Convergent route to the purpuromycin bisphenolic spiroketal: hydrogen bonding control of spiroketalization stereochemistry

Article abstract of DOI:10.1016/j.tetlet.2006.05.044

A mild and efficient [3+2] nitrile oxide/olefin cycloaddition provided a rapid and convergent entry into precursors of bisphenolic spiroketals, a structural type unique to the rubromycin family of natural products. In addition, implementation of the premi

Full text of DOI:10.1016/j.tetlet.2006.05.044

Tetrahedron Letters 47 (2006) 5409–5413
Convergent route to the purpuromycin bisphenolic
spiroketal: hydrogen bonding control of spiroketalization
stereochemistry
Stephen P. Waters, Michael W. Fennie and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia,
PA 19104-6323, United States
Received 11 April 2006; revised 3 May 2006; accepted 8 May 2006
Available online 9 June 2006
Abstract—A mild and efficient [3+2] nitrile oxide/olefin cycloaddition provided a rapid and convergent entry into precursors of
bisphenolic spiroketals, a structural type unique to the rubromycin family of natural products. In addition, implementation of
the premise that a hydrogen bond from the C4-OH controls the stereochemistry of the purpuromycin core resulted in moderate
diastereocontrol in the spiroketalization. Spectroscopic and X-ray data of these systems have provided the first assignment of
the relative configuration of purpuromycin.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Purpuromycin (1),1 c-rubromycin (2),2 heliquinomycin
(3),3 and the griseorhodins (4–5)4 are a set of structurally
related polyketides consisting of highly functionalized
naphthazarin and isocoumarin ring systems linked
through a bisbenzannulated 5,6-spiroketal (Fig. 1).
Our particular interest in purpuromycin (1), isolated
from the soil bacterium A. ianthinogenes, followed re-
ports of its potent antimicrobial5 and human telomerase
inhibitory properties.6 Moreover, its unique ability to
bind with high affinity to all tRNAs, thereby inhibiting
their acceptor capacity and disrupting further protein
synthesis, represents a novel mode of activity.7
While a formidable array of oxidation is present within
the hexacyclic ring system, the most striking feature is
the highly unusual 5,6-bisbenzannulated spiroketal core.
Indeed, the only reported synthesis of a natural product
featuring this linkage is that of heliquinomycin aglycone
by Danishefsky and co-workers, which was realized
through coupling of a lithiated naphthofuran with an
arylacetaldehyde and Mitsunobu-like ring closure to
form the spiroketal.8 In early model studies toward the
rubromycins by de Koning, Henry condensation of
two aryl moieties furnished a nitroalkene which, after
a Nef reaction revealed the ketone function, standard
acid-catalyzed spirocyclization formed the core bisbenz-
annulated spiroketal.9 Later model studies by Brimble
employed a similar spiroketalization after uniting a lith-
iated arylacetylene with an arylacetaldehyde.10 None of
these programs addressed substitution at C4 nor the
controlled assembly of defined spiroketal diastereomers.
O
naphthazarin
HO
O
O
OH
R4
MeO
O
O
2'
2
isocoumarin
3
4
3'
R1
R3
R2
O
OH
Purpuromycin (1, R1=H, R2=H, R3=OH, R4 = CO2Me)
1
2
3
4
γ
-Rubromycin (2, R =H, R =H, R =H, R = CO2Me)
Heliquinomycin (3, R1=cymarose, R2=OH, R3=H, R4 = CO2Me)
Griseorhodin C (4, R1=OH, R2=OH, R3 = OH, R4 = Me)
Griseorhodin G (5, R1=OH, R2=OH, R3 = H, R4 = Me)
In this letter, we disclose a rapid, convergent strategy as
a general means for construction of the C4-functional-
ized bisphenolic spiroketal array found in purpuromycin
and congeners (Fig. 2). A key feature is the [3+2] cyclo-
addition11 strategy to unite different left hand and right
hand fragments. In addition to enabling rapid model
studies, such an approach is amenable to the synthesis
Figure 1. The rubromycin family of natural products.
*
Corresponding author. Tel.: +1 215 898 3048; fax: +1 215 573
7165; e-mail: marisa@sas.upenn.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.044

5410
S. P. Waters et al. / Tetrahedron Letters 47 (2006) 5409–5413
OH
OH
H
HO
HO
OP
O
O
N
O
1
Y
3
1'
HO
H
OH
4
O
H
X
X
HO
H
Y
O
O
H
6
OH
PO
O
7
1'
HO
O
H
4
3
OP OP
OH
OP
O
H
MeO
OP
10ax
0.00 kcal/mol
10eq
PO
2.19 kcal/mol
Rel ΔHf
OMe
NO2
Figure 4. Calculated energies (AM1) of the model spiroketal dia-
stereomers.
OP OP
8
9
O
Figure 2. Retrosynthesis of purpuromycin.
OBn
H
BnO
PPh3=CH2
92%
of multiple analogs from a few fragments. The mild
conditions afforded by this method are highly desirable
due to the sensitive functional arrays present including
the b-hydroxyketone, the electron rich naphthalene (8),
and the electrophilic isocoumarin (9). Finally, we report
that hydrogen bonding is key to setting the spiroketal
stereochemistry.
O
11
13
12
MeNO2
AcOH
NH4OAc
84%
OBn
OBn
NaBH4
90%
NO2
NO2
14
As a first step in defining the stereochemistry of the
purpuromycin spiroketal, we recorded the NMR spectra
from a sample of natural purpuromycin12 in CDCl3 at
500 MHz (Fig. 3). Together with computational models,
this information permitted a tentative assignment of the
relative configuration and conformation of the spiro-
ketal core. Specifically, coupling of C3-Hb with C4-Ha
(J = 1.1 Hz) is consistent with an equatorial–equatorial
arrangement whereas the coupling of C3-Ha with C4-
Ha (J = 5.3 Hz) is consistent with an axial–equatorial
arrangement. Thus, the C4-OH group occupies a pseudo-
axial position within the pyran ring which occupies
a twist boat form due to the aromatic ring of the iso-
coumarin (Fig. 3).
Scheme 1. Synthesis of [3+2] coupling substrates.
undesirable during spiroketalization of 6 as the free
hydroxyl is needed. For example, the equatorial form
10eq would predominate with a silyl group on the
C4-OH.
We thus commenced studies with model substrates that
would allow formation of precursors with the free C4-
OH. Both required precursors could be prepared from
the benzyl ether 1116 obtained from salicylaldehyde
(Scheme 1). Olefination of 11 by Wittig homologation17
produced styrene derivative 12 in 92% yield. Alternately,
treatment with nitromethane and catalytic NH4OAc
effected Henry condensation18 to give nitrostyrene 13
Further, an anomeric effect is proposed to cause O10 to
occupy a pseudo-axial position in purpuromycin leading
to a syn relationship between O10 and C4-OH.13 We
propose that this form is stabilized by an intramolecular
hydrogen bond between C4-OH and O10.14 Unfortu-
nately, direct evidence for this hydrogen bond could
not be obtained since the alcohol proton signal was
not distinct. However, calculations provide strong sup-
port for the stabilizing nature of this interaction
(Fig. 4).15 The 10ax form was more stable even when
a continuum water solvent model was employed.
19
in 84% yield. Conjugate reduction with NaBH4 then
provided nitroalkane 14 in 90% yield.
Styrene 12 and nitroalkane 14 underwent smooth [3+2]
cycloaddition in the presence of PhNCO and catalytic
Et3N to afford isoxazoline 15 in 91% yield (Scheme 2).
Hydrogenolysis of the isoxazoline using the conditions
described by Curran (catalytic Raney Ni, B(OH)3, aque-
ous MeOH) gave the keto-alcohol 16 in 81% yield.11
At this point, an attempt was made to combine the benz-
yl ether hydrogenolyses and the spirocyclization. When
this protocol was applied to 16, hydrogenolysis of the
Assuming that thermodynamic control operates during
the spiroketalization, then protection of the C4-OH is
Ha
MeO
OBn
Hd
PhNCO,
O
OBn
BnO
H
N
O
OBn
4.87 ppm, dd
J = 1.1, 5.3 Hz
Et3N, PhH
+
O
not evident
NO2
91%
1'
O
Hd
14
12
OBn
15
O
H
O
O
O
O
CO2Me
H
O
O
Hb
H2
Ha
Raney Ni,
H2, B(OH)3,
H2O, MeOH
4
3
Hc
O
OH OBn
O
Pd/C
O
H+
4
4
purpuromycin (1)
81%
16
17
Figure 3. Proposed relative configuration and conformation of pur-
puromycin (1).
Scheme 2. [3+2] Cycloaddition and spirocyclization.

S. P. Waters et al. / Tetrahedron Letters 47 (2006) 5409–5413
5411
16
1) Pd/C, H2, EtOAc
2) TsOH, CH2Cl2
87%
(2 steps)
Hc
1'
O
Hd
O
O
3
OHd
4
Hb
O
Hb
Ha
O
Ha
4
3
1'
Hc
18a (major)
18b (minor)
Ha
5.29 ppm, ddd
2:1
Ha
Hd
Hd
4.78 ppm, ddd
3.50 ppm, d
1.89 ppm, d
J = 1.7, 5.0, 11.8 Hz J = 11.8 Hz
J = 6.1, 7.0, 10.4 Hz J = 7.0 Hz
Scheme 3. Spiroketal diastereomers 18a and 18b.
crucial C4-OH was observed yielding 17 in analogy to
prior reports from de Koning.9
Figure 5. X-ray structure of spiroketal 18a.
To circumvent this problem, sequential hydrogenolysis
and acid induced spirocyclization was undertaken. Dia-
stereomeric spiroketals 18a and 18b were produced as a
2:1 mixture in a combined yield of 87% over the two
steps (Scheme 3). Assignment of the relative configura-
tions and conformations of spiroketals 18a and 18b
was possible by examination of their respective 1H
NMR spectra (CDCl3, 500 MHz). For the major diaste-
reomer (18a), coupling between C4-Ha and the diaste-
reotopic C3-Hb and C3-Hc protons gave J values of
1.7 and 5.0 Hz. As expected from our prior analysis
(see above), these values indicate that, within the pyran
ring of 18a, the C4-OH occupies a pseudo-axial position
(Scheme 3). For the minor diastereomer (18b), coupling
between C4-Ha and the diastereotopic C3-Hb and C3-Hc
gave J values of 6.1 and 10.4 Hz. These values support
that, within the pyran ring of 18b, the C4-OH now occu-
pies a pseudo-equatorial position. Due to an anomeric
effect, O10 was reasoned to be pseudo-axial position in
both spiroketal diastereomers.
ing considerable promise for control of this stereochem-
ical element in syntheses of the natural products.
In conclusion, a convergent method for the construction
of bisbenzannulated 5,6-spiroketals is reported consist-
ing of [3+2] cycloaddition of nitrile oxides with olefins,
reduction of the resultant isoxazolines to b-keto alco-
hols, and subsequent spirocyclization.22 In addition,
implementation of our premise that a hydrogen bond
from the C4-OH controls the stereochemistry of the
purpuromycin core resulted in moderate stereocontrol
in the spiroketalization.14 This premise may also be use-
ful for other members of this class of compounds. Struc-
tural analysis of the resultant diastereomeric 5,6-
spiroketals provided a definitive assignment of the purp-
uromycin conformation and stereochemistry.
Acknowledgements
Support for this work was provided by the American
Cancer Society (RSG-02-137-01-CDD) and by a Sloan
Foundation Research Fellowship (MCK). We thank
Dr. Patrick Carroll for the X-ray crystal analysis. We
The relatively high C4-OH chemical shift at 3.50 ppm in
18a indicates an intramolecular hydrogen bond which
further supports the pseudo-axial C4-OH orientation
(Scheme 3).20 In comparison, the 1.89 ppm shift for
the pseudo-equatorial C4-OH of minor diastereomer
18b, indicates an absence of hydrogen bonding.
thank Biosearch Italia SpA for
purpuromycin.
a
sample of
An X-ray crystal analysis of major diastereomer 18a
secured unambiguous proof for these structural assign-
ments (Fig. 5).21 The pyran ring was found to adopt a
flattened conformation best characterized as a twist-
boat. The C4-OH and O10 occupy pseudo-axial posi-
tions within the pyran ring, leading to a syn relationship.
References and notes
1. (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G.
C. J. Antibiot. 1974, 27, 161–168; (b) Bardone, M. R.;
Martinelli, E.; Zerilli, E. F.; Coronelli, C. Tetrahedron
1974, 30, 2747.
2. Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709.
3. (a) Chino, M.; Nishikawa, K.; Umekita, M.; Hayashi, C.;
Yamazaki, T.; Tsuchida, T.; Sawa, R.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1996, 49, 752; (b) Chino, M.;
Nishikawa, K.; Tsuchida, T.; Sawa, R.; Nakamura, H.;
Nakamura, K. T.; Muraoka, M. Y.; Ikeda, D.; Naga-
nawa, H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997, 50,
143.
This data provided further support for the original ste-
reochemical assignment of purpuromycin (Fig. 2). The
chemical shifts and coupling constants obtained from
purpuromycin were in excellent agreement with those
from major spiroketal 18a while differing substantially
with those from minor diastereomer 18b. Interestingly,
similar yields and diastereomeric ratios were observed
with aprotic (TsOH/CH2Cl2) and protic (HCl/EtOH,
and PPTS/MeOH) spiroketalization conditions provid-
4. (a) Yang, J.; Fan, S.; Pei, H.; Zhu, B.; Xu, W.; Naganawa,
H.; Hamada, M.; Takeuchi, T. J. Antibiot. 1991, 44, 1277;

5412
S. P. Waters et al. / Tetrahedron Letters 47 (2006) 5409–5413
(b) Panzone, G.; Trani, A.; Ferrari, P.; Gastaldo, L.;
Colombo, L. J. Antibiot. 1997, 50, 665.
5. (a) Trani, A.; Dallanoce, C.; Ferarri, P.; Goldstein, B. P.;
Ripamonti, F.; Ciabatti, R. Il Farmaco 1996, 51, 503; (b)
Trani, A.; Kettenring, J.; Ripamonti, F.; Goldstein, B.;
Ciabatti, R. Il Farmaco 1993, 48, 637.
6. Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.;
Yokoyama, A.; Goto, Y.; Mizushina, Y.; Sakaguchi, K.;
Hayashi, H. Biochemistry 2000, 39, 5995.
7. Krillov, S.; Vitali, L. A.; Goldstein, B. P.; Monti, F.;
Semenkov, Y.; Makhno, V.; Ripa, S.; Pon, C. L.;
Gualerzi, C. O. RNA 1997, 3, 905.
8. (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S.
J. Angew. Chem., Int. Ed. 2001, 40, 4709; (b) Siu, T.; Qin,
D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4713.
9. (a) Capecchi, T.; de Koning, C. B.; Michael, J. P.
Tetrahedron Lett. 1998, 39, 5429; (b) Capecchi, T.; de
Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans.
1 2000, 2681.
J = 11.9 Hz, 1H), 3.64 (d, J = 15.1 Hz, 1H), 3.58 (d,
J = 15.1 Hz, 1H), 3.15 (dd, J = 11.0, 17.3 Hz, 1H), 2.64
(dd, J = 7.8, 17.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
157.7, 156.4, 155.1, 136.9, 136.8, 130.4, 130.1, 128.6, 128.5
(2C), 128.2, 127.8 (2C), 127.1 (2C), 126.3, 124.7, 121.0,
120.9, 111.8, 111.5, 77.2, 70.0, 69.9, 44.3, 28.1; HRMS
(ESI) m/z calcd for C30H27NO3Na (MNa+) 472.1889,
found 472.1880.
1,4-Bis-(2-benzyloxy-phenyl)-4-hydroxy-butan-2-one (16).
To a solution of isoxazoline 15 (418 mg, 0.93 mmol) in
MeOH (50 mL) and H2O (5 mL) were added boric acid
(172 mg, 2.79 mmol) and Raney Ni (10 drops, 50% slurry
in H2O). After stirring under H2 (1 atm) for 5 h at rt, the
reaction mixture was filtered, poured into H2O (50 mL),
and extracted with CH2Cl2 (2 · 50 mL). The combined
organic layers were washed with brine (100 mL), dried
(Na2SO4), and concentrated. Purification of the residue by
flash chromatography (33% EtOAc/hexanes) afforded
keto-alcohol 16 (339 mg, 81% yield) as a clear colorless
1
oil: IR (neat) 3501 (br), 1710, 1602, 1015 cmꢀ1; H NMR
10. Tsang, K. T.; Brimble, M. A.; Bremner, J. B. Org. Lett.
2003, 5, 4425.
11. (a) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826; (b)
Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024.
12. Obtained from Biosearch Italia SpA.
13. For reviews, see: (a) Anomeric Effects; Szarek, W. A.,
Horton, D., Eds. ACS Symposium Series 87; American
Chemical Society: Washington, DC, 1979; (b) Kirby, A. J.
The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen; Springer: Berlin, 1983.
14. For a review of spiroketals including examples controlled
by hydrogen bonding, see: (a) Perron, F.; Albizati, K. F.
Chem. Rev. 1989, 89, 1617–1661; For a specific example of
hydrogen bonding being used to control spiroketal con-
figuration, see: (b) Ireland, R. E.; Habich, D.; Norbeck, D.
W. J. Am. Chem. Soc. 1985, 107, 3271–3278.
15. Spartan ’02 Windows, Wavefunction, Inc., 2001.
16. Harris, T. D.; Roth, G. P. J. Org. Chem. 1979, 44, 2004.
17. Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37,
4209.
18. (a) Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.;
Mihara, S.; Fujita, S.; Tohma, H. J. Org. Chem. 1996,
61, 223; (b) Dauzonne, D.; Royer, R. Synthesis 1984, 1054.
19. Sinhababu, A. K.; Borchardt, R. T. Tetrahedron Lett.
1983, 24, 227.
(500 MHz, CDCl3) d 7.41 (dd, J = 1.6, 7.5 Hz, 1H), 7.33–
7.24 (m, 10H), 7.19 (dd, J = 1.6, 7.4 Hz, 1H), 7.16 (dd,
J = 1.6, 7.5 Hz, 1H), 7.03 (dd, J = 1.6, 7.4 Hz, 1H), 6.94
(t, J = 7.4 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.85 (t,
J = 7.5 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 5.42 (dd,
J = 2.7, 9.0 Hz, 1H), 4.98 (s, 2H), 4.95 (s, 2H), 3.66 (d,
J = 16.1 Hz, 1H), 3.62 (d, J = 16.1 Hz, 1H), 3.53 (br s,
1H), 2.96 (dd, J = 2.7, 17.3 Hz, 1H), 2.72 (dd, J = 9.0,
17.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 209.6, 156.4,
154.8, 136.8 (2C), 131.3 (2C), 128.6, 128.5 (2C), 128.1,
127.9, 127.8, 127.2, 127.0, 126.6, 123.3, 121.1, 121.0, 111.8,
111.5, 70.0, 69.9, 65.6, 48.6, 45.5; HRMS (ESI) m/z calcd
for C30H28O4Na (MNa+) 475.1885, found 475.1874.
Spiroketal (17). To a solution of ketone 16 (200 mg,
0.442 mmol) in EtOH (10 mL) were added HCl (1 drop,
12 M) and Pd/C (40 mg, 10% Pd). After stirring under H2
(1 atm) for 12 h at rt, the reaction mixture was filtered and
concentrated. Purification of the residue by flash chroma-
tography (33% EtOAc/hexanes) afforded spiroketal 17
(82 mg, 78% yield) as a clear colorless oil: IR (neat) 3042,
1
2934, 1586 cmꢀ1; H NMR (500 MHz, CDCl3) d 7.25 (d,
J = 7.5 Hz. 1H), 7.16 (m, 3H), 6.94 (t, J = 7.5 Hz, 2H),
6.82 (d, J = 8.1 Hz, 2H), 3.49 (d, J = 16.5 Hz, 1H), 3.32
(d, J = 16.5 Hz, 1H), 3.28 (ddd, J = 6.2, 13.1, 16.8 Hz,
1H), 2.85 (ddd, J = 3.1, 6.2, 16.2 Hz, 1H), 2.35 (ddd,
J = 2.5, 6.2, 13.1 Hz, 1H), 2.24 (ddd, 6.2, 13.1, 13.1 Hz,
1H); 13C NMR (125 MHz, CDCl3) d 157.8, 152.3, 129.0,
128.1, 127.4, 125.3, 124.8, 121.3, 121.1, 121.0, 117.1, 109.8,
108.9, 41.8, 30.4, 21.9; HRMS (CI) m/z calcd for
C16H14O2 (M+) 238.0994, found 238.0997.
Spiroketals 18a and 18b. A suspension of keto-alcohol 16
(168 mg, 0.37 mmol) and 10% Pd/C (50 mg) in EtOAc
(10 mL) at rt was stirred under H2 (1 atm) overnight. The
reaction mixture was filtered through Celite and the
solvent removed. The residue was then dissolved in
CH2Cl2 (10 mL), and to this solution was added TsOH
(21 mg, 0.11 mmol). After stirring at rt for 45 min, the
reaction mixture was concentrated, and the residue puri-
fied by flash chromatography (25% EtOAc/hexanes) to
afford first spiroketal 18a (57 mg), followed by spiroketal
18b (25 mg) in 87% combined yield. Major diastereomer
18a: white solid; mp 126–127 ꢁC; IR (film) 3489 (br), 1586,
1212, 1065 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 7.49 (dd,
J = 1.9, 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.24 (td,
J = 1.9, 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.06 (td,
J = 1.3, 7.5 Hz, 1H), 6.97 (td, J = 1.3, 7.5 Hz, 1H), 6.83
(d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 4.78 (ddd,
J = 1.7, 5.0, 11.8 Hz, 1H), 3.53 (d, J = 16.4 Hz, 1H), 3.50
(d, J = 11.8 Hz, 1H, OH), 3.38 (d, J = 16.4 Hz, 1H), 2.67
20. Kumar, G. A.; McAllister, M. A. J. Org. Chem. 1998, 63,
6968–6972.
21. Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
604209. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
22. 4-(2-Benzyloxy-benzyl)-6-(2-benzyloxy-phenyl)-5,6-dihydro-
2H-[1,3] oxazine (15). To a solution of nitroalkane 14
(257 mg, 1.00 mmol) and styrene 12 (210 mg, 1.00 mmol)
in PhH (10 mL) at rt were added PhNCO (435 lL,
4.00 mmol) and Et3N (28 lL, 0.20 mmol). After 24 h, the
reaction mixture was filtered and the solvent removed.
Purification by flash chromatography (20% EtOAc/hex-
anes) afforded isoxazoline 15 (418 mg, 93% yield) as a
clear colorless oil: IR (neat) 1602, 1494, 1243, 1015 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 7.32 (d, J = 7.5 Hz, 1H),
7.27–7.19 (m, 10H), 7.11 (t, J = 7.5 Hz, 1H), 7.08 (d,
J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.83 (t,
J = 7.5 Hz, 1H), 6.80–6.77 (m, 3H), 5.69 (dd, J = 7.8,
11.0 Hz, 1H), 4.93 (d, J = 11.9 Hz, 1H), 4.92 (d, J =
11.2 Hz, 1H), 4.90 (d, J = 11.2 Hz, 1H), 4.89 (d,

S. P. Waters et al. / Tetrahedron Letters 47 (2006) 5409–5413
5413
(dd, J = 1.7, 14.5 Hz, 1H), 2.53 (dd, J = 5.0, 14.5 Hz, 1H);
13C NMR (125 MHz, CDCl3) d 157.3, 151.0, 130.6, 129.8,
128.2, 124.9, 124.6, 123.8, 122.1, 121.7, 117.5, 110.1, 109.4,
63.5, 42.2, 38.5; HRMS (CI) m/z calcd for C16H14O3 (M+)
254.0943, found 254.0953. Minor diastereomer 18b: white
solid; mp 85–86 ꢁC; IR (film) 3350 (br), 1586, 1204,
7.5 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 8.0 Hz,
1H), 6.79 (d, J = 8.0 Hz, 1H), 5.29 (ddd, J = 6.1, 7.0,
10.4 Hz, 1H), 3.48 (d, J = 16.6 Hz, 1H), 3.36 (d,
J = 16.6 Hz, 1H), 2.68 (dd, J = 6.1, 13.0 Hz, 1H), 2.28
(dd, J = 10.4, 13.0 Hz, 1H), 1.89 (d, J = 7.0 Hz, 1H, OH);
13C NMR (125 MHz, CDCl3) d 157.7, 151.4, 129.2, 128.2,
126.5, 125.1, 125.0, 124.9, 121.8, 121.4, 116.9, 110.0, 109.9,
63.4, 41.9, 39.9; HRMS (CI) m/z calcd for C16H12O2
([MꢀOH]+) 236.0837, found 236.0827.
1038 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.54 (d,
;
J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.21 (td, J =
1.9, 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (td, J = 1.3,