Stereoselectivity and regioselectivity in the segment-coupling prins cyclization

Article abstract of DOI:10.1021/jo010232w

The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined in Scheme 1 and involves esterification of a homoallylic alcohol.(1), reductive acetylation to give the α-acetoxy ether (3), and cyclization on treatment wit

Full text of DOI:10.1021/jo010232w

J . Org. Chem. 2001, 66, 4679-4686
4679
Ster eoselectivity a n d Regioselectivity in th e Segm en t-Cou p lin g
P r in s Cycliza tion
J ames J . J aber, Kazuhiko Mitsui, and Scott D. Rychnovsky*
Department of Chemistry, University of California, Irvine, California, 92697-2025
srychnov@uci.edu
Received March 5, 2001
The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined
in Scheme 1 and involves esterification of a homoallylic alcohol (1), reductive acetylation to give
the R-acetoxy ether (3), and cyclization on treatment with a Lewis acid to produce a tetrahydropyran
(4). Alkene geometries dictate the product configurations, with E-alkenes leading to equatorial
substituents and Z-alkenes leading to axial substituents (Table 1). Not unexpectedly, applying the
method to allylic alcohols leads to fragmentation rather than a disfavored 5-endo-trig cyclization.
Dienols in which one alkene is allylic and the other alkene is homoallylic cyclize efficiently and
produce the tetrahydropyrans 49-54, Table 3. Dienols with two homoallylic alkenes cyclize with
modest to high regioselectively, generating tetrahydropyrans 40-45, Table 2. The relative rates
for cyclization decrease in the order of vinyl > Z-alkene > E-alkene > alkyne. The configurations
of the products are consistent with cyclization via a chair conformation, Figure 1. The 2-oxonia
Cope rearrangement may be a factor in the regioselectivity of diene cyclizations and in the erosion
of stereoselectivity with Z-alkenes. This investigation establishes the stereoselectivity and
regioselectivity for a number of synthetically useful segment-coupling Prins cyclizations.
The Prins cyclization is a powerful synthetic reaction
that can produce a cis-2,6-dialkyltetrahydropyran ring
from an aldehyde and a homoallylic alcohol in the
presence of an acid catalyst.1 With some substrates, a
competing ene reaction leads to unsaturated products.2
Classic conditions involved the use of mineral acids to
promote the reaction, and these harsh conditions limited
its utility to unfunctionalized substrates.3 Using cyclic
acetals or mixed acetals as precursors to the intermediate
oxocarbenium ions extended the versatility of the reac-
tion.4 Overman developed cyclizations using mixed ac-
etals and found that medium rings could be prepared
efficiently.5 Although simple alkenes participate in the
cyclization, more complex nucleophiles such as allyl
trimethylsilanes, vinylsilanes, and vinyl sulfides have
been introduced to exert control over the cyclization
process.6 The use of allylsilanes provides a route to the
otherwise inaccessible trans-2,6-disubstituted tetrahy-
dropyrans.7 Tandem reactions have been developed to
extend the utility of the Prins cyclization.8,9 Despite the
potential of the reaction to build up structural complexity
rapidly, the Prins cyclization remains underutilized as
a synthetic tool. We have developed a new implementa-
tion of the reaction, a segment-coupling Prins cyclization
that brings together an acid and a homoallylic alcohol to
form a new tetrahydropyran ring. The segment-coupling
Prins cyclization overcomes the major limitations of
previous methods.10 Described herein is an investigation
of the scope and utility of this reaction.
The segment-coupling Prins cyclization is designed
around the reductive acetylation of acyclic esters to give
R-acetoxy ethers, Scheme 1.11 The R-acetoxy ethers are
ideal precursors to the oxocarbenium ion intermediates
of the Prins cyclization because the acetate is solvolyzed
regioselectively upon treatment with a Lewis acid. More
importantly, in complex structures, the R-acetoxy ethers
are much easier to prepare than the mixed acetals
(1) (a) Hanschke, E. Chem. Ber. 1955, 88, 1053-1061. (b) Stapp, P.
R. J . Org. Chem. 1969, 34, 479-485.
(2) (a) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661-672.
(b) Snider, B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Ed.; Pergamon Press: New York, 1991;
Vol. 2, pp 527-561.
(3) For milder versions of the classic Prins cyclization see: (a) Wei,
Z. Y.; Wang, D.; Li, J . S.; Chan, T. H. J . Org. Chem. 1989, 54, 5768-
5774. (b) Yang, J .; Viswanathan, G. S.; Li, C. J . Tetrahedron Lett. 1999,
40, 1627-1630. (c) Zhang, W. C.; Viswanathan, G. S.; Li, C. J . Chem.
Commun. 1999, 291-292. (d) Yang, X. F.; Li, C. J . Tetrahedron Lett.
2000, 41, 1321-1325. (e) Zhang, W. C.; Li, C. J . Tetrahedron 2000,
56, 2403-2411.
(4) (a) Bunnelle, W. H.; Seamon, D. W.; Mohler, D. L.; Ball, T. F.;
Thompson, D. W. Tetrahedron Lett. 1984, 25, 2653-2654. (b) Winstead,
R. C.; Simpson, T. H.; Lock, G. A.; Schiavelli, M. D.; Thompson, D. W.
J . Org. Chem. 1986, 51, 275-277. (c) Nikolic, N. A.; Gonda, E.;
Longford, C. P. D.; Lane, N. T.; Thompson, D. W. J . Org. Chem. 1989,
54, 2748-2751.
(6) For example, see (a) Overman, L. E.; Castaneda, A.; Blumenkopf,
T. A. J . Am. Chem. Soc. 1986, 108, 1303-4. (b) Mohr, P. Tetrahedron
Lett. 1993, 34, 6251-6254. (c) Bratz, M.; Bullock, W. H.; Overman, L.
E.; Takemoto, T. J . Am. Chem. Soc. 1995, 117, 5958-5966. (d) Chen,
C. F.; Mariano, P. S. J . Org. Chem. 2000, 65, 3252-3254.
(7) (a) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N.
J . Org. Chem. 1997, 62, 3426-3427. (b) Huang, H. B.; Panek, J . S. J .
Am. Chem. Soc. 2000, 122, 9836-9837.
(8) (a) Marko, I. E.; Mekhalfia, A.; Bayston, D. J .; Adams, H. J . Org.
Chem. 1992, 57, 2211-2213. (b) Marko, I. E.; Bayston, D. J . Tetrahe-
dron Lett. 1993, 34, 6595-6598. (c) Coppi, L.; Ricci, A.; Taddei, M.
Tetrahedron Lett. 1987, 28, 973-976.
(9) (a) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927-
8940. (b) Cloninger, M. J .; Overman, L. E. J . Am. Chem. Soc. 1999,
121, 1092-1093.
(5) (a) Blumenkopf, T. A.; Bratz, M.; Castaneda, A.; Look, G. C.;
Overman, L. E.; Rodriguez, D.; Thompson, A. S. J . Am. Chem. Soc.
1990, 112, 4386-4399. (b) Overman, L. E.; Thompson, A. S. J . Am.
Chem. Soc. 1988, 110, 2248-2256. (c) Castaneda, A.; Kucera, D. J .;
Overman, L. E. J . Org. Chem. 1989, 54, 5695-5707.
(10) Rychnovsky, S. D.; Hu, Y. Q.; Ellsworth, B. Tetrahedron Lett.
1998, 39, 7271-7274.
(11) (a) Dahanukar, V. H.; Rychnovsky, S. D. J . Org. Chem. 1996,
61, 8317-8320. (b) Kopecky, D. J .; Rychnovsky, S. D. J . Org. Chem.
2000, 65, 191-198.
10.1021/jo010232w CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001

4680 J . Org. Chem., Vol. 66, No. 13, 2001
J aber et al.
Sch em e 1
Sch em e 2
previously used in the cyclization.4,5 Lewis acid or protic
acid induced cyclizations of unsaturated R-acetoxy ether
substrates lead to cis-2,6-dialkyltetrahydropyrans with
an equatorial halide or acetate at the 4-position, Figure
1. The segment-coupling Prins cyclization has been
applied to a short and efficient synthesis of the C22-
C26 tetrahydropyran segment of the natural product
phoroboxazole B.12 This method is well suited to the
synthesis of complex tetrahydropyrans in a highly con-
vergent manner and should be a powerful tool in natural
product synthesis.
several simple homoallylic alcohols, and these alcohols
were prepared by the route shown in Scheme 2. The
Z-alkene 8 was prepared as a single geometric isomer
by selective hydrogenation15 of alkyne 7, followed by
esterification. The E-alkene 9 was prepared by dissolving
metal reduction of the alkyne 7, followed by esterification.
The stereoselectivity of the dissolving metal reduction
varied, but the material used in subsequent studies was
contaminated with <10% of the Z-isomer by GC analy-
sis.16 The 1-phenyl-3-acetyloxy-5-hexene (10) was pre-
pared by addition of allylmagnesium bromide to 3-
phenylpropanal, followed by esterification. The alkyne
ester 11 was prepared from 7 by esterification. Esters
8-11 were used in the Prins cyclization studies.
The R-acetoxy ethers of 8-10 were prepared by
DIBAL-H reduction and in situ acetylation using the
improved protocol recently reported from our laboratory.11b
In each case, the yield of the R-acetoxy ether was
satisfactory, although minor amounts of the starting
ester were present. The R-acetoxy ethers were normally
used without further purification, but they could be
purified by chromatography on Et3N-deactivated silica
gel. The Prins cyclizations were carried out using either
SnBr4 in CH2Cl2 at -78 °C or BF3‚OEt2 and HOAc in
hexanes. With the latter promoter, fluorine was occasion-
ally incorporated into the tetrahydropyran competitively
with the acetate. Polar solvents promoted fluorine incor-
poration: cyclization of the R-acetoxy ether from 10 gave
the fluoride 14 in 64% yield when the solvent was
trifluoromethylbenzene. Fluorine incorporation was sup-
pressed by running the reaction in a nonpolar solvent
such as hexanes and by premixing the acetic acid and
BF3‚OEt2 in hexanes, cooling to 0 °C, and then transfer-
ring this heterogeneous mixture to the cooled solution of
the R-acetoxy ether by cannula. The cyclization reactions
for each of these three substrates are shown in Table 1,
and all of the cyclizations proceeded in good yield. The
terminal alkene 10 led to the cyclized products with
F igu r e 1. Chair conformation is preferred in Prins cycliza-
tions with R-acetoxy ethers.
Prins cyclizations are often highly stereoselective. In
general, the major stereoisomer arises by cyclization of
an E-oxocarbenium ion13 in a chairlike conformation. The
electrophilic cyclization is concerted with addition of the
nucleophile and electrophile to the alkene taking place
with an anti-periplanar geometry. A proposed geometry
for the transition state is illustrated in Figure 1. The C2
substituent in the incipient THP ring takes the equatorial
position and thus influences the stereochemical outcome
of the newly generated stereogenic centers. Prins cycliza-
tion reactions are not completely stereoselective, however,
and some reactions lead to unexpected stereoisomers as
minor products.14 The first topic of investigation is a
systematic exploration of the Prins cyclization stereo-
selectivity using R-acetoxy ether precursors to produce
4-heteroatom-substituted tetrahydropyrans. A second
area of interest is the cyclization of substrates with more
than one type of internal nucleophile. For instance, with
two nonequivalent alkenes in the R-acetoxy ether sub-
strate, will the cyclization take place on one alkene
preferentially, or will it be nonselective? Understanding
the stereoselectivity and regioselectivity of the segment-
couping Prins cyclization will facilitate its application to
natural product synthesis.
Resu lts
Cycliza tion s of Alk en es a n d Alk yn es. Investigation
of the stereoselectivity of the Prins cyclization required
(12) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217-
1219.
(15) Brown, C. A.; Ahuja, V. K. J . Chem. Soc., Chem. Commun. 1973,
553-554. The P-2 Ni hydrogenations produced Z-alkenes with >100:1
selectivity in our hands.
(16) The E-alkene 9 was contaminated with <10% of the Z-alkene
8. Products 17 and 18 were identified as impurities in the Prins
cyclization products in the amounts expected from cyclization of the
Z-alkene impurity in 9.
(13) (a) Broeker, J . L.; Hoffmann, R. W.; Houk, K. N. J . Am. Chem.
Soc. 1991, 113, 5006-5017. (b) Cremer, D.; Gauss, J .; Childs, R. F.;
Blackburn, C. J . Am. Chem. Soc. 1985, 107, 2435-41.
(14) Hu, Y.; Skalitzky, D. J .; Rychnovsky, S. D. Tetrahedron Lett.
1996, 37, 8679-8682.

Segment-Coupling Prins Cyclization
J . Org. Chem., Vol. 66, No. 13, 2001 4681
Ta ble 1. Cycliza tion of r-Acetoxy Eth er s w ith Sn Br 4 a n d
BF 3‚OEt2/HOAc P r om oter s
Sch em e 3
was confirmed by an NOE enhancement between the
vinyl methyl group and the allylic CH group in the ring.
The cyclization was also carried out with SnBr4 in
trifluoromethylbenzene at 23 °C to give 20b and 20a in
a 1.5:1 ratio. Cyclization with acetic acid and BF3‚OEt2
also gave a mixture of five- and six-membered ring
products contaminated with impurities. The tetrahydro-
furan 21b was the major product of the 3:1 mixture, and
both 21a and 21b were present as single diastereomers
by NMR analysis. The structure of 21a was confirmed
by hydrolysis with K2CO3 in MeOH to give the tetrahy-
dropyran 22a , the configuration of which was assigned
on the basis of 1H coupling constants and NOE measure-
ments. The configuration of 21b was tentatively assigned
by analogy to tetrahydrofuran 20b. With both cyclization
promoters, a modest preference for the five-membered
ring product was observed. There was a pronounced
preference for the cis dialkyl substitution across the
oxygen bridge, which presumably reflects the expected
conformational preference of the intermediate oxocarbe-
nium ion.
a
Condition A: SnBr4, CH2Cl2, -78 °C. Condition B: BF3‚OEt2,
HOAc, hexanes, 8 °C. Condition C: BF3‚OEt2, HOAc, C6H5CF3,
b
25 °C. The isomer ratios were determined by GC analysis of the
reaction mixtures before chromatography. c Ratio corrected for the
d
small amount of Z-alkene impurity in the SM. The minor
diastereomer from this cyclization reaction was 15. e The minor
diastereomer from this cyclization reaction was 16. f The remain-
ing mass (at least 90% reisolated) in the reductive acetylation was
recovered SM.
excellent selectivity. The E-alkene 9 gave tetrahydro-
pyrans 15 and 16 with very high stereoselectivity.16 The
configurations of the products were assigned by analysis
1
of the H NMR coupling constants and by NOE measure-
ments. The stereoselectivities of the Z-alkene cyclizations
were slightly lower, with the equatorial bromide 17
isolated as a 97:3 mixture with 15 and the equatorial
acetate 18 isolated as a 93:7 diastereomeric mixture with
16. Reactions with these simple substrates demonstrate
that Prins cyclizations of R-acetoxy ethers generally show
high selectivities and that such Prins cyclizations will
be useful for creating highly substituted tetrahydropyran
rings.
The Prins cyclization of allylic alcohols was investi-
gated, Scheme 4. In no case was any cyclized material
isolated. The substrates were prepared by addition of
vinylmagnesium bromide or propargylmagnesium bro-
mide to 3-phenylpropanal. The E- and Z-alkenes were
prepared by selective reduction of the propyne adduct.
Esterification and reductive acetylation proceeded un-
eventfully to produce R-acetoxy ethers 25 and 28-30. The
attempted cyclization of the R-acetoxy ether 25 was
typical of these allylic substrates. Treatment with SnBr4
gave allylic alcohol 26 in modest yield. The BF3‚OEt2 and
acetic acid promoted reaction gave the rearranged allylic
acetate 27 in good yield. Using the SnBr4 conditions with
R-acetoxy ethers 29 and 30 led to E,Z- or E,E-1-phenyl-
2,4-hexadiene, respectively, in modest yields. We con-
clude that the allylic and propargylic R-acetoxy ethers
do not cyclize and are prone to solvolytic decomposition.
Prins cyclizations of alkynes have also been reported.4
The Prins cyclization of alkyne ester 11 was investigated.
Reductive acetylation of 11 gave the R-acetoxy ether 19
in good yield (Scheme 3). Cyclization with SnBr4 gave a
mixture of two isomers in a 2.5:1 ratio. The major isomer
was tetrahydrofuran 20b, resulting from a 5-exo-dig
cyclization.17 The minor isomer was the tetrahydropyran
20a . Both products were isolated as single diastereomers,
with 2,5- and 2,6-cis substituents, respectively, as shown
by NOE measurements. The geometry of the alkene 20b
(17) (a) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-
736. (b) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 736-
738.

4682 J . Org. Chem., Vol. 66, No. 13, 2001
J aber et al.
Sch em e 4
Sch em e 5
Regioselectivity of Dien e a n d En yn e Cycliza -
tion s. Many of the natural products that are interesting
targets for a Prins cyclization strategy have multiple
alkenes present in their structure.18 These additional
functional groups complicate the synthetic analysis be-
cause they also may react with the oxocarbenium ion
intermediate and could give rise to alternate cyclization
products. In response to this potential problem, we have
investigated the cyclization of a series of simple diene
and enyne substrates to determine the intrinsic regio-
selectivity of the process.
The substrates used to probe the regioselectivity of the
Prins cyclization were prepared as illustrated in Scheme
5. Chloroacetaldehyde (50% in water) was coupled with
allyl indium generated in situ from allyl bromide and
indium metal.19 The indium metal must be combined
with the allyl bromide and allowed to stir for 15 min prior
to addition of the chloroacetaldehyde solution. This
procedure is particularly convenient, as the commercially
available 50% aqueous chloroacetaldehyde may be used
directly without any purification or drying. Treatment
of 32 with KOH afforded the epoxide, and BF3‚OEt2
promoted addition of 1-lithiopropyne gave the enyne
alcohol 33. Esterification followed by reductive acetyla-
tion gave the first cyclization substrate 34 in good yield.
The Z- and E-alkenes 35 and 36 were prepared by
selective reductions of the alkyne 33, followed by esteri-
fication and reductive acetylation. The final substrate,
39, was prepared by propyne addition to epichlorohydrin,
followed by P-2 Ni hydrogenation to give the expected
Z-alkene.15 Epoxide formation, propyne addition, dissolv-
ing metal reduction, and acetylation produced E,Z-diene
38. Reductive acetylation gave R-acetoxy ether 39, the
final Prins substrate for the regioselectivity study.
Prins cyclizations of the 4-alkoxy 1,6-diene substrates
gave some surprises as shown in Table 2. The enyne
substrate 34 led to cyclization of the alkene in the
presence of the alkyne, which is not unexpected based
on the greater nucleophilicity of alkenes over alkynes.
The acetate 40 was isolated as a single diastereomer.
Competition between the Z-alkene and the terminal
alkene in the cyclization of 35 led to preferential cycliza-
Ta ble 2. Regioselectivity of 1,6-En yn e a n d 1,6-Dien e
Cycliza tion s
a
Condition A: BF3‚OEt2, HOAc, hexanes 0 °C. B: BF3‚OEt2,
b
HOAc, hexanes, -78 °C. Reductive acetylation product was
accompanied by 16% of the recovered SM.
(18) For example, see phorboxazole A and B: (a) Searle, P. A.;
Molinski, T. F.; Brzezinski, L. J .; Leahy, J . W. J . Am. Chem. Soc. 1996,
118, 9422-9423. (b) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879-
7880.
tion of the terminal alkene and a 5:1 ratio of tetrahy-
(19) Li, C.-J .; Chan, T.-H. Tetrahedron 1999, 55, 11149-11176.
dropyrans 41 and 42. The selectivity for the terminal

Segment-Coupling Prins Cyclization
J . Org. Chem., Vol. 66, No. 13, 2001 4683
Ta ble 3. Cycliza tion of 1,5-Dien es w ith Sn Br 4 a n d
BF 3‚OEt2/HOAc P r om oter s
a
Condition A: BF3‚OEt2, HOAc, hexanes -78 °C. Condition B:
b
BF3‚OEt2, HOAc, hexanes, 0 °C. The reductive acetylation
product was accompanied by recovered SM to bring the total mass
balance to at least 85%.
F igu r e 2. Origin of the minor isomer on the cyclization of
the Z-alkene derived from ester 8.
alkene was even more pronounced in the cyclization of
36, where tetrahydropyran 43 was isolated as the sole
product in 87% yield. Apparently the E-alkene cyclizes
onto the oxocarbenium ion more slowly than the Z-
alkene, and this conclusion is reinforced by the behavior
of R-acetoxy ether 39. Cyclization of 39 led to tetrahy-
dropyran 45, resulting from cyclization on the Z-alkene,
with 2:1 selectivity over tetrahydropyran 44. The relative
rates of cyclization observed for these groups are vinyl
> Z-alkene > E-alkene > alkyne. The diene cyclizations
were also run under standard SnBr4 conditions (results
not shown). The yields were in the range of 68-79%, but
the dienes gave lower regioselectivity with the best
product ratio of only 2:3. Prins cyclizations of R-acetoxy
ethers 34, 35, and 36 promoted by BF3‚OEt2 and HOAc
each led to synthetically useful ratios favoring regio-
selective closure on the terminal alkene.
oxocarbenium ion intermediate adopting a chair confor-
mation as illustrated in Figure 1. The oxocarbenium ions
prefer an E-geometry with the hydrogen atom roughly
eclipsing the hydrogen atom of the methine across the
ether link, and this preference results in the cis-2,6-
dialkyl tetrahydropyran products observed.13 Cyclization
of an E-alkene introduces three new stereogenic centers.
The configuration of the products can be explained by
invoking a concerted anti addition across the alkene and
a chair geometry of the nascent tetrahydropyran. The
major products observed in Tables 1-3 are consistent
with the chair intermediate. A complicating factor is the
possible 2-oxonia Cope rearrangement of the intermedi-
ate oxocarbenium ion, Figure 1. The 2-oxonia Cope
cyclization has been invoked to explain the outcome of
several unusual Prins cyclizations,20 and the analogous
aza-Cope process is well established.21
Attempted Prins cyclization of the allylic substrates
led to solvolytic decomposition as shown in Scheme 4.
Would this mode of decomposition preclude cyclization
in a 3-alkoxy 1,5-diene substrate? A number of simple
substrates were prepared by adding allylmagnesium
bromide to R,â-unsaturated aldehydes, followed by acety-
lation. Reductive acetylation gave the R-acetoxy ether
substrates shown in Table 3. These R-acetoxy ethers were
submitted to Prins cyclization conditions. In each case,
the Prins cyclization product was isolated in good to
excellent yield as a single diastereomer. Particularly
impressive is the cyclization of 48, where competing
solvolysis through the highly stabilized benzylic cation
was not observed. The 3-alkoxy 1,5-diene substrates
cyclize efficiently under the optimized conditions.
Cyclization of the Z-alkene 8 produced a minor stere-
oisomer that accompanied the expected major isomer,
Figure 2. The minor isomer could have arisen from
several pathways including the presence of E-alkene 9
in samples of 8, isomerization of the Z-alkene to an
E-alkene in the reaction, or a competing boat transition
state in the cyclization. A fourth possibility is a noncon-
certed alkene cyclization in which an intermediate sec-
ondary cation could react from either face to form the
major product or the minor axial bromide product. Three
of these pathways will produce different minor isomers.
Cyclization of Z-alkene 8 (Table 1) with HOAc and BF3‚
OEt2 gave the major isomer 17 accompanied by the minor
isomer 15 in a 93:7 ratio. The minor products arise most
(20) (a) Lolkema, L. D. M.; Hiemstra, H.; Mooiweer, H. H.; Speck-
amp, W. N. Tetrahedron Lett. 1988, 29, 6365-6368. (b) Lolkema, L.
D. M.; Hiemstra, H.; Semeyn, C.; Speckamp, W. N. Tetrahedron 1994,
50, 7115-7128. (c) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron 1994, 50, 7129-7140.
(21) Blechert, S. Synthesis 1989, 71-82.
Discu ssion
The stereoselectivity of the Prins cyclizations with
R-acetoxy ether substrates is consistent with an E-

4684 J . Org. Chem., Vol. 66, No. 13, 2001
J aber et al.
simply from cyclization of the E-alkene. Compound 8
contained less than one percent of the E-alkene, and the
most plausible source of 15 is an in situ isomerization of
the Z-alkene 8 to the E-alkene 9. An E/Z isomerization
could arise from protonation of the alkene or from a
reversible 2-oxonia Cope rearrangement with incomplete
chair/boat selectivity. At this time we cannot distinguish
between these two possible mechanistic origins of the
E-alkene. Most Prins cyclizations are highly stereoselec-
tive, but when minor isomers are encountered they can
provide insight into the mechanism of the reaction.
The regioselective cyclizations of 1,6-diene-4-ols, Table
2, are surprising because the most electron-rich alkene
is not preferred. For substrates such as 35 and 36,
bromination or epoxidation would prefer the more highly
substituted double bond.22 The Prins cyclizations of 35
and 36 show the opposite trend, with the terminal alkene
reacting preferentially in each case. One explanation is
that the transition state for the Prins cyclization is late,
and that the stability of the nascent secondary cation is
not materially affected by the presence of an adjacent
methyl group. A similar selectivity is observed in the
protonation of simple alkenes, where unlike the bromi-
nation, no bridged intermediate spreads the charge
across the alkene.23 The rate retardation of the substi-
tuted alkene could be ascribed to steric hindrance in the
transition state near the forming carbon-carbon bond.
However, such rate retardations are not observed in the
reaction of diarylmethyl carbenium ions with substituted
alkenes, but instead a modest rate accelerations are
noted.24 The explanation for the observed selectivity may
be complex, and could involve competition between
alternate 2-oxonia Cope rearrangement pathways. More
experimental work will be needed to identify the origins
of regioselectivity in these systems.
Cyclization of the 1,5-dien-4-ol substrates proceeded
without solvolytic decomposition as shown in Table 3. The
simple allylic R-acetoxy ethers do not cyclize but rather
undergo solvolysis and decomposition, Scheme 4. This
outcome is not unexpected, as these reactions are dis-
favored 5-endo-trig cyclizations.17 Given the instability
of the simple substrates, cyclization of the 1,5-dien-4-ol
substrates in Table 3 is remarkably effective. These Prins
reactions can be rationalized either as direct cyclizations
or as 2-oxonia Cope rearrangements followed by cycliza-
tion. The later pathway would be consistent with the
divergent behavior of the simple allylic substrates (e.g.,
26) and the 1,5-diene substrates 46-48. In the future,
we plan to investigate the role of 2-oxonia Cope rear-
rangements in segment-coupling Prins cyclizations.
present study demonstrates that the cyclizations are
highly stereoselective, and that the cyclizations of dienes
often take place with useful levels of regioselectivity. The
configuration of the products can be rationalized based
on a chair conformation of the intermediate oxocarbe-
nium ion. Prins cyclizations form up to three new
contiguous stereogenic centers with high levels of selec-
tivity. We will continue to investigate the segment-
coupling Prins cyclization as a tool in natural product
synthesis.
Exp er im en ta l Section 25
Gen er a l P r oced u r e for th e DIBALH Red u ctive Acety-
la tion Ester s. The ester was dissolved in dichloromethane.
After the solution was cooled to -78 °C, DIBALH (1 M in
toluene, 2 equiv) was added dropwise via syringe. After 45 min,
the reaction was treated sequentially with pyridine (3.0 equiv),
neat DMAP (3.0 equiv), and acetic anhydride (6.0 equiv)
dropwise via syringe. The mixture was stirred at -78 °C for
12-19 h, warmed to 0 °C, and stirred for an additional 30 min,
and then the reaction was quenched at 0 °C with saturated
aqueous ammonium chloride (10 mL) and saturated aqueous
sodium potassium tartrate (7.5 mL). The resultant mixture
was warmed to room temperature and stirred vigorously for
30 min to promote clean separation of the layers. After
extraction with dichloromethane (×4), the combined dichlo-
romethane extracts were washed with ice-cooled 1 M sodium
bisulfate (×2), saturated aqueous sodium bicarbonate (×3),
and brine (×1). The solution was dried over MgSO4 and
concentrated under reduced pressure. The crude product was
usually contaminated with a few percent of the starting ester.
4-Br om o-2-m eth yl-6-p h en eth yltetr a h yd r op yr a n (12).
To a cooled solution (-78 °C) of R-acetoxy ether 10 (316 mg,
1.21 mmol, 1 equiv) in CH2Cl2 (5 mL) was added SnBr4 (2.42
mL, 1.0 M in CH2Cl2, 2.42 mmol, 2 equiv). The resulting
solution was stirred at -78 °C for 1 h, whereupon saturated
aqueous NaHCO3 (15 mL) was added. The reaction mixture
was warmed to 25 °C, extracted with CH2Cl2 (2 × 10 mL),
washed with saturated aqueous NaHCO3 (15 mL) and brine
(25 mL), dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The resulting crude oil was purified by flash
chromatography on silica gel (2.5-10% EtOAc/hexanes) to
yield 249 mg of 12 as a single diastereomer (73%): IR (neat)
1
3026, 2972, 2952 cm-1; H NMR (400 MHz, CDCl3) δ 7.34-
7.20 (m, 5 H), 4.13 (tt, J ) 8.8, 4.4 Hz, 1 H), 3.44 (ddt, J )
10.8, 1.6, 4.8 Hz, 1 H), 3.29 (m, 1 H), 2.80-2.73 (m, 2 H), 2.27-
2.20 (m, 2 H), 1.93-1.87 (m, 1 H), 1.80-1.72 (m, 3 H), 1.28 (d,
J ) 6.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 141.7, 128.4,
128.3, 125.7, 76.2, 73.5, 46.7, 44.9, 42.9, 37.2, 31.4, 21.4 Hz;
HRMS (CI/isobutane) m/z calcd for C14H19BrO (M + H)+
283.0677, found 283.0653.
2-Meth yl-6-ph en eth yltetr ah ydr opyr an -4-yl Acetate (13).
A premixed solution of BF3‚OEt2 (335 µL, 2.1 mmol, 3 equiv)
and AcOH (378 µL, 6.0 mmol, 8.6 equiv) in hexanes (2.0 mL)
was added by cannula into a cooled solution (0 °C) of R-acetoxy
ether 10 (187 mg, 0.70 mmol, 1 equiv) in hexanes (6.0 mL).
The reaction mixture was stirred for 1 h at 0 °C and then
warmed to 25 °C, whereupon saturated aqueous NaHCO3 (15
mL) was added. The reaction mixture was diluted with
hexanes (5 mL), washed with brine (20 mL), filtered, and
concentrated in vacuo. The resulting orange oil was purified
by flash chromatography on silica gel (2.5-10% EtOAc/
hexanes) to afford 114 mg (62%) of THP 13 as a single
diastereomer: IR (neat) 3085-3027, 1738 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.36-7.24 (m, 5 H), 9.93 (tt, J ) 11.2, 4.7 Hz,
1 H), 3.54 (ddt, J ) 11.1, 1.7, 6.3 Hz, 1 H), 3.42-3.37 (m, 1
H), 2.87-2.72 (m, 2 H), 2.10 (s, 3 H), 2.05-1.93 (m, 3 H), 1.82-
1.76 (m, 1 H), 1.38-1.29 (m, 5 H); 13C NMR (100 MHz, CDCl3)
δ 170.4, 141.8, 128.4, 128.2, 125.7, 74.1, 71.3, 70.4, 38.9, 37.5,
Con clu sion
Segment-coupling Prins cyclizations bring an acid and
a homoallylic alcohol together to form a new tetrahydro-
pyran ring. These reactions are made possible by the
discovery of a reductive acetylation procedure to produce
new R-acetoxy ethers from simple acyclic esters.11 The
(22) (a) Bromination: Anantakrishnan, S. V.; Ingold, C. K. J . Chem.
Soc. 1935, 1396-1398. (b) Epoxidation: Swern, D. Chem. Rev. 1945,
49, 1-68.
(23) For discussions of alkene protonation, see: (a) Riesz, P.; Taft,
R. W. J .; Boyd, R. H. J . Am. Chem. Soc. 1957, 79, 3724-3729. (b)
Bartlett, P. D.; Sargent, G. D. J . Am. Chem. Soc. 1965, 87, 1297-
1307. (c) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley
& Sons: New York, 1992; p 739.
(25) The general Experimental Section is included in the Supporting
Information.
(24) Mayr, H.; Pock, R. Chem. Ber. 1986, 119, 2473-2396.

Segment-Coupling Prins Cyclization
J . Org. Chem., Vol. 66, No. 13, 2001 4685
36.9, 31.6, 21.6, 21.2 Hz; HRMS (CI/isobutane) m/z calcd for
C
276.1730. Anal. Calcd for C17H24O3: C, 73.88; H, 8.75. Found:
C, 73.52; H, 8.67.
16H22O3 (M + H)+ 263.1569, found 263.1624. Anal. Calcd for
C16H22O3: C, 73.25; H, 8.45. Found: C, 73.60; H, 8.28.
4-F lu or o-2-m eth yl-6-p h en eth yltetr a h yd r op yr a n (14). A
premixed solution of BF3‚OEt2 (335 µL, 2.1 mmol, 3 equiv) and
AcOH (378 µL, 6.0 mmol, 8.6 equiv) in trifluorotoluene (2 mL)
was added by cannula into a 0 °C solution of R-acetoxy ether
10 (183 mg, 0.70 mmol, 1 equiv) in trifluorotoluene (6 mL).
The reaction mixture was stirred for 1 h and then warmed to
25 °C, whereupon saturated aqueous NaHCO3 (15 mL) was
added. The reaction mixture was diluted with EtOAc (10 mL),
washed with brine (20 mL), filtered, and concentrated in vacuo.
The resulting orange oil was purified by flash chromatography
on silica gel (2.5-10% EtOAc/hexanes) to afford THP 14 as a
single diastereomer (100 mg, 64%): 1H NMR (500 MHz, CDCl3)
δ 7.34-7.23 (m, 5 H), 4.67 (dtt, J ) 49.3, 10.8, 5.1 Hz, 1 H),
3.48-3.43 (m, 1 H), 3.32-3.28 (m, 1 H), 2.86-2.73 (m, 2 H),
2.13-2.08 (m, 3 H), 2.0-1.94 (m, 1 H), 1.83-1.76 (m, 1 H),
1.46-1.32 (m, 1 H and d, J ) 6.2 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 141.8, 128.5, 128.4, 125.8, 89.4 (d, J ) 174.7),
73.7 (d, J ) 10.9), 71.0 (d, J ) 11.5), 40.1 (d, J ) 15.9), 38.1
(d, J ) 17.2), 37.4, 31.7, 21.7 Hz; HRMS (CI/isobutane) m/z
calcd for C14H19FO (M+) 222.1420, found 222.1420.
Dih yd r op yr a n 20a a n d Tetr a h yd r ofu r a n 20b. To a -78
°C solution of R-acetoxy ether 19 (80 mg, 0.29 mmol, 1 equiv)
in of CH2Cl2 (5 mL) was added SnBr4 (560 µL, 1.0 M in CH2-
Cl2, 1.93 equiv). The reaction mixture was stirred for 1 h at
-78 °C, whereupon saturated aqueous NaHCO3 (20 mL) was
added. Upon warming to 25 °C the reation mixture was
extracted with CH2Cl2 (3 × 10 mL), washed with saturated
aqueous NaHCO3 (15 mL) and brine (20 mL), dried over
anhydrous MgSO4, and concentrated in vacuo. The crude oil
was purified by flash chromatography on silica gel (gravity
flow, 2.5%-7.5% EtOAc/hexanes) to afford 47 mg of 20b and
18 mg of 20a (76% overall yield) as yellow oils.
Data for 20a : 1H NMR (500 MHz, CDCl3) δ 7.33-7.17 (m,
5 H), 4.17 (m, 1 H), 3.55 (m, 1 H), 2.82-2.68 (m, 2 H), 2.57-
2.51 (m, 1 H), 2.36 (d, J ) 16.8 Hz, 1 H), 1.90 (dtd, J ) 19.9,
8.6, 5.6 Hz, 1 H) 1.73-1.71 (m, 4 H), 1.31 (d, J ) 6.6 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 141.7, 134.8, 128.4, 128.3, 125.8,
116.1, 75.4, 73.5, 42.1, 36.6, 31.5, 19.9, 18.2 Hz; HRMS (CI/
isobutane) m/z calcd for C15H19BrO (M + H)+ 296.0600, found
296.0606.
Data for 20b: 1H NMR (400 MHz, CDCl3), δ 7.33-7.20 (m,
5 H) 4.60 (q, J ) 6.4 Hz, 1 H), 3.89 (dq, J ) 6.4, 5.2 Hz, 1 H),
2.81-2.71 (m, 3 H), 2.35-2.26 (m, 4 H), 2.04-1.88 (m, 2 H),
1.36 (d, J ) 6.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 141.3,
141.7, 128.2, 128.2, 125.7, 111.5, 77.3, 75.7, 41.9, 37.0, 32.0,
25.0, 21.2 Hz; HRMS (CI/isobutane) m/z calcd for C15H19BrO
(M + H)+ 296.0600, found 296.0604.
4-Br om o-2,3-d im et h yl-6-p h en et h ylt et r a h yd r op yr a n
(15). Using the procedure described to prepare 12, R-acetoxy
ether 9 (52 mg) was converted into 38 mg (68%) of THP 15,
which was isolated as a single diastereomer: IR (neat) 3040,
1
700 cm-1; H NMR (400 MHz, CDCl3) δ 7.32-7.17 (m, 5 H),
3.86 (dt, J ) 12.0, 4.8 Hz, 1 H), 3.30-3.28 (m, 1 H), 3.13 (dq,
J ) 12.0, 6.4 Hz, 1 H), 2.79-2.72 (m, 2 H), 2.32-2.27 (m, 1
H), 2.02-1.89 (m, 2 H), 1.74-1.60 (m, 2 H), 1.31 (d, J ) 6.4
Hz, 3 H), 1.09 (d, J ) 6.4, 3 H); 13C NMR (100 MHz, CDCl3) δ
141.7, 128.4, 128.2, 125.7, 78.4, 76.1, 57.1, 46.8, 44.2, 37.0, 31.4,
20.1, 16.2 Hz; HRMS (CI/isobutane) m/z calcd for C15H21BrO
(M + H)+ 297.0851, found 297.0854.
Tetr a h yd r op yr a n on e 22a a n d tetr a h yd r ofu r a n 22b. A
premixed solution of BF3‚OEt2 (316 µL, 2.49 mmol, 3.7 equiv)
and AcOH (368 µL, 6.43 mmol, 9.6 equiv) in hexanes (2 mL)
was added by cannula into a 0 °C solution of R-acetoxy ether
19 (183 mg, 0.67 mmol, 1 equiv) in hexanes (6 mL). The
reaction mixture was stirred for 1 h at 0 °C and then warmed
to 25 °C, whereupon saturated aqueous NaHCO3 (15 mL) was
added. The reaction mixture was diluted with hexanes (10 mL),
washed with brine (25 mL), dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The resulting orange oil
was purified by flash chromatography (1% Et3N, 5% EtOAc/
hexanes) to afford a 3:1 mixture of 21a and 21b (171 mg, 93%,
combined yield of regioisomers): IR (neat) 3028, 1754, 1722
2,3-Dim eth yl-6-ph en eth yltetr ah ydr opyr an -4-yl Acetate
(16). Using the procedure described to prepare 13, R-acetoxy
ether 9 (52 mg) was converted into 35 mg (67%) of THP 16,
which was isolated as a clear oil: IR (neat) 3027, 1738, 978
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5 H), 4.59
(dt, J ) 11.2, 4.8 Hz, 1 H), 3.36-3.31 (m, 1 H), 3.19-3.15 (m,
1 H), 2.79-2.69 (m, 2 H), 2.08 (s, 3 H), 2.03 (ddd, J ) 12.0,
6.4, 1.6 Hz, 1 H), 1.92-1.87 (m, 1 H), 1.74-1.71 (m, 1 H), 1.46-
1.43 (m, 1 H), 1.31 (q, J ) 11.2 Hz, 1 H), 1.29 (d, J ) 6.0 Hz,
3 H), 0.87 (d, J ) 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
170.9, 141.9, 128.4, 128.3, 125.8, 77.20, 75.4, 73.9, 42.5, 37.6,
37.4, 31.7, 21.2, 19.5, 13 Hz; HRMS (CI/isobutane) m/z cald
for C17H24O3 (M)+ 276.1725, found 276.1720. Anal. Calcd for
cm-1
.
A small sample of the mixture of compounds 21a and 21b
was dissolved in MeOH (5 mL) and K2CO3 (solid, 2.0 g) was
added, and the mixture was stirred for 12 h. The reaction
mixture was concentrated in vacuo and diluted with EtOAc
(15 mL), washed with saturated aqueous NH4Cl (10 mL) and
brine (20 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo to afford an orange oil. The crude oil
was purified by flash chromatography (2.5% EtOAc/hexanes)
to afford samples of 22a and 22b.
C
17H24O3: C, 73.88; H, 8.75. Found: C, 73.69; H, 8.68.
4-Br om o-2,3-d im et h yl-6-p h en et h ylt et r a h yd r op yr a n
(17). Using the procedure described to prepare 12, the R-ac-
etoxy ether 8 (101 mg,) was converted 70 mg (64%) of THP
17. GC analysis found a 97:3 mixture of diastereomers (tR
(major) ) 15.198 min, tR (minor) ) 15.000 min). 17: IR (neat)
3040, 699 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.29-7.17 (m, 5
H), 4.41 (dt, J ) 9.5, 4.6 Hz, 1 H), 3.56 (dq, J ) 1.8, 6.4, Hz,
1 H), 3.33-3.27 (m, 1 H), 2.77-2.64 (m, 2 H), 1.95-1.84 (m, 4
H), 1.73-1.66 (m, 1 H), 1.21 (d, J ) 6.4 Hz, 3 H), 1.95 (d, J )
6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 142.2, 128.9, 128.8,
126.3, 77.6, 76.1, 55.5, 41.1, 37.9, 37.6, 32.0, 19.9, 7.8 Hz;
HRMS (CI/isobutane) m/z calcd for C15H21BrO (M)+ 296.0775,
found 296.0782.
Data for 22a : IR (neat) 1736, 1715 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.22-7.10 (m, 5 H), 3.51-3.46 (m, 1 H), 3.24 (dq, J
) 12.0, 6.0 Hz, 1 H), 2.76-2.12 (m, 2 H), 2.33-2.24 (m, 3 H),
1.95-1.88 (m, 1 H), 1.75-1.68 (m, 1 H), 1.31 (d, J ) 6.1 Hz, 3
H), 0.91 (d, J ) 6.7 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
208.8, 141.4, 128.4, 128.4, 125.9, 78.9, 76.0, 51.7, 47.9, 37.9,
31.5, 20.5, 9.4 Hz; HRMS (CI/isobutane) m/z calcd for C15H20O2
(M)+ 232.1463, found 232.1453.
Data for 22b: IR (neat) 3027, 1710 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.28-7.17 (m, 5 H), 4.02-3.96 (m, 1 H), 3.92-3.85
(m, 1 H), 2.78-2.70 (m, 2 H), 2.67-2.60 (m, 1 H), 2.21-2.16
(m, 1 H and s, 3 H), 1.96-1.87 (m, 1 H), 1.83-1.43 (m, 2 H),
1.34 (d, J ) 6.1 Hz, 3 H); 13C NMR (100 MHZ, CDCl3) δ 208.2,
141.9, 128.4, 128.3, 125.8, 78.3, 77.1, 58.8, 37.4, 35.3, 32.3, 29.9,
20.8 Hz; HRMS (EI/GC-MS) m/z calcd for C15H20O2 (M)+
232.1463, found 232.1465.
Tetr a h yd r op yr a n 40. A premixed solution of BF3‚OEt2
(127 µL, 1.0 mmol, 4 equiv) and AcOH (143 µL, 2.5 mmol, 10
equiv) in hexanes (2 mL) was added by cannula to a 0 °C
solution of R-acetoxy ether 34 (55 mg, 0.26 mmol, 1 equiv) in
hexanes (5 mL). The mixture was stirred for 1 h at 0 °C and
then warmed to 25 °C. The reaction was quenched with
saturated aqueous NaHCO3 (15 mL). The mixture was diluted
2,3-Dim eth yl-6-ph en eth yltetr ah ydr opyr an -4-yl Acetate
(18). Using the procedure described to prepare 13, the R-ac-
etoxy ether 8 (101 mg) was converted into 75 mg (74%) of THP
18. GC analysis found a 93:7 mixture of diastereomers (tR
(major) ) 15.209 min, tR (minor) ) 15.035 min). 18: IR (neat)
3033, 1738 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.29-7.17 (m,
5 H), 4.93 (dt, J ) 11.8, 4.8 Hz, 1 H), 3.55 (dq, J ) 1.8, 6.5 Hz,
1 H), 3.37-3.32 (m, 1H) 2.79-2.65 (m, 2 H), 2.05 (s, 3 H), 1.95-
1.86 (m, 2 H), 1.74-1.64 (m, 2 H), 1.49 (q, J ) 12.0 Hz, 1 H),
1.18 (d, J ) 6.5 Hz, 3 H), 0.91 (d, J ) 6.9 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 170.5, 141.9, 128.4, 128.3, 125.7, 74.8,
73.9, 73.7, 37.4, 36.5, 31.6, 31.4, 21.3, 18.4, 5.4 Hz; HRMS (CI/
isobutane) m/z calcd for
C
17H24O3 (M)+ 276.1725, found

4686 J . Org. Chem., Vol. 66, No. 13, 2001
J aber et al.
1
with hexanes (20 mL), washed with brine (20 mL), dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resulting orange oil was purified by flash chromatography on
silica gel (5-10% EtOAc/hexanes) to afford 46 mg (84%) of
THP 40 as a clear oil: IR (neat) 1741 cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.90 (tt, J ) 11.3, 4.7 Hz, 1 H), 3.55-3.44 (m, 2 H),
2.47 (ddq, J ) 16.4 5.2, 2.6 Hz, 1 H), 2.27 (ddq, J ) 15.5, 7.7,
2.5 Hz, 1 H), 2.18 (ddd, J ) 12.2, 4.4, 4.3 Hz, 1 H), 2.04 (s, 3
H), 1.95 (dt, J ) 12.3, 4.3 Hz, 1 H), 1.78 (t, J ) 2.6 Hz, 3 H),
1.27 (q, J ) 11.3 Hz, 2 H), 1.21 (d, J ) 6.2 Hz, 3 H); 13C NMR
(500 MHz, CDCl3) δ 170.5, 77.7, 74.8, 74.1, 71.6, 70.3, 38.8,
36.2, 26.1, 21.6, 21.3, 3.5 Hz; Anal. Calcd for C12H18O3: C,
68.55; H, 8.63. Found: C, 68.80; H, 8.50.
cm-1; H NMR (500 MHz, CDCl3) δ 5.84 (ddd, J ) 17.2, 10.6,
5.7 Hz, 1 H), 5.25 (dd, J ) 17.2, 1.4 Hz, 1 H), 5.11 (dd, J )
10.6, 1.3 Hz, 1 H), 4.91 (tt, J ) 11.3, 4.9 Hz, 1 H), 3.89 (dddd,
J ) 7.5, 5.7, 3.4, 1.8 Hz, 1 H), 3.56 (dq, J ) 1.9, 6.2 Hz, 1 H),
2.03 (s, 3 H), 2.02-1.94 (m, 2 H), 1.33 (q, J ) 11.5 Hz, 1 H),
1.30-1.25 (m, 1 H), 1.24 (d, J ) 6.2 Hz, 2 H); 13C NMR (125
MHz, CDCl3) δ 170.5, 137.9, 115.6, 75.9, 71.5, 70.2, 38.7, 36.7,
21.6, 21.2 Hz; HRMS (EI/GC-MS) m/z calcd for C10H16O3 (M
- C2H3O2)+ 125.0922, found 125.0924. Anal. Calcd for
C
10H16O3: C, 65.19; H, 8.75. Found: C, 65.24; H, 8.94.
4-Br om o-2-m eth yl-6-pr open yltetr ah ydr opyr an (51). The
procedure described for the preparation of 12 was followed,
using R-acetoxy ether 47 (73 mg) to produce 65 mg (81%) of
THP 51 as a clear oil: IR (near) 2972, 1446, 965 cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.68 (dq, J ) 15.4, 6.4 Hz, 1 H), 5.44 (dd,
J ) 15.4, 6.6 Hz, 1 H), 4.12 (tt, J ) 12.0, 4.3 Hz, 1 H), 3.76-
3.73 (m, 1 H), 3.45 (dq, J ) 12.2, 6.2 Hz, 1 H), 2.19 (dt, J )
4.0, 2.0 Hz, 2 H), 1.75 (q, J ) 11.6 Hz, 1 H), 1.69-1.62 (m, 4
H), 1.98 (d, J ) 6.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
130.6, 128.2, 78.0, 73.7, 46.3, 44.5, 42.9, 21.5, 17.7 Hz; HRMS
(EI/GC-MS) m/z calcd for C9H15BrO (M)+ 218.0306, found
218.0304. Anal. Calcd for C9H20BrO; C, 49.33; H, 6.90.
Found: C, 49.50; H, 6.87.
Tetr a h yd r op yr a n s 41 a n d 42. The procedure described
for the preparation of 40 was followed, using R-acetoxy ether
35 (20 mg) to produce 17 mg (85%) of a clear oil. The product
was a 5:1 mixture of the regioisomers of 41 (major) and 42
(minor) by NMR analysis. Data for 41: IR (neat) 1741 cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.80 (ddt, J ) 17.3, 10.1, 7.1 Hz,
0.2 H), 5.57-5.50 (m, 1 H), 5.41-5.37 (m, 1 H), 5.08-5.02 (m,
0.4 H), 4.93 (ddd, J ) 9.5, 4.7, 4.7 Hz, 0.2 H), 4.85 (tt, J )
16.1, 4.8 Hz, 1 H), 3.58-3.34 (m, 2.4 H), 2.37-2.17 (m, 2.4 H),
2.05 (s, 0.6 H), 2.03 (s, 3 H), 1.98-1.92 (m, 2 H), 1.60 (m, 0.4
H), 1.58 (dd, J ) 6.8, 0.8 Hz, 3 H), 1.42 (q J ) 12.4 Hz, 2 H),
1.21 (q, J ) 12.4 Hz, 2 H, d, J ) 6.5 Hz, 3 H), 1.13 (d, J ) 6.5
Hz, 0.6 H), 0.87 (d, J ) 7.0 Hz, 0.6 H); 13C NMR (125 MHz,
CDCl3) δ (major) 170.6, 126.2, 125.6, 75.2, 71.5, 70.6, 39.0, 36.5,
33.5, 21.7, 21.3, 13.0; (minor) 170.6, 134.3, 117.1, 75.3, 74.1,
73.7, 36.5, 31.6, 30.8, 18.4, 14.1, 5.4; LRMS (CI) m/z calcd for
2-Meth yl-6-pr open yltetr ah ydr opyr an -4-yl Acetate (52).
The procedure described for the preparation of 13 was followed,
using R-acetoxy ether 47 (308 mg) to produce 274 mg (89%) of
52 as an oil: IR (neat) 2973, 1742, 967 cm-1; H NMR (500
1
MHz, CDCl3) δ 5.70 (ddq, J ) 15.4, 1.0, 6.5 Hz, 1 H), 5.48 (ddd,
J ) 15.4, 3.3, 1.6 Hz, 1 H), 4.88 (tt, J ) 9.5, 4.7 Hz, 1 H), 3.82
(ddd, J ) 10.5, 6.7, 1.0 Hz, 1 H), 3.52 (ddt, J ) 11.3, 2.0, 6.2
Hz, 1 H), 2.02 (s, 3 H), 2.06-1.91 (m, 2 H), 1.66 (ddd, J ) 6.5,
1.6, 0.74 Hz, 3 H), 1.34 (q, J ) 11.4 Hz, 1 H), 1.26-1.16 (m, 4
H); 13C NMR (125 MHz, CDCl3) δ 170.5, 131.0, 128.0, 76.0,
71.2, 70.3, 38.7, 37.0, 21.7, 21.3, 122.8 Hz; HRMS (CI/
isobutane) m/z calcd for C11H18O3 (M + H)+ 199.1334, found
199.1340. Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found:
C, 66.47; H, 9.41.
Tetr a h yd r op yr a n 53. The procedure described for the
preparation of 12 was followed, using R-acetoxy ether 48 (213
mg) to produce 131 mg (57%) of 53 as a colorless oil: IR (neat)
3081, 3026, 747, 693 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.40-
7.24 (m, 5 H), 6.63 (d, J ) 16.0 Hz, 1 H), 6.20 (ddd, J ) 16.0,
6.2, 1.5 Hz, 1 H), 4.24 (tt, J ) 12.0, 4.5 Hz, 1 H), 4.04 (ddd, J
) 9.2, 6.2, 1.2 Hz, 1 H), 3.59 (ddq, J ) 11.0, 1.8, 6.2 Hz, 1 H),
2.38 (ddd, J ) 11.0, 4.3, 2.0 Hz, 1 H), 2.29 (ddd, J ) 11.0, 4.3,
2.0 Hz, 1 H), 1.93 (q, J ) 12.7 Hz, 1 H), 1.78 (q, J ) 12.5 Hz,
1 H), 1.30 (d, J ) 6.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
136.4, 131.2, 128.6, 128.5, 127.8, 126.5, 76.7, 73.6, 46.1, 44.6,
43.0, 21.5 Hz; HRMS (CI/isobutane) m/z calcd for C14H17BrO
(M)+ 280.0462, found 280.0463.
C
12H20O3 (M + H)+ 213, found 213; HRMS (EI/GC-MS) m/z
calcd for C12H20O3 (M - C4H8)+ 156.0785, found 156.0790.
Tetr a h yd r op yr a n 43. The procedure described for the
preparation of 40 was followed, using R-acetoxy ether 36 (50
mg) to produce 43 mg (87%) of 43 as a clear oil: IR (neat) 1741
cm-1; H NMR (500 MHz, CDCl3) δ 5.50-5.26 (m, 2 H), 4.85
1
(tt, J ) 16.1, 4.8 Hz, 1 H), 3.51-3.45 (m, 1 H), 3.36-3.31 (m,
1 H), 2.32-2.27 (m, 1 H), 2.1 (q, J ) 7.2 Hz, 1 H), 2.0 (s, 3 H),
1.97-1.91 (m, 2 H), 1.63 (dd, J ) 6.0, 1.0 Hz, 3 H), 1.25-1.16
(m, 2 H, d, J ) 6.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
170.6, 127.7, 126.6, 75.3, 71.5, 70.6, 39.3, 38.9, 36.4, 21.7, 21.3,
18.0; LRMS (CI/NH4) m/z for C12H20O3 (M + H)+ 213, found
213; HRMS (EI/GC-MS) m/z for C12H20O3 (M - C4H8)+
156.0785, found 156.0781.
Tetr a h yd r op yr a n s 44 a n d 45. The procedure described
for the preparation of 40 was followed, using R-acetoxy ether
39 (16 mg) to produce 12.5 mg (76%) of a clear oil. The product
was a 2:1 mixture of regioisomers of 45 (major) and 44 (minor)
1
by NMR analysis: IR (neat) 1741 cm-1; H NMR (500 MHz,
CDCl3) δ 5.62-5.43 (m, 3 H), 5.0 (dt, J ) 12.0, 4.8 Hz, 1 H),
4.63 (td, J ) 10.8, 4.7 Hz, 0.5 H), 3.65-3.61 (m, 1 H), 3.49-
3.41 (m, 1.5 H), 3.25-3.19 (m, 0.5 H), 2.38-2.10 (m, 1.5 H),
2.06 (s, 4.5 H), 1.98 (m, 1 H), 1.74-1.65 (m, 3 H), 1.61 (d, J )
6.8 Hz, 1.5 H), 1.53-1.40 (m, 1.5 H), 1.35-1.30 (m, 0.5 H) 1.28
(d, J ) 6.0 Hz, 1.5 H), 1.20 (d, J ) 6.5 Hz, 3 H), 0.93 (d, J )
6.9 Hz, 3 H), 0.90 (d, J ) 6.6 Hz, 1.5 H); 13C NMR (100 MHz,
CDCl3) δ (major) 170.1, 127.5, 126.4, 75.8, 74.0, 73.8, 39.3, 36.6,
31.0, 21.5, 18.7, 18.2, 5.6; (minor) 170.1, 125.9, 125.4, 79.2,
75.6, 74.9, 42.6, 37.2, 33.6, 21.4, 18.2, 13.4, 13.2; HRMS (EI/
GC-MS) m/z calcd for C13H22O3 (M)+ 226.1569, found 226.1567.
4-Br om o-2-m eth yl-6-vin yltetr a h yd r op yr a n (49). The
procedure described for the preparation of 12 was followed,
using R-acetoxy ether 46 (108 mg) to produce 73 mg (61%) of
Tetr a h yd r op yr a n 54. The procedure described for the
preparation of 13 was followed, using R-acetoxy ether 48 (107
mg) to produce 86 mg (80%) of THP 54 as a colorless oil: IR
(neat) 3059, 3027, 1740 cm-1; H NMR (500 MHz, CDCl3) δ
1
7.39-7.20 (m, 5 H), 6.60 (d, J ) 16.0 Hz, 1 H), 6.21 (dd, J )
16.0, 6.1 Hz, 1 H), 4.96 (tt, J ) 11.3, 4.7 Hz, 1 H), 4.12-4.06
(m, 1 H), 3.63 (ddq, J ) 12.4, 1.9, 6.2 Hz, 1 H), 2.13-2.06 (m,
1 H), 2.05 (s, 3 H), 2.04-1.98 (m, 1 H) 1.45 (t, J ) 11.5 Hz, 1
H), 1.33 (t, J ) 11.3 Hz, 1 H), 1.28 (d, J ) 6.2 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 170.5, 136.5, 130.8, 129.1, 128.4,
127.6, 126.5, 75.8, 71.6, 70.2, 38.2, 37.1, 21.7, 21.3 Hz. Anal.
Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C, 73.70; H,
7.62.
1
49 as a light yellow oil: IR (neat) 3027, 3058 cm-1; H NMR
(500 MHz, CDCl3) δ 5.84 (ddd, J ) 17.2, 10.6, 5.7 Hz, 1 H),
5.26 (dd, J ) 17.2, 1.4 Hz, 1 H), 5.11 (dd, J ) 10.6, 1.3 Hz, 1
H), 4.17 (tt, J ) 12.0, 4.3 Hz, 1 H), 3.85-3.82 (m, 1 H), 3.51
(dq, J ) 1.9, 6.2 Hz, 1 H), 2.29-2.06 (m, 2 H), 1.78 (q, J )
12.3 Hz, 1 H), 1.72 (q, J ) 12.3 Hz, 1 H), 1.23 (d, J ) 6.2 Hz,
3 H); 13C (125 MHz, CDCl3) δ 137.5, 115.9, 78.0, 73.5, 46.3,
Ack n ow led gm en t. Support has been provided by
the National Institutes of Health (CA 81635) and the
University of California, Irvine, UROP program.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for cyclization precursors 8, 9, 11, 32, 33, and 38. This
material is available free of charge via the Internet at
http://pubs.acs.org.
44.6, 42.6, 21.5 Hz; HRMS (CI/isobutane) m/z calcd for C8H13
-
BrO (M - Br)+ 125.0966, found 125.0969.
2-Meth yl-6-vin yltetr ah ydr opyr an -4-yl Acetate (50). The
procedure described for the preparation of 13 was followed,
using R-acetoxy ether 46 (108 mg) to produce 59 mg (55%) of
50 as a single diastereomer: IR (neat) 3010, 1740, 1380, 962
J O010232W