5.30 (d, J ) 19.5 Hz,
1H), 5.13 (m, 2H), 4.05 (m, 3H), 3.60 (m, 1H), 2.57 (m, 1H),
2.12 (m, 1H), 1.61 (m, 1H), 0.83 (m, 6H). 13C-NMR (CDCl3,
75 MHz): δ 137.4, 118.6, 110.0, 84.3, 67.0, 35.8, 32.5, 25.3,
18.5, 18.3 (first diastereomer); δ 136.4, 116.6, 107.1, 82.1, 66.6,
35.5, 32.3, 25.3, 18.3, 18.1 (second diastereomer). MS (EI):
197 (100), 70 (81), 55 (34). Anal. Calcd for C10H17IO2
(295.22): C, 40.68; H, 5.76. Found: C, 40.59; H, 5.80.
P r ep a r a tion of 2-Bu toxy-1-iod o-3-oxa -4-p h en yl-5-h ex-
en e (6h ). The literature procedure9 was followed with n-butyl
vinyl ether (4a ) (0.71 g, 10.0 mmol, 1 equiv), 1-phenyl-2-
propen-1-ol28 (5b) (1.3 g, 10.0 mmol, 1 equiv), and NIS31 (2.2
g, 10 mmol, 1 equiv). The reaction mixture was allowed to
warm from -40 to 0 °C within 1 h. After usual workup, the
crude residue was filtered (hexanes/ether 9:1) over a short plug
of silica gel, affording the alkyl iodide 6h (2.57 g, 7.2 mmol,
72% yield) as a yellow oil that was directly submitted to further
transformations.
IR (neat): 2920 (s), 1710 (w), 1110 (vs) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.84 (m, 1H), 5.17 (d, J ) 17.2 Hz, 1H),
5.12 (d, J ) 10.3 Hz, 1H), 4.59 (t, J ) 5.5 Hz, 1H), 4.09 (dd, J
) 16.5, 9.9 Hz, 1H), 3.95 (dd, J ) 16.5, 9.9 Hz, 1H), 3.55 (m,
2H), 3.15 (d, J ) 5.4 Hz, 2H), 1.80 (t, J ) 7.0 Hz, 3H). 13C-
NMR (CDCl3, 75 MHz): δ 134.0, 117.1, 101.1, 67.2, 62.0, 15.0,
5.2. MS (EI): 213 (M+ - C3H5, 9), 129 (68), 41 (100). Anal.
Calcd for C7H13IO2 (255.14): C, 32.94; H, 5.98. Found: C,
32.90; H, 5.93.
P r ep a r a tion of tr a n s-3-Iod o-2-(2-p r op en yloxy)tetr a h y-
d r ofu r a n (6d ). The literature procedure9 was followed with
2,3-dihydrofuran (4d ) (1.70 g, 24.0 mmol, 1.2 equiv), 2-propen-
1-ol (5a ) (1.40 mL, 20 mmol, 1 equiv), and NIS31 (4.5 g, 20
mmol, 1 equiv). After usual workup the residual oil was
purified by bulb-to-bulb distillation (0.1 mmHg, 80 °C), af-
fording the iodo acetal 6d (3.1 g, 12.0 mmol, 61% yield) as a
colorless oil.
P r ep a r a t ion of 1-Br om o-2-et h oxy-4-p h en yl-3-oxa -5-
h exen e (7a ). A 100 mL three-necked flask with argon inlet,
septum cap, and internal thermometer was charged with a
suspension of NBS (3.45 g, 20 mmol, 1 equiv) in 1-phenyl-2-
propen-1-ol28 (5b) (4.0 mL, 29.8 mmol, 1.5 equiv) and dichlo-
romethane (4 mL). The suspension was cooled to 0 °C, and
ethyl vinyl ether (4c) (1.34 g, 20.0 mmol, 1 equiv) was added
dropwise. The reaction mixture was stirred for 12 h at 0 °C,
diluted with ether (50 mL), and poured on ice-water (100 mL).
After filtration and separation of the organic layer the aqueous
layer was extracted with ether (3 × 50 mL). The combined
organic layer was dried (MgSO4) and filtered, and the solvent
was evaporated. Purification by silica gel chromatography
(hexanes) of the residual oil afforded a 1:1 diastereomeric
mixture of the alkyl bromide 7a (4.5 g, 15.4 mmol, 77% yield)
as a colorless liquid.
IR (neat): 3040 (s), 1305 (s), 1220 (vs) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.82 (m, 2H), 5.14 (d, J ) 17.2 Hz, 1H),
5.12 (d, J ) 10.3 Hz, 1H), 4.08 (m, 5H), 2.61 (m, 1H), 2.16 (m,
1H). 13C-NMR (CDCl3, 75 MHz): δ 134.2, 117.3, 109.8, 68.0,
67.1, 35.6, 24.8. MS (EI): 254 (M+ + 1, 3), 168 (92), 70 (100).
Anal. Calcd for C7H11IO2 (253.14): C, 33.21; H, 4.35. Found:
C, 33.23; H, 4.41.
P r ep a r a tion of tr a n s-3-Iod o-2-(2-p r op en yloxy)tetr a h y-
d r op yr a n (6e). The literature procedure9 was followed with
3,4-dihydro-2H-pyran (4e) (1.68 g, 20.0 mmol, 1 equiv), 2-pro-
pen-1-ol (5a ) (1.70 mL, 20.0 mmol, 1 equiv), and NIS31 (4.5 g,
20 mmol, 1 equiv). Purification by silica gel chromatography
(hexanes/ether 9:1) afforded the iodo acetal 6e (4.1 g, 15.0
mmol, 75% yield) as a colorless oil.
IR (neat): 2980 (s), 1120 (s), 1030 (vs) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.39 (m, 5H), 5.96 (m, 1H), 5.29 (m, 3H),
4.92 (t, J ) 5.7 Hz, 1H), 3.64 (m, 2H), 3.40 (m, 2H), 1.28 (t, J
) 7.0 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ 140.5, 138.9,
128.6, 128.1, 127.4, 117.4, 99.7, 79.7, 62.0, 32.2, 15.3 (first
diastereomer); δ 140.1, 138.1, 128.5, 128.0, 126.8, 115.9, 99.5,
79.4, 61.7, 32.1, 15.2 (second diastereomer). MS (EI): 159 (11),
117 (100), 72 (15). Anal. Calcd for C13H17BrO2 (284.14): C,
54.93; H, 6.02. Found: C, 54.89; H, 5.97.
P r ep a r a tion of 1-Br om o-2-eth oxy-4-isop r op yl-3-oxa -5-
h exen e (7b). The procedure described above for the prepara-
tion of 7a was followed with ethyl vinyl ether (4c) (1.34 g, 20.0
mmol, 1 equiv), 4-methyl-1-penten-3-ol30 (5c) (4.0 mL, 40
mmol, 2 equiv), and NBS (3.45 g, 20 mmol, 1 equiv) in
dichloromethane (4 mL). The reaction mixture was stirred for
1 h at 0 °C and then for 4 h at rt. Usual workup and
purification by silica gel chromatography (hexanes/ether 9:1)
of the residual oil afforded a 1:1 mixture of diastereoisomers
IR (neat): 2799 (vs), 1715 (s), 1440 (s) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.85 (ddd, J ) 17.2, 9.1, 5.2 Hz, 1H), 5.15
(d, J ) 17.2 Hz, 1H), 5.13 (d, J ) 9.3 Hz, 1H), 4.61 (d, J ) 5.3
Hz, 1H), 4.17 (dd, J ) 12.1, 5.2 Hz, 1H), 4.03 (m, 3H), 3.45
(m, 1H), 2.29 (m, 1H), 1.96 (m, 1H), 1.67 (m, 1H), 1.47 (m,
1H). 13C-NMR (CDCl3, 75 MHz): δ 133.9, 117.4, 101.5, 68.9,
63.4, 32.7, 29.3, 25.5. MS (EI): 268 (M+ + 1, 1), 154 (43), 142
(60), 84 (73), 41 (100). Anal. Calcd for C8H13IO2 (267.15): C,
35.96; H, 4.87. Found: C, 36.09; H, 4.84.
P r ep a r a tion of tr a n s-3-Iod o-2-[(1-p h en yl-2-p r op en yl)-
oxy]tetr a h yd r op yr a n (6f). The literature procedure9 was
followed with 3,4-dihydro-2H-pyran (4e) (2.5 g, 30 mmol, 1.5
equiv), 1-phenyl-2-propen-1-ol28 (5b) (2.68 g, 20.0 mmol, 1
equiv), and NIS31 (4.5 g, 20 mmol, 1 equiv). The crude product
was purified by flash chromatography (hexanes/ether 4:1),

5748 J . Org. Chem., Vol. 61, No. 17, 1996
Vaupel and Knochel
of the alkyl bromide 7b (3.9 g, 15.6 mmol, 78% yield) as a
solvent was distilled off, and the residual oil was dissolved in
hexanes (150 mL). The resulting solution was washed with
MeOH/H2O (4:1) (3 × 100 mL). The combined aqueous phase
was extracted with hexanes (3 × 200 mL). The combined
organic layer was dried (MgSO4) and filtered, and the solvent
was evaporated. The crude residue was purified by flash
chromatography (hexanes/ether 9:1) to afford alkyl iodide 8
(4.3 g, 12.2 mmol, 68% yield) as a yellow oil.
colorless liquid.
IR (neat): 2975 (vs), 1115 (s), 950 (vs), 925 (vs) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 5.64 (ddd, J ) 17.2, 10.4, 8.1 Hz,
1H), 5.13 (m, 2H), 4.60 (m, 1H), 3.55 (m, 3H), 3.29 (m, 2H),
1.72 (m, 1H), 1.14 (t, J ) 6.0 Hz, 3H), 0.85 (2d, J ) 6.8 Hz,
6H). 13C-NMR (CDCl3, 75 MHz): δ 137.4, 118.8, 100.8, 85.0,
62.6, 32.7, 32.6, 18.6, 15.4 (first diastereomer); δ 136.7, 117.7,
98.9, 83.7, 61.3, 32.5, 32.3, 18.3, 15.3 (second diastereomer).
IR (neat): 2933 (vs), 2846 (m), 2805 (w), 1145 (m) cm-1 1H-
.
MS (EI): 153 (94), 83 (100), 55 (67). Anal. Calcd for C10H19
-
NMR (CDCl3, 300 MHz): δ 7.37 (m, 5H), 5.98 (m, 1H), 5.20
(d, J ) 17.3 Hz, 1H), 5.11 (d, J ) 10.0 Hz, 1H), 4.26 (td, J )
11.6, 4.2 Hz, 1H), 3.86 (d, J ) 13.7 Hz, 1H), 3.42 (d, J ) 13.7
Hz, 1H), 3.26 (d, J ) 14.2 Hz, 1H), 2.96 (dd, J ) 14.2, 8.3 Hz,
1H), 2.66 (m, 2H), 2.08 (m, 3H), 1.57 (m, 1H), 1.27 (m, 3H).
13C-NMR (CDCl3, 75 MHz): δ 139.8, 137.4, 129.1, 127.9, 126.7,
116.5, 64.4, 53.7, 52.7, 41.0, 38.5, 29.2, 25.8, 25.2. MS (EI):
355 (M+ + 1, 7), 187 (35), 91 (100). Anal. Calcd for C16H22IN
(354.31): C, 54.31; H, 6.21; N, 3.95. Found: C, 54.20; H, 6.37;
N, 3.94.
BrO2 (250.23): C, 47.99; H, 7.64. Found: C, 47.65; H, 7.51.
P r ep a r a tion of 1-Br om o-2-eth oxy-4-h exyl-3-oxa -5-h ex-
en e (7c). The procedure for the preparation of 7a was followed
with ethyl vinyl ether (4c) (1.34 g, 20.0 mmol, 1 equiv),
1-nonen-3-ol29 (5d ) (4.0 g, 27.7 mmol, 1.4 equiv), and NBS (3.6
g, 20.0 mmol, 1 equiv). Usual workup and purification by silica
gel chromatography (hexanes/ether 9:1) of the residual oil
afforded the alkyl bromide 7c (4.5 g, 15.4 mmol, 77% yield) as
a colorless liquid.
IR (film): 2820 (vs), 1120 (s), 920 (m) cm-1
.
1H-NMR
P r ep a r a tion of tr a n s-2-[N-Ben zyl-N-(2-p r op en yl)a m i-
n o]cycloh exa n -1-ol (10). A 250 mL three-necked flash
equipped with an argon inlet, magnetic stirring bar, and
internal thermometer was charged with a 0.86 M solution of
EtMgBr (68 mL, 60 mmol) in THF. The magnesium amide
was generated by dropwise addition of a solution of N-benzyl-
3-amino-1-propene (19.8 g, 60.0 mmol) in THF (15 mL) at rt.
After completion of the addition the reaction mixture was
stirred for 1 h at 35 °C. It was allowed to cool again to rt, and
cyclohexene oxide (5.0 mL, 50.0 mmol, 0.83 equiv) was added
dropwise. After being stirred for 4 h at rt, the reaction mixture
was poured into ice-cooled saturated aqueous NH4Cl solution
(300 mL). Ether (300 mL) was added, and the organic layer
was separated. The aqueous layer was washed twice with
ether (300 mL), the combined organic layer was dried (MgSO4)
and filtrated, and the solvent was evaporated. Purification
by silica gel chromatography of the residual oil (hexanes/ether
9:1) afforded the product 10 (8.5 g, 34.6 mmol, 69% yield) as
a colorless oil.
(CDCl3, 300 MHz): δ 5.65 (m, 1H), 5.10 (m, 2H), 4.61 (m, 1H),
3.89 (m, 1H), 3.59 (m, 2H), 3.42 (m, 1H), 3.28 (m, 2H), 1.54
(m, 1H), 1.23 (m, 8H), 1.13 (t, 3H, J ) 7.6 Hz), 0.80 (m, 3H).
13C-NMR (CDCl3, 75 MHz): δ 139.3, 116.6, 100.5, 79.6, 76.6,
62.5, 35.5, 35.4, 32.2, 29.2, 25.2, 22.6, 14.0 (first diastereomer);
δ 138.5, 116.5, 98.9, 78.6, 77.6, 61.2, 35.5, 31.7, 29.1, 25.0, 15.2
(second diastereomer). MS (EI): 153 (95), 151 (100), 125 (32),
123 (33), 83 (31). Anal. Calcd for C13H25BrO2 (292.28): C,
53.42; H, 8.56. Found: C, 53.44; H, 8.52.
P r ep a r a tion of tr a n s-3-Br om o-2-[(1-isop r op yl-2-p r o-
p en yl)oxy]tetr a h yd r op yr a n (7d ). The procedure described
above for the preparation of 7a was followed with 3,4-dihydro-
2H-pyran (4e) (2.5 g, 30 mmol, 1 equiv), 4-methyl-1-penten-
3-ol30 (5c) (5.4 g, 54 mmol, 1.8 equiv), and NBS (5.2 g, 30 mmol,
1 equiv) in CH2Cl2 (5 mL). The reaction mixture was stirred
for 1 h at 0 °C and for 1 h at rt. Usual workup and purification
by silica gel chromatography of the residual oil afforded a 1:1
diastereomeric mixture of the alkyl bromide 7d (4.2 g, 16.0
mmol, 80% yield) as a colorless liquid.
IR (film): 3466 (s, br), 2933 (vs), 1445 (s), 1076 (s) cm-1
.
IR (neat): 2950 (vs), 1205 (m) cm-1
.
1H-NMR (CDCl3, 300
1H-NMR (CDCl3, 300 MHz): δ 7.28 (m, 5H), 5.73 (m, 1H), 5.12
(d, J ) 15.2 Hz, 1H), 5.06 (d, J ) 9.3 Hz, 1H), 3.82 (d, J )
13.6 Hz, 1H), 3.80 (d, J ) 3.6 Hz, 1H), 3.40 (m, 1H), 3.31 (d,
J ) 16.9 Hz, 2H), 2.38 (m, 1H), 2.06 (m, 1H), 1.84 (m, 1H),
1.74 (m, 1H), 1.64 (m, 1H), 1.58 (m, 1H), 1.15 (m, 4H). 13C-
NMR (CDCl3, 75 MHz): δ 139.5, 136.7, 128.7, 128.3, 126.9,
69.0, 64.9, 53.4, 52.6, 33.1, 25.4, 24.0, 22.4. MS (EI): 245 (M+,
10), 186 (50), 91 (100). Anal. Calcd for C16H23NO (245.32):
C, 78.36; H, 9.38; N, 5.71. Found: C, 78.23; H, 9.45; N, 5.71.
Typ ica l P r oced u r e for th e Cycliza tion of Iod o Aceta ls
of Typ e 4 a n d 6. P r ep a r a tion of tr a n s-2-Bu toxy-4-(3-
ca r beth oxy-3-bu ten yl)tetr a h yd r ofu r a n (14a ). A 50 mL
three-necked flask equipped with an argon inlet, a magnetic
stirring bar, an internal thermometer, and a septum cap was
charged with Ni(acac)2 (15 mg, 0.06 mmol, 2 mol %), and a
solution of the alkyl iodide 6a (0.85 g, 3.0 mmol, 1 equiv) in
THF (5 mL) was added. The resulting green suspension was
cooled to -78 °C, and Et2Zn (0.6 mL, 6.0 mmol, 2 equiv) was
added dropwise. The reaction mixture was allowed to warm
to 0 °C and stirred at this temperature for 2 h. The excess of
Et2Zn and the solvent were removed in vacuo (rt, 2 h). After
addition of THF (5 mL) and cooling to -50 °C, CuCN‚2LiCl
(CuCN: 0.27 g, 3.0 mmol; LiCl: 0.25 g, 6.0 mmol) in THF (5
mL) was added. The reaction mixture was warmed to 0 °C
(10 min) and cooled to -78 °C. Ethyl (R-bromomethyl)-
acrylate26 (1.78 g, 9.0 mmol, 3 equiv) was added. The reaction
mixture was allowed to warm to 0 °C within 12 h and was
quenched by addition of saturated aqueous NH4Cl solution (15
mL). Precipitated copper salts were dissolved by addition of
small portions of an aqueous NH3 solution. The aqueous phase
was extracted with ether (3 × 30 mL). The combined organic
layer was dried (MgSO4) and filtered, and the solvent was
evaporated. The residue was purified by flash chromatography
(hexanes/ether 6:1), affording the product 14a (0.56 g, 2.1
mmol, 70% yield) as a colorless oil.
MHz): δ 5.52 (ddd, J ) 17.1, 10.3, 8.5 Hz, 1H), 5.19 (d, J )
10.3 Hz, 1H), 5.10 (d, J ) 17.1 Hz, 1H), 4.57 (d, J ) 3.9 Hz,
1H), 3.84 (m, 2H), 3.71 (t, J ) 7.1 Hz, 1H), 3.50 (m, 1H), 2.29
(m, 1H), 1.86 (m, 2H), 1.81 (m, 1H), 1.45 (m, 1H), 0.87 (d, J )
6.8 Hz, 3H), 0.85 (d, J ) 6.8 Hz, 3H). 13C-NMR (CDCl3, 75
MHz): δ 135.9, 119.2, 97.0, 82.4, 49.7, 32.3, 29.7, 22.9, 18.3,
18.2 (first diastereomer); δ 136.9, 116.5, 100.9, 85.6, 63.1, 49.9,
31.9, 30.9, 23.8, 18.1, 17.6 (second diastereomer). MS (EI):
165 (49), 83 (100), 55 (99). Anal. Calcd for C11H19BrO2
(262.24): C, 50.38; H, 7.25. Found: C, 50.20; H, 7.39.
P r ep a r a tion of tr a n s-3-Br om o-2-[(1-h exyl-2-p r op en yl)-
oxy]tetr a h yd r op yr a n (7e). The procedure described above
for the preparation of 7a was followed with 3,4-dihydro-2H-
pyran (4e) (2.5 g, 30 mmol, 1 equiv), 1-nonen-3-ol29 (5d ) (2.5
g, 20.0 mmol, 0.6 equiv), and NBS (5.2 g, 30 mmol, 1 equiv).
The reaction mixture was stirred for 1 h at 0 °C and for 1 h at
rt. After usual workup, the crude product was purified by flash
chromatography (hexanes/ether 4:1) to afford a 1:1 diastere-
omeric mixture of the alkyl bromide 7e (5.0 g, 17.0 mmol, 85%
yield) as a colorless liquid.
IR (neat): 2815 (vs), 2780 (s), 1205 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.58 (m, 1H), 5.14 (d, J ) 11.6 Hz, 1H),
5.11 (d, J ) 5.0 Hz, 1H), 4.58 (d, J ) 4.3 Hz, 1H), 4.00 (q, J )
6.7 Hz, 1H), 3.83 (m, 2H), 3.46 (m, 1H), 2.32 (m, 1H), 1.85 (m,
2H), 1.54 (m, 1H), 1.47 (m, 2H), 1.32 (m, 8H), 0.80 (m, 3H).
13C-NMR (CDCl3, 75 MHz): δ 138.0, 117.8, 97.4, 77.7, 62.2,
49.6, 35.3, 31.6, 29.9, 29.1, 25.2, 23.1, 22.5, 13.9. MS (EI): 221
(1), 165 (74), 163 (88), 83 (64), 69 (100). Anal. Calcd for C14H25
-
BrO2 (304.29): C, 55.26; H, 8.22. Found: C, 55.06; H, 8.34.
P r ep a r a tion of cis-N-Ben zyl-N-(2-p r op en yl)-2-a m in o-
1-iodocycloh exan e (8). A 250 mL three-necked flask equipped
with an argon inlet, magnetic stirring bar, and internal
thermometer was charged with a solution of the amino alcohol
10 (4.40 g, 18.0 mmol) in THF (140 mL). 2 DCC‚MeI12 (10.0
g, 32 mmol, 1.8 equiv) was added in small portions at rt. The
reaction mixture was then stirred for 3 days at 35 °C. The
IR (neat): 2920 (s), 2850 (s), 1730 (s), 1720 (s) cm-1
.
1H-
NMR (CDCl3, 300 MHz): δ 6.15 (s, 1H), 5.52 (s, 1H), 5.10 (dd,

Synthesis of Heterocyclic Zinc Reagents
J . Org. Chem., Vol. 61, No. 17, 1996 5749
J ) 5.6, 3.1 Hz, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 3.96 (m, 1H),
3.64 (m, 1H), 3.45 (dd, J ) 8.4, 2.4 Hz, 1H), 3.38 (m, 1H), 2.27
(m, 4H), 1.57 (m, 4H), 1.34 (m, 3H), 1.32 (t, J ) 7.1 Hz, 3H),
0.94 (t, J ) 7.3 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ 167.0,
140.7, 124.5, 104.4, 71.6, 67.3, 60.6, 38.9, 38.1, 32.2, 31.9, 30.9,
19.4, 14.2, 13.9 (first diastereomer); δ 140.6, 124.4, 104.1, 72.2,
66.9, 39.2, 36.7, 33.1, 30.8 (second diastereomer). MS (EI):
211 (4), 183 (58), 69 (100), 41 (48). Anal. Calcd for C15H26O4:
C, 66.66; H, 9.63. Found: C, 66.51; H, 9.60.
6b (0.81 g, 3.0 mmol, 1 equiv) in THF (5 mL). 3-Iodo-2-
cyclohexen-1-one27 (1.35 g, 6.0 mmol, 2 equiv) was used as an
electrophile. Reaction conditions: -78 to 0 °C, 12 h. After
usual workup the crude product was purified by flash chro-
matography (hexanes/ether 6:1), affording the ketone 14e (0.45
g, 1.7 mmol, 62% yield) as a colorless oil.
IR (neat): 2920 (vs), 2880 (s), 1687 (vs), 1630 (m) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 5.80 (s, 1H), 5.04 (dd, J ) 5.4, 2.0
Hz, 1H), 3.90 (t, J ) 8.5 Hz, 1H), 3.43 (t, J ) 8.5 Hz, 1H), 3.23
(td, J ) 9.4, 2.1 Hz, 1H), 3.51 (td, J ) 9.4, 2.1 Hz, 1H), 2.26
(m, 8H), 1.92 (m, 2H), 1.48 (m, 3H), 0.84 (t, J ) 7.4 Hz, 3H).
13C-NMR (CDCl3, 75 MHz): δ 199.3, 164.2, 126.2, 103.9, 71.2,
68.9, 41.8, 58.4. 37.1, 35.1, 29.7, 22.7, 22.5, 10.6 (first
diastereomer); δ 163.9, 126.5, 71.5, 68.8, 67.2, 42.3, 38.9, 34.6,
31.7, 29.6, 22.8, 19.3, 13.7, 10.5 (second diastereomer). MS
(EI): 210 (1), 179 (23), 110 (60), 69 (100). Anal. Calcd for
C14H22O3 (238.26): C, 70.29; H, 9.20. Found: C, 69.96; H, 9.20.
P r ep a r a t ion of tr a n s-4-(3-Ca r b et h oxy-3-b u t en yl)-2-
p r op oxytetr a h yd r ofu r a n (14b). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6b (1.34 g, 5.0 mmol) and PdCl2(dppf)13 (100 mg, 0.15
mmol, 3 mol %) as a catalyst. Ethyl (R-bromomethyl)acrylate26
(1.98 g, 10.0 mmol, 2 equiv) was used as an electrophile.
Reaction conditions: -78 to 0 °C, 1 h. Usual workup and
purification by silica gel chromatography (hexanes/ether 9:1)
of the crude product afforded the acetal 14b (0.82 g, 3.2 mmol,
64% yield) as a colorless oil.
P r ep a r a tion of en d o-4-(3-Ca r beth oxy-3-bu ten yl)-2,8-
d ioxa bicyclo[3.3.0]octa n e (16a ). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6d (1.35 g, 5.0 mmol) and ethyl R-(bromomethyl)-
acrylate26 (2.97 g, 15.0 mmol, 3 equiv) as an electrophile.
Reaction conditions: -78 °C to rt, 2 h. Usual workup and
purification by silica gel chromatography (hexanes/ether 9:1)
of the residue afforded the product 16a (1.00 g, 4.2 mmol, 80%
yield) as a colorless oil.
IR (neat): 2923 (vs), 2885 (s), 1715 (vs), 1635 (m) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 6.08 (s, 1H), 5.45 (s, 1H), 5.04 (dd,
J ) 5.6, 3.1 Hz, 1H), 4.12 (q, J ) 7.2 Hz, 2H), 3.90 (d, J ) 7.4
Hz, 1H), 3.59 (dt, J ) 16.2, 6.9 Hz, 1H), 3.39 (d, J ) 8.9 Hz,
1H), 3.27 (dt, J ) 16.2, 6.7 Hz, 1H), 2.18 (m, 4H), 1.52 (m,
5H), 1.42 (t, J ) 7.2 Hz, 3H), 0.86 (t, J ) 7.1 Hz, 3H). 13C-
NMR (CDCl3, 75 MHz): δ 167.1, 140.7, 124.5, 104.4, 71.6, 69.3,
60.6, 38.9, 38.1, 32.1, 10.9, 23.0, 14.3, 10.7 (first diastereomer);
δ 104.1, 72.2, 68.9, 39.2, 36.7, 33.0, 30.8 (second diastereomer).
MS (EI): 168 (29), 123 (35), 82 (40), 69 (100). Anal. Calcd
for C14H24O4 (256.30): C, 65.62; H, 9.37. Found: C, 65.93; H,
9.13.
IR (neat): 2830 (vs), 1620 (s), 1430 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 6.10 (s, 1H), 5.66 (d, J ) 5.0 Hz, 1H,
1-H), 5.49 (s, 1H), 3.96 (q, J ) 7.2 Hz, 2H), 3.90 (m, 1H), 3.80
(dd, J ) 7.5, 6.3 Hz, 2H), 3.36 (dd, J ) 11.4, 8.4 Hz, 2H), 2.79-
2.74 (m, 1H, 5-H), 2.28-2.23 (m, 3H, 4-H), 1.83 (m, 1H), 1.52
(m, 2H), 1.24 (t, J ) 7.3 Hz, 3H). 1H-NMR-NOE (CDCl3, 500
MHz) irradiation in the resonance frequency of 1-H increased
the intensity of the signal of 5-H; irradiation in the resonance
frequency of 4-H increased the intensity of the signal of 4-H.
13C-NMR (CDCl3, 75 MHz): δ 166.8, 140.2, 124.9, 109.6, 72.3,
69.0, 60.6, 45.1, 41.7, 30.9, 27.1, 24.9, 14.1. MS (EI): 222 (15),
167 (11), 149 (12), 97 (100). Anal. Calcd for C13H20O4
(240.23): C, 64.99; H, 8.33. Found: C, 64.89; H, 8.32.
P r ep a r a t ion of tr a n s-4-(3-Ca r b et h oxy-3-b u t en yl)-2-
eth oxytetr a h yd r ofu r a n (14c). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6c (1.27 g, 5.0 mmol). Ethyl (R-bromomethyl)acrylate26
(2.97 g, 15.0 mmol, 3 equiv) was used as an electrophile.
Reaction conditions: -78 °C to rt, 2 h. Usual workup and
purification by silica gel chromatography (hexanes/ether 9:1
to 4:1) of the crude product afforded the acetal 14c (0.83 g,
3.4 mmol, 69% yield) as a colorless oil.
P r ep a r a tion of en d o-7-(3-Ca r beth oxy-3-bu ten yl)-2,9-
d ioxa bicyclo[4.3.0]n on a n e (16b). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6e (0.81 g, 3.0 mmol) and PdCl2(dppf)13 (76 mg, 0.1
mmol, 3.3 mol %) as a catalyst. Ethyl (R-bromomethyl)-
acrylate26 (1.18 g, 6.0 mmol, 2 equiv) was used as an electro-
phile. Usual workup and purification by silica gel chroma-
tography (hexanes/ether 9:1) of the crude residue afforded the
cyclic acetal 16b (0.50 g, 2.0 mmol, 66% yield) as a yellow oil.
IR (neat): 2920 (vs), 1710 (vs), 1635 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 6.07 (s, 1H), 5.48 (s, 1H), 5.04 (dd, J )
5.0, 3.2 Hz, 1H), 4.14 (q, J ) 7.3 Hz, 2H), 3.89 (m, 1H), 3.63
(m, 1H), 3.42 (q, J ) 8.6 Hz, 2H), 3.33 (m, 1H), 2.15 (m, 3H),
1.58 (q, J ) 7.5 Hz, 2H), 1.43 (m, 1H), 1.24 (t, J ) 7.2 Hz,
3H), 1.22 (t, J ) 7.3 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ
167.1, 140.5, 124.5, 104.2, 71.5, 63.0, 60.6, 39.0, 38.1, 31.9, 30.9,
15.3, 14.2 (first diastereomer); δ 124.6, 103.9, 72.2, 62.5, 39.2,
36.6, 32.9, 30.8, 15.2 (second diastereomer). MS (EI): 241 (M+
- 1, 6), 95 (50), 69 (100). Anal. Calcd for C13H22O4 (240.23):
C, 64.99; H, 8.38. Found: C, 64.92; H, 8.40.
IR (film): 2915 (s), 2860 (s), 1710 (vs), 1630 (m) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 6.09 (s, 1H), 5.47 (s, 1H), 5.17 (d,
J ) 3.7 Hz, 1H), 3.92 (q, J ) 7.2 Hz, 2H), 3.87 (d, J ) 7.0 Hz,
1H), 3.59 (m, 3H), 2.24 (m, 3H), 1.92 (m, 1H), 1.64 (m, 2H),
1.52 (m, 2H), 1.40 (m, 2H), 1.26 (t, J ) 7.2 Hz, 3H). 13C-NMR
(CDCl3, 75 MHz): δ 166.8, 140.3, 124.6, 101.8, 69.6, 60.8, 60.5,
40.5, 36.2, 36.6, 26.1, 23.0, 19.0, 14.0. MS (EI): 239 (14), 127
(24), 97 (79), 81 (100). Anal. Calcd for C14H22O4 (254.25): C,
66.14; H, 8.66. Found: C, 66.12; H, 8.69.
P r ep a r a tion of tr a n s-4-((E)-3-Ca r beth oxy-2-p r op en yl)-
2-eth oxytetr a h yd r ofu r a n (14d ). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6c (1.27 g, 5.0 mmol), and ethyl propiolate (1.47 g, 15.0
mmol, 3 equiv) was used as electrophile. Reaction condi-
tions: -78 to 0 °C, 12 h. Usual workup and purification by
silica gel chromatography of the crude residue (hexanes/ether
9:1 to 4:1) afforded an 85:15 mixture of diastereomers of the
product 14d (0.71 g, 3.1 mmol, 63%) as a colorless oil.
P r ep a r a t ion of en d o-4-(2-Oxo-2-p h en ylet h yl)-2,8-d i-
oxa bicyclo[3.3.0]octa n e (16d ). The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6d (1.30 g, 5.0 mmol) and benzoyl chloride (2.12 g, 15.0
mmol, 3 equiv) as an electrophile. Reaction conditions: -78
to -20 °C, 12 h. After usual workup the crude product was
purified by bulb-to-bulb distillation (0.1 mmHg, 170 °C),
affording the ketone 16d (0.73 g, 3.2 mmol, 63% yield) as a
colorless oil.
IR (neat): 2900 (vs), 1715 (vs), 1650 (s) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 6.85 (m, 1H), 5.75 (d, J ) 15.6 Hz, 1H),
5.05 (dd, J ) 8.1, 5.3 Hz, 1H), 4.11 (q, J ) 7.2 Hz, 2H), 3.88
(m, 1H), 3.62 (m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 2.29 (m,
2H), 2.17 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H, J ) 7.2 Hz), 1.12
(t, 3H, J ) 7.0 Hz). 13C-NMR (CDCl3, 300 MHz): δ 166.4,
146.9, 122.4, 104.1, 71.4, 62.9, 60.2, 38.5, 36.8, 36.0, 15.2, 14.2
(first diastereomer); δ 166.3, 146.5, 122.7, 103.7, 62.6, 38.9,
36.5, 15.2 (second diastereomer). MS (EI): 227 (M+ - 1, 2),
183 (18), 109 (14), 85 (20), 81 (39), 69 (100), 57 (26), 41 (38).
Anal. Calcd for C12H20O4 (228.25): C, 63.16; H, 8.77. Found:
C, 63.16; H, 8.77.
IR (neat): 2880 (m), 1685 (s), 1600 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.19 (m, 2H), 7.51 (m, 1H), 7.43 (m, 2H),
5.70 (d, J ) 4.5 Hz, 1H), 4.05 (dd, J ) 8.3, 7.3 Hz, 1H), 3.80
(m, 2H), 3.44 (dd, J ) 11.1, 8.4 Hz, 1H), 3.15-2.99 (m, 3H),
2.86 (m, 1H), 1.80 (m, 2H). 13C-NMR (CDCl3, 75 MHz): δ 198.1,
136.5, 133.4, 128.7, 127.9, 109.5, 71.8, 69.0, 45.2, 37.3, 36.6,
25.6. MS (EI): 232 (M+, 4), 162 (19), 105 (100). Anal. Calcd
for C14H16O3 (232.25): C, 72.41; H, 6.89. Found: C, 72.38; H,
6.89.
P r ep a r a tion of tr a n s-3-[(2-P r op oxytetr a h yd r ofu r a n yl-
)m et h yl]-2-cycloh exen -1-on e (14e). The procedure de-
scribed for the preparation of 14a was followed with Ni(acac)2
(15 mg, 0.06 mmol, 2 mol %) and a solution of the alkyl iodide

5750 J . Org. Chem., Vol. 61, No. 17, 1996
Vaupel and Knochel
P r ep a r a t ion of en d o-7-[2-Oxo-2-(1,1-d im et h ylet h yl)]-
2,9-d ioxa bicyclo[4.3.0]n on a n e. The procedure described
above for the preparation of 14a was followed with the alkyl
iodide 6e (1.33 g, 5.0 mmol) and pivaloyl chloride (1.80 g, 15.0
mmol, 3 equiv) as an electrophile. Reaction conditions: -78
°C to 0 °C, 12 h. After usual workup the residue was purified
by flash chromatography (hexanes/ether 4:1 to 100% ether),
affording the title ketone (0.72 g, 3.2 mmol, 64% yield) as a
colorless oil.
221 (19), 97 (100). Anal. Calcd for C16H26O4 (282.30): C,
68.09; H, 9.22. Found: C, 67.93; H, 9.16.
P r ep a r a tion of 2-Bu toxy-4-(3-ca r beth oxy-3-bu ten yl)-
5-p h en yltetr a h yd r ofu r a n (16h ). The procedure described
for the preparation of 14a was followed with the iodo acetal
6h (1.63 g, 5.0 mmol) and ethyl (R-bromomethyl)acrylate26
(2.97 g, 15.0 mmol, 3 equiv) as electrophile. Reaction condi-
tions: -78 °C to rt, 1 h). Usual workup and purification by
silica gel chromatography of the residual oil afforded the
product 16h (1.10 g, 3.3 mmol, 66% yield) as a colorless oil.
IR (neat): 2830 (s), 1710 (vs), 1145 (s) cm-1
.
1H-NMR
IR (neat): 2830 (vs), 1715 (vs), 1645 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 5.52 (d, J ) 3.8 Hz, 1H), 4.03 (d, J ) 8.5
Hz, 1H), 3.74 (m, 1H), 3.62 (m, 1H), 3.59 (d, J ) 8.3 Hz, 1H),
2.55 (m, 4H), 2.08 (m, 1H), 1.54 (m, 2H), 1.35 (m, 1H), 1.15 (s,
3H). 13C-NMR (CDCl3, 75 MHz): δ 214.5, 101.8, 70.0, 61.1,
44.1, 36.3, 35.9, 34.7, 27.1, 23.1, 19.8 (first diastereomer); δ
101.5, 73.9, 64.3, 44.1, 27.2, 26.4, 22.5, 20.6 (second diastere-
omer). MS (EI): 226 (M+, 4), 127 (30), 111 (11), 85 (29), 57
(100). Anal. Calcd for C13H22O3 (226.28): C, 69.03; H, 9.73.
Found: C, 69.10; H, 9.91.
(CDCl3, 300 MHz): δ 7.38 (m, 5H), 6.11 (s, 1H), 5.42 (s, 1H),
5.35 (dd, J ) 5.7, 3.0 Hz, 1H), 4.61 (d, J ) 8.7 Hz, 1H), 4.19
(q, J ) 7.2 Hz, 2H), 3.80 (td, J ) 9.7, 6.8 Hz, 1H), 3.46 (td, J
) 9.7, 6.7 Hz, 1H), 2.53 (m, 1H), 2.33 (m, 1H), 2.22 (m, 1H),
2.04 (m, 1H), 1.81-1.58 (m, 5H), 1.50-1.36 (m, 2H), 1.37 (t, J
) 7.1 Hz, 3H), 0.95 (t, J ) 7.3 Hz, 3H). 13C-NMR (CDCl3, 75
MHz): δ 167.0, 141.0, 140.6, 128.4, 126.8, 124.5, 104.0, 84.7,
67.6, 60.5, 47.0, 39.4, 31.9, 31.0, 30.6, 19.4, 14.1, 13.9. MS
(EI): 272 (5), 127 (44), 91 (100), 71 (76), 57 (98), 41 (63). Anal.
Calcd for C21H30O4 (346.38): C, 72.83; H, 8.67. Found: C,
72.90; H, 8.70.
P r ep a r a tion of en d o-7-((E)-3-Ca r beth oxy-2-p r op en yl)-
2,9-d ioxa bicyclo[4.3.0]n on a n e (16e). The procedure de-
scribed for the preparation of 14a was followed with the alkyl
iodide 6e (813 mg, 3.0 mmol) and ethyl propiolate (580 mg,
6.0 mmol, 2 equiv) as an electrophile. Reaction conditions:
-78 to 0°C, 12 h. Purification by silica gel chromatography
(hexanes/ether 4:1) of the crude product afforded the cyclic
acetal 16e (468 mg, 1.9 mmol, 65% yield) as a yellow oil.
P r ep a r a tion of 2-Bu toxy-4-(2-h yd r oxy-2-p h en yleth yl)-
5-p h en yltetr a h yd r ofu r a n (16i). The procedure described
for the preparation of 14a was followed with the iodo acetal
6h (1.63 g, 5.0 mmol). After completion of the cyclization
reaction the reaction mixture was cooled to -78 °C, and BF3‚-
Et2O (4.23 g, 30.0 mmol) was added followed by dropwise
addition of benzaldehyde (1.59 g, 15.0 mmol, 3 equiv). The
reaction mixture was allowed to warm to -20 °C within 12 h,
was diluted with ether (30 mL), and was poured into cold
saturated aqueous NH4Cl solution (50 mL). The organic layer
was separated, and the aqueous phase was extracted with
ether (3 × 50 mL). The combined organic layer was dried
(MgSO4) and filtered, and the solvent was evaporated. Puri-
fication by silica gel chromatography (hexanes/ether 4:1) of the
residual oil afforded the alcohol 16i (1.01 g, 3.0 mmol, 60%
yield) as a colorless oil.
IR (neat): 2985 (vs), 1700 (s), 1655 (s) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.29 (m, 5H), 6.69 (dt, J ) 15.8, 7.4 Hz,
1H), 5.77 (d, J ) 15.5 Hz, 1H), 5.60 (d, J ) 3.5 Hz, 1H), 4.73
(d, J ) 8.5 Hz, 1H), 4.08 (q, J ) 7.2 Hz, 2H), 3.75 (m, 1H),
3.66 (m, 1H), 2.19 (m, 4H), 1.71 (m, 1H), 1.58 (m, 3H), 1.22 (t,
J ) 7.2 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ 166.1, 145.9,
141.8 (first diasteromer); 128.4, 127.7, 126.1, 122.7, 101.8, 82.9,
60.8, 60.2, 49.5, 36.9, 28.5, 22.9, 20.6, 14.1 (second diastere-
omer). MS (EI): 316 (M+, 20), 129 (20), 117 (34), 97 (100), 41
(17). Anal. Calcd for C19H24O4 (316.33): C, 72.15; H, 7.59.
Found: C, 72.30; H, 7.54.
IR (neat): 3350 (s), 2850 (vs), 1330 (s) cm-1
.
1H-NMR
P r ep a r a t ion of en d o-7-(3-Ca r b et h oxy-3-b u t en yl)-8-
p h en yl-2,9-d ioxa bicyclo[4.3.0]n on a n e (16f). The proce-
dure described for the preparation of 14a was followed with
the alkyl iodide 6f (1.72 g, 5.0 mmol) and ethyl (R-bromom-
ethyl)acrylate26 (2.97 g, 15.0 mmol, 3 equiv) as an electrophile.
Reaction conditions: -78 °C to rt, 2 h. Purification by silica
gel chromatography (hexanes/ether 4:1) of the crude product
afforded a 1:1 diastereomeric mixture of the ester 16f (1.22 g,
3.7 mmol, 75% yield) as a yellow oil.
(CDCl3, 300 MHz): δ 7.32 (m, 10H), 5.26 (m, 1H), 4.56 (m,
2H), 3.75 (dt, J ) 8.7, 6.7 Hz, 1H), 3.40 (dt, J ) 8.6, 6.7 Hz,
1H), 2.42 (m, 1H), 2.20 (m, 1H), 1.89 (m, 2H), 1.80-1.76 (m,
2H), 1.56 (m, 2H), 1.40 (m, 2H), 1.35 (t, J ) 7.2 Hz, 3H). 13C-
NMR (CDCl3, 75 MHz): δ 144.6, 140.5, 128.4, 127.8, 127.5,
126.8, 125.7, 104.0, 84.7, 73.3, 67.6, 43.9, 41.3, 39.4, 31.8, 19.3,
13.8 (first diastereomer); δ 144.2, 140.4, 127.5, 126.7, 125.6,
103.9, 73.1, 43.8, 41.0, 39.2 (second diastereomer). MS (EI):
218 (35), 160 (100), 107 (83), 104 (98), 57 (74). Anal. Calcd
for C22H28O3 (340.39): C, 77.65; H, 8.24. Found: C, 77.46; H,
8.22.
IR (neat): 2930 (vs), 1710 (vs), 1630 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.27 (m, 5H), 6.01 (s, 1H), 5.62 (s, 1H),
5.33 (s, 1H), 4.68 (d, J ) 9.4 Hz, 1H), 4.11 (q, J ) 7.1 Hz, 2H),
3.78 (m, 1H), 3.65 (m, 1H), 2.24 (m, 1H), 2.13 (m, 1H), 2.05
(m, 2H), 1.81 (m, 1H), 1.57 (m, 3H), 1.47 (m, 2H), 1.21 (t, J )
7.1 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ 166.9, 142.6, 140.3,
128.3, 127.7, 126.3, 124.8, 101.9, 83.3, 60.9, 60.6, 50.3, 37.1,
30.5, 24.7, 23.2, 19.6, 14.1. MS (EI): 330 (M+, 2), 224 (28),
110 (67), 97 (100). Anal. Calcd for C20H26O4 (330.37): C,
72.73; H, 7.88. Found: C, 72.71; H, 7.81.
Typ ica l P r oced u r e for th e Cycliza tion Rea ction of
Br om o Aceta ls of Typ e 7. P r ep a r a tion of 4-(3-Ca r be-
th oxy-3-bu ten yl)-2-eth oxy-5-ph en yltetr ah ydr ofu r an (17a).
A 50 mL three-necked flask equipped with an argon inlet, an
internal thermometer, a magnetic stirring bar, and a septum
cap was charged with Ni(acac)2 (66 mg, 0.25 mmol, 5 mol %)
and dry LiI (160 mg, 1.25 mmol, 25 mol %). A solution of the
bromo acetal 7a (1.42 g, 5.0 mmol) in THF (5 mL) was added,
and the mixture was cooled to -78 °C. At this temperature
Et2Zn (1.0 mL, 10.0 mL, 2 equiv) was added dropwise, and
after completion of the addition the reaction mixture was
gradually warmed to 40 °C. It was stirred at this temperature
for 12 h. The solvent and excess of Et2Zn was removed in
vacuo, and the further preparation was carried out as de-
scribed for 14a . Ethyl (R-bromomethyl)acrylate26 (2.79 g, 15.0
mmol, 3 equiv) was added at -78 °C, and the reaction mixture
was warmed to 0 °C and stirred for 1 h. Usual workup and
purification by silica gel chromatography of the residual oil
afforded the product 17a (0.97 g, 3.2 mmol, 64% yield) as a
yellow oil.
P r ep a r a tion of en d o-4-(3-Ca r beth oxy-2-p r op en yl)-3-
isop r op yl-2,8-d ioxa bicyclo[3.3.0]octa n e (16g). The pro-
cedure described above for the preparation of 14a was followed
with the alkyl iodide 6g (1.47 g, 5.0 mmol) and ethyl propiolate
as an electrophile. Reaction conditions: -78 to 0 °C, 1.5 h.
Purification by silica gel chromatography (hexanes/ether 9:1
to 4:1) of the crude product afforded a 1:1 mixture of diaster-
eomers of the ester 16g (0.93 g, 3.4 mmol, 67% yield) as a
yellow oil.
IR (film): 2850 (s), 1615 (vs), 1525 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz) δ 6.15 (s, 1H), 5.62 (d, J ) 4.9 Hz, 1H),
5.53 (s, 1H), 3.88 (q, J ) 7.1 Hz, 2H), 3.89 (m, 2H), 3.52 (dd,
J ) 10.3, 2.7 Hz, 1H), 2.42 (m, 2H), 2.30 (m, 1H), 1.88 (m,
3H), 1.73-1.44 (m, 3H), 1.29 (t, J ) 7.2 Hz, 3H), 1.10 (d, J )
6.7 Hz, 3H), 1.00 (m, 1H), 0.85 (d, J ) 6.7 Hz, 3H). 13C-NMR
(CDCl3, 75 MHz): δ 166.9, 140.6, 124.8, 108.4, 87.0, 68.7, 66.6,
45.8, 42.9, 31.5, 30.8, 29.1, 25.0, 20.5, 15.4, 14.2 (first dias-
teromer); δ 140.5, 124.5, 108.0, 89.2, 50.1, 46.5, 33.1, 32.9, 30.3,
19.8, 17.1 (second diastereomer). MS (EI): 240 (6), 239 (38),
IR (neat): 2820 (s), 1725 (vs), 1645 (m) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.26 (m, 5H), 6.22 (s, 1H), 6.05 (s, 1H),
5.28 (dd, J ) 5.7, 3.2 Hz, 1H), 4.53 (d, J ) 8.7 Hz, 1H), 4.11
(m, 3H), 3.76 (m, 1H), 3.43 (m, 1H), 2.49 (m, 1H), 2.24 (m,
2H), 1.62 (m, 3H), 1.20 (m, 6H). 13C-NMR (CDCl3, 75 MHz):
δ 166.8, 142.2, 140.4, 128.2, 127.4, 126.4, 103.6, 84.6, 66.8, 63.1

Synthesis of Heterocyclic Zinc Reagents
J . Org. Chem., Vol. 61, No. 17, 1996 5751
IR (neat): 2830 (s), 1720 (vs), 1650 (m) cm-1
1H-NMR
(first diastereomer); δ 165.7, 140.6, 137.8, 127.7, 125.2, 124.3,
81.9, 37.6, 31.5, 13.9 (second diasteromer). MS (EI): 159 (11),
117 (100), 72 (15). Anal. Calcd for C19H26O4 (306.35): C,
70.59; H, 8.49. Found: C, 70.31; H, 8.36.
.
(CDCl3, 300 MHz): δ 6.84 (dt, J ) 15.6, 7.2 Hz, 1H), 5.77 (d,
J ) 15.6 Hz, 1H), 5.00 (d, J ) 5.5 Hz, 1H), 4.11 (q, J ) 7.1 Hz,
2H) 3.64 (m, 2H), 3.35 (m, 1H), 2.30 (m, 1H), 2.19 (m, 2H),
1.80 (m, 1H), 1.52-1.40 (m, 8H), 1.21 (2t, J ) 7.1 Hz, 6H),
1.07 (t, J ) 7.1 Hz, 3H), 0.81 (m, 3H). 13C-NMR (CDCl3, 75
MHz): δ 166.5, 147.1, 122.6, 103.2, 82.5, 62.7, 60.2, 42.3, 38.9,
36.1, 34.4, 31.8, 29.4, 26.2, 22.6, 15.4, 14.3, 14.1. MS (EI): 227
(38), 85 (100), 57 (29). Anal. Calcd for C18H32O4 (312.36): C,
69.32; H, 10.26. Found: C, 69.39; H, 10.30.
P r ep a r a tion of 4-(3,3-Dica r beth oxy-2-p h en ylp r op yl)-
2-eth oxy-5-p h en yltetr a h yd r ofu r a n (17b). The procedure
described for the preparation of 17a was followed with the
bromo acetal 7a (1.42 g, 5.0 mmol). Diethyl benzylidenema-
lonate (3.72 g, 15.0 mmol, 3 equiv) was used as an electrophile.
Reaction conditions: -78 °C to rt, 12 h. After usual workup,
the residual oil was purified by flash chromatography (hex-
anes/ether 9:1 to 4:1), affording the product 17b (1.30 g, 3.1
mmol, 61% yield).
P r ep a r a tion of 4-(3,3-Dica r beth oxy-2-p h en ylp r op yl)-
2-eth oxy-5-h exyltetr a h yd r ofu r a n (17f). The procedure
described above for the preparation of 17a was followed with
the bromo acetal 7c (1.46 g, 5.0 mmol). Diethyl benzyliden-
emalonate (3.72 g, 15.0 mmol, 3 equiv) was used as an
electrophile. Reaction conditions: -78 to 10 °C, 12 h. Usual
workup and purification by silica gel chromatography (hex-
anes/ether 9:1) of the residual oil afforded the product 17f (1.30
g, 3.0 mmol, 60% yield) as a colorless oil.
IR (neat): 2990 (s), 2940 (s), 1715 (vs), 1455 (s) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 7.28 (m, 10H), 5.24 (dd, J ) 5.8,
3.4 Hz, 1H), 4.70 (d, J ) 7.8 Hz, 1H), 4.28 (q, J ) 7.2 Hz, 2H),
3.82 (m, 3H), 3.50 (m, 3H), 2.49 (m, 1H), 1.84 (m, 4H), 1.27
(m, 6H), 0.96 (t, J ) 7.2 Hz, 3H). 13C-NMR (CDCl3, 75 MHz):
δ 168.1, 141.2, 139.9, 128.5, 128.3, 127.9, 127.1, 126.8, 103.8,
85.3, 63.5, 61.6, 59.3, 44.9, 44.4, 40.7, 38.7, 35.2, 15.3, 14.2,
13.7 (first diasteromer); δ 167.7, 140.4, 140.4, 139.8, 128.5,
128.4, 128.1, 127.5, 127.0, 103.7, 84.4, 63.2, 61.1, 59.2, 44.4,
14.1 (second diastereomer). MS (EI): 409 (M+ - OC2H5, 5),
188 (100), 45 (12). Anal. Calcd for C27H34O6 (454.50): C,
71.37; H, 7.49. Found: C, 71.31; H, 7.28.
P r ep a r a tion of 4-(3,3-Dica r beth oxy-2-p h en ylp r op yl)-
2-eth oxy-5-isop r op yltetr a h yd r ofu r a n (17c). The proce-
dure described for the preparation of 17a was followed with
the bromo acetal 7b (1.25 g, 5.0 mmol). Diethyl benzyliden-
emalonate (3.72 g, 15.0 mmol, 3 equiv) was used as an
electrophile. Reaction conditions: -78 °C to rt, 12 h. Usual
workup and purification by silica gel chromatography (hex-
anes/ether 9:1 to 4:1) of the residual oil afforded the product
17c (1.30 g, 3.1 mmol, 61% yield) as a pale yellow oil.
IR (neat): 2840 (vs), 1640 (vs), 1350 (s), 1260 (s) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 7.21 (m, 5H), 4.85 (dd, J ) 5.5, 2.2
Hz, 1H), 4.14 (q, J ) 7.1 Hz, 2H), 3.64-3.41 (m, 4H), 3.30 (m,
2H), 1.93 (m, 1H), 1.72 (m, 2H), 1.48 (m, 2H), 1.24 (12H), 1.08
(t, J ) 7.1 Hz, 3H), 0.84 (m, 6H). 13C-NMR (CDCl3, 75 MHz):
δ 168.2, 167.7, 140.6, 128.7, 128.4, 127.1, 103.2, 82.8, 62.5, 61.5,
61.1, 59.2, 45.2, 41.4, 40.2, 38.3, 34.7, 31.8, 29.4, 26.0, 22.6,
15.3, 14.1, 14.0, 13.6 (first diastereomer); δ 140.3, 129.4, 128.3,
103.3, 82.3, 62,7, 44.5, 40.8, 37.1, 33.6, 22.5 (second diaster-
omer). MS (EI): 371 (2), 203 (19), 153 (47), 45 (100). Anal.
Calcd for C27H42O6 (462.50): C, 70.11; H, 9.14. Found: C,
69.91; H, 9.25.
P r ep a r a tion of en d o-7-(3-Ca r beth oxy-3-bu ten yl)-8-iso-
p r op yl-2,9-d ioxa bicyclo[4.3.0]n on a n e (17g). The proce-
dure described for the preparation of 17a was followed with
the bromo acetal 7d (1.0 g, 3.5 mmol). Ethyl (R-bromomethyl)-
acrylate26 (1.38 g, 7.0 mmol, 2 equiv) was used as an electro-
phile. Reaction conditions: -78 °C to rt, 1 h. Usual workup
and purification by silica gel chromatography of the residual
oil afforded the product 17g (0.68 g, 2.3 mmol, 66% yield) as
a colorless oil.
IR (neat): 2850 (s), 1810 (s), 2790 (m), 1760 (vs), 1740 (vs)
cm-1 1H-NMR (CDCl3, 300 MHz): δ 7.20 (m, 5H), 4.94 (dd, J
.
) 5.3, 2.8 Hz, 1H), 4.15 (q, J ) 7.1 Hz, 2H), 3.79 (q, J ) 7.1
Hz, 2H), 3.25 (m, 3H), 3.32 (m, 2H), 1.99 (m, 1H), 1.69 (m,
3H), 1.49 (m, 1H), 1.22 (t, J ) 7.0 Hz, 3H), 1.09 (m, 4H), 0.88
(m, 3H), 0.85 (d, J ) 6.8 Hz, 3H), 0.62 (d, J ) 6.8 Hz, 3H).
13C-NMR (CDCl3, 75 MHz): δ 168.1, 167.6, 140.8, 140.6, 128.6,
128.5, 128.2, 127.0, 103.3, 103.2, 102.9, 90.7, 87.9, 87.6, 65.7,
62.2 (2C), 61.4 (2C), 60.9, 59.1, 45.5, 44.5, 40.6, 40.0, 38.9, 38.7,
38.1, 37.8, 37.0, 32.8, 31.5, 31.3 (2 C), 19.9, 19.5, 18.5, 18.0
(2C), 17.7, 16.8, 15.3, 14.9, 13.9, 13.6. 1. MS (EI): 420 (M+,
19), 331 (97), 229 (56), 171 (100). Anal. Calcd for C24H36O6
(420.43): C, 68.57; H, 8.57. Found: C, 68.72; H, 8.44.
IR (neat): 2950 (s), 1710 (vs), 1660 (w) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 6.13 (s, 1H), 5.36 (s, 1H), 5.14 (s, 1H),
4.13 (q, J ) 7.0 Hz, 2H), 3.72 (m, 1H), 3.56 (m, 2H), 2.20 (m,
1H), 1.97 (m, 1H), 1.66 (m, 4H), 1.55 (m, 4H), 1.49 (m, 7H),
1.23 (t, J ) 7.1 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ 166.9,
140.6, 124.5, 101.1, 85.3, 60.9, 60.6, 43.0, 37.1, 31.6, 30.9, 26.5,
23.4, 20.3, 19.8, 16.6, 14.2. MS (EI): 254 (M+ - CH3, 16), 253
(100), 97 (31). Anal. Calcd for C17H28O4 (269.36): C, 68.91;
H, 9.45. Found: C, 68.95; H, 9.57.
P r ep a r a tion of 4-(3-Ca r beth oxy-3-bu ten yl)-2-eth oxy-
5-h exyltetr a h yd r ofu r a n (17d ). The procedure described
above for the preparation of 17a was followed with the bromo
acetal 7c (1.50 g, 5.0 mmol). Ethyl (R-bromomethyl)acrylate26
(2.97 g, 15.0 mmol, 3 equiv) was used as an electrophile.
Reaction conditions: -78 °C to rt, 1 h. After usual workup
the residual oil was purified by flash chromatography (hex-
anes/ether 95:5), affording the product 17d (970 mg, 3.1 mmol,
61% yield) as a colorless oil.
P r ep a r a t ion of en d o-7-(3-Ca r b et h oxy-3-b u t en yl)-8-
h exyl-2,9-d ioxa bicyclo[4.3.0]n on a n e (17h ). The procedure
described for the preparation of 17a was followed with the
bromo acetal 7e (1.30 g, 4.0 mmol). Ethyl (R-bromomethyl)-
acrylate26 (2.37 g, 12.0 mmol, 3 equiv) was used as an
electrophile. Reaction conditions: -78 to 0 °C, 1 h. Usual
workup and purification by silica gel chromatography (hex-
anes/ether 9:1) of the residual oil afforded the product 17h
(0.87 g, 2.6 mmol, 65% yield) as a colorless oil.
IR (neat): 2930 (vs), 1990 (m), 1720 (vs) cm-1
.
1H-NMR
IR (neat): 2921 (vs), 1709 (vs), 1640 (w) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 6.25 (s, 1H), 5.44 (s, 1H), 5.02 (m, 1H),
4.13 (q, J ) 7.2 Hz, 2H), 3.64 (m, 2H), 3.38 (m, 1H), 3.32 (m,
1H), 2.23 (m, 3H), 1.60 (m, 2H), 1.45 (m, 2H), 1.45-1.32 (m,
6H), 1.29-1.15 (m, 7H), 1.13 (t, J ) 7.1 Hz, 3H), 0.81 (m, 3H).
13C-NMR (CDCl3, 75 MHz): δ 166.9, 140.7, 124.2, 103.1, 82.5,
62.5, 60.4, 43.3, 39.1, 34.3, 31.9, 31.7, 30.7, 29.3, 26.2, 22.5,
15.2, 14.1, 13.9. MS (EI): 280 (6), 153 (100), 96 (35), 55 (38),
43 (52). Anal. Calcd for C19H34O4 (326.38): C, 69.93; H, 10.43.
Found: C, 69.90; H, 10.40.
P r ep a r a t ion of 4-((E)-3-Ca r b et h oxy-2-p r op en yl)-2-
eth oxy-5-h exyltetr a h yd r ofu r a n (17e). The procedure de-
scribed for the preparation of 17a was followed with the bromo
acetal 7c (1.46 g, 5.0 mmol). Ethyl propiolate (1.45 g, 15.0
mmol, 3 equiv) was used as an electrophile. Reaction condi-
tions -78 to -10 °C, 12 h. Usual workup and purification by
silica gel chromatography (hexanes/ether 4:1) of the residual
oil afforded the product 17e (940 mg, 3.1 mmol, 61% yield) as
a colorless oil.
(CDCl3, 300 MHz): δ 6.13 (s, 1H), 5.46 (s, 1H), 5.19 (s, 1H),
4.15 (q, J ) 7.2 Hz, 2H), 3.69 (m, 2H), 3.54 (m, 1H), 2.29 (m,
1H), 2.13 (m, 1H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 1H),
1.29 (m, 10H), 1.13 (t, J ) 7.2 Hz, 3H), 0.80 (m, 3H). 13C-
NMR (CDCl3, 75 MHz): δ 166.9, 140.6, 124.5, 100.7, 80.8, 60.8,
60.5, 46.3, 36.9, 35.5, 31.7, 30.8, 29.4, 26.2, 25.8, 23.3, 22.5,
19.7, 14.1, 13.9. MS (EI): 338 (M+, 2), 253 (100), 97 (40), 55
(31). Anal. Calcd for C20H34O4 (338.44): C, 70.97; H, 10.11.
Found: C, 70.84; H, 10.35.
Typ ica l P r oced u r e for th e Oxid a tion of Cyclic Aceta ls
to γ-Bu tyr ola cton es (Meth od A).18 P r ep a r a tion of tr a n s-
4-(3-Ca r beth oxy-3-bu ten yl)-5-p h en yltetr a h yd r ofu r a n -2-
on e (18a ). A 25 mL three-necked flask equipped with an
argon inlet, a magnetic stirring bar, and a septum cap was
charged with m-CPBA (50% by weight (Aldrich), 1.0 g, 2.4
mmol, 1.2 equiv), CH2Cl2 (9 mL), and MgSO4 (0.5 g). The
suspension was stirred at rt for 0.5 h, and the magnesium salt

5752 J . Org. Chem., Vol. 61, No. 17, 1996
Vaupel and Knochel
IR (neat): 2830 (s), 1760 (vs), 1710 (vs), 1630 (m) cm-1
1H-
was removed by filtration. BF3‚Et2O (0.12 mL, 0.8 mmol, 0.4
equiv) was added to the clear solution of the peracid, followed
by the acetal 16h (0.68 g, 2.0 mmol) dissolved in CH2Cl2 (0.5
mL). The reaction mixture was stirred for 1.5 h at rt. It was
diluted with ether (50 mL) and washed successively with
aqueous Na2S2O3 solution (10%, 30 mL), saturated aqueous
Na2CO3 solution (30 mL), and brine (30 mL). The organic layer
was dried (MgSO4) and filtered, and the solvent was evapo-
rated. The residual oil was purified by flash chromatography
(hexanes/ether 1:1), affording the lactone 18a (0.40 g, 1.4
mmol, 70% yield) as a colorless oil.
.
NMR (CDCl3, 300 MHz): δ 6.10 (s, 1H), 5.47 (s, 1H), 4.14 (q,
J ) 7.1 Hz, 2H), 3.89 (dd, J ) 5.4 Hz, 1H), 2.62 (dd, J ) 19.8,
11.2 Hz, 1H), 2.18 (m, 5H), 1.76 (m, 1H), 1.67 (m, 1H), 1.24 (t,
J ) 7.1 Hz, 3H), 0.90 (t, J ) 7.5 Hz, 6H). 13C-NMR (CDCl3,
75 MHz): δ 176.3, 166.6, 139.8, 125.1, 90.0, 60.6, 37.2, 34.9,
33.4, 32.1, 29.9, 18.6, 17.0, 14.1. MS (EI): 211 (57), 165 (100),
137 (97), 81 (58). Anal. Calcd for C14H22O4 (206.28): C, 66.14;
H, 8.66. Found: C, 66.16; H, 8.92.
P r ep a r a t ion of tr a n s-4-(3-Ca r b et h oxy-3-b u t en yl)-5-
h exylt et r a h yd r ofu r a n -2-on e (18e). The procedure de-
scribed above for the preparation of 18d was followed with
the bromo acetal 7c (420 mg, 1.42 mmol, 1 equiv). Ethyl (R-
bromomethyl)acrylate26 (820 mg, 4.2 mmol, 3 equiv) was used
as an electrophile. Reaction conditions: -78 °C to rt, 1 h. After
usual workup volatile components were distilled off, and the
residual oil was submitted to the oxidation procedure. The
oxidation was complete after 1 h at rt. Usual workup and
purification by silica gel chromatography (hexanes/ether 4:1)
afforded the lactone 18e (220 mg, 0.73 mmol, 50% yield) as a
colorless oil.
IR (neat): 2820 (s), 1770 (vs), 1705 (vs), 1630 (m) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 7.30 (m, 5H), 6.06 (s, 1H), 5.38 (s,
1H), 5.97 (d, J ) 8.8 Hz, 1H, 5-H), 4.10 (q, J ) 7.1 Hz, 2H),
2.76 (dd, J ) 14.4, 6.3 Hz, 1H), 2.42-2.20 (m, 1H, 4-H), 1.73
(m, 1H, 4-H), 1.61 (m, 1H, 4-H), 1.21 (t, J ) 7.1 Hz, 3H). 1H-
NMR-NOE (500 MHz, CDCl3): irradiation on the resonance
frequency of 5-H increases the intensity of 4-H. 13C-NMR
(CDCl3, 75 MHz): δ 175.9, 166.6, 139.5, 138.1, 128.8, 128.7,
126.1, 125.3, 86.6, 60.8, 44.4, 35.2, 31.0, 30.1, 14.2. MS (EI):
288 (M+, 3), 174 (100), 105 (77), 81 (65), 41 (54). Anal. Calcd
for C17H20O4 (288.27): C, 70.82; H, 6.98. Found: C, 70.51; H,
6.86.
P r ep a r a t ion of tr a n s-4-(3,3-Dica r bet h oxy-2-p h en yl-
pr opyl)-5-isopr opyltetr ah ydr ofu r an -2-on e (18b). The pro-
cedure described for the preparation of 18a was followed with
the acetal 17c (294 mg, 0.70 mmol, 1 equiv). The oxidation
was complete after 3 h of stirring at rt. Usual workup and
purification by silica gel chromatography of the residual oil
afforded the lactone 18b (240 mg, 0.61 mmol, 87% yield) as a
colorless oil.
IR (film): 2910 (vs), 2870 (m), 1780 (vs), 1710 (vs) cm-1 1H-
.
NMR (CDCl3, 300 MHz): δ 6.10 (s, 1H), 5.48 (s, 1H), 4.13 (q,
J ) 7.2 Hz, 2H), 4.04 (dt, J ) 10.4, 4.3 Hz, 1H), 2.40 (dd, J )
17.0, 8.2 Hz, 1H), 2.10 (m, 3H), 2.05 (m, 1H), 1.84 (m, 1H),
1.80 (m, 2H), 1.76 (m, 3H), 1.25 (m, 10H), 0.82 (m, 3H). 13C-
NMR (CDCl3, 75 MHz): δ 176.3, 166.8, 139.4, 125.2, 85.8, 60.8,
40.9, 35.1, 34.7, 32.2, 311.7, 30.2, 29.1, 25.6, 22.5, 14.2, 14.0.
MS (EI): 296 (M+ - 1, 19), 137 (77), 81 (69), 41 (100). Anal.
Calcd for C17H29O4 (297.33): C, 68.69; H, 9.76. Found: C,
68.42; H, 9.64.
P r ep a r a tion of en d o-4-(Deu ter iom eth yl)-2-a za bicyclo-
[4.3.0]n on a n e (20). The procedure described for the prepara-
tion of 14a was followed with the alkyl iodide 8 (1.06 g, 3.0
mmol). The cyclization was performed in the presence of Ni-
(acac)2 (15 mg, 0.06 mmol, 2 mol %) as well as in the presence
of PdCl2(dppf)13 (76 mg, 0.09 mmol, 3 mol %) as a catalyst.
The resulting alkylzinc species were quenched by addition of
a solution of AcOD (D2O: 1.0 mL, 50 mmol; AcCl: 1.7 mL, 25
mmol) in THF (2 mL) at -78 °C. The cooling bath was
removed, and the reaction mixture was allowed to warm to rt
and was diluted with ether (15 mL) and saturated aqueous
NH4Cl solution (15 mL). The organic layer was separated, and
the aqueous phase was extracted with ether (3 × 50 mL). The
combined organic layer was dried (MgSO4) and filtered, and
the solvent was evaporated. The residual oil was purified by
flash chromatography (hexanes/ether 9:1), affording the mono-
deuterated product 20 (490 mg, 2.13 mmol, 71% yield) as a
colorless oil.
IR (neat): 2980 (vs), 2950 (vs), 2890 (s), 1780 (vs), 1750 (vs)
cm-1
.
1H-NMR (CDCl3, 300 MHz): δ 7.21 (m, 5H), 4.17 (m,
2H), 3.80 (m, 3H), 3.53 (dd, J ) 10.6, 2.7 Hz, 1H), 3.28 (m,
1H) 2.08-1.56 (m, 7H), 1.18 (t, J ) 5.3 Hz, 3H), 0.83 (m, 6H),
0.68 (dd, J ) 11.9, 6.8 Hz, 3H). 13C-NMR (CDCl3, 75 MHz):
δ 176.3, 168.0, 167.5, 139.6, 128.6, 128.0, 127.6, 89.9, 61.6, 58.6,
44.3, 38.8, 36.1, 35.3, 34.5, 31.5, 18.3, 16.9, 13.9, 13.5 (first
diastereomer); δ 175.9, 167.9, 139.2, 128.3, 127.5, 89.6, 61.4,
58.4, 43.8, 39.7, 35.8, 31.8, 18.9, 16.8, 13.6 (second diastere-
omer). MS (EI): 390 (M+ - 1, 8), 249 (15), 189 (100), 171 (19).
Anal. Calcd for C22H31O6 (391.37): C, 67.52; H,7.93. Found:
C, 67.40; H, 7.93.
P r ep a r a tion of tr a n s-4-((E)-3-Ca r beth oxy-2-p r op en yl)-
5-h exyltetr a h yd r ofu r a n -2-on e (18c). The procedure de-
scribed above for the preparation of 18a was followed with the
acetal 17e (178 mg, 0.57 mmol, 1 equiv). The oxidation was
complete after 1.5 h of stirring at rt. After usual workup the
residual oil was purified by flash chromatography (hexanes/
ether 4:1), affording the lactone 18c (160 mg, 0.56 mmol, 98%
yield) as a colorless oil.
IR (neat): 3300 (s), 2955 (m), 2890 (w) cm-1
.
1H-NMR
(CDCl3, 300 MHz): δ 7.37 (m, 5H), 4.00 (d, J ) 13.8 Hz, 1H),
3.29 (d, J ) 13.7 Hz, 1H), 2.85 (m, 1H), 2.64 (d, J ) 9.4 Hz,
1H), 2.49 (dd, J ) 9.8 Hz, 1H), 2.20 (m, 1H), 1.87 (d, J ) 9.8
Hz, 1H), 1.81-1.76 (m, 2H), 1.66-1.61 (m, 1H), 1.48-1.20 (m,
5H), 0.87 (d, J ) 5.2 Hz, 2H). 13C-NMR (CDCl3, 75 MHz): δ
141.3, 128.2, 128.0, 126.3, 63.9, 59.1, 58.2, 42.7, 34.5, 27.1, 25.6,
22.9, 20.7, 13.2 (t). MS (EI): 231 (M+ + 1, 7), 230 (M+, 45),
91 (100). Anal. Calcd for C16H22DN (230.31): C, 83.48; H,
10.43; N, 6.08. Found: C, 83.34; H, 10.29; N, 6.30.
For m al Syn th esis of (-)-Meth ylen olactocin (3). P r epa-
r a tion of (E)-(S)-(+)-(Tr im eth ylsilyl)-1-octen -3-ol (26).32
A 50 mL three-necked flask equipped with a magnetic stirring
bar, a septum cap, and an argon inlet was charged with
(1R,2R)-1,2-bis(trifluoromethanesulfonamido)cyclohexane33 (25)
(316 mg, 0.8 mmol, 8 mol %) and Ti(O-i-Pr)4 (6.0 mL, 20.0
mmol, 2 equiv) in toluene (5 mL). The reaction mixture was
stirred for 45 min at 45 °C. It was cooled to -40 °C, Pent2Zn
(4.2 mL, 20.0 mmol, 2 equiv) was added, and the resulting deep
red solution was stirred for 10 min followed by dropwise
addition of (E)-3-(trimethylsilyl)-2-propenal32 (23) (1.28 g, 10.0
mmol, 1 equiv). After 1 h of stirring at -40 °C the reaction
was complete, the reaction mixture was quenched with an
aqueous HCl solution (10%), ether (60 mL) was added, and
the organic layer was separated. The aqueous layer was
extracted with ether (3 × 60 mL), and the combined organic
layer was washed with saturated NaHCO3 solution (60 mL)
IR (neat): 2920 (vs), 1780 (vs), 1720 (vs), 1660 (m) cm-1
.
1H-NMR (CDCl3, 300 MHz): δ 6.76 (dt, J ) 8.6, 7.0 Hz, 1H),
5.81 (d, J ) 5.5 Hz, 1H), 3.94 (q, J ) 7.1 Hz, 2H), 3.88 (m,
1H), 2.64 (m, 2H), 2.31 (m, 2H), 2.19 (m, 3H), 1.57 (m, 3H),
1.41 (m, 1H), 1.23 (m, 7H), 0.81 (m, 3H). 13C-NMR (CDCl3,
75 MHz): δ 175.6, 165.8, 144.0, 124.1, 85.0, 60.4, 39.7, 35.4,
34.5, 34.5, 31.5, 28.8, 25.8, 22.4, 14.2, 14.0. MS (EI): 282 (M+,
3), 197 (80), 151 (100), 123 (84), 41 (86). Anal. Calcd for
C16H26O4 (282.30): C, 68.09; H, 9.22. Found: C, 68.09; H, 8.97.
Typ ica l P r oced u r e for th e P r ep a r a tion of γ-Bu tyr o-
la cton es fr om Br om o Aceta ls of Typ e 7 (Meth od B).
P r ep a r a tion of tr a n s-4-(3-Ca r beth oxy-3-bu ten yl)-5-iso-
p r op yltetr a h yd r ofu r a n -2-on e (18d ). First the procedure
described for the preparation of 17a was followed with the
bromo acetal 7b (0.75 g, 3.0 mmol). Ethyl (R-bromomethyl)-
acrylate26 (1.77 g, 9.0 mmol, 3 equiv) was used as an electro-
phile. Reaction conditions: -78 °C to rt, 2 h. After usual
workup the residual oil was filtered over a short plug of silica
gel. After evaporation of the solvents the residual oil was
directly submitted to the oxidation procedure described for the
preparation of 18a . The oxidation was complete after 1.5 h
at rt. Usual workup and purification by silica gel chromatog-
raphy (hexanes/ether 4:1) afforded the lactone 18d (0.30 g, 1.5
mmol, 53% yield) as a colorless oil.

Synthesis of Heterocyclic Zinc Reagents
J . Org. Chem., Vol. 61, No. 17, 1996 5753
and brine (60 mL). It was dried (MgSO4) and filtered, and
after evaporation of the solvents the crude residue was purified
by flash chromatography (hexanes/ether 9:1), affording the
alcohol 26 (1.42 g, 7.1 mmol, 71% yield) as a colorless oil.
and stirred vigorously for 4 h. It was quenched by addition of
a saturated aqueous NH4Cl solution (5 mL), ether (5 mL) was
added, and the organic layer was separated. The aqueous
layer was extracted with ether (3 × 15 mL). The combined
organic layer was dried (MgSO4), the solvent was evaporated,
and the crude residue was purified by flash chromatography
(hexanes/ether 95:5), affording the aldehyde 30 (133 mg, 0.55
mmol, 55% yield) as a pale yellow oil.
1H-NMR (CDCl3, 300 MHz): δ 9.56 (d, J ) 3.0 Hz, 1H), 5.03
(d, J ) 3.9 Hz, 1H), 4.13 (dd, J ) 12.9, 7.4 Hz, 1H), 3.60 (m,
1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.11 (m, 3H), 1.46 (m, 6H),
1.30 (m, 9H), 1.22 (t, J ) 7.8 Hz, 3H). 13C-NMR (CDCl3, 75
MHz): δ 200.3, 103.5, 79.7, 66.9, 55.7, 37.2, 34.6, 32.0, 31.6,
25.6, 22.4, 19.2, 13.8, 13.7 (major diastereomer); δ 66.7, 54.7,
31.5, 26.5 (minor diastereomer).
[R]25
:
9.22 (c ) 6.00, benzene). 1H-NMR (CDCl3, 300
589
MHz): δ 5.99 (dd, J ) 17.6, 3.7 Hz, 1H), 5.75, (d, J ) 17.6 Hz,
1H), 4.00 (td, J ) 6.3, 6.2 Hz, 1H), 1.77 (s, 1H), 1.47-1.36 (m,
2H), 1.35-1.17 (m, 6H), 0.83 (t, J ) 6.7 Hz, 3H), 0.01 (s, 9H).
13C-NMR (CDCl3, 75 MHz): δ 148.8, 129.1, 74.7, 36.9, 31.8,
25.1, 22.6, 14.0, -1.4.
P r ep a r a t ion of (E)-(4S)-(-)-1-Br om o-2-b u t oxy-6-(t r i-
m eth ylsilyl)-3-oxa -4-p en tyl-5-h exen e (22). A 50 mL three-
necked flask equipped with a gas inlet, a septum cap, and a
magnetic stirring bar was charged with (E)-(S)-(+)-(trimeth-
ylsilyl)-1-octen-3-ol (26) (1.60 g, 8.0 mmol, 1 equiv) dissolved
in dichloromethane (3 mL). NBS (2.4 g, 13.3 mmol, 1.6 equiv)
was added, and the resulting suspension was cooled to 0 °C.
Butyl vinyl ether (4a ) (1.76 mL, 13.3 mmol, 1.6 equiv) was
added dropwise at this temperature. After 1 h of stirring, the
reaction mixture was diluted with ether (30 mL) and poured
on ice-cooled brine (50 mL). The organic layer was separated,
and the aqueous layer was extracted with ether (3 × 50 mL).
The combined organic layer was dried (MgSO4), and the
solvents were evaporated. Purification by silica gel chroma-
tography (hexanes/ether 9:1) afforded the alkyl bromide 22
(2.48 g, 7.1 mmol, 88% yield) as a colorless liquid.
P r ep a r a t ion of tr a n s-(4R,5S)-(-)-2-Oxo-5-p en t ylt et -
r a h yd r ofu r a n -4-ca r boxylic Acid (21). A 10 mL three-
necked flask equipped with an argon inlet, a magnetic stirring
bar, and a septum cap was charged with a solution of the
aldehyde 30 (120 mg, 0.5 mmol) in acetone (1 mL). This
solution was cooled to 0 °C, and the J ones reagent (3.0 mL)
was added dropwise. After being stirred for 5 min at 0 °C,
the excess of the oxidizing agent was quenched by addition of
2-propanol (1 mL). The reaction mixture was diluted with
ether (5 mL), and the precipitated chromium salts were
dissolved by addition of a saturated aqueous NH4Cl solution.
The organic layer was separated, and the aqueous layer was
extracted with ether (3 × 10 mL). The combined organic layer
was dried (MgSO4). After filtration and evaporation of the
solvents, the solid residue was purified by recrystallization
(dichloromethane/hexanes), affording the carboxylic acid 21 (90
mg, 0.45 mmol, 90% yield) as a white crystalline solid, mp 104
°C (lit.8b mp ) 105 -106 °C).
[R]25589: -30.46 (c ) 5.36, CHCl3). IR (neat): 2940 (s), 2920
(s), 1250 (s) cm-1 1H-NMR (CDCl3, 300 MHz): δ 5.86 (d, J )
.
6.9 Hz, 1H), 5.73 (d, J ) 3.2 Hz, 1H), 4.56 (q, J ) 5.4 Hz, 2H),
3.85 (m, 1H), 3.47 (m, 2H), 3.31 (m, 2H), 1.51 (m, 4H), 1.46
(m, 7H), 0.85 (m, 6H), 0.00 (s, 9H). 13C-NMR (CDCl3, 75
MHz): δ 146.9, 133.6, 101.1, 81.7, 67.1, 65.7, 35.3, 32.5, 31.9
(2 C), 24.9, 22.5, 19.3, 13.9, -1.4 (first diastereomer); δ 146.1,
132.0, 99.4, 80.7, 65.7, 35.2, 32.3, 31.7 (2 C), 19.2, 13.8 (second
diastereomer). MS (EI): 181 (30), 179 (30), 73 (34), 57 (100).
Anal. Calcd for C17H35BrO2Si (378.41): C, 53.95; H, 9.31.
Found: C, 53.68; H, 9.58.
[R]25589: -50.3 (c ) 0.41, CHCl3) (lit.8b [R]25589: -50.5 (c )
0.40, CHCl3)). IR (KBr): 3438 (s, br), 2956 (s), 2929 (s), 1749
(vs), 1241 (s) cm-1 1H-NMR (CDCl3, 300 MHz): δ 9.93 (s, 1H),
.
4.56 (dt, J ) 7.3, 4.9 Hz, 1H), 3.10 (ddd, J ) 9.3, 8.3, 7.3 Hz,
1H), 2.89 (dd, J ) 17.8, 9.7 Hz, 1H), 2.79 (dd, J ) 17.9, 9.7
Hz, 1H), 1.75 (m, 2H), 1.25 (m, 6H), 0.85 (t, J ) 7.2 Hz, 3H).
13C-NMR (CDCl3, 300 MHz): δ 176.3, 174.6, 81.9, 45.4, 35.3,
31.9, 31.3, 24.8, 22.4, 13.9. MS (EI): 199 (M+ - 1, 14), 180
(44), 179 (46), 129 (55), 57 (100). Anal. Calcd for C10H16O4
(200.17): C, 59.99; H, 8.05. Found: C, 59.91; H, 8.19.
P r ep a r a t ion of tr a n s-(4R,5S)-5-P en t yl-2-b u t oxyt et -
r a h yd r ofu r a n -4-ca r ba ld eh yd e (30). A 25 mL three-necked
flask equipped with an argon inlet, a magnetic stirring bar, a
septum cap, and an internal thermometer was charged with
Ni(acac)2 (11.6 mg, 0.05 mmol, 5 mol %) and LiI (31.0 mg, 0.25
mmol, 25 mol %). A solution of the bromo acetal 22 (0.35 g,
1.0 mmol) in THF (1.5 mL) was added, and the resulting
suspension was cooled to -78 °C. At this temperature Et2Zn
(0.25 mL, 2.5 mmol, 2.5 equiv) was added. The cooling bath
was removed, and the reaction mixture was gradually warmed
to 40 °C. It was stirred for 12 h at this temperature, and the
excess of Et2Zn was removed in vacuo (6 h, rt, 0.1 mmHg).
The solid residue was dissolved in THF (3 mL) and cooled to
-15 °C. At this temperature TMSCl (0.25 mL, 2.0 mmol, 2
equiv) was added, and the argon supply was replaced by
oxygen. The reaction mixture was allowed to warm to -5 °C
Ack n ow led gm en t. We thank the DFG (SFB 260
and SPP "Sauerstofftransfer/Peroxidchemie), the Fonds
der Chemischen Industrie, for generous financial sup-
port. We thank WITCO AG, BASF AG, BAYER AG,
Chemetall, Sipsy, and Chiroscience for the generous gift
of chemicals.
J O960617S