Preparation of a cis-isoprostane synthon

Full text of DOI:10.1021/jo000565d

5436
J . Org. Chem. 2000, 65, 5436-5439
P r ep a r a tion of a cis-Isop r osta n e Syn th on
Douglass F. Taber,* J ohn H. Green, Wei Zhang, and
Renhua Song
Department of Chemistry and Biochemistry,
University of Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received April 10, 2000
In tr od u ction
Based on previous analyses,5,6 we hypothesized that
the two most likely competing transition states for
rhodium-mediated cyclization of diazo ester 5 would be
6 and 7. In the transition states depicted, the Rh catalyst
is equatorial on the forming ring.
Isoprostanes, a new family of eicosanoids, were dis-
covered in humans in 1990.1 They are generated in vivo
independent of the cyclooxygenase enzymes by free-
radical mediated oxidation of arachidonic acid. While the
physiological importance of the isoprostanes is still under
investigation, it has already been demonstrated that
endogenously produced isoprostanes are responsible for
the kidney failure and subsequent death associated with
oxidative liver disease.2 Both trans- and cis-isoprostanes,
exemplified by 12-F2t-isoprostane (1) and 12-F2c-isopros-
tane (2) are formed in vivo. While stereodivergent routes
to the trans3 isoprostanes have been described, the routes
described to the cis isoprostanes4 have largely relied on
enantiomerically pure percursors. The isoprostanes are
formed in vivo in racemic form, and studies of their
physiological activity will require the preparation of both
enantiomers. We have therefore developed a route to the
diastereomerically pure, but racemic, cis synthon 4, as a
general precursor to the cis isoprostanes.
To prepare the diazoester 5, we coupled7 cinnamyl
chloride with propargyl alcohol, then hydrogenated8 the
resulting alkyne 8 to give diene 9, as shown in Scheme
1. Epoxidation of the diene with tert-butyl hydroperoxide
and vanadylacetylacetonate gave the epoxide 10. The
opening of 10 with lithioacetonitrile showed remarkable
selectivity for addition at the 2-position, leading to the
1,3-diol.9,10 Protection of the 1,3-diol with 2,2-dimeth-
oxypropane gave the acetonide 11. Ozonolysis of the
(1) (a) Morrow, J . D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Bodr,
K. F.; Roberts, L. J ., II. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383.
(b) Morrow, J . D.; Awad, J . A.; Kato, T.; Takahashi, K.; Badr, K. F.;
Roberts, L. J ., II; Burk, R. F. J . Clin. Invest. 1992, 90, 2502. (c) Morrow,
J . D.; Awad, J . A.; Boss, H. J .; Blair, J . A.; Roberts, L. J ., II. Proc.
Natl. Acad. Sci. U.S.A. 1992, 89, 10721. (d) Morrow, J . D.; Minton, T.
A.; Mukundan, C. R.; Campell, M. D.; Zackert, W. E.; Daniel, V. C.;
Badr, K. F.; Blair, I. A.; Roberts, L. J ., II. J . Biol. Chem. 1994, 269,
4317. (c) For an introduction to the nomenclature of the isoprostanes,
see Taber, D. F.; Morrow, J . D. J ackson, R., II. Prostaglandings 1997,
53, 63.
(2) (a) Banerjee, M.; Kang, K. H.; Morrow, J . D.; Roberts, J . D., II;
Newman, J . H. Am. J . Physiol. (Heart Circ. Physiol. 32) 1992, 263,
H660. (b) Morrow, J . D.; Moore, K. P.; Awad, J . A.; Ravenscraft, M.
D.; Marini, G.; Badr, K. F.; Williams, R.; Roberts, L. J ., II. J . Lipid
Mediators 1993, 6, 417.
(3) For leading references to syntheses of the trans isoprostanes,
see: (a) Corey, E. J .; Shih, C.; Shih, N.-Y.; Shimoji, K. Tetrahedron
Lett. 1984, 25, 5013. (b) Taber, D. F.; Hoerrner, R. S. J . Org. Chem.
1992, 57, 441. (c) Hwang, S. W.; Adiyaman, M.; Khanapure, S.; Schio,
L.; Rokach, J . J . Am. Chem. Soc. 1994, 116, 10829. (d) Adiyaman, M.;
Lawson, J . A.; Hwang, S.-W.; Khanapure, S. P.; FitzGerald, G. A.;
Rokach, J . Tetrahedron Lett. 1996, 37, 4849. (e) Taber, D. F.; Herr, R.
J .; Gleave, D. M. J . Org. Chem. 1997, 62, 194. (f) Adiyaman, M.; Li,
H.; Lawson, J . A.; Hwang, S.-W.; Khanapure, S. P.; FitzGerald, G. A.;
Rokach, J . Tetrahedron Lett. 1997, 38, 3339. (g) Rokach, J .; Khanapure,
S. P.; Hwang, S.-W.; Adiyaman, M.; Schio, L.; FitzGerald, G. A.
Synthesis 1998, 569. (h) Taber, D. F.; Kanai, K. Tetrahedron 1998, 54
11767. Pudukulathan, Z.; Manna, S.; Hwang, S.-W.; Khanapure, S.
P.; Lawson, J . A.; FitzGerald, G. A.; Rokach, J . J . Am. Chem. Soc. 1998,
120, 11953. (j) Taber, D. F., Kanai, K.; Pina, R. J . Am. Chem. Soc.
1999, 121, 7773.
(4) For leading references to syntheses of the cis isoprostanes, see:
(a) Larock, R. C.; Lee, N. H. J . Am. Chem. Soc. 1991, 113, 7815. (b)
Vionnet, J .-P.; Renaud, P. Helv. Chim. Acta 1994, 77, 1781. (c) Hwang,
S. W.; Adiyaman, M.; Khanapure, S. P.; Rokach, J . Tetrahedron Lett.
1996, 37, 779. (d) Hwang, S. W.; Adiyaman, M.; Lawson, J . A.;
FitzGerald, G. A.; Rokach, J . Tetrahedron Lett. 1999, 40, 6167. (e) Lai,
S.; Lee, D.; U, J . S.; Cha, J . K. J . Org. Chem. 1999, 64, 7213.
(5) (a) For a general review of rhodium mediated C-H insertion see
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; J ohn Wiley & Sons: New
York, 1998. For leading references to more recent studies of selectivity
in Rh-mediated C-H insertion, see (b) Davies, H. M. L.; Hansen, T.;
Rutberg, J .; Bruzinski, P. R. Tetrahedron Lett. 1997, 38, 1741. (c)
Taber, D. F.; Malcolm, S. C. J . Org. Chem. 1998, 63, 3717. (d) Wang,
J .; Liang, F.; Chen, B. J . Org. Chem. 1998, 63, 8589. (e) Anada, M.;
Hashimoto, S.-I. Tetrahedron Lett. 1998, 39, 79. (f) Kablean, S. N.;
Marsden, S. P.; Craig, A. M. Tetrahedron Lett. 1998, 39, 5109. (g) Buck,
R. T.; Coe, D. M.; Drysdale, M. J .; Moody, C. J .; Pearson, N. D.
Tetrahedron Lett. 1998, 39, 7181. (h) Anderson, J .-A. M.; Karodia, M.;
Miller, D. J .; Stones, D.; Gani, D. Tetrahedron Lett. 1998, 39, 7815. (i)
Yakuri, T.; Ueki, A.; Kitamura, T.; Tanaka, K.; Nameki, M.; Ikeda,
M. Tetrahedron 1999, 55, 7461. (j) Anada, M.; Kitagaki, S.; Hashimoto,
S. Heterocycles 2000, 52, 875. (k) Wee, A. G. H.; Yu, Q. Tetrahedron
Lett. 2000, 41, 587.
(6) Structural optimizations were carried out using Mechanics as
provided on the Oxford Scientific CAChe Workstation. CAChe uses
an augmented version of Allinger’s MM2 force field.
(7) (a) Bumagin, N. A.; Ponomarev, A. B.; Beletskaya, I. P. Bull.
Acad. Sci. USSR, Div. Chem. Sci. 1987, 36, 1445. (b) Colonge, J .;
Falcotet, R. Bull. Soc. Chim. Fr. 1957, 1166.
(8) (a) Brown, C. A.; Ahuja, V. K. J . Org. Chem. 1973, 38, 2226. (b)
Brown, C. A.; Ahuja, V. K.; Martin, J . C. J . Am. Chem. Soc. 1991, 113,
7277.
10.1021/jo000565d CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/22/2000

Notes
J . Org. Chem., Vol. 65, No. 17, 2000 5437
Ta ble 1. Resu lts of Cycliza tion of Dia zoester 5
Sch em e 1
entry
Rh cat
reaction temp (°C) yield (%) ratio (3/4)
1
2
3
4
5
6
7
8
9
Rh2(piv)4
Rh2(piv)4
Rh2(oct)4
Rh2(oct)4
Rh2 (OAc)4
Rh2(TFA)4
Rh2(MEPY)4
Rh2(TPA)4
Rh2(TPA)4
-78
rt
-78
rt
rt
rt
60
rt
-78
87
90
90
80
83
74
77
91
87
1:1.2
1.2:1
2.6:1
2.8:1
3:1
6.4:1
4.3:1
1:6.5
1:6.8
the two alkyl substuents on the cyclopentane ring were
cis one to another. The lack of an NOE between H3 and
H4 suggested that the benzyloxy group was exo on the
bicyclic system. This was confirmed by an NOE of 3.2%
between H1 and H5, and an NOE of 2.6% between H4 and
H6. In ester 4, the NOE's between NOE between H1 and
H2 and between H2 and H3 demonstrated the same
stereochemical relationship as ester 3. The relative
configuration of the benzyloxy group was confirmed by
an NOE of 3.5% between H3 and H4.
The nearly one-to-one ratio of 3 to 4 was surprising,
given the expected steric preference for cyclization to 3.14
We hypothesized that the competing transition state in
which the benzyloxy group is axial (7) might be electroni-
cally preferred, the improved overlap of the nonbonding
electrons on the oxygen with the target C- -H bond
making the latter more reactive toward the electrophilic
Rh carbene. We further hypothesized that with rhodium
pivalate, the steric and electronic factors were just
balanced, so 3 and 4 were formed in nearly equal
amounts.
We reasoned that if such were the case, then rhodium
complexes that gave more reactive carbenes might show
improved selectivity in the reaction. J ust the opposite
effect has usually been observed,14 with more reactive
rhodium carbenes showing poorer diastereoselectivity.
Indeed (Table 1), rhodium catalysts that are known15 to
give more reactive (and, usually, less selective) carbenes
in fact show increased selectivity in the cyclization of 5.
The cyclization yields dropped off slightly with those
catalysts that gave the most reactive carbenes, as with
those catalysts products from â-H elimination16 were
formed also. Reaction temperature had a modest influ-
ence on the diastereoselectivity of the cyclization. Al-
though the Doyle rhodium carboxamide catalysts5b,g have
sometimes been found to be stereochemically comple-
styrene double bond of 16 followed by reduction led to
the alcohol 12, which was benzylated to give the ether
13. Hydrolysis followed by esterification11 then gave the
ester 14.
Diazo transfer was accomplished by a combination of
our procedure12 with that of Danheiser.13 Thus, the ester
enolate was first added to trifluoroethyl trifluoroacetate,
then the crude trifluoroacetylated product was reacted
with DBU and p-nitrobenzenesulfonyl azide to give the
diazo ester 5. We have found that this modified procedure
works more efficiently with sterically congested esters
than the benzoylation method we had previously re-
ported.12
In the event, cyclization of 5 with catalytic Rh(II)
pivalate (CH2Cl2, rt) gave the diastereomeric esters 3 and
4 in a ratio of 1.2:1. The relative configurations of 3 and
4 were assigned by COSY and NOE experiments. In ester
3, a 3.7% NOE between H1 and H2 confirmed the cis ring
fusion. The 3.8% NOE between H2 and H3 demonstrated
(9) (a) Matsuda, I.; Murata, S.; Izumi, Y. J . Org. Chem. 1980, 45,
237. (b) Bartlett, P. A.; Ting, P. C. J . Org. Chem. 1986, 51, 2230. (c)
Zhou, S.-Z.; Anne, S.; Vandewalle, M. Tetrahedron Lett. 1996, 37, 7637.
(d) Taber, D. F.; Kong, S. J . Org. Chem. 1997, 62, 8575 (e) Tius, M. A.;
Fauq, A. H. J . Org. Chem. 1983, 48, 4131.
(10) The 1,2-diol was less than 10% of the total product. We were
not able to isolate it.
(11) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Williard, P. G.; Zutter, U. J . Am. Chem. Soc.
1986, 108, 1039.
(12) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
(13) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z.
J . Org. Chem. 1990, 55, 1959. (b) A recently reported preparation of
diazoacetates relies on a similar approach: Sato, H.; Kim, Y. S.;
Shibasaki, M. Tetrahedron Lett. 1999, 40, 2973.
(14) Taber, D. F.; Song, Y. J . Org. Chem. 1996, 61, 6706.
(15) Doyle has also observed a preference for the cis diastereomer
from Rh-mediated C-H insertion R to an ether: Doyle, M. P.; Kalinin,
A. V. Tetrahedron Lett. 1996, 37, 1371.
(16) (a) Taber, D. F.; Hennessy, M. J .; Louey, J . P. J . Org. Chem.
1992, 57, 436. (b) Taber, D. F.; Malcolm, S. C. J . Org. Chem. 1998, 63,
3717.

5438 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
52%) as a pale yellow oil: TLC Rf (40% MTBE/petroleum
ether) ) 0.20; 1H NMR δ 2.17 (bs, 1H), 2.36-2.64 (m, 2H), 3.15-
3.26 (m, 2H), 3.76 (dd, J ) 6.4 Hz, 12.2 Hz, 1H), 3.91 (dd, J )
4.0 Hz,12.2 Hz, 1H), 6.22 (dt, J ) 15.9 Hz, 6.8 Hz, 1H), 6.51 (d,
J ) 15.9 Hz, 1H), 7.18-7.42 (m, 5H); 13C NMR δ u 137.0, 60.7,
mentary to the rhodium carboxylates, Rh2[(5R)-MEPY]4
also showed a marked preference for the trans diastere-
omer.
Reasoning that rhodium pivalate, the most sterically
demanding of the rhodium carboxylates employed, had
given the highest fraction of cis product, we then tried
the cyclization with the even more sterically demanding
rhodium triphenylacetate.17 We were delighted to observe
that with this catalyst, the all-cis 3 was the dominant
product from the cyclization. Again, lower reaction tem-
perature modestly improved the diastereoselectivity of
the cyclization.
In 9, we have found a diazo ester in which steric and
electronic demands are very closely balanced. By tuning
the electronic demands of the intermediate Rh carbenes,
we can make either 3 or 4 the preferred product from
the cyclization. It is especially noteworthy that in this
system, rhodium complexes that give more reactive
intermediate carbenes show improved diastereoselectivity
in the cyclization. We expect that 4 will be a useful
synthon for the preparation of the cis isoprostanes.
31.7; d 132.5, 128.5, 127.4, 126.1, 124.6, 56.7, 56.1; IR (cm-1
)
3408, 1449, 1039, 967; MS m/z 190 (58), 159 (31), 129 (82), 117
(100); HRMS calcd for C12H14O2 190.0994, obsd 190.1001.
Nitr ile 11. To n-butyllithium (2.32 M in THF, 3.10 mL) in
THF (8.60 mL) was added acetonitrile (0.41 mL, 7.76 mmol)
dropwise over 10 min at -78 °C. After 1 h, the mixture was
warmed to 0 °C, and the epoxide 10 (0.53 g, 2.87 mmol) in THF
(3.40 mL) was added quickly. After 3 h, the mixture was
partitioned between saturated aqueous NH4Cl and MTBE. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was dissolved in 2,2-dimethoxypropane (8.78 mL,
71.40 mmol) and p-toluenesulfonic acid monohydrate (0.20 g,
1.05 mmol) was added. After 12 h at RT, the mixture was
partitioned between aqueous NaHCO3 and MTBE. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 11 (0.53 g, 1.95 mmol, 71%)
as a pale yellow oil: TLC Rf (20% MTBE/petroleum ether) )
0.32; 1H NMR δ 1.40 (s, 3H), 1.45 (s, 3H), 1.76-1.82 (m, 1H),
2.16-2.28 (m, 1H), 2.36-2.56 (m, 3H), 2.82 (dd, J ) 10.1 Hz,
16.9 Hz, 1H), 3.95 (d, J ) 1.5 Hz, 1H), 4.06-4.16 (m, 2H), 6.11
(ddd, J ) 6.1, 8.1, 15.8 Hz, 1H), 6.48 (d, J ) 15.8 Hz, 1H), 7.19-
7.37 (m, 5H); 13C NMR δ u 136.9, 119.3, 99.3, 63.3, 36.1, 13.4; d
Exp er im en ta l Section 18
133.0, 128.5, 127.4, 126.0, 124.2, 70.3, 34.1, 29.5, 18.7; IR (cm-1
)
Alk yn e 8. To propargyl alcohol (0.50 g, 8.95 mmol) and
cinnamyl chloride (1.64 g, 10.7 mmol) in acetone (30 mL) was
added potassium carbonate (2.48 g, 17.9 mmol), sodium iodide
(2.68 g, 17.9 mmol), copper iodide (1.71 g, 8.95 mmol) and
heptane (1.31 mL). After 48 h at rt, the mixture was partitioned
between saturated aqueous NH4Cl and MTBE. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 8 (1.30 g, 7.55 mmol, 84%)
as a pale yellow oil: TLC Rf (20% MTBE/petroleum ether) )
0.19; 1H NMR δ 2.26 (s, 1H), 3.12-3.17 (m, 2H), 4.30 (t, J ) 2.0
Hz, 2H), 6.14 (dt, J ) 15.7 Hz, 5.7 Hz, 1H), 6.61 (d, J ) 15.7 Hz,
1H), 7.18-7.37 (m, 5H); 13C NMR δ u 136.8, 82.9, 80.6; 51.1,
22.2; d 131.3, 128.4, 127.3, 126.1, 123.8; IR (cm-1) 3346, 1495,
1448, 1416, 1135, 1010, 965, 732, 692; MS m/z 172 (87), 154 (68),
153 (100), 141 (83); HRMS calcd for C12H14O 172.0888, obsd
172.0888.
2244, 1382, 1198, 1163, 1081; MS m/z 256 (12), 155 (18), 154
(100); HRMS calcd for C17H21NO2 271.1572, obsd 271.1571.
Alcoh ol 12. The acetonide 11 (0.48 g, 1.77 mmol) was
dissolved in CH2Cl2 (5.5 mL) and methanol (11.0 mL). Ozone
was bubbled through for 30 min at -78°C. After excess ozone
was purged with N2, sodium borohydride (0.13 g, 3.55 mmol)
was added. After 3 h at rt, the solvent was evaporated and the
residue was partitioned between MTBE and, sequentially,
saturated aqueous NH4Cl and saturated brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 12 (0.27 g, 1.36 mmol, 77%)
1
as a pale yellow oil: TLC Rf (15% acetone/CH2Cl2) ) 0.33; H
NMR δ 1.38 (s, 3H), 1.48 (s, 3H), 1.55-1.81 (m, 3H), 2.49-2.58
(m, 2H), 2.80 (dd, J ) 9.8 Hz, 17.0 Hz, 1H), 3.71 (t, J ) 5.0 Hz,
2H), 3.90 (dd, J ) 1.5 Hz, 12.4 Hz, 1H), 4.14 (dd, J ) 1.5 Hz,
12.4 Hz, 1H), 4.26-4.32 (m, 1H); 13C NMR δ u 119.4, 99.2, 63.2,
59.4, 35.0, 13.6; d 68.8, 34.8, 29.4, 18.7; IR (cm-1) 3470, 2245,
1383, 1198, 1078; MS m/z 184 (100), 110 (26), 94 (65); HRMS
calcd for C10H17NO3 (M + H+) 200.1287, obsd 200.1287. Anal.
Calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Obsd: C, 60.37;
H, 8.65; N, 7.09.
Dien e 9. To nickel(II) acetate tetrahydrate (0.29 g, 1.17 mmol)
in methanol (10.0 mL) was added sodium borohydride (0.07 g,
1.83 mmol). The resulting black solution was evacuated, then
maintained under an H2 atmosphere. Ethylenediamine (0.65
mL) and 8 (1.26 g, 7.32 mmol) in a little methanol were added
quickly. The reaction flask was evacuated, then maintained
under an H2 atmosphere. After 24 h, the solvent was evaporated
and the residue was partitioned between MTBE and, sequen-
tially, saturated aqueous NH4Cl and saturated brine. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to give 9 (1.06 g, 6.07 mmol,
83%) as a pale yellow oil: TLC Rf (20% MTBE/petroleum
Eth er 13. Sodium hydride (60% in mineral oil, 82.0 mg, 2.06
mmol) was added to benzyl bromide (0.18 mL, 1.51 mmol) in
THF (0.7 mL). After 5 min, alcohol 12 (0.27 g, 1.36 mmol) in
THF (6.0 mL) was added dropwise over 10 min. After 24 h at
rt, the mixture was partitioned between saturated aqueous NH4-
Cl and MTBE. The combined organic extract was dried (Na2-
SO4) and concentrated. The residue was chromatographed to give
13 (0.32 g, 1.11 mmol, 82%) as a pale yellow oil, TLC Rf (40%
MTBE/petroleum ether) ) 0.40; 1H NMR δ 1.36 (s, 3H), 1.42 (s,
3H), 1.63-1.76 (m, 3H), 2.48 (dd, J ) 4.7 Hz, 16.8 Hz , 1H),
2.76 (dd, J ) 10.1 Hz, 16.8 Hz, 1H), 3.53 (t, J ) 5.9 Hz, 2H),
3.90 (d, J ) 12.3 Hz, 1H), 4.10 (d, J ) 12.3 Hz, 1H), 4.25 (dt,
J ) 2.1, 6.6 Hz, 1H), 4.48 (d, J ) 2.5 Hz, 2H), 7.26-7.39 (m,
5H); 13C NMR δ u 138.1, 119.5, 99.3, 73.2, 65.8, 63.3, 33.1, 13.7;
d 128.4, 127.7, 127.7, 67.4, 34.9, 29.6, 18.8; IR (cm-1) 2244, 1382,
1198, 1084, 699; MS m/z 274 (100), 154 (34), 107 (29), 105 (96);
HRMS for C17H23NO3 calcd 289.1665, obsd 289.1668. Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Obsd: C, 70.91; H,
8.02; N, 4.93.
Ester 14. A mixture of the nitrile 13 (2.13 g, 7.35 mmol),
ethylene glycol (5.6 mL), water (9.3 mL), methanol (17.8 mL)
and sodium hydroxide (2.73 g, 68.3 mmol) was heated and
methanol was distilled off until the temperature of the mixture
reached 110 °C. The mixture was then maintained at reflux
(bath)110 °C) until no ammonia emission could be detected with
moist pH paper. The mixture was cooled to rt, and DMF (54.3
mL) and methyl iodide (7.3 mL, 117.5 mmol) were added. After
12 h at RT, the mixture was partitioned between water and
1
ether) ) 0.17; H NMR δ 1.54 (s, 1H), 3.00 (t, J ) 6.4 Hz, 2H),
4.26 (d, J ) 4.3 Hz, 2H), 5.58-5.78 (m, 2H), 6.18 (dt, J ) 15.9
Hz, 6.4 Hz, 1H) 6.40 (d, J ) 15.9 Hz, 1H), 7.16-7.39 (m, 5H);
13C NMR δ u 137.4, 58.5, 30.8; d 130.5, 129.8, 129.7, 128.5, 128.0,
127.1, 126.0; IR (cm-1) 3334, 1494, 1448, 1016, 965, 741, 692;
MS m/z 156 (100), 141 (30), 128 (48), 115 (54); HRMS calcd for
C12H14O 174.1045, obsd 174.1037.
Ep oxid e 10. Vanadyl acetylacetonate (57.2 mg, 0.22 mmol)
was added to diene 9 (1.50 g, 8.61 mmol) in CH2Cl2 (12.6 mL)
at -78 °C. After 30 min, tert-butyl hydroperoxide (5.8 mL of 3.74
M in CH2Cl2 21.6 mmol) was added dropwise over 10 min. After
24 h at rt, the mixture was partitioned between MTBE and,
sequentially, 1 N aqueous NaOH and saturated brine. The
combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to give 10 (0.85 g, 4.47 mmol,
(17) For the preparation and applications of rhodium triphenyl-
acetate, see Hashimoto, S.-I.; Watanabe, N.; Ikegami, S. J . Chem. Soc.,
Chem. Commun. 1992, 1508.
(18) For general experimental procedures, see Taber, D. F.; Meagley,
R. P.; Doren, D. J . J . Org. Chem. 1996, 61, 5723.

Notes
J . Org. Chem., Vol. 65, No. 17, 2000 5439
MTBE. The combined organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to give 14 (1.85
g, 5.74 mmol, 78%) as a pale yellow oil: TLC Rf (20% MTBE/
petroleum ether) ) 0.33; 1H NMR δ 1.36 (s, 3H), 1.42 (s, 3H),
1.63-1.72 (m, 2H), 1.84-1.89 (m, 1H), 2.48 (dd, J ) 4.1 Hz, 16.7
Hz, 1H), 2.73 (dd, J ) 9.4 Hz, 16.7 Hz, 1H), 3.48-3.64 (m, 2H),
3.66 (s, 3H), 3.74 (dd, J ) 1.0 Hz, 12.0 Hz, 1H), 4.03-4.08 (m,
1H), 4.19-4.25 (m, 1H), 4.48 (d, J ) 3.2 Hz, 2H), 7.25-7.38 (m,
5H); 13C NMR δ u 173.9, 138.3, 98.8, 73.0, 66.2, 64.3, 33.1, 29.4;
d 128.3, 127.6, 127.5, 68.0, 51.5, 34.0, 29.6, 19.0; IR (cm-1) 1738,
1382, 1197, 1169, 1090, 738, 699; MS m/z 323 (7), 266 (16), 265
(100), 235 (5), 157 (44); HRMS for C18H26O5 calcd 323.1858, obsd
323.1867. Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Obsd: C,
67.26; H, 8.05.
Dia zoester 5. To lithium bis(trimethylsilyl) amide (0.57 g,
3.41 mmol) in THF (3.5 mL) at -78 °C was added ester 14 (0.26
g, 0.81 mmol) in THF (1.9 mL) dropwise over 5 min. After 40
min, the mixture was warmed to -40 °C, and 2,2,2-trifluoroethyl
trifluoroacetate (0.15 mL, 1.13 mmol) was added quickly. After
18 h at RT, the mixture was partitioned between saturated NH4-
Cl and MTBE. The combined organic extract was dried (Na2-
SO4) and concentrated. The residue was dissolved in CH2Cl2 (2.5
mL) at 0 °C and DBU was added in the dark. After 10 min,
p-nitrobenzenesulfonyl azide (0.48 g, 2.43 mmol) was added.
After 36 h at RT, the mixture was partitioned between MTBE
and 1N aqueous NaOH. The combined organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed
to give 5 (0.22 g, 0.63 mmol, 78%) as a bright yellow oil: TLC
Rf (20% MTBE/petroleum ether) ) 0.30; 1H NMR δ 1.31 (s, 3H),
1.46 (s, 3H), 1.74-1.82 (m, 2H), 2.35 (d, J ) 1.2 Hz, 1H), 3.49-
3.63 (m, 2H), 3.74 (s, 3H), 3.94 (dd, J ) 1.4, 11.8 Hz, 1H), 4.27
(dd, J ) 2.6, 11.8 Hz, 1H), 4.33-4.39 (m, 1H), 4.48 (d, J ) 4.1
Hz, 2H), 7.25-7.38 (m, 5H); 13C NMR δ u 138.3, 99.3, 73.0, 65.7,
65.3, 33.7; d 128.3, 127.6, 127.5, 68.3, 51.9, 33.2, 28.4, 18.6; IR
(cm-1) 2089, 1694, 1437, 1230, 1097, 743, 699; MS m/z 321 (25),
264 (16), 263 (100), 231 (6), 171 (6), 155 (23); HRMS for
Cyclop en ta n e 3 a n d 4. To diazoester 5 (83.8 mg, 0.24 mmol)
in CH2Cl2 (1.5 mL) was added rhodium pivalate (1.4 mg, 0.002
mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. After 20 min at
rt, the solvent was evaporated and the residue was chromato-
graphed to give 3 (37.4 mg, 0.12 mmol, 49%) and 4 (32.1 mg,
0.10 mmol, 42%) as pale yellow oils. For 3: TLC Rf (25% MTBE/
petroleum ether) ) 0.32; 1H NMR δ 1.26 (s, 3H), 1.38 (s, 3H),
1.72-1.85 (m, 1H), 2.30 (dd, J ) 6.8 Hz, 13.6 Hz, 1H), 2.48 (m,
1H), 2.92 (dd, J ) 5.3, 11.1 Hz, 1H), 3.71 (s, 3H), 3.91 (d, J )
4.4 Hz, 2H), 4.34 (t, J ) 4.3 Hz, 1H), 4.51 (dd, J ) 11.8, 12.4
Hz, 2H), 4.81-4.89 (m, 1H), 7.25-7.37 (m, 5H); 13C NMR δ u
173.4, 138.3, 98.1, 72.1, 58.2, 39.6, d 128.3, 127.7, 127.6, 81.6,
71.1, 51.8, 50.3, 40.2, 27.9, 20.1; IR (cm-1) 1737, 1372, 1199,
1174, 1060, 738, 699; MS m/z 305 (20), 171 (20), 156 (100), 137
(40); HRMS for C18H24O5 calcd 320.1624, obsd 320.1625.
For 4: TLC Rf (25% MTBE/petroleum ether) ) 0.27; 1H NMR
δ 1.30 (s, 3H), 1.36 (s, 3H), 1.89-2.00 (m, 1H), 2.66-2.35 (m,
1H), 2.64-2.78 (m, 1H), 2.95 (dd, J ) 4.8, 9.0 Hz, 1H), 3.67 (s,
3H), 3.91-4.07 (m, 2H), 4.20 (dt, J ) 3.5, 4.6 Hz, 1H), 4.37 (dt,
J ) 2.0, 7.2 Hz, 1H), 4.46 (d, J ) 11.9 Hz, 1H), 4.63 (d, J ) 11.9
Hz, 1H), 7.23-7.38 (m, 5H); 13C NMR δ u 170.7, 138.6, 98.9,
70.8, 59.2, 36.8, d 128.1, 127.3, 127.3, 80.1, 70.4, 51.4, 51.0, 41.3,
26.0, 23.5; IR (cm-1) 1740, 1379, 1222, 870, 737, 698; MS m/z
305 (54), 156 (100), 125 (30); HRMS for C18H24O5 calcd 320.1624,
obsd 320.1628.
Ack n ow led gm en t. We thank M. D. Bruch for NMR
spectra and G. R. Nicol for mass spectra. We also thank
M. P. Doyle for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
C
18H24N2O5 calcd 349.1763, obsd 349.1782.
J O000565D