Two approaches to diverting the course of a free-radical cyclization: Application of cyclopropylcarbinyl radical fragmentations and allenes as radical acceptors

Article abstract of DOI:10.1021/jo901834q

(Chemical Equation Presented) Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along with considerable amounts of products derived from a cyclization-atom transfer-secondary cyclization process (6 and 9). Two

Full text of DOI:10.1021/jo901834q

pubs.acs.org/joc
Two Approaches to Diverting the Course of a Free-Radical Cyclization:
Application of Cyclopropylcarbinyl Radical Fragmentations and Allenes
as Radical Acceptors†
Dexi Yang, Valerie Cwynar, Matthew G. Donahue,† David J. Hart,* and Grace Mbogo
Department of Chemistry, The Ohio State University 100 West 18th Avenue, Columbus, Ohio 43210.
†Wyeth Research-Radiosynthesis Group, Chemical and Pharmaceutical Development, 401 N.
Middletown Rd, Pearl River, NY 10965.
hart@chemistry.ohio-state.edu
Received August 26, 2009
Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along
with considerable amounts of products derived from a cyclization-atom transfer-secondary
cyclization process (6 and 9). Two approaches to avoiding these unexpected products were explored.
Use of a cyclopropylcarbinyl fragmentation avoided the secondary cyclization reaction (25 or
43 f 26 or 44), whereas use of an allene as a radical acceptor avoided the atom-transfer reaction
altogether (49 f 52).
Introduction
during the course of our attempt to develop a free-radical
cyclization route to several C19 quassinoids (1-3), along
with some solutions to those problems.3
The use of free-radical cyclizations in complex target-
oriented synthesis has become commonplace during the last
30-40 years.1 Once in a while, however, a free-radical
process rears its head and causes unanticipated problems.2
This paper describes several such problems, encountered
† This paper is dedicated to the memory of Peter Wagner (1938-2009).
(1) For a synthesis of azadirachtin using an allene as the a radical
acceptor, see: Ley, S. V.; Abad-Somovilla, A.; Anderson, J. C.; Ayats, C.;
Banteli, R.; Beckmann, E.; Boyer, A.; Brasca, M. G.; Brice, A.; Broughton,
H. B.; Burke, B. J.; Cleator, E.; Craig, D.; Denholm, A. A.; Denton, R. M.;
Durand-Reville, T.; Gobbi, L. B.; Bobel, M.; Gray, B. L.; Grossmann, R. B.;
Gutteridge, C. E.; Hahn, N.; Harding, S. L.; Jennens, D. C.; Jennens, L.;
Lovell, P. J.; Lovell, H. J.; de la Puente, M. L.; Kolb, H. C.; Koot, W.-J.;
Maslen, S. L.; McCusker, C. F.; Mattes, A.; Pape, A. R.; Pinto, A.;
Santafianos, D.; Scott, J. S.; Smith, S. C.; Somers, A. Q.; Spilling, C. D.;
Stelzer, F.; Toogood, P. L.; Turner, R. M.; Veitch, G. E.; Wood, A.;
Zumbrunn, C. Chem.;Eur. J. 2008, 14, 10683–10704. For a review of
radical cyclizations, see: Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.;
Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301–856.
(2) For a radical cyclization-atom transfer-radical cyclization sequence
related to that encountered in this work, see: Clive, D. L. J.; Khodabocus, A.;
Cantin, M.; Tao, Y. J. Chem. Soc., Chem. Commun. 1991, 1755–1757.
(3) For lead references on the structures and/or synthesis of polyan-
dranes, see: Walker, D. P.; Grieco, P. A. J. Am. Chem. Soc. 1999, 121, 9891–
9892. For compound 1, see: Aono, H.; Koike, K.; Kaneko, J.; Ohmoto, T.
Phytochemistry 1994, 37, 579–584. For compound 2, see: Grieco, P. A.;
Vander Roest, J. M.; Pineiro-Nunez, M. M.; Campaigne, E. E.; Carmack, M.
Phytochemistry 1995, 38, 1463–1465. For compound 3, see: Itokawa, H.;
Qin, X.-R.; Morita, H.; Takeya, K. J. Nat. Prod. 1993, 56, 1766–1771.
We had planned to use a free-radical cyclization of bro-
mide 4 to trans-perhydroindan 5 as a key step in our
approach to the polyandranes.4,5 We had not anticipated
that a hydrogen atom transfer-radical cyclization sequence
would intervene and thus were caught off guard when
treatment of 4 with tri-n-butyltin hydride provided 6 in
(4) For earlier publications in this series, see: Donahue, M. G.; Hart, D. J.
Can. J. Chem. 2004, 82, 314–317. Hart, D. J.; Yang, D. Heterocycles 2007, 73,
197–201.
(5) For a preliminary account of work shown in Schemes 1 and 2, see:
Cwynar, V.; Donahue, M. G.; Hart, D. J.; Yang, D. Org. Lett. 2006, 8, 4577–
4580.
8726 J. Org. Chem. 2009, 74, 8726–8732
Published on Web 10/15/2009
DOI: 10.1021/jo901834q
r
2009 American Chemical Society

Yang et al.
JOCArticle
SCHEME 1
SCHEME 3
SCHEME 2
that this would be followed by rapid radical translocation
from 12 to provide 13. Based on ample literature precedence,
it was expected that fragmentation of 13 to afford 15 (via
homoallylic radical 14) would be faster than cyclization to
provide 17 (via radical 16).7 This plan was not only expected
to deal with the aforementioned difficulties but was also
expected to provide a vinyl ether at C11, which we thought
might have advantages later in the synthesis when the time
came to reveal the C11 hemiacetal of the polyandranes.
31% yield, along with 42% of the anticipated product 5
(Scheme 1).6 A labeling experiment (n-Bu3SnD) indicated
that 93% of 5 incorporated a single deuterium in the C11
methoxy group. This suggested that increasing the concen-
tration of tri-n-butyltin hydride would afford more 5 at the
expense of 6 and indeed this was the case (Scheme 1). This
was not an operationally pleasant solution to the problem,
however, because the product had to be separated from large
amounts of excess tin hydride and other tin-containing
materials.6
Results and Discussion
Similar results were obtained with cyclization substrate 7
(Scheme 2). In this case the rate of cyclization of the initial
radical generated from 7 was slower than the initial radical
generated from bromide 4. Therefore we were never able to
obtain high yields of the desired cyclization product 8. The
major product was 10 (57% yield) at high tri-n-butyltin
hydride concentrations and 9 (72%) at low concentrations
of tri-n-butyltin hydride.6
The results shown in Schemes 1 and 2 posed the following
problem. How could high yields of products of type 5 and 8
be obtained without intervention of the cyclization-atom
transfer-cyclization (to give 6 and 9) or reduction (to give
10)? The first solution we investigated was based on the plan
set forth in Scheme 3. We reasoned that a substrate of type 11
(R = SiMe3 or CO2Et) would undergo radical generation
and cyclization at low tin hydride concentrations. Based on
our experience with substrates 4 and 7, it seemed reasonable
Our initial test of this plan began with a synthesis of
cyclization substrate 25 (11 where R = SiMe3 and X =
SePh). This represented a system for which adjusting tin
hydride concentration had not provided a solution to the
problem at hand (Scheme 2). The synthesis of this substrate is
presented in Scheme 4. Treatment of phenol 18 with cyclo-
propylcarbinol under Mitsunobu conditions gave 19 in 82%
yield.8,9 Birch reductive alkylation of 19 using iodomethyl
pivalate gave 20, which was reduced to provide diol 21 in
72% overall yield.10,11 Treatment of 21 with phenylselenenyl
chloride provided 22 in 67% yield.12 Swern oxidation of 22
gave 23 in 82% yield.13 Treatment of aldehyde 23 with
dimethylsulfonium methylide provided a separable 3:1 mix-
ture of epoxide 24 and its C7 diastereomer in a combined
(7) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317–323.
(8) Turner, F. A.; Gearien, J. E. J. Org. Chem. 1959, 24, 1952.
(9) Mitsunobu, O. Synthesis 1981, 1–28.
(6) Compounds 5 and 6 were obtained in 42% and 31% yields, respec-
tively, when the initial concentrations of 4 and n-Bu3SnH were 8.8 and 18
mM, respectively. Compounds 5 and 6 were obtained in 75% and 10% yields,
respectively, when the initial concentrations of 4 and n-Bu3SnH were 10 and
100 mM, respectively (see the Supporting Information for details of the
cyclizations shown in Schemes 1 and 2).
(10) Van Bekkum, H.; Van Den Bosch, C.; Van Minnenpathuis, G.;
DeMos, J. C.; van Wijk, A. M. Recueil 1971, 90, 137–149.
(11) Schultz, A. G.; Taylor, R. E. J. Am. Chem. Soc. 1992, 114, 3937.
(12) Nicolaou, K. C.; Lysenko, Z. Tetrahedron Lett. 1977, 1257–1260.
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
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SCHEME 4
SCHEME 6
plan shown in Scheme 3. We decided to introduce an ethyl
group into the cyclopropane that would eliminate the possi-
bility of geometrical isomerism. Thus, we set out to prepare
cyclization substrate 28.
The synthesis of the required reductive alkylation sub-
strate was somewhat interesting (Scheme 6). We began by
preparing tert-butyl cyclopropanecarboxylate (30) in 76%
yield from the commercially available acid chloride 29.17
Alkylation of the lithium enolate derived from 30, with
bromoethane, gave 31 in 95% yield. Reduction of the ester
provided cyclopropylcarbinol 32 in 85% yield. The next task
was to alkylate phenol 18 with alcohol 32. We began by
trying to prepare the triflate of 32 (Tf2O, pyridine, CH2Cl2),
but instead obtained ether 33 (74%). An attempt to prepare
the corresponding mesylate (MeSO2Cl, pyridine, CH2Cl2)
resulted in formation of rearranged mesylate 34 (60%). The
coupling of 18 and 32 was eventually accomplished using a
classical Mitsunobu reaction to give 35 in a 57% yield.9
With the reductive alkylation substrate 35 in hand, the
synthesis of 28 followed established protocols (Scheme 7).
Reductive alkylation of 35 was followed by lithium alumi-
num hydride reduction to provide diol 36 (55%). The diol
was subjected to bromoetherification conditions to provide
37.18 A Swern oxidation gave 38 and sulfur ylide chemistry
gave 39 as a 2:1 mixture of geometrical isomers (major
isomer shown) that was separated by column chromato-
graphy.14 Alcohol 37 and aldehyde 38 decomposed quickly,
and this sequence had to be conducted without storing these
intermediates as indicated in the Experimental Section.
Epoxide 39 was opened with the appropriate acetylide to
give a 90% yield of 28.15,19
SCHEME 5
69% yield.14 The stereochemical assignment at C7 was infer-
red from similar compounds prepared during the course of this
research (vide infra). Treatment of epoxide 24 with the orga-
nometallic reagent derived from lithium trimethylsilylacety-
lide and boron trifluoride etherate gave an 84% yield of 25.15
The cyclization of 25 proceeded as expected, giving 26 as
the major product (2:1 mixture of Z and E geometrical
isomers, respectively) in 79% combined yield along with
reduction product 27 in 19% yield (Scheme 5).16 These
results were regarded as a partial success. The operational
problem of dealing with mixtures of vinyl ether geometrical
isomers, however, led us to evaluate a modification of the
Free-radical cyclization of 28 gave the desired product
40 in 40% yield (Scheme 8). Another unanticipated reaction,
however, reared its head. The other product of this reaction
was 41 (42%), isolated as a 2:1 mixture of geometrical
isomers. Thus, the initially formed radical apparently under-
goes a 1,6-hydrogen atom transfer to give 42 at about the
same rate as which it cyclizes. Fragmentation of 42 and
reduction of the resulting radical provides 41.
(17) For some relevant literature, see: Gorrichon, L.; Maroni, P.; Zedde,
C.; Dobrev, A. J. Organomet. Chem. 1983, 252, 267–274. Haener, R.;
Maetzke, T.; Seebach, D. Helv. Chim. Acta 1986, 69, 1655–65. Reichelt, I.;
Reissig, H. U. Chem. Ber. 1983, 116, 3895–914.
(14) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345–
1353. Kutsuma, T.; Nagayama, I.; Okazaki, T.; Sakamoto, T.; Akaboshi, S.
Heterocycles 1977, 8, 397.
(15) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
(16) Compounds 26 and 27 were characterized as a mixture. Manipula-
tion of this mixture provided compounds 26 (free of 27) as a mixture (see the
Supporting Information for details).
(18) Omission of the K2CO3 (acid sponge) resulted in formation of a large
number of products.
(19) Alcohol 40 was sensitive and was used in the subsequent free-radical
cyclization on the same day it was prepared.
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SCHEME 7
SCHEME 9
SCHEME 10
SCHEME 8
the C7 hydroxyl group provided TBS ether 45.20 Reduction
of the ester with lithium aluminum hydride gave alcohol 46 in
92% overall yield from 44. An Eschenmoser-Claisen rear-
rangement converted 46 to amide 47 in 76% yield with good
control of stereochemistry at C10.21 An unattractive feature
of this approach, however, is that it will require degradation
of a vinyl group to a methyl group at C10.
We also thought that vinylsilane 26 might be a useful
intermediate. For example, we were able to convert 26 into
cyclopentenone 48 using a two-step oxidation-isomeriza-
tion/desilylation sequence (Scheme 11).22,23 This intermedi-
ate is attractive because it might provide a handle for
establishing the C10 quaternary carbon, with the desired
methyl group in place, via conjugate addition chemistry.
A drawback to this approach, however, is that alcohol
stereochemistry at C7 would have to be reestablished at a
later stage of the synthesis.
This unwanted diversion led us to examine 43, prepared
from 39 as shown in Scheme 9. We knew that this electron-
deficient acetylene would be a better radical acceptor than
silyl acetylene 28 and anticipated that cyclization would
compete favorably with the aforementioned 1,6-H-atom
transfer. This proved to be the case as perhydroindan 44
was obtained in 60% overall yield from 39.
At this point, we had developed syntheses of at least two
compounds (26 and 44) that held some promise as inter-
mediates in projected approaches to the polyandranes. From
compound 44, we hoped that the endocyclic olefin and C7
hydroxyl group would provide handles for introduction of
the required C- and D-ring functionality. We also hoped the
unsaturated ester might serve as a handle for introduction of
the C10 furanone. One promising reaction sequence directed
toward the latter goal is shown in Scheme 10. Protection of
The unsatisfactory aspects of 26 and 44 as possible inter-
mediates in a total synthesis led us to explore another
(20) Stewart, Ray F.; Miller, Larry L. J. Am. Chem. Soc. 1980, 102, 4999–
5004. Corey, E. J.; Cho, H.; Ruecker, C.; Hua, D. H. Tetrahedron Lett. 1981,
22, 3455–3458.
(21) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta
1964, 47, 2425–2429.
(22) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(23) For an analogous isomerization-desilylation, see: Paquette, L. A.;
Wells, G. J.; Horn, K. A.; Yan, T.-H. Tetrahedron Lett. 1982, 23, 263–266.
J. Org. Chem. Vol. 74, No. 22, 2009 8729

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SCHEME 11
SCHEME 13
SCHEME 12
to controlling stereochemistry at C7 without the need for
chromatographic separation. Treatment of 49 with tri-n-
butyltin hydride gave the expected cyclization product 52
in 95% yield. Evidence supporting the assigned stereochem-
istry at C7 and C9 was obtained by a series of NOE experi-
ments that revealed the proximity of the C7 and C20
hydrogens and an absence of an interaction between the C7
and C9 hydrogens. A more direct proof of stereochemistry
was obtained by X-ray crystallography of the cyclization
product derived from the C7 isomer of 49.28
solution to the radical translocation problems described in
Schemes 1 and 2. The idea is described in Scheme 12. We
imagined that an allenic cyclization substrate such as 49
would provide allylic radical 50.24,25 Radical 50 is no longer
geometrically disposed to undergo a 1,6-hydrogen atom
transfer to provide 51, and we thought it would probably
simply be reduced to give perhydroindan 52. If this was the
case, one can imagine ways to use the cyclopentenol sub-
structure of 52 to introduce the C10 furanone. Even if radical
translocation were to occur, it seemed unlikely that 51 would
undergo a cyclization at an appreciable rate. The product of
Conclusions
In summary, this paper describes two solutions to pro-
blems encountered during the course of attempts to develop
a free-radical cyclization strategy for the synthesis of the
polyandranes. Although we would have preferred to foresee
the problems that were encountered (Schemes 1, 2, and 8),
this research demonstrates that logical solutions to these
problems could be developed. Although this will not always
be the case, we hope that our observations are helpful to
others as they develop their own radical cyclization strategies
to molecules of interest.
such
a cyclization would be a strained trans-fused
oxabicyclo[3.3.0]octane!26
Cyclization substrate 49 was prepared from aldehyde
53 by reaction with the borane derived from lithiated
1-trimethylsilylpropyne and 9-methoxy-9-BBN in the pre-
sence of boron trifluoride etherate (Scheme 13).27 This
reaction provided 49 in 51% yield along with 3% of the
corresponding C7-diastereomer. This reaction not only gave
the desired cyclization substrate but also provided a solution
Experimental Section
3-(1-Ethylcyclopropyl)methoxy-5-methyl-2,5-cyclohexadiene-
1,1-dimethanol (36). To a solution of 5.0 g (20.2 mmol) of ester 35
and 1.55 g (21.0 mmol) of tert-butyl alcohol in 50 mL of dry
THF at -78 °C under N2 was added 90 mL of liquid ammonia.
To the mixture was added 0.32 g (46.2 mmol) of lithium in small
pieces over a period of 30 min. The resulting dark blue solution
was stirred for 30 min, and the excess lithium was then destroyed
by addition of 0.1 mL of 1,3-pentadiene. To the resulting pale
yellow solution was added a solution of 4.91 g (20.2 mmol) of
freshly prepared iodomethyl pivalate29 in 20 mL of dry THF via
an addition funnel. The mixture was stirred for 2 h, and the
reaction was then quenched by addition of 2.4 g (45.3 mmol) of
solid NH4Cl. The ammonia was allowed to evaporate over 2 h
(24) For radical cyclizations in which allenes are the acceptor, see:
Apparu, M.; Crandall, J. K. J. Org. Chem. 1984, 49, 2125–2130. Hart, D.
J. Science 1984, 223, 883–887. Dener, J. M.; Hart, D. J. Tetrahedron 1988, 44,
7037–7046. For other relevant cyclizations, see: Roumestant, M. L.;
Arseniyadis, S.; Gore, J.; Laurent, A. J. Chem. Soc., Chem. Commun.
1976, 479–480. Pattenden, G.; Robertson, G. M. Tetrahedron Lett. 1983,
24, 4617–4620.
(25) It is also possible that the slow rate at which allylic radicals undergo
hydrogen atom transfer may also contribute to the success of this strategy.
For some relevant references, see: Hayes, C. J.; Burgess, D. R. Jr. J. Phys.
Chem. A 2009, 113, 2473–2482. DeZutter, C. B.; Horner, J. H.; Newcomb, M.
J. Phys. Chem. A 2008, 112, 1891–1896. Stork, G.; Reynolds, M. E. J. Am.
Chem. Soc. 1988, 110, 6911–6913.
(26) For strain in bicyclo[3.3.0]octanes, see: Barrett, J. W.; Linstead, R.
P. J. Chem. Soc. 1935, 436–442.
(27) Wang, K. K.; Liu, C. J. Org. Chem. 1985, 50, 2578–2580.
(28) Tri-n-butyltin hydride mediated cyclization of 7-epi-49 provided
7-epi-52 (mp 101-105 °C) in 63% yield. The structure of this compound
was established by X-ray crystallography.
(29) Prepared from commercially available chloromethyl pivalate using a
Finkelstein reaction (36 mmol of chloromethyl pivalate and 54 mmol of sodium
iodide in 40 mL of acetone at room temperature for 12 h) and used within 24 h:
Finkelstein, H. Chem. Ber. 1910, 43, 1528–1532.
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Yang et al.
JOCArticle
under N2. The mixture was filtered and concentrated in vacuo to
give 7.31 g of a pale yellow oil which showed one spot by TLC
(silica gel, hexanes-ethyl acetate, 2:1). The pale yellow oil was
used directly in the next reaction without further purification.
To a slurry of 1.6 g (42.0 mmol) of lithium aluminum hydride in
50 mL of diethyl ether cooled to -78 °C (dry ice-acetone bath)
was added a solution of 7.31 g (20.1 mmol) of the crude diester in
20 mL of diethyl ether over 20 min. The mixture was allowed to
stir at -78 °C for 5 h and then at room temperature for 16 h. The
mixture was cooled in an ice-water bath and quenched by slow
sequential addition of 1.6 mL of water, 1.6 mL of 15% aqueous
sodium hydroxide, and 4.8 mL of water over 2 h. The mixture
was stirred for another 6 h and filtered, and the filter cake was
rinsed with two 20-mL portions of diethyl ether. The filtrate was
dried (MgSO4), filtered, and concentrated in vacuo to give a
mixture of white solid and yellow oil from which 3.03 g (60%) of
diol 36 was separated via filtration as a white solid: mp 105-107
(t, J = 7.6 Hz, 3H, CH3), 1.54 (s, 3H, CH3), 1.59 (q, J = 7.6 Hz,
2H, CH2), 2.42 and 2.81 (ABq, J = 17.6 Hz, 2H, CH2C=), 3.36
and 3.53 (ABq, J = 8.8 Hz, 2H, CH2O), 3.62 and 3.76 (ABq,
J = 5.8 Hz, 2H, CH2O), 4.50 (s, 1H, CHBr), 5.77 (s, 1H, =CH),
9.18 (s, 1H, CHO); 13C NMR (C6D6, 100 MHz) δ 10.1 (t), 10.3
(t), 10.8 (q), 20.7 (s), 21.5 (q), 27.3 (t), 43.1 (t), 47.7 (d), 59.4 (s),
66.9 (t), 73.7 (t), 107.2 (s), 118.4 (d), 136.9 (s), 197.0 (d); exact
mass calcd for C15H2179BrO3 (M þ Na)þ m/z 351.0572, found
m/z 351.0579. This material exhibited signals due to impurities
in the NMR spectra (see the Supporting Information).
(1S,5S,8S)-rel-8-Bromo-5-(1-ethylcyclopropyl)methoxy-3-
methyl-1-[(2S)-2-oxiranyl]-6-oxabicyclo[3.2.1]oct-2-ene (39) and
(1S,5S,8S)-rel-8-Bromo-5-(1-ethylcyclopropyl)methoxy-3-
methyl-1-[(2R)-2-oxiranyl]-6-oxabicyclo[3.2.1]oct-2-ene (7-epi-
39). To a solution of 1.14 g (9.0 mmol) of dimethyl sulfate in
3 mL of acetonitrile was added a solution of 0.62 g (9.9 mmol)
of dimethyl sulfide in 2 mL of acetonitrile. After being stirred at
room temperature overnight, the mixture was cooled in an ice
bath, and 0.54 g (9.9 mmol) of sodium methoxide was added.
After 30 min, the mixture became a milky suspension. A solution
of 1.97 g (6.0 mmol) of aldehyde 38 in 5 mL of acetonitrile was
added dropwise. After being stirred for 30 min, the reaction
gradually turned dark green. The suspension was concentrated
in vacuo, and the residue was washed with 10 mL of water. The
aqueous phase was extracted with two 10-mL portions of
dichloromethane. The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
chromatographed over 30 g of silica gel (hexanes-ethyl acetate,
5:1) to afford 1.28 g of a 2:1 mixture of diastereomeric epoxides
39 and 7-epi-39 as a colorless oil. This material contained
starting aldehyde as an impurity. The oil was chromatographed
again using MPLC (hexanes-ethyl acetate, 20:1) to afford 0.53
g (26%) of epoxide 39 and 0.26 g (13%) of 7-epi-39 as colorless
°C; IR (in CHCl3) 3312, 2870, 1694, 1658 cm-1 1H NMR
;
(CD2Cl2, 500 MHz) δ 0.42 (m, 2H, CH2), 0.47 (m, 2H, CH2),
0.96 (t, J = 7.5 Hz, 3H, CH3), 1.48 (q, J = 7.5 Hz, 2H, CH2),
1.64 (t, J = 6.0 Hz, 2H, OH), 1.82 (s, 3H, CH3), 2.71 (s, 2H,
dCCH2), 3.47 (m, 4H, CH2OH), 3.58 (s, 2H, OCH2), 4.41 (s,
1H, OCdCH), 5.29 (s, 1H, CdCH); 13C NMR (CD2Cl2, 125
MHz) δ 9.7 (t), 10.44 (q), 20.4 (s), 22.5 (q), 27.3 (t), 34.1 (t), 47.6
(s), 68.8 (t), 71.9 (t), 93.1 (d), 121.9 (d), 134.6 (s), 156.4 (s); exact
mass calcd for C15H24O3 (M þ Na)þ m/z 275.1623, found
m/z 275.1630. Anal. Calcd for C15H24O3: C, 71.39; H, 9.59.
Found: C, 71.15; H, 9.80.
rel-(1R,5S,8S)-8-Bromo-5-(1-ethylcyclopropyl)methoxy-3-
methyl-6-oxabicyclo[3.2.1]oct-2-ene-1-methanol (37). To a solu-
tion of 1.5 g (6.0 mmol) of diol 36 in 22 mL of dry dichlor-
omethane at 0 °C (dry ice-acetone) was added 1.0 g (7.2 mmol)
of powdered potassium carbonate, followed by slow addition of
1.24 g (6.3 mmol) of solid N-bromosuccinimide over 5 min. The
solution was stirred for 5 min and then poured into 20 mL of
water. The aqueous phase was extracted with two 20-mL por-
tions of dichloromethane. The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo to afford a
solution of the alcohol 37 in 10 mL of dichloromethane which
was used immediately in the next step. Due to instability of pure
1
oils. Epoxide 39: IR 3072, 2875, 1665 cm-1; H NMR (C6D6,
500 MHz) δ 0.27 (m, 2H, CH2), 0.42 (m, 2H, CH2), 0.99 (t, J =
7.5 Hz, 3H, CH3), 1.44 (s, 3H, dCCH3), 1.48 (m, 2H, CH2CH3),
2.12 and 2.27 (m, 2H, oxirane-CH2), 2.34 and 2.77 (ABq, J =
18.0 Hz, 2H, CH2Cd), 2.67 (m, 1H, oxirane-CH), 3.25 and 3.45
(ABq, J = 9.0 Hz, 2H, CH2O), 3.61 and 3.66 (ABq, J = 7.0 Hz,
2H, CH2O), 4.45 (s, 1H, CHBr), 5.15 (s, 1H, dCH); 13C NMR
(C6D6, 125 MHz) δ 10.0 (t), 10.2 (t), 10.7 (q), 20.6 (s), 21.5 (q),
27.3 (t), 42.8 (t), 42.9 (t), 48.2 (s), 50.7 (d), 51.0 (d), 66.4 (t),
74.7 (t), 106.8 (s), 119.7 (d), 136.3 (s); exact mass calcd for
C16H2379BrO3 (M þ Na)þ m/z 365.0728, found m/z 365.0723.
1
alcohol in air or even when stored in solvents, only H NMR
spectral data were collected: 1H NMR (CD2Cl2, 400 MHz)
δ 0.39 (m, 2H, CH2), 0.43 (m, 2H, CH2), 0.96 (t, J = 7.2 Hz,
3H, CH3), 1.44 (q, J = 7.2 Hz, 2H, CH2), 1.75 (s, 3H, dCCH3),
2.32 and 2.68 (ABq, J = 17.2 Hz, 2H, CH2Cd), 2.42 (m, 1H,
OH), 3.37, 3.53 (ABq, J = 9.6 Hz, 2H, CH2O), 3.68 (m, 2H,
CH2OH), 3.86, 4.08 (ABq, J = 6.8 Hz, 2H, CH2O), 4.47 (s, 1H,
CHBr), 5.22 (s, 1H, dCH). An impurity (probably succinimide)
appeared as a singlet at δ 2.8 in the 1H NMR spectrum.
1
Epoxide 7-epi-39: IR (neat) 3073, 2875, 1664 cm-1; H NMR
(C6D6, 500 MHz) δ 0.33 (m, 2H, CH2), 0.47 (m, 2H, CH2), 1.02
(t, J = 7.2 Hz, 3H, CH3), 1.48 (s, 3H, CH3), 1.51 (q, J = 7.2 Hz,
2H, CH2CH3), 2.23 and 2.66 (m, 2H, oxirane-CH2), 2.38 and
2.81 (ABq, J = 17.6 Hz, 2H, CH2Cd), 2.59 (m, 1H, oxirane-
CH), 3.30 and 3.49 (ABq, J = 8.8 Hz, 2H, CH2O), 3.72 (s, 2H,
CH2O), 4.26 (s, 1H, CHBr), 5.19 (s, 1H, dCH); 13C NMR
(C6D6, 125 MHz) δ 10.0 (t), 10.2 (t), 10.7 (q), 20.6 (s), 21.4 (q),
27.3 (t), 43.1 (t), 43.2 (t), 47.7 (s), 49.6 (d), 51.8 (d), 66.5 (t), 75.3
(t), 107.1 (s), 121.8 (d), 135.8 (s); exact mass calcd for
C16H2379BrO3 (M þ Na)þ m/z 365.0728, found m/z 365.0723.
This material contained trace impurities by NMR.
Ethyl (5R)-rel-5-[(1S,5S,8S)-8-Bromo-5-(1-ethylcyclopropyl)-
methoxy-3-methyl-6-oxabicyclo[3.2.1]oct-2-en-1-yl]-2-pentynoate
(43). To a solution of 1.1 g (11.2 mmol, 1.14 mL) of ethyl
propiolate in 20 mL of freshly distilled THF, cooled to -85 °C
(ethyl acetate-liquid nitrogen), was added 4.48 mL (11.2 mmol)
of 2.5 M n-butyllithium in hexanes, and the mixture was stirred
for 10 min. To the solution was added 1.5 mL (1.6 g, 11.2 mmol)
of boron trifluoride etherate via a syringe followed by stirring
for 5 min. A solution of 960 mg (2.8 mmol) of epoxide 39 in 5 mL
of dry tetrahydrofuran was then added via a syringe, followed by
1 mL of tetrahydrofuran rinse. The mixture was stirred for 3 h at
-85 °C. The temperature was warmed to room temperature,
rel-(1S,5S,8S)-8-Bromo-5-(1-ethylcyclopropyl)methoxy-3-
methyl-6-oxabicyclo[3.2.1]oct-2-ene-1-carboxaldehyde (38). To a
solution of 1.22 g (9.6 mmol, 0.82 mL) of oxalyl chloride in
30 mL of dry dichloromethane at -78 °C (dry ice-acetone) was
added a solution of 1.5 g (19.2 mmol, 1.36 mL) of dry dimethyl
sulfoxide by syringe over 2 min. The solution was stirred cold for
30 min, and a solution of 1.98 g (6.0 mmol) of alcohol 37
(material from previous reaction) in 10 mL of dry dichloro-
methane was added by cannula over 10 min. The solution was
stirred cold for 2 h, and 3.9 g (30 mmol, 5.0 mL) of diisopropy-
lethylamine was added via a syringe. The mixture was stirred
cold for 30 min and then warmed to room temperature. The
mixture was poured into 50 mL of dichloromethane in an ice
bath and then washed with three 50-mL portions of 4% aqueous
NH4Cl and 10 mL of saturated aqueous NaHCO3. The organic
phase was dried (MgSO4), filtered, and concentrated in vacuo to
afford 1.97 g of aldehyde 38 as a brown oil that was sufficiently
pure for the next reaction: IR 3072, 2730, 1730 cm-1; 1H NMR
(C6D6, 400 MHz) δ 0.41 (m, 2H, CH2), 0.55 (m, 2H, CH2), 1.11
J. Org. Chem. Vol. 74, No. 22, 2009 8731

Yang et al.
JOCArticle
and then 5 mL of saturated aqueous NaHCO3 was added to
quench the reaction. The aqueous phase was extracted with two
20-mL portions of ether. The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo to give a
colorless oil. The oil was immediately chromatographed over
30 g of silica gel (hexanes-ethyl acetate, 10:1), and the resulting
43 was concentrated as a solution in 20 mL of degassed benzene
and immediately used in the next step. Due to instability of pure
alcohol in air, only NMR spectral data were collected: 1H NMR
(C6D6, 500 MHz) δ 0.25 (m, 2H, CH2), 0.42 (m, 2H, CH2), 0.89
(t, J = 7.0 Hz, 3H, CH3), 0.99 (t, J = 7.5 Hz, 3H, CH3), 1.45
(s, 3H, dCCH3), 1.48 (m, 2H, CH2CH3), 1.76 (dd, J = 17.0, 9.0
Hz, 1H, CH2CHOH), 1.83 (d, J = 5.0 Hz, 1H, OH), 2.10 (dd,
J = 17.0, 2.5 Hz, 1H, CH2CHOH), 2.37 and 2.77 (ABq, J =
17.5 Hz, 2H, dCCH2), 3.33 and 3.52 (ABq, J = 9.0 Hz, 2H,
OCH2), 3.52 (m, 1H, CHOH), 3.61 and 3.96 (ABq, J = 6.5 Hz,
2H, OCH2), 3.92 (q, J = 7.0 Hz, 2H, OCH2CH3), 4.63 (s, 1H,
CHBr), 4.84 (s, 1H, dCH); 13C NMR (C6D6, 125 MHz) δ 10.0
(t), 10.2 (t), 10.7 (q), 13.6 (q), 20.6 (s), 21.6 (q), 22.8 (t), 27.3 (t),
43.2 (t), 50.3 (d), 51.8 (s), 61.4 (t), 66.4 (t), 68.4 (d), 72.7 (t), 75.5
(s), 85.4 (s), 106.5 (s), 121.1 (d), 136.6 (s), 153.2 (s).
1.22 g (4.2 mmol) of tri-n-butylstannane and 115 mg (0.70
mmol) of azo-bis-isobutyronitrile in 10 mL of dry, degassed
benzene over a period of 1 h. The mixture was warmed under
reflux for 1 h and then concentrated in vacuo. The residual crude
oil was purified by chromatography over 30 g of silica gel
(hexanes-ethyl acetate, 5:1) to afford 608 mg (60% from
epoxide 39) of 44 as a colorless oil: IR (neat) 3477, 2966, 1713,
1658 cm-1; 1H NMR (C6D6, 500 MHz) δ 0.94 (t, J = 7.5 Hz, 3H,
CH3), 0.98 (t, J = 7.0 Hz, 3H, CH3), 1.02 (m, 1H, OH), 1.18
(t, J = 7.5 Hz, 3H, CH3), 1.42 (s, 3H, dCCH3), 1.91 (q, J =
7.5 Hz, 2H, CH2CH3), 2.31 (m, 2H, CH2CH3), 2.31 and 2.58
(ABq, J = 17.0 Hz, 2H, dCCH2), 3.04 (s, 1H, CH), 3.08 (dd,
J = 20.5, 2.5 Hz, 1H, CH2CHOH), 3.57 (m, 1H, CH2CHOH),
3.37 and 3.54 (ABq, J = 7.5 Hz, 2H, OCH2), 3.56 (m, 1H,
CHOH), 4.05 (q, J = 7.5 Hz, 2H, OCH2CH3), 5.62 (s, 1H,
dCH), 6.49 (s, 1H, dCHOR), 6.88 (m, 1H, dCHCO2Et); 13C
NMR (C6D6, 125 MHz) δ 12.7 (q), 13.0 (q), 14.0 (q), 20.6 (t),
21.5 (q), 24.7 (t), 43.5 (t), 47.0 (t), 55.9 (d), 58.4 (s), 59.3 (t), 70.4
(d), 77.4 (t), 110.4 (s), 117.8 (d), 124.1 (s), 126.3 (d), 133.1 (d),
134.7 (s), 158.4 (s), 166.3 (s); exact mass calcd for C21H30O5
(M þ Na)þ m/z 385.1991, found m/z 385.1990.
rel-(1E,3R,3aS,7R,7aR)-7-(2-Ethyl-1-butenyloxy)-1,2,3,6,7,7a-
hexahydro-1,5-dimethyl-1-[(carbethoxy)methylene]-7,3a-(epoxy-
methano)-3aH-inden-3-ol (44). To a solution of 1.23 g (2.8 mmol)
of 43 in 130 mL of dry, degassed benzene at 105 °C was added
Supporting Information Available: Experimental proce-
dures and NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
8732 J. Org. Chem. Vol. 74, No. 22, 2009