Diastereoselective Rh-mediated construction of 2,3,5-trisubstituted tetrahydrofurans

Article abstract of DOI:10.1021/jo960758u

Dirhodium(II) carboxylate catalyzed cyclization of a series of γ-alkoxy-α-diazo esters 1 has been shown to proceed with substantial diastereoselectivity, producing the 2,3,5-trisubstituted tetrahydrofurans 2 and 3. The diastereoselectivity of the cyclizat

Full text of DOI:10.1021/jo960758u

6706
J . Org. Chem. 1996, 61, 6706-6712
Dia ster eoselective Rh -Med ia ted Con str u ction of
2,3,5-Tr isu bstitu ted Tetr a h yd r ofu r a n s
Douglass F. Taber* and Ying Song
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received April 25, 1996X
Dirhodium(II) carboxylate catalyzed cyclization of a series of γ-alkoxy-R-diazo esters 1 has been
shown to proceed with substantial diastereoselectivity, producing the 2,3,5-trisubstituted tetrahy-
drofurans 2 and 3. The diastereoselectivity of the cyclization improved as the electron-withdrawing
ability of the substituent R increased. A mechanistic hypothesis is presented.
We recently reported1 that Rh-mediated cyclization2-4
of 1 (R ) CH3) proceeded with high diastereoselectivety,
to give predominantly 2. We describe here a detailed
study of the scope of this cyclization. It is particularly
noteworthy that the diastereoselectivity of the cyclization
is a function of the electron-withdrawing ability of the
substituent R.
Sch em e 1
We have presented5,6 a computational model that
accurately predicts the dominant diastereomer from the
Rh-mediated cyclizations of simple R-diazo esters (e.g.,
4 f 5). Applying this model to the cyclization of 1
target C-H bond. There are four diastereomeric chair-
like transition states (12) for the cyclization of 1, each
leading to one of the four possible diastereomeric prod-
ucts. With the positions of the ligands on Rh locked and
the angles and bonds defined as before,5 we minimized
each of the four transition states with molecular mechan-
ics. The transition state 12 in which both substituents
are equatorial on the “chair” was found to be 3.5 kcal/
mol lower in energy then the next most stable transition
state. Consequently, we predicted that 2 should be the
dominant product from the cyclization of 1.
(Scheme 1), the point of commitment to a particular
diastereomer is represented by transition state 12, in
which there is overlap between the CdRh bond and the
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Taber, D. F.; Song, Y. Tetrahedron Lett. 1995, 36, 2587.
(2) (a) Galatsis, P.; Millan, S. D.; Nechala, P.; Ferguson, G. J . Org.
Chem. 1994, 59, 6643. (b) Hopkins, M. H.; Overman, L. E; Rishton, G.
M. J . Am. Chem. Soc. 1991, 113, 5354. (c) Brown, M. J .; Harrison, T.;
Herrinton, P. M.; Hopkins, M. H.; Hutchinson, K. D.; Mishra, P.;
Overman, L. E. J . Am. Chem. Soc. 1991, 113, 5365. (d) Brown, M. J .;
Harrison, T.; Overman, L. E. J . Am. Chem. Soc. 1991, 113, 5378. (e)
Iqbal, J .; Pandey, A.; Chauhan, B. P. S.; Tetrahedron 1991, 47, 4143.
(f) Hosokawa, T.; Nakajima, F.; Iwasa, S.; Murahashi, S. I. Chem. Lett.
1990, 1387. (g) Kozikowski, A.; Lin, G. Q.; Springer, J . P. Tetrahedron
Lett. 1987, 28, 2211. (h) Overman, L. E.; Hopkins, M. H.; J . Am. Chem.
Soc. 1987, 109, 4748.
(3) For leading references to Rh-mediated intramolecular C-H
insertions see: (a) Taber, D. F. Methods of Organic Chemistry (Houben-
Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E.,
Eds.; Georg Thieme Verlag: Stuttgart, 1995; p 1127. (b) Padwa, A.;
Austin, D. J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1797. (c)
McKervey, M. A.; Ye, T. Chem. Rev. 1994, 94, 1091. (d) Doyle, M. P.;
Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; van Basten,
A.; Mu¨ller, P.; Polleux, P. J . Am. Chem. Soc. 1994, 116, 4507. (e) Wang,
P.; Adams, J . J . Am. Chem. Soc. 1994, 16, 3296. (f) Doyle, M. P. In
Homogeneous Transition Metal Catalysts in Organic Synthesis; Moser,
W. R., Slocum, D. W., Eds.; ACS Advanced Chemistry Series 230;
American Chemical Society: Washington, DC, 1992; Chapter 30. (g)
Taber, D. F. Comprehensive Organic Synthesis; Pattenden, G., Ed.;
Pergamon Press: Oxford, 1991; Vol. 3, p 1045.
(4) (a) For the first observation of the efficient cyclization of simple
R-diazo esters, see: Taber, D. F.; Hennessy, M. J .; Louey, J . P. J . Org.
Chem. 1992, 57, 436. (b) For a detailed account of regioselectivity and
diastereoselectivity in the Rh-mediated cyclization of R-diazo-â-keto
esters, see: Taber, D. F.; Ruckle, R. E., J r. J . Am. Chem. Soc. 1986,
108, 7686.
(5) (a) For the first report of the highly diastereocontrolled cycliza-
tion of a substituted R-diazo ester, see: Taber, D. F.; You, K. K. J .
Am. Chem. Soc. 1995, 117, 5757. (b) For a computational model that
rationalizes the diastereoselectivity of intramolecular Rh-mediated
C-H insertion, see: Taber, D. F.; You, K. K.; Rheingold, A. L. J . Am.
Chem. Soc. 1996, 118, 547.
(6) For related analyses of transition states for Rh carbene inser-
tions, see: (a) Doyle, M. P.; Westrum, L. J .; Wolthius, W. N. E.; See,
M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J . Am. Chem. Soc.
1993, 115, 958. (b) Brown, K. C.; Kodadek, T. J . Am. Chem. Soc. 1992,
114, 8336. (c) Pirrung, M. C.; Morehead, A. T., J r. J . Am. Chem. Soc.
1994, 116, 8991. (d) Davies, H. M. L.; Huby, N. J . S.; Cantrell, W. R.,
J r.; Olive, J . L. J . Am. Chem. Soc. 1993, 115, 9468.
S0022-3263(96)00758-X CCC: $12.00 © 1996 American Chemical Society

Construction of 2,3,5-Trisubstituted Tetrahydrofurans
J . Org. Chem., Vol. 61, No. 19, 1996 6707
Ta ble 1. Dia ster eoselectivity in th e Cycliza tion of
Sch em e 3
r-Dia zo Ester s 1
entry
R
yield, % (2 + 3)
ratio (2/3)
1
2
3
4
5
6
7
8
9
1a : 4-MeOPh
1b: Ph
89
92
93
94
94
93
92
93
92
89
1.7:1 (2a :3a )
3:1 (2b:3b)
3.1:1 (2c:3c)
3.2:1 (2d :3d )
3:1 (2e:3e)
3.3:1 (2f:3f)
3.4:1 (2g:3g)
4 :1 (2h :3h )
8:1 (2i:3i)
1c: 4-BrPh
1d : 4-NO2Ph
1e: CHdCH2
1f: CH2CH3
1g: CH2CH2OMe
1h : CH3
Diazo transfer was then effected directly by treating 16d
with NaHMDS and PNBSA.14b
Catalytic rhodium octanoate in CH2Cl2 at room tem-
perature smoothly cyclized 1a -j to mixtures of 2a -j and
3a -j (Table 1). No â-H elimination product4 was de-
tected in any of these cyclizations. This may be due to
the inductively electron-withdrawing γ-alkoxy group,16
which makes the â-H less electron rich.
1i: CH2OMe
1j: CH2OPh
10
11.4:1 (2j:3j)
Sch em e 2
As two new stereogenic centers are created in the
cyclization of 1, four diastereomeric products are possible.
However, in general only two diastereomers were ob-
served.17 The major diastereomer was the 2,3-trans-3,5-
trans trisubstituted tetrahydrofuran 2, and the minor
diastereomer was the 2,3-cis-3,5-cis trisubstituted tet-
rahydrofuran 3, as demonstrated by NOE experiments.
As shown in Figure 1, irradiation of H1 in 2e gave a 6.5%
enhancement of H2b and irradiation of H3 in 2e gave a
3.9% enhancement of H2a. For the minor diastereomer,
irradiation of H1 in 3e gave a 2.0% enhancement of H3
and H4. The irradiation of H3 in 3e gave a 5.8%
enhancement of H4.
The diastereoselectivity observed for the cyclization of
1b and 1e was lower than that which we had observed
in cyclopentane-forming cyclizations.5 Even more strik-
ing, the minor diastereomer observed was the least likely
from the analysis in Scheme 1 (both substituents axial
in the chairlike transition state leading to cyclization).
This observation led us to an intriguing hypothesis. The
computational analysis5 that we employ does not distin-
guish between “chair” transition states such as 12 and
Resu lts a n d Discu ssion
The γ-alkoxy-R-diazo esters 1a -1j (Table 1) were
generally prepared from 1,2-epoxy-3-phenoxypropane
(14) (Scheme 2). The epoxide was opened with allylmag-
nesium bromide, and the resultant secondary alcohol was
alkylated with an alkyl halide to give the phenyl ethers
15. Ozonolysis in CH2Cl2 following the procedure of
Marshall7,8 gave the γ-alkoxy esters 16. Diazo trans-
fer10,11 was then effected by benzoylation12 of the esters
16 followed by exposure to DBU13 and 4-nitrobenzene-
sulfonyl azide (PNBSA).14
The γ-alkoxy-R-diazo ester 1d was prepared by a
different route, because the 4-nitrobenzyl group is readily
decomposed by NaH and by NaOH. As shown in Scheme
3, the secondary alcohol from the opening of the expoxide
was alkylated with Ag2O15 and 4-nitrobenzyl bromide to
give phenyl ether 15d . Selective ozonolysis of 15d in
CH2Cl2 followed by reduction with PPh3 gave the alde-
hyde. This phenoxy aldehyde was further oxidized with
PDC10 in DMF and MeOH to give the γ-alkoxy ester 16d .
“boat” transition states such as 17. Empirically, the
products observed in the all-carbon case were derived
from chair transition states, suggesting an electronic
preference for a chairlike transition state. We recognized
that the C-H insertion site adjacent to oxygen was
particularly electron rich and thus more reactive than
the C-H of a simple alkyl group.3e Thus, the point of
commitment to bond formation might be occurring earlier
on the reaction coordinate, when the chair preference
might not be as pronounced. We therefore hypothesized
(7) Marshall, J . A.; Garofalo, A. W. J . Org. Chem. 1993, 58, 3675.
(8) Substrate 15b was ozonized to the aldehyde (O3/CH2Cl2, Ph3P),
which was then oxidized to the methyl ester (PDC/MeOH).10
(9) O’Connor, B.; J ust, G. Tetrahedron Lett. 1987, 28, 3235.
(10) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
(11) (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and
Synthesis; Academic Press: Orlando, 1986. (b) Askani, R.; Taber, D.
F. Comprehensive Organic Synthesis; Winterfeldt, E., Ed.; Pergamon:
Oxford, 1991; Vol. 6, p 103.
(12) Metcalf, B. W.; J und, K.; Burkhart, J . P. Tetrahedron Lett. 1980,
21, 15.
(13) (13) For the use of DBU in diazo transfer, see: (a) Baum, J . S.;
Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987,
17(14), 1709. (b) Koteswar Rao, Y.; Nagarajan, M. J . Org. Chem. 1989,
54, 5678.
(14) (14) (a) Reagan, M. T.; Nickon, A. J . Am. Chem. Soc. 1968, 90,
4096. (b) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J .
Am. Chem. Soc. 1990, 112, 4011.
(15) (15) Fukase, K.; Tanaka, H,; Torii, S.; Kusumoto, S. Tetrahedron
Lett. 1990, 31, 389.
(16) (a) Hennessy, M. J . Ph.D Thesis, University of Delaware, 1989.
(b) Stork, G.; Nakatani, K. Tetrahedron Lett. 1988, 29, 2283.
(17) For R ) 4-MeOPh, all four diasteromers are observed, in a ratio
of 56:33:4:4.

6708 J . Org. Chem., Vol. 61, No. 19, 1996
Taber and Song
It is apparent that both steric and electronic effects
can contribute to diastereoselectivity in Rh-mediated
intramolecular C-H insertion. We expect that the family
of diazo esters 1 and their derivatives will become very
useful probes for the study of electronic effects in these
Rh-mediated cyclizations.3 The work described here also
opens the way for the highly diastereocontrolled con-
struction of 2,3,5-trisubstituted tetrahydrofurans.
F igu r e 1. NOE of tetrahydrofuans 2e and 3e
Exp er im en ta l Section 20
that the diastereoselectivity of the cyclization might
improve if the reactivity of the target C-H were attenu-
ated by an electron-withdrawing substituent.16
Meth yl 2-Dia zo-4-((4-m eth oxyp h en yl)m eth oxy)-5-p h e-
n oxyp en ta n oa te (1a ). At 0 °C, NaH (185 mg, 4.62 mmol,
60% in mineral) was added to 16a (0.53 g, 1.54 mmol) in 4
mL of dry THF. After 10 min at 0 °C, methyl benzoate (422
mg, 3.1 mmol) was added all at once; then the reaction mixture
was heated to reflux for 10 h. The reaction was cooled and
quenched by cautiously adding 1 N aqueous HCl, to pH ) 4.
The mixture was partitioned between 20% EtOAc/petroleum
ether and, sequentially, 1 N aqueous HCl and saturated
aqueous NaCl. The combined organic extract was dried (Na2-
SO4), concentrated, and chromatographed to give methyl 2-
ben zoyl-4-((4-m et h oxyph en yl)m et h oxy)-5-ph en oxypen -
tanoate (0.533 g, yield 77%).
Two sets of experiments are summarized in Table 1: a
substituted benzyl series and a substituted ethyl series.
In the substituted benzyl series, when the substituent R
was the strongly electron-donating 4-methoxyphenyl
group (entry 1), the ratio of the two major diastereomers
was only 1.7:1, and all four of the possible diastereomers
were observed.17 When the substituent R was phenyl,
only two diastereomers were observed, with the ratio of
major to minor increasing to 3:1. When the substituents
were electron-withdrawing, 4-bromophenyl and 4-nitro-
phenyl (entries 3 and 4), the diastereoselectivity in-
creased slightly, to 3.1:1 and 3.2:1, respectively. This
experimental result agrees well with the rate of solvolysis
of substituted benzylic halides.18 As reported,19 the
solvolysis rate of 4-methoxybenzyl bromide (18b) is 160
times faster than that of benzyl bromide (18a ), whereas
the solvolyses of the 4-bromobenzyl and 4-nitrobenzyl
bromides 18c and 18d , are only slightly slower than that
of benzyl bromide (18a ) (0.67 and 0.35, respectively).
DBU (468 mg, 3.08 mmol) was added to a solution of methyl
2-ben zoyl-4-((4-m et h oxyph en yl)m et h oxy)-4-ph en oxypen -
tanoate (0.69 g, 1.54 mmol) in 4 mL of CH2Cl2 at 0 °C. After
10 min, 702 mg of 4-nitrobenzenesulfonyl azide (3.08 mmol)
was added. The reaction mixture was warmed up to rt for 2
h; then the mixture was partitioned between 6 mL of 0.5 M
aqueous phosphate buffer (pH ) 7.0) and CH2Cl2. The
combined organic extract was dried (Na2SO4), concentrated,
and chromatographed to give 1a (490 mg, 66% yield from 16a )
as a bright yellow oil: TLC Rf(20% EtOAc/petroleum ether) )
1
0.38; H NMR δ 7.23 (m, 4H), 6.85 (m, 5H), 4.66 (d, 1H, J )
11.3 Hz), 4.55 (d, 1H, J ) 11.3 Hz), 4.01 (m, 2H), 3.93 (m, 1H),
3.78 (s, 3H), 3.70 (s, 3H), 2.66 (dd, 1H, J ) 4.5, 15.4 Hz), 2.56
(dd, 1H, J ) 7.1, 15.4 Hz); 13C NMR δ u, 167.7, 159.3, 158.5,
130.0, 72.0, 69.2, 26.5; d, 129.5, 129.4, 121.0, 114.5, 113.8, 75.6,
55.2, 51.8; IR cm-1 2952, 2089, 1693, 1600, 1514, 1497, 1438,
1344, 1248, 1134, 1036, 821, 755, 692.
Meth yl 2-Dia zo-4-(4-p h en ylm eth oxy)-5-p h en oxyp en -
ta n oa te (1b). The procedure described for 1a was employed.
The overall yield was 77%. 1b: TLC Rf(20% EtOAc/petroleum
1
ether) ) 0.40; H NMR δ 7.28 (m, 7 H), 6.95 (m, 3H), 4.73 (d,
J ) 11.7 Hz, 1H), 4.62 (d, J ) 11.7 Hz, 1H), 4.03 (m, 2H), 3.97
(m, 1H,), 3.70 (s, 3H), 2.68 (dd, J ) 4.6, 15.4 Hz, 1H), 2.56
(dd, J ) 4.6, 16.4 Hz, 1H); 13C NMR δ u,158.3, 137.9, 72.2,
68.9, 26.3; d, 129.3, 128.2, 127.7, 127.5, 120.9, 114.3, 75.9, 51.6;
IR cm-1 2089, 1694, 1599, 1497, 1437, 1346, 1245, 1133, 754,
693.
Met h yl 2-Dia zo-4-((4-b r om op h en yl)m et h oxy)-5-p h e-
n oxyp en ta n oa te (1c). The procedure described for 1a was
employed. The overall yield was 72%. 1c: TLC Rf(20%
EtOAc/petroleum ether) ) 0.51; 1H NMR δ 7.44 (m, 2H), 7.29
(m, 2H), 7.25 (m, 2H), 6.96 (m, 3H), 4.68 (d, 1H, J ) 11.9 Hz),
4.57 (d, 1H, J ) 11.9 Hz), 4.04 (d, 2H, J ) 5.1 Hz), 3.94 (m,
1H), 3.71 (s, 3H), 2.68 (dd, 1H, J ) 4.6, 15.3 Hz), 2.58 (dd, 1H,
J ) 7.2, 15.3 Hz); 13C NMR δ u, 158.4, 136.9, 121.6, 71.6, 69.2,
26.5; d, 131.4, 129.5, 129.4, 121.1, 114.5, 76.2, 51.9; IR cm-1
2925, 2088, 1694, 1600, 1496, 1437, 1344, 1244, 1137, 1011,
805, 755, 692.
Meth yl 2-Dia zo-4-((4-n itr op h en yl)m eth oxy)-5-p h en ox-
yp en ta n oa te (1d ). NaHMDS (1.1 mL, 1 N in THF) was
added to a solution of 16d (186 mg) in 6 mL of dry THF at
-78 °C. The mixture was stirred at -78 °C for 20 min and
the warmed up to 0 °C for 10 min. After the mixture was
cooled again to -78 °C, PNBSA (236 mg) was added all at once.
The mixture was stirred at -78 °C for 1 h, and then 0.5 M
aqueous phosphate buffer (pH ) 7.0) was added. The mixture
was warmed up to rt; then partitioned between the aqueous
layer and EtOAc. The combined organic extract was dried
In the substituted ethyl series (Table 1), the electron-
withdrawing effect on the diastereoselectivity of C-H
insertion is more pronounced. Comparing the substitu-
ents (R) vinyl and ethyl (entries 5 and 6), the diastereo-
selectivity ratio increased only slightly from 3:1 to 3.3:1.
The influence of the â-methoxy group is stronger, with
the ratio increasing to 8:1 (entry 9).18 The â-phenoxy
group, still more strongly electron-withdrawing, gave a
ratio of 11.4:1.
These two series of experiments strongly support the
hypothesis that the diastereoselectivity of the cyclization
improves if the reactivity of the target C-H is attenuated
by an electron-withdrawing substituent. To further
probe this hypothesis, we cyclized 1f with rhodium
trifluoroacetate, a catalyst that is known to make a very
reactive carbene,6c with a very early (and thus open)
transition state. In fact, exposure of 1f to rhodium
trifluroacetate gave an approximately equal mixture of
all four of the product diastereomers.
(18) Such remote substituent effects are well-known for nucleophilic
displacement reactions: (a) Shaik S. S. J . Am. Chem. Soc. 1983, 105,
4395. (b) Streitwieser, A., J r. Solvolytic Displacement Reactions;
McGraw-Hill: New York, 1962; pp 15-17.
(19) (19) (a) Baker, J . W. J . Chem. Soc. 1932, 2631. (b) Baker, J .
W. J . Chem. Soc. 1933, 1128. (c) Baker, J . W. J . Chem. Soc. 1936,
1448.
(20) (20) Taber, D. F.; Houze, J . B. J . Org. Chem. 1994, 59, 4004.

Construction of 2,3,5-Trisubstituted Tetrahydrofurans
J . Org. Chem., Vol. 61, No. 19, 1996 6709
(Na2SO4), concentrated, and chromatographed to give 1d (62
mg, 36% yield) as a bright yellow oil: TLC Rf(30% EtOAc/
petroleum ether) ) 0.43; 1H NMR δ 8.20 (m, 2H), 7.51 (m, 2H),
7.27 (m, 2H), 6.90 (m, 3H), 4.88 (d, 1H, J ) 12.9 Hz), 4.76 (d,
1H, J ) 12.9 Hz), 4.09 (m, 2H), 4.02 (m, 1H), 3.74 (s, 3H),
2.69 (m, 2H); 13C NMR δ u, 172.4, 158.5, 146.0, 71.2, 69.3, 26.5;
d,129.6, 127.9, 123.6, 121.3, 114.5, 77.2, 52.3; IR cm-1 2088,
1734, 1693, 1600, 1521, 1496, 1437, 1244, 1188, 1086.
Meth yl 2-Diazo-4-(2-pr open yloxy)-5-ph en oxypen tan oate
(1e). The procedure described for 1a was employed. The
overall yield was 64%. 1e: TLC Rf(20% EtOAc/petroleum
ether) ) 0.50; 1H NMR δ 7.28 (m, 2H), 6.92 (m, 3H), 5.89 (m,
1H), 5.21 (m, 2H), 4.21 (dd, J ) 5.6, 12.6 Hz, 1H), 4.09 (dd, J
) 5.6, 12.6 Hz, 1H), 4.00 (m, 2H), 3.92 (m, 1H), 3.75 (s, 3H),
2.69 (dd, J ) 4.7, 5.3 Hz, 1H), 2.59 (dd, J ) 4.7, 5.3 Hz. 1H);
13C NMR δ u,158.5, 117.4, 71.4, 69.0, 26.4; d, 134.4, 129.4,
121.0, 114.5, 76.4, 51.9; IR cm-1 2088, 1691, 1599, 1496, 1437,
1345, 1244, 1131, 755.
9.9 Hz), 4.10 (dd, 1H, J ) 2.5, 9.9 Hz), 3.77 (s, 3H), 3.68 (s,
3H), 3.11 (q, 1H, J ) 8.0 Hz), 2.51 (m, 1H), 2.35 (m, 1H); 13C
NMR δ u, 173.4, 159.4, 158.8, 132.4, 69.8, 33.0; d, 129.4, 127.4,
120.9, 114.5, 113.8, 83.9, 77.1, 55.2, 51.9; IR cm-1 2952, 1732,
1600, 1514, 1455, 1366, 1302, 1248, 1173, 1035, 830, 755, 692;
MS (m/z, relative intensity) 342 (8), 311 (1), 282 (5), 249 (12),
203 (73), 175 (28), 147 (48), 135 (100), 121 (85); HRMS calcd
for C20H22O5 342.1467, obsd 342.474. 3a : TLC Rf(20% EtOAc/
petroleum ether) ) 0.31; 1H NMR δ 7.30 (m, 4H), 7.00 (m, 3H),
6.84 (m, 2H), 5.20 (d, 1H, J ) 8.3 Hz), 4.44 (m, 1H), 4.35 (dd,
1H, J ) 6.0, 9.5 Hz), 4.23 (dd, 1H, J ) 4.3, 9.5 Hz), 3.76 (s,
3H), 3.42 (q, 1H, J ) 8.3 Hz), 3.21 (s, 3H), 2.36 (m, 2H); 13C
NMR δ u, 172.3, 159.2, 158.8, 130.4, 69.8, 31.4; d, 129.4, 127.7,
120.9, 114.6, 113.3, 82.6, 77.5, 55.2, 51.3, 49.9; IR cm-1 2950,
1732, 1600, 1514, 1496, 1456, 1378, 1302, 1248, 1173, 1097,
1036, 840, 757; MS (m/z, relative intensity) 342 (52), 282 (12),
249 (27), 203 (100), 175 (22), 147 (27), 135 (59), 121 (51); HRMS
calcd for C20H22O5 342.1467, obsd 342.1450.
Met h yl 2-Dia zo-4-(p r op yloxy)-5-p h en oxyp en t a n oa t e
(1f). The procedure described for 1a was employed. The
overall yield was 74%. 1f: TLC Rf(20% EtOAc/petroleum
ether) ) 0.35; 1H NMR δ 7.16 (m, 2H), 6.82 (m, 3H), 3.88 (m,
2H), 3.69 (m,1H), 3.62 (s, 3H), 3.50 (m, 1H), 3.38 (m, 1H), 2.57
(dd, J ) 4.4, 15.3 Hz, 1H), 2.44 (dd, J ) 4.4, 15.3 Hz, 1H),
1.46 (m, 2H), 0.81 (t, J ) 7.3 Hz, 3H); 13C NMR δ u, 167.6,
158.4, 72.0, 68.8, 26.2, 23.0; d, 129.2, 120.8, 114.4, 76.9, 51.6,
10.2; IR cm-1 2960, 2088, 1694, 1600, 1497, 1437, 1342, 1245,
1133, 997, 814, 754.
Meth yl 2-Dia zo-4-((3-m eth oxyp r op yl)oxy)-5-p h en oxy-
p en ta n oa te (1g). The procedure described for 1a was em-
ployed. The overall yield was 73%. 1a : TLC Rf(20% EtOAc/
petroleum ether) ) 0.45; 1H NMR δ 7.28 (m, 2H), 6.94 (m, 3H),
4.00 (d, J ) 4.8 Hz, 2H), 3.77 (m, 2H), 3.75 (s, 3H), 3.62 (m,
1H), 3.44 (t, J ) 6.3 Hz, 2H), 3.31 (s, 3H), 2.64 (m, 2H), 1.83
(t, J ) 6.2 Hz, 2H); 13C NMR δ u, 158.8, 69.3, 68.8, 67.3, 30.2,
26.3; d, 129.4, 121.0, 114.5, 77.2, 58.5, 51.8; IR cm-1 2924,
2088, 1694, 1600, 1496, 1436, 1345, 1245, 1121.
Met h yl 2-Dia zo-4-et h oxy-5-p h en oxyp en t a n oa t e (1h ).
The procedure described for 1a was employed. The overall
yield was 72%. 1h : TLC Rf(20% EtOAc/petroleum ether) )
0.50; 1H NMR δ 7.2 (m, 2H), 6.85 (m, 3H), 3.9 (m, 2H), 3.8 (m,
2H), 3.7 (s, 3H), 3.6 (m, 1H), 2.6 (dd, J ) 4.7, 15.3 Hz, 1H),
2.49 (dd, J ) 4.7, 15.3 Hz, 1H), 1.12 (t, J ) 7.0 Hz, 3H); 13C
NMR δ u,158.5, 69.0, 69.5, 26.3; d, 129.4, 121.0, 114.5, 76.9,
51.9, 15.4.
Meth yl 2-Dia zo-(2-m eth oxyeth oxy)-5-p h en oxyp en ta n -
oa te (1i). The procedure described for 1a was employed. The
overall yield was 73%. 1i: TLC Rf(20% EtOAc/petroleum
ether) ) 0.35; 1H NMR δ 7.24 (m, 2H), 6.92 (m, 3H), 4.01 (m,
2H), 3.86 (m, 2H), 3.73 (s, 3H), 3.70 (m, 1H), 3.67 (m, 2H),
3.34 (s, 3H), 2.67 (dd, J ) 4.6, 5.3 Hz, 1H), 2.56 (dd, J ) 4.6,
5.3 Hz, 1H); 13C NMR δ u, 167.6, 158.3, 72.0, 69.8, 68.9, 26.1;
d, 129.2, 120.8, 114.3, 77.6, 58.7, 51.6; IR cm-1 2927, 2086,
1600, 1498, 1439, 1344, 1246, 2235, 1042.
Meth yl (R*,S*,R*)-2-P h en yl-5-(p h en oxym eth yl)-2,3,4,5-
t et r a h yd r o-3-fu r a n ca r b oxyla t e
(2b ) a n d
Met h yl
(R*,R*,R*)-2-P h en yl-5-(p h en oxym eth yl)-2,3,4,5-tetr a h y-
d r o-3-fu r a n ca r boxyla te (3b). The procedure described for
2a and 3a was employed. 2b: TLC Rf(20% EtOAc/petroleum
1
ether) ) 0.35; H NMR δ 7.31 (m, 7H), 6.96 (m, 3H), 5.12 (d,
J ) 7.9 Hz, 1H), 4.56 (m, 1H), 4.12 (m, 2H), 3.67 (s, 3H), 3.12
(m, 1H), 2.49 (m, 1H), 2.30 (m, 1H) ; 13C NMR δ u, 173.3, 158.7,
140.5, 69.6, 32.9; d, 129.4, 128.3, 127.8, 126.0, 120.9, 114.5,
84.0, 77.3, 51.9; IR cm-1 2951, 1734, 1599, 1497, 1455, 1364,
1245, 1172; MS (m/z, relative intensity) 312 (29), 263 (2), 252
(4), 219 (21), 205 (12), 190 (9), 187 (18), 173 (100), 159 (12),
145 (52), 131 (13), 117 (79), 115 (65); HRMS calcd for C19H20O4
312.1362, obsd 312.1361. 3b: TLC Rf(20% EtOAc/petroleum
1
ether) ) 0.30; H NMR δ 7.27 (m, 7H), 6.96 (m, 3H), 5.22 (d,
J ) 8.2 Hz, 1H), 4.44 (m, 1H), 4.39 (m, 1H), 4.26 (m, 1H), 3.45
(dd, J ) 8.2, 15.4 Hz, 1H), 3.14 (s, 3H), 2.33 (m, 2H); 13C NMR
δ u, 172.2, 158.7, 138.1, 69.7, 31.3; d, 129.4, 128.3, 127.8, 126.3,
126.0, 120.8, 114.5, 82.8, 77.6, 51.2, 49.9; IR cm-1 2948, 1735,
1600, 1497, 1456, 1245, 1171, 1036, 753; MS (m/z, relative
intensity) 312 (4), 252 (1), 219 (75), 187 (16), 173 (100), 159
(10), 117 (78), 105 (54); HRMS calcd for C19H20O4 312.1362,
obsd 312.1371.
Meth yl (R*,S*,R*)-2-P h en yl-5-((4-br om op h en yl)m eth -
oxy)-2,3,4,5-tetr ah ydr o-3-fu r an car boxylate (2c) an d Meth -
yl (R*,R*,R*)-2-P h en yl-5-((4-b r om op h en yl)m et h oxy)-
2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (3c). The procedure
described for 2a and 3a was employed. 2c: TLC Rf(20%
EtOAc/petroleum ether) ) 0.48; 1H NMR δ 7.45 (m, 2H), 7.30
(m, 4H), 6.97 (m, 3H), 5.06 (d, 1H, J ) 7.3 Hz), 4.57 (m, 1H),
4.16 (dd, 1H, J ) 3.9, 10.2 Hz), 4.08 (dd, 1H, J ) 4.3, 10.2
Hz), 3.70 (s, 3H), 3.06 (q, 1H, J ) 7.9 Hz), 2.47 (m, 1H), 2.33
(m, 1H); 13C NMR δ u, 173.1, 158.6, 139.7, 121.7, 69.6, 32.8;
d, 131.4, 129.5, 127.7, 121.0, 114.5, 83.3, 77.5, 52.1; IR cm-1
2951, 1732, 1600, 1494, 1454, 1367, 1244, 1070, 818, 752, 692;
MS (m/z, relative intensity) 391 (4), 330 (6), 299 (36), 253 (100),
223 (23), 185 (29); HRMS calcd for C19H19O4Br 390.0467, obsd
390.0449. 3c: TLC Rf(20% EtOAc/petroleum ether) ) 0.44;
1H NMR δ 7.40 (m, 2H), 7.30 (m, 2H), 7.22 (m, 2H), 6.98 (m,
3H), 5.18 (d, 1H, J ) 8.2 Hz), 4.44 (m, 1H), 4.33 (dd, 1H, J )
6.0, 9.8 Hz), 4.22 (dd, J ) 4.2, 9.8 Hz), 3.46 (q, 1H, J ) 8.1
Hz), 3.2 (s, 3H), 2.33 (m, 2H); 13C NMR δ u, 172.0, 158.7, 137.3,
121.7, 69.5, 31.2; d, 131.0, 129.4, 128.2, 121.0, 114.6, 82.2, 77.8,
51.4, 49.8; IR cm-1 2949, 1735, 1600, 1496, 1453, 1244, 1204,
1171, 1072, 1014, 1010, 754; MS (m/z, relative intensity) 390
(6), 297 (100), 264 (21), 251 (74), 223 (21), 183 (29); HRMS
calcd for C19H19O4Br 390.0467, obsd 390.0460.
Meth yl (R*,S*,R*)-2-P h en yl-5-((4-n itr oph en yl)m eth oxy)-
2,3,4,5-t et r a h yd r o-3-fu r a n ca r b oxyla t e (2d ) a n d Met h yl
(R*,R*,R*)-2-P h en yl-5-((4-n itr op h en yl)m eth oxy)-2,3,4,5-
tetr a h yd r o-3-fu r a n ca r boxyla te (3d ). The procedure de-
scribed for 2a and 3a was employed. 2d : TLC Rf(30% EtOAc/
petroleum ether) ) 0.40; 1H NMR δ 8.19 (m, 2H), 7.61 (m, 2H),
7.32 (m, 2H), 6.96 (m, 3H), 5.22 (d, 1H, J ) 7.9 Hz), 4.63 (m,
1H), 4.24 (dd, 1H, J ) 3.5, 10.2 Hz), 4.12 (dd, 1H, J ) 4.2,
10.2 Hz), 3.75 (s, 3H), 3.11 (q, 1H, J ) 7.9 Hz), 2.44 (m, 2H);
13C NMR δ u, 172.8, 158.6, 148.3, 69.5, 32.6; d, 129.6, 126.8,
123.6, 121.2, 114.5, 82.8, 78.0, 52.3; IR cm-1 1734, 1600, 1521,
Meth yl 2-Dia zo-(2-p h en oxyeth oxy)-5-p h en oxyp en ta n -
oa te (1j). The procedure described for 1a was employed. The
overall yield was 69%. 1j: TLC Rf(20% EtOAc/petroleum
ether) ) 0.35; 1H NMR δ 7.21 (m, 4H), 6.86 (m, 6H), 4.04-
3.85 (m, 7H), 3.64 (s, 3H), 2.63 (dd, J ) 4.3, 5.1 Hz, 1H), 2.52
(dd, J ) 4.3, 5.1 Hz, 1H); 13C NMR δ u, 158.7, 158.5, 69.3,
69.2, 67.3, 27.4; d, 129.4, 129.3, 121.0, 120.8, 114.5, 77.9, 51.8;
IR cm-1 2926, 2089, 1686, 1600, 1497, 1340, 1245, 1134, 754.
Met h yl (R*,S*,R*)-2-P h en yl-5-((4-m et h oxyp h en yl)-
m eth oxy)-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (2a ) a n d
Meth yl (R*,R*,R*)-2-P h en yl-5-((4-m eth oxyp h en yl)m eth -
oxy)-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (3a ). Diazo
ester 1a (370 mg, 1 mmol) in a 25 mL round bottom flask
containing a magnetic stir bar was evaporated with toluene
(3 × 7 mL). Methylene chloride was then added by filtration
through a pad of anhydrous K2CO3. Dirhodium tetraoctanoate
(1 mg) was added. The reaction was completed in 30 min. The
reaction mixture was concentrated, and the residue was
chromatographed to give 192 mg of 2a (63% yield) and 72 mg
of 3a (37% yield). 2a : TLC Rf(20% EtOAc/petroleum ether)
1
) 0.34; H NMR δ 7.30 (m, 4H), 6.93 (m, 3H), 6.87 (m, 2H),
5.04 (d, 1H, J ) 8.2 Hz), 4.55 (m, 1H), 4.15 (dd, 1H, J ) 4.1,

6710 J . Org. Chem., Vol. 61, No. 19, 1996
Taber and Song
1496, 1455, 1349, 1245, 1173, 1095, 1045; MS (m/z, relative
intensity) 357 (24), 343 (62), 328 (100), 264 (48), 232 (36);
HRMS calcd for C19H19O6N (m + H) 358.1291, obsd 358.1274.
1044; MS (m/z, relative intensity) 294 (2), 231 (5), 201 (29),
169 (15), 155 (100); HRMS calcd for C16H21O5 294.1467, obsd
294.1469.
1
3d : TLC Rf(30% EtOAc/petroleum ether) ) 0.37; H NMR δ
Meth yl (R*,S*,R*)-2-Meth yl-5-(p h en oxym eth yl)-2,3,4,5-
8.16 (m, 2H), 7.52 (m, 2H), 7.29 (m, 2H), 6.99 (m, 3H), 5.32 (d,
1H, J ) 8.4 Hz), 4.52 (m, 1H), 4.34 (m, 2H), 3.56 (q, 1H, J )
7.3 Hz), 3.2 (s, 3H), 2.40 (m, 2H); 13C NMR δ u, 171.6, 158.6,
145.8, 69.3, 31.2; d, 129.5, 127.4, 123.1, 121.1, 114.6, 81.7, 78.2,
51.6, 49.9; IR cm-1 1735, 1600, 1521, 1496, 1455, 1348, 1244,
1171, 1097, 1043; MS (m/z, relative intensity) 358 (100), 345
(4), 328 (30), 264 (44), 232 (7), 175 (3); HRMS calcd for
C19H19O6N (m + H) 358.1291, obsd 358.1299.
t et r a h yd r o-3-fu r a n ca r b oxyla t e
(2h ) a n d
Met h yl
(R*,R*,R*)-2-Met h yl-5-(p h en oxym et h yl)-2,3,4,5-t et r a h y-
d r o-3-fu r a n ca r boxyla te (3h ). The procedure described for
2a and 3a was employed. 2h (major): TLC Rf(10% EtOAc/
petroleum ether) ) 0.25; 1H NMR δ 7.27 (m, 2H), 6.90 (m, 3H),
4.40 (m, 1H), 4.13 (m, 1H), 3.98 (d, J ) 4.8 Hz, 2H), 3.73 (s,
3H) 2.73 (m, 1H), 2.43 (m, 1H), 2.12 (m, 1H), 1.38 (d, 3H, J )
6.0 Hz); 13C NMR δ u, 173.6, 158.8, 70.1, 32.6; d, 129.4, 120.9,
114.6, 78.9, 76.9, 52.0, 50.5, 20.3; IR cm-1 2952, 1736, 1600,
1497, 1372, 1246, 1200, 1043, 755; MS (m/z, relative intensity)
250 (4), 219 (1), 175 (1), 156 (38), 143 (68), 111(100); HRMS
calcd for C14H18O4 250.1205, obsd 250.1216. 3h (minor): TLC
Rf(10% EtOAc/petroleum ether) ) 0.20; 1H NMR δ 7.27 (m,
2H), 6.90 (m, 3H), 4.3 (m, 2H), 4.16 (m, 1H), 4.05 (m, 1H), 3.70
(s, 3H), 3.14 (m, 1H), 2.23 (m, 2H), 1.22 (d, J ) 6.4 Hz, 2H);
13C NMR δ u, 173.6, 158.8, 70.4, 31.5; d, 129.4, 120.9, 114.6,
77.1, 76.9, 51.7, 47.7, 17.4; IR cm-1 2977, 1736, 1600, 1497,
1246, 1202, 1170, 1043, 756, MS (m/z, relative intensity) 250
(3), 219 (2), 175 (1), 143 (48), 125 (18), 111 (100); HRMS calcd
for C14H18O4 250.1205, obsd 250.1214.
Meth yl (R*,S*,R*)-2-Eth en yl-5-(ph en oxym eth yl)-2,3,4,5-
t et r a h yd r o-3-fu r a n ca r b oxyla t e
(2e) a n d
Met h yl
(R*,R*,R*)-2-Eth en yl-5-(p h en oxym eth yl)-2,3,4,5-tetr a h y-
d r o-3-fu r a n ca r boxyla te (3e). The procedure described for
2a and 3a was employed. 2e: TLC Rf(20% EtOAc/petroleum
ether) ) 0.45; 1H NMR δ 7.23 (m, 2H), 6.93 (m, 3H), 5.90 (m,
1H), 5.34 (d, J ) 17.2 Hz, 1H), 5.17 (d, J ) 10.4 Hz, 1H), 4.46
(m, 2H), 3.97 (dd, J ) 1.2, 4.8 Hz, 2H), 3.69 (s, 3H), 2.92 (dd,
J ) 7.6, 16.6 Hz, 1H), 2.42 (m, 1H), 2.18 (m, 1H); 13C NMR δ
u, 172.9, 158.5, 116.8, 69.6, 32.2; d, 136.7, 129.2, 120.7, 114.3,
83.1, 77.0, 51.8, 49.2; IR cm-1 2951, 1738, 1600, 1497, 1245,
1041, GCMS m/z (relative intensity) 262 (5), 230 (2), 175 (3),
168 (25), 155 (28), 123 (100); HRMS calcd for C15H18O4
262.1205, obsd 262.1206. 3e: TLC Rf(20% EtOAc/petroleum
ether) ) 0.40; 1H NMR δ 7.27 (m, 2H), 6.94 (m, 3H), 5.91 (m,
1H), 5.30 (m, 2H), 4.63 (m, 1H), 4.37 (m, 1H), 4.15 (m, 2H),
3.65 (s, 3H), 3.31 (dd, 1H, J ) 8.1, 16.2 Hz), 2.23 (m, 2H); 13C-
NMR δ u, 172.0, 158.6, 117.8, 70.0, 31.1; d, 134.6, 129.3, 120.8,
114.5, 81.3, 77.5, 51.6, 48.3; IR cm-1 2951, 1738, 1600, 1497,
1245, 1041; GCMS m/z (relative intensity) 262 (8), 231 (1), 185-
(1), 169 (83), 137 (100); HRMS calcd for C15H18O4 262.1205,
obsd 262.1202.
Meh tyl (R*,S*,R*)-2-Eth yl-5-(p h en oxym eth yl)-2,3,4,5-
tetr ah ydr o-3-fu r an car boxylate (2f) an d Meth yl (R*,R*,R*)-
2-E t h yl-5-(p h en oxym et h yl)-2,3,4,5-t et r a h yd r o-3-fu r a n -
ca r boxyla te (3f). The procedure described for 2a and 3a was
employed. 2f: TLC Rf(20% EtOAc/petroleum ether) ) 0.30;
1H NMR δ 7.17 (m, 2H), 6.85 (m, 3H), 4.31 (m, 1H), 3.91 (m,
3H), 3.62 (s, 3H), 2.72 (m, 1H), 2.31 (m, 1H), 2.00 (m, 1H),
1.60 (m, 2H), 0.87 (t, J ) 7.4 Hz, 3H); 13C NMR δ u, 173.9,
158.7, 69.8, 32.6, 27.7; d, 129.3, 120.8, 114.5, 83.9, 76.8, 51.8,
48.1, 9.7; IR cm-1 2963, 2878, 1736, 1600, 1497, 1455, 1369,
1246, 1174, 1045, 982; MS (m/z, relative intensity) 264 (1), 233
(1), 203 (1), 170 (27), 157 (41), 125 (100); HRMS calcd for
C15H20O4 264.1362, obsd 264.1353. 3f: TLC Rf(20% EtOAc/
petroleum ether) ) 0.28; 1H NMR δ 7.20 (m, 2H), 6.86 (m, 3H),
4.28 (m, 1H), 4.11 (m, 1H), 3.92 (m, 2H), 3.63 (s, 3H), 3.12 (m,
1H), 2.18 (m, 2H), 1.47 (m, 2H), 0.92 (t, J ) 7.4 Hz, 3H); 13C
NMR δ u, 173.8, 158.7, 70.2, 31.5, 28.4; d, 129.2, 120.7, 114.4,
87.5, 76.6, 51.9, 46.8, 10.6; IR cm-1 2927, 2359, 1734, 1600,
1497, 1456, 1436, 1386, 1245, 1200, 1171, 1077, 1047, 981, 754;
MS (m/z, relative intensity) 264 (2), 233 (2), 203 (2), 171 (26),
157 (28), 125 (100); HRMS calcd for C15H20O4 264.1362, obsd
264.1352.
Met h yl
(S*,S*,R*)-2-(Met h oxym et h yl)-5-(p h en oxy-
m eth yl)-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (2i) a n d
Meth yl (S*,R*,R*)-2-(Meth oxym eth yl)-5-(ph en oxym eth yl)-
2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (3i). The procedure
described for 2a and 3a was employed. 2i: TLC Rf(20% EtOAc/
petroleum ether) ) 0.30; 1H NMR δ 7.18 (m, 2H), 6.84 (m, 3H),
4.35 (m, 1H), 4.18 (m, 1H), 3.92 (m, 2H), 3.64 (s, 3H), 3.48 (m,
2H), 3.30 (s, 3H), 2.98 (m, 1H), 2.34 (m, 1H), 2.08 (m, 1H); 13
C
NMR δ u, 173.4, 158.6, 73.7, 69.6, 32.0; d, 129.2, 120.7, 114.4,
81.2, 77.4, 59.2, 51.9, 45.1; IR cm-1 2927, 1735, 1600, 1497,
1456, 1266, 1174, 1105, 1046, 910, 736; MS (m/z, relative
intensity) 280 (2), 235 (2), 186 (11), 173 (12), 133 (50), 113
(100); HRMS calcd for C15H20O5 280.1311, obsd 280.1317. 3i:
1
TLC Rf(20% EtOAc/petroleum ether) ) 0.28; H NMR δ 7.18
(m, 2H), 6.84 (m, 3H), 4.33 (m, 2H), 4.00 (m, 2H), 3.89 (s, 3H),
3.50 (m, 2H), 3.27 (s, 3H), 3.18 (m, 1H), 2.06 (m, 2H); 13C NMR
δ u, 173.4, 158.6, 72.2, 69.7, 31.5; d, 129.3, 120.8, 114.5, 79.0,
77.4, 59.1, 51.7, 45.4.
Met h yl
(S*,S*,R*)-2-(P h en oxym et h yl)-5-(p h en oxy-
m eth yl)-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (2j) a n d
Meth yl (S*,R*,R*)-2-(P h en oxym eth yl)-5-(ph en oxym eth yl)-
2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (3j). The procedure
described for 2a and 3a was employed. 2j: TLC Rf(20%
EtOAc/petroleum ether) ) 0.30; 1H NMR δ 7.27 (m, 4H), 6.93
(m, 6H), 4.51 (m, 2H), 4.13 (m, 2H), 4.02 (d, J ) 4.8 Hz, 2H),
3.73 (s, 3H), 3.21 (m, 1H), 2.45 (m, 1H), 2.28 (m, 1H); 13C NMR
δ u, 173.3, 158.5, 69.6, 68.9, 32.0; d, 129.3, 120.9, 114.5, 80.5,
77.7, 52.1, 45.5; IR cm-1 2927, 2359, 1734, 1600, 1497, 1456,
1436, 1386, 1245, 1200, 1171, 1077, 1047, 981, 754; MS (m/z,
relative intensity) 342 (3), 248 (10), 203 (10), 175 (16), 133
(100), 113 (97); HRMS calcd for C20H22O5 342.1467, obsd
342.1469. 3j: TLC Rf(20% EtOAc/petroleum ether) ) 0.28;
1H NMR δ 7.27 (m, 4H), 6.86 (m, 6H), 4.43 (m, 2H), 4.06 (m,
2H), 3.96 (s, J ) 4.8 Hz, 2H), 3.52 (s, 3H), 3.30 (m, 1H), 2.22
(m, 2H); 13C NMR δ u, 173.4, 158.7, 70.1, 67.6, 32.2; d, 129.3,
120.9, 114.5, 78.4, 77.7, 51.9, 45.7.
6-P h en oxy-5-((4-m et h oxyp h en yl)m et h oxy)-1-h exen e
(15a ). At 0 °C, 100 mL of 2 M allylmagnesium chloride was
added slowly to 1,2-epoxy-3-phenoxypropane (15 g, 100 mmol)
in 100 mL of dry THF. The reaction mixture was warmed to
rt. After 4 h, the reaction mixture was partitioned between
the aqueous 2 N HCl and 50% EtOAc/petroleum ether. The
combined organic extract was washed sequentially with satu-
rated aqueous NaHCO3 and saturated aqueous NaCl. The
combined organic extract was dried (Na2SO4) and concentrated
to give 19.2 g of crude 1-phenoxy-5-hexen-2-ol.
Met h yl
(R*,S*,R*)-2-(2-Met h oxyet h yl)-5-(p h en oxy-
m eth yl)-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (2g) a n d
Meth yl (R*,R*,R*)-2-(2-Meth oxyeth yl)-5-(ph en oxym eth y)-
2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (3g). The procedure
described for 2a and 3a was employed. 2g: TLC Rf(20%
EtOAc/petroleum ether) ) 0.40; 1H NMR δ 7.28 (m, 2H), 6.93
(m, 3H), 4.40 (m, 1H), 4.17 (m, 1H), 3.99 (d, J ) 4.7 Hz, 2H),
3.72 (s, 3H), 3.48 (m, 2H), 3.30 (s, 3H), 2.89 (m, 1H), 2.39 (m,
1H), 2.15 (m, 1H), 1.92 (m, 2H); 13C NMR δ u, 173.7, 158.8,
69.8, 69.4, 34.9, 32.6; d, 148.9, 129.4, 120.9, 114.5, 80.1, 76.9,
58.5, 51.9; IR cm-1 2923, 1732, 1600, 1496, 1455, 1245, 1173,
1115; MS (m/z, relative intensity) 294 (2), 231 (5), 201 (5), 187
(7), 168 (26), 155 (60, 137 (12), 129 (100); HRMS calcd for
C16H21O5 294.1467, obsd 294.1478. 3g: TLC Rf(20% EtOAc/
petroleum ether) ) 0.35; 1H NMR δ 7.21 (m, 2H), 6.86 (m, 3H),
4.22 (m, 1H), 4.08 (m, 1H), 3.92 (d, J ) 4.5 Hz, 2H), 3.63 (s,
3H), 3.44 (t, J ) 6.0 Hz, 2H), 3.26 (s, 3H), 3.14 (m, 1H), 2.16
(m, 2H), 1.70 (m, 2H); 13C NMR δ u, 173.7, 158.8, 70.2, 69.6,
32.6, 32.0; d, 129.4, 120.9, 114.6, 77.7, 77.1, 58.6, 51.7, 47.1;
IR cm-1 2922, 1738, 1600, 1496, 1455, 1386, 1246, 1171, 1115,
NaH (1.1 g, 26 mmol, 60% in mineral oil) was added in
portions to the crude 1-phenoxy-5-hexen-2-ol (1.69 g) in 10 mL
of dry THF at 0 °C. 4-Methoxybenzyl chloride (1.65 g, 10.6
mmol) and Bu4NI (100 mg) were then added. The reaction
mixture was warmed up to rt. After 4 h, the reaction mixture
was partitioned between 2 M aqueous HCl and 20% EtOAc/

Construction of 2,3,5-Trisubstituted Tetrahydrofurans
J . Org. Chem., Vol. 61, No. 19, 1996 6711
petroleum ether. The combined organic extract was washed
sequentially with saturated aqueous NaHCO3 and saturated
aqueous NaCl. The combined organic extract was dried (Na2-
SO4) and concentrated. The residue was chromatographed to
yield 2.43 g of 15a (88% yield from 1,2-epoxy-3-phenoxypro-
pane) as a colorless oil: TLC Rf(20% EtOAc/petroleum ether)
) 0.66; 1H NMR δ 7.3 (m, 4H), 6.88 (m, 5H), 5.81 (m, 1H),
4.99 (m, 2H), 4.68 (d, 1H, J ) 11.2 Hz), 4.55 (d, 1H, J ) 11.2
Hz), 3.99 (m, 2H), 3.79 (s, 3H), 3.76 (m, 1H), 2.19 (m, 2H),
1.72 (m, 2H); 13C NMR δ u,159.2, 158.8, 130.7, 114.8, 71.9,
70.4, 31.3, 29.5; d, 138.3, 129.4, 120.8, 114.5, 113.7, 76.3, 55.2;
IR cm-1 2933, 1600, 1513, 1496, 1455, 1302, 1247, 1173, 1037,
912; MS (m/z, relative intensity) 121 (100), 135 (31), 187 (2),
205 (9), 219 (2), 312 (1); HRMS calcd for C20H24O3 312.1725,
obsd 312.1710.
colorless oil. The yield was 63%. 15g: TLC Rf(10% EtOAc/
petroleum ether) ) 0.70; 1H NMR δ 7.21 (m, 2H), 6.86 (m, 3H),
5.77 (m, 1H), 4.94 (m, 2H), 3.88 (m, 2H), 3.65 (m, 1H), 3.54
(m, 2H), 3.40 (t, J ) 6.2 Hz, 3H), 3.24 (s, 3H), 2.14 (m, 2H),
1.77 (m, 2H), 1.65 (m, 2H); 13C NMR δ u, 158.8, 114.8, 69.6,
67.1, 31.2, 30.4, 29.6; d, 138.3, 129.4, 120.7, 114.5, 77.4, 58.6;
IR cm-1 3074, 2923, 2872, 1600, 1588, 1497, 1456, 1245, 1118;
MS (m/z, relative intensity) 264 (5), 174 (5), 157 (100), 119
(15); HRMS calcd for C16H24O3 264.1725, obsd 264.1712.
6-P h en oxy-5-eth oxy-1-h exen e (15h ). The procedure de-
scribed for 15a was employed for the alkylation of 1-phenoxy-
5-hexen-2-ol with ethyl iodide. The yield was 93%. 15h : TLC
Rf(20% EtOAc/petroleum ether) ) 0.85; 1H NMR δ 7.20 (m,
2H), 6.85 (m, 3H), 5.77 (m, 1H), 5.00 (m, 2H), 3.66 (m, 1H),
3.54 (m, 2H), 2.14 (m, 2H), 1.63 (m, 2H), 1.14 (t, J ) 7.0 Hz,
3H); 13C-NMR δ u,158.8, 114.7, 70.1, 69.6, 31.3, 29.5; d, 138.3,
129.3, 120.7, 114.5, 77.0, 15.6; IR cm-1 3075, 2975, 2926, 2872,
1600, 1588, 1497, 1245, 1172, 1110, 1080, 1044, 912, 752, 691;
MS (m/z, relative intensity) 220 (25), 174 (5), 119 (35), 113
(100); HRMS calcd for C14H20O2 220.1463, obsd 220.1460.
6-P h en oxy-5-(2-m eth oxyeth oxy)-1-h exen e (15i). The
procedure described for 15a was employed for the alkylation
of 1-phenoxy-5-hexen-2-ol with 1-iodo-2-methoxyethane. 15i:
6-P h en oxy-5-(ph en ylm eth oxy)-1-h exen e (15b). The pro-
cedure described for 15a was employed. The overall yield was
1
92%. 15b: TLC Rf(10% EtOAc/petroleum ether) ) 0.85; H
NMR δ 7.29 (m, 7H), 6.95 (m, 3H), 5.82 (m, 1H), 5.10 (m, 2H),
4.74 (d, J ) 11.6 Hz, 1H), 4.60 (d, J ) 11.6 Hz, 1H), 4.00 (m,
2H), 3.80 (m, 1H), 2.21 (m, 2H), 1.74 (m, 2H); 13C NMR δ u,
158.8, 138.6, 114.9, 72.3, 70.7, 31.3, 29.5; d, 138.2, 129.4, 128.3,
127.9, 127.6, 120.8, 114.5, 76.7, 120.8, 114.3, 76.1; IR cm-1
3064, 3030, 2925, 2869, 1830, 1640, 1599, 1587, 1540, 1496,
1454, 1349, 1245, 1079, 912, 753; MS (m/z, relative intensity)
282 (5), 175 (23), 157 (14), 131 (5), 108 (5), 107 (59), 105 (100);
HRMS calcd for C19H20O2 282.1620, obsd 282.1621.
1
TLC Rf(10% EtOAc/petroleum ether) ) 0.65; H NMR δ 7.26
(m, 2H), 6.92 (m, 3H), 5.82 (m, 1H), 5.03 (m, 2H), 4.01 (dd, J
) 5.7, 9.8 Hz, 1H), 3.92 (dd, J ) 5.7, 9.8 Hz, 1H), 3.85 (m,
1H), 3.70 (m, 2H), 3.54 (m, 2H), 3.36 (s, 3H), 2.22 (m, 2H),
1.71 (m, 2H); 13C NMR δ u, 158.7, 114.7, 72.2, 70.2, 69.6, 31.1,
29.4; d, 138.2, 129.3, 120.6, 114.4, 77.8, 58.8; IR cm-1 2927,
2359, 1734, 1600, 1497, 1456, 1436, 1386, 1245, 1200, 1171,
1077, 1047, 981, 754; MS (m/z, relative intensity) 250 (10), 174
(10), 143 (100), 119 (30); HRMS calcd for C15H22O3 250.1669,
obsd 250.1562.
6-P h en oxy-5-((4-br om oph en yl)m eth oxy)-1-h exen e (15c).
The procedure described for 15a was employed. The overall
yield was 94%. 15a : TLC Rf(10% EtOAc/petroleum ether) )
0.69; 1H NMR δ 7.43 (m, 2H), 7.23 (m, 4H), 6.91 (m, 3H), 5.81
(m, 1H), 5.00 (m, 2H), 4.69 (d, 1H, J ) 11.9 Hz), 4.00 (m, 2H),
3.80 (m, 1H), 2.20 (m, 2H), 1.73 (m, 2H); 13C NMR δ u, 158.7,
137.7, 121.4, 115.0, 71.5, 70.4, 31.2, 29.6; d, 138.1, 131.4, 129.5,
129.4, 120.9, 114.5, 77.0; IR cm-1 2924, 2868, 1641, 1600, 1496,
1456, 1348, 1300, 1244, 1070, 1012, 912, 802, 692; MS (m/z,
relative intensity) 360 (1), 253 (12), 183 (32), 168 (100), 107
(56); HRMS calcd for C19H21O2Br 360.0725, obsd 360.0708.
6-P h en oxy-5-((4-n itr op h en yl)m eth oxy)-1-h exen e (15d ).
A solution of 1-phenoxy-5-hexen-2-ol (1.5 g) and 4-nitrobenzyl
bromide (2.0 g) and Ag2O (2.0 g) in 10 mL of CH2Cl2 was
maintained under irradiation in an ultrasonic cleaning bath
at rt for 24 h. The mixture was filtered, concentrated, and
chromatographed to give 1.8 g of 15d (71% yield): TLC Rf-
(20% EtOAc/petroleum ether) ) 0.62; 1H NMR δ 8.17 (m, 2H),
7.52 (m, 2H), 7.28 (m, 2H), 6.92 (m, 3H), 5.83 (m, 1H), 5.01
(m, 2H), 4.86 (d, 1H, J ) 13.1 Hz), 4.04 (m, 2H), 3.84 (m, 1H),
2.24 (m, 2H), 1.80 (m, 2H); 13C NMR δ u, 158.5, 147.2, 146.4,
115.1, 71.0, 70.5, 31.0, 29.5; d, 137.8, 129.4, 127.6, 123.4, 120.9,
114.4, 77.8; IR cm-1 2924, 1600, 1519, 1495, 1454, 1345, 1244,
1108, 914, 850, 755; MS (m/z, relative intensity) 427 (20), 220
(71), 202 (27), 176 (25), 152 (11), 136 (100), 107 (90); HRMS
calcd for C19H21O4N 327.1471, obsd 327.1466.
6-P h en oxy-5-(2-p h en oxyeth oxy)-1-h exen e (15j). The
procedure described for 15a was employed for the alkylation
of 1-phenoxy-5-hexen-2-ol with 1-bromo-2-phenoxyethane. The
yield was 65%. 15j: TLC Rf(10% EtOAc/petroleum ether) )
0.70; 1H NMR δ 7.24 (m, 4H), 6.93 (m, 6H), 5.83 (m, 1H), 5.01
(m, 2H), 4.11 (m, 4H), 4.03 (m, 2H), 3.78 (m, 1H), 2.24 (m,
2H), 1.72 (m, 2H); 13C NMR δ u, 158.7, 114.9, 70.4, 68.9, 67.4,
31.1, 29.4; d, 138.2, 129.3, 120.7, 114.5, 78.0; IR cm-1 2925,
2873, 1600, 1587, 1497, 1456, 1301, 1246, 112; MS (m/z,
relative intensity) 312 (5), 205 (9), 174 (2), 139 (4), 121 (100);
HRMS calcd for C20H24O3 312.1725, obsd 312.1728.
Meth yl 4-((4-Meth oxyp h en yl)m eth oxy)-5-p h en oxyp en -
ta n oa te (16a ). A solution of 1.1 g of 15a (3.4 mmol) in 28
mL of CH2Cl2 and 7 mL of 2.5 M methanolic NaOH was stirred
at -78 °C as ozone was passed through the solution. After
60 min, the reaction mixture was warmed up to rt and then
partitioned between water and CH2Cl2. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield 0.774 g of 16a (64% yield) as a
colorless oil. 16a : TLC Rf(20% EtOAc/petroleum ether) ) 0.41;
1H NMR δ 7.27 (m, 4H), 6.88 (m, 5H), 4.66 (d, 1H, J ) 11.2
Hz), 4.52 (d, 1H, J ) 11.2 Hz) 4.03 (dd, 1H, J ) 5.5, 9.7 Hz),
3.83 (m, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 2.45 (m, 2H), 1.93 (m,
2H); 13C NMR δ u,173.8, 159.2, 158.6, 130.4, 71.9, 70.0, 29.8,
27.2; d, 129.5, 129.4, 120.9, 114.5, 113.7, 75.7, 55.2, 51.4; IR
cm-1 2950, 1736, 1600, 1514, 1497, 1455, 1301, 1247, 1173,
1035; MS (m/z, relative intensity) 344 (1), 230 (5), 207 (1), 137
(41), 121 (100), 107 (3); HRMS calcd for C20H24O5 344.1624,
obsd 344.1653.
6-P h en oxy-5-(p r op yloxy)-1-h exen e (15f). The procedure
described for 15a was employed for the alkylation of 1-phe-
noxy-5-hexen-2-ol with 1-iodopropane. The yield was 63%.
1
15f: TLC Rf(10% EtOAc/petroleum ether) ) 0.60; H NMR δ
7.27 (m, 2H), 6.92 (m, 3H), 5.84 (m, 1H), 5.00 (m, 2H), 3.95
(m, 2H), 3.61 (m, 2H), 3.48 (m, 1H), 2.21 (m, 2H), 1.69 (m,
2H), 1.58 (m, 2 H), 0.93 (t, J ) 7.3 Hz, 3H); 13C NMR δ u,
158.9, 114.8, 72.1, 70.1, 31.4, 29.6, 23.3; d, 138.4, 129.4, 120.7,
114.5, 10.6; IR cm-1 2934, 2875, 1641, 1600, 1455, 1245, 1080,
1044, 911,753; MS (m/z, relative intensity) 234 (24), 192 (4),
179 (8), 133 (8), 127 (100), 119 (32), 107 (32); HRMS calcd for
C15H22O2 234.1620, obsd 234.1629.
Meth yl 4-(P h en ylm eth oxy)-5-ph en oxypen tan oate (16b).
The procedure described for 16a was employed. The overall
yield was 63%. 16b: TLC Rf(20% EtOAc/petroleum ether) )
1
0.40; H NMR δ 7.29 (m, 7H), 6.95 (m, 3H), 4.73 (d, J ) 11.6
6-P h en oxy-5-((3-m eth oxyp r op yl)oxy)-1-h exen e (15g).
NaH (500 mg, 60% in mineral oil) was added in portions to
the crude 1-phenoxy-5-hexen-2-ol (479 mg) in 4 mL of dry DMF
at 0 °C. 1-Methoxy-3-chloropropane (1 g) and Bu4NI (60 mg)
were then added. The reaction mixture was irradiated in an
ultrasonic cleaning bath at rt for 8 h. The reaction mixture
was partitioned between 20% EtOAc/petroleum ether and,
sequentially, 2 N aqueous HCl and saturated aqueous NaCl.
The combined organic layers were dried (Na2SO4) and con-
centrated. The residue was chromatographed to yield 415 mg
of 15g (63% yield from 1,2-epoxy-3-phenoxypropane) as a
Hz, 1H), 4.59 (d, J ) 11.6 Hz, 1H), 4.04 (m, 2H), 3.82 (m, 1H),
3.62 (s, 3H), 2.47 (dt, J ) 3.2, 7.4 Hz, 2H), 2.00 (m, 2H); 13C
NMR δ u, 173.8, 158.6, 138.3, 72.2, 69.9, 29.8, 27.1; d, 129.4,
128.3, 127.9, 127.6, 120.9, 114.5, 76.1, 51.5; IR cm-1 3064,
2949, 2872, 1737, 1599, 1587, 1497, 1351, 1245, 1172, 1079,
755; MS (m/z, relative intensity) 221 (7), 207 (21), 133 (7), 105
(36), 107 (71), 105 (100); HRMS calcd for C19H22O3 221.1177,
obsd 221.1178.
Meth yl 4-((4-Br om op h en yl)m eth oxy)-5-p h en oxyp en -
ta n oa te (16c). The procedure described for 16a was em-

6712 J . Org. Chem., Vol. 61, No. 19, 1996
Taber and Song
ployed. The yield was 69%. 16c: TLC Rf(20% EtOAc/
petroleum ether) ) 0.47; 1H NMR δ 7.43 (m, 2H), 7.22 (m, 4H),
6.90 (m, 3H), 4.68 (d, 1H, J ) 11.9 Hz), 4.53 (d, 1H, J ) 11.9
Hz), 4.01 (m, 2H), 3.81 (m, 1H), 3.62 (s, 3H), 2.46 (t, 2H, J )
6.9 Hz), 1.98 (m, 2H); 13C NMR δ u, 173.7, 158.5, 137.3, 121.5,
71.5, 70.0, 29.7, 27.0; d, 131.4, 129.4, 120.9, 114.4, 76.2, 51.5;
IR cm-1 3640, 2949, 1732, 1600, 1495, 1246, 1080, 1012, 805,
754, 694; MS (m/z, relative intensity) 939 2), 375 (34), 301 (42),
208 (100), 185 (32), 170 (83).
intensity) 264 (2), 215 (1), 207 (16), 171 (15), 157 (58), 115
(100); HRMS calcd for C15H20O4 264.1362, obsd 264.1367.
Meth yl 4-(P r op yloxy)-5-p h en oxyp en ta n oa te (16f). The
procedure described for 16a was employed. The yield was
68%. 16f: TLC Rf(20% EtOAc/petroleum ether) ) 0.35; 1H
NMR δ 7.18 (m, 2H), 6.82 (m, 3H), 3.85 (m, 2H), 3.58 (s, 3H),
3.56 (m, 2H), 3.34 (m, 1H), 2.40 (t, J ) 7.3 Hz, 2H), 1.86 (m,
2H), 1.48 (m, 2H), 0.83 (t, J ) 7.3 Hz, 3H); 13C NMR δ u, 173.8,
158.7, 72.1, 69.6, 29.8, 27.2, 23.2; d, 129.4, 120.7, 114.4, 76.7,
51.4, 10.5; IR cm-1 2960, 2876, 1738, 1600, 1696, 1456, 1246,
1173, 1122, 1044, 755; MS (m/z, relative intensity) 266 (22),
206 (4), 193 (4), 159 (80), 117 (100); HRMS calcd for C15H22O4
266.1518, obsd 266.1515
Meth yl 4-((3-Meth oxypr opyl)oxy)-5-ph en oxypen tan oate
(16g). The procedure described for 16a was employed. The
yield was 68%. 16g: TLC Rf(20% EtOAc/petroleum ether) )
0.45; 1H NMR δ 7.28 (m, 2H), 6.93 (m, 3H), 3.97 (m, 2H), 3.71
(m, 2H), 3.66 (s, 3H), 3.59 (m, 1H), 3.45 (t, J ) 6.3 Hz, 2H),
3.31 (s, 3H), 2.48 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H); 13C NMR
δ u, 173..9, 158.6, 69.6, 69.5, 67.2, 30.3, 29.8, 27.2; d, 129.4,
120.8, 114.5, 76.9, 58.5, 51.5; IR cm-1 2927, 1738, 1600, 1498,
1246, 1173, 1115, 888, 756; MS (m/z, relative intensity) 296
(5), 233 (5), 203 (25), 189 (75), 133 (40), 101 (100); HRMS calcd
for C16H24O5 296.1623, obsd 296.1615.
Meth yl 4-Eth oxy-5-p h en oxyp en ta n oa te (16h ). The pro-
cedure described for 16a was employed. The yield was 67%.
16h : TLC Rf(20% EtOAc/petroleum ether) ) 0.50; 1H NMR δ
7.21 (m, 2H), 6.85 (m, 3H), 3.92 (dd, J ) 5.4, 9.8 Hz, 1H), 3.84
(dd, J ) 5.4, 9.8 Hz, 1H), 3.65 (m, 3H), 3.60 (s, 3H), 3.47 (m,
1H), 2.41 (t, J ) 7.6 Hz, 2H), 1.96 (m, 2H), 1.12 (t, J ) 7.1 Hz,
3H); 13C NMR δ u, 173.8, 158.6, 69.9, 65.2, 29.8, 27.2; d, 129.3,
120.7, 114.4, 75.6, 51.4, 15.4; IR cm-1 2975, 1738, 1600, 1588,
1497, 1245, 1173, 755, 692; MS (m/z, relative intensity) 251
(2), 206 (4), 159 (13), 145 (100), 113 (15); HRMS calcd for
C14H20O4 252.1362, obsd 252.1368.
Met h y 4-(2-Met h oxyet h yoxy)-5-p h en oxyp en t a n oa t e
(16i). The procedure described for 16a was employed. The
yield was 62%. 16i: TLC Rf(20% EtOAc/petroleum ether) )
0.35; 1H NMR δ 7.27 (m, 2H), 6.86 (m, 3H), 4.28 (m, 1H), 3.99
(m, 2H), 3.94 (m, 1H), 3.72 (m, 2H), 3.66 (s, 3H), 3.52 (m, 2H),
3.36 (s, 3H), 2.51 (m, 2H), 1.95 (m, 2H); 13C NMR δ u, 173.7,
158.5, 72.1, 69.8, 69.6, 29.7, 27.1; d, 1129.3, 120.7, 114.3, 77.3,
58.8, 51.3; IR cm-1 2928, 1734, 1653, 1600, 1497, 1457, 1246,
1173, 1108; MS (m/z, relative intensity) 282 (5), 189 (20), 175
(100), 133 (35), 115 (50); HRMS calcd for C15H22O5 282.1467,
obsd 282.1468.
Met h yl 4-((4-Nit r op h en yl)m et h oxy)-5-p h en oxyp en -
ta n oa te (16d ). A solution of 3.6 g of 15d and 1 mg of sudan
red in 30 mL of CH2Cl2 was stirred at -78 °C while O3 was
passed through until the red color of the solution was
discharged. Ph3P (4.0 g) was added, and the reaction mixture
was warmed up to rt for 6 h. Evaporation of the solvent and
chromatography of the residue afforded 3.3 g of 4-((4-nitro-
phenyl)methoxy)-5-phenoxy-1-pentanal as a light yellow oil
(92% yield). 16d : TLC Rf(30% EtOAc/petroleum ether) ) 0.37;
1H NMR δ 9.79 (s, 1H), 8.18 (m, 2H), 7.47 (m, 2H), 7.30 (m,
2H), 6.91 (m, 3H), 4.85 (d, 1H, J ) 12.9 Hz), 4.69 (d, 1H, J )
12.9 Hz), 4.05 (m, 2H), 3.87 (m, 1H), 2.63 (t, 2H, J ) 7.0 Hz),
2.06 (m, 2H); 13C NMR δ u, 158.4, 147.3, 145.8, 71.0, 70.1, 39.7,
24.5; d, 201.4, 129.5, 127.8, 123.5, 121.1, 114.4, 77.3; IR cm-1
2928, 1722, 1600, 1519, 1496, 1345, 1244, 1108, 757, 692; MS
(m/z, relative intensity) 329 (8), 236 (10), 222 (22), 136 (100),
107 (25); HRMS calcd for C18H19O5N1 329.1263, obsd 329.1262.
The procedure described for 16e was employed to oxidize the
aldehyde to 16d . The overall yield was 66% from 15d . 16d :
1
TLC Rf(30% EtOAc/petroleum ether) ) 0.43; H NMR δ 8.20
(m, 2H), 7.49 (m, 2H), 7.29 (m, 2H), 6.91 (m, 3H), 4.88 (d, 1H,
J ) 13.0 Hz), 4.72 (d, 1H, J ) 13.0 Hz), 4.06 (m, 2H), 3.89 (m,
1H), 3.64 (s, 3H), 2.51 (t, 2H, J ) 7.4 Hz), 2.04 (m, 2H); 13C
NMR δ u, 173.6, 158.5, 146.0, 71.1, 70.2, 29.8, 27.0; d, 129.5,
127.8, 123.5, 121.1, 114.5, 77.3, 51.6; IR cm-1 2950, 1732, 1679,
1600, 1519, 1494, 1455, 1345, 1171, 1107, 860; MS (m/z,
relative intensity) 359 (22), 266 (23), 252 (19), 231 (5), 136
(100), 120 (9) ; HRMS calcd for C19H22O6N (m + H) 360.1447,
obsd 360.1430.
Meth yl 4-(2-P r op en yloxy)-5-p h en oxyp en ta n oa te (16e).
A solution of 2.32 g of 15e (10 mmol) (prepared as 15a from
14) in 30 mL of CH2Cl2 was stirred at -78 °C while 10 mmol
of O3 was passed through. Then 4.0 g of Ph3P (15 mmol) was
added, and the reaction mixture was warmed up to rt for 6 h.
Evaporation of the solvent and chromatography of the residue
afforded 0.98 g of 4-(2-propenyloxy)-5-phenoxy-1-pentanal as
a colorless oil (42% yield). 16e: TLC Rf(20% EtOAc/petroleum
ether) ) 0.40; 1H NMR δ 9.75 (bs, 1H), 7.27 (m, 2H), 6.93 (m,
3H), 5.95 (m, 1H), 5.22 (m, 2H), 4.22 (m, 1H), 4.04 (m, 3H),
Meth y 4-(2-P h en oxyeth oxy)-5-ph en oxypen tan oate (16j).
The procedure described for 16a was employed. The yield was
68%. 16j: TLC Rf(20% EtOAc/petroleum ether) ) 0.35; 1H
NMR δ 7.27 (m, 4H), 6.92 (m, 6H), 4.08 (m, 4H), 4.03 (m, 2H),
3.97 (m, 1H), 3.64 (s, 3H), 2.53 (t, J ) 7.4 Hz, 2H), 2.00 (m,
2H); 13C NMR δ u, 173.6, 158.5, 158.4, 69.9, 68.8, 67.2, 29.5,
27.0; d, 129.2, 129.1, 120.7, 120.6, 114.3, 77.4, 51.2; IR cm-1
2930, 2875, 1736, 1600, 1497, 1247; MS (m/z, relative intensity)
344 (5), 281 (1), 237 (16), 205 (45), 177 (26), 133 (21), 121 (100);
HRMS calcd for C20H24O5 344.1623, obsd 344.1618.
3.70 (m, 1H), 2.57 (dt, J ) 1.3, 7.0 Hz, 2H), 1.96 (m, 2 H); 13
C
NMR δ u,158.4, 117.0, 71.1, 69.5, 39.7, 24.6; d, 201.8, 134.6,
129.3, 120.8, 114.3, 76.1; IR cm-1 2928, 2872, 2727, 1723, 1600,
1497, 1456, 1247, 1079, 996; MS (m/z, relative intensity) 234
(3), 177 (13), 149 (3), 127 (100), 107 (45); HRMS calcd for
C14H18O3 234.1256, obsd 234.1263.
PDC (6.3 g, 18 mmol) and 0.58 g of MeOH were added to
0.7 g of the aldehyde in 6 mL of dry DMF. The reaction
mixture was sirred at rt for 20 h. Ether (200 mL) and celite
(24 g) were added. The mixture was filtered, and the residue
was washed with ether. The combined filtrate was washed
with saturated aqueous NaCl and dried with Na2SO4. Evapo-
ration of the solvent and chromatography of the residue
afforded 600 mg of ester 16e as a colorless oil (32% yield from
Ack n ow led gm en t. We thank M. P. Doyle, M. C.
Pirrung, and H. M. L. Davies for helpful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds (91 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of this journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
15e). 16e: TLC Rf(20% EtOAc/petroleum ether) ) 0.50; H
NMR δ 7.26 (m, 2H), 6.90 (m, 3H), 5.88 (m, 1H), 5.22 (m, 2H),
4.06 (m, 2H), 3.98 (dd, J ) 4.8, 9.8 Hz, 1H), 3.92 (dd, J ) 4.8,
9.8 Hz, 1H), 3.72 (m, 1H), 3.64 (s, 3H), 2.46 (t, J ) 7.4 Hz,
2H), 1.94 (m, 2H); 13C NMR δ u, 173.5, 158.4, 116.6, 71.0, 69.6,
29.6, 27.0; d, 134.7, 129.2, 120.6, 114.3, 75.9, 51.2; IR cm-1
2950, 1735, 1600, 1497, 1455, 1246, 1173; MS (m/z, relative
J O960758U