Advanced Tetracycles in a Stereoselective Approach to d,l-Spongiatriol and Related Metabolites: The Use of Radicals in the Synthesis of Angular Electrophores

Article abstract of DOI:10.1021/jo971632f

A stereoselective radical cascade cyclization of polyene 6, containing an α,β-unsaturated cyano group, was employed to control six contiguous chiral centers and to introduce a C-8 angular CN group in tricycle 7. The cyano group was ultimately utilized as an entry to a C-8 angular hydroxymethyl group. Compound 7 was converted into two key tetracycles 22 and 25, respectively, each possessing an intact D-furan ring system and containing the necessary functionality for further chemical elaboration to the highly oxygenated spongians 1-5.

Full text of DOI:10.1021/jo971632f

1162
J . Org. Chem. 1998, 63, 1162-1167
Ad va n ced Tetr a cycles in a Ster eoselective Ap p r oa ch to
d ,l-Sp on gia tr iol a n d Rela ted Meta bolites: Th e Use of Ra d ica ls in
th e Syn th esis of An gu la r Electr op h or es
Phillip A. Zoretic,* Yongzheng Zhang, and Haiquan Fang
Department of Chemistry, East Carolina University, Greenville, North Carolina 27858
Anthony A. Ribeiro† and George Dubay§
Duke NMR Spectroscopy Center, Department of Radiology, Duke University Medical Center,
Durham, North Carolina 27710, and Department of Chemistry, Duke University, P. M. Gross Chemical
Laboratories, Durham, North Carolina 27708
Received September 3, 1997
A stereoselective radical cascade cyclization of polyene 6, containing an R,â-unsaturated cyano group,
was employed to control six contiguous chiral centers and to introduce a C-8 angular CN group in
tricycle 7. The cyano group was ultimately utilized as an entry to a C-8 angular hydroxymethyl
group. Compound 7 was converted into two key tetracycles 22 and 25, respectively, each possessing
an intact D-furan ring system and containing the necessary functionality for further chemical
elaboration to the highly oxygenated spongians 1-5.
In tr od u ction
cyclization to introduce stereoselectively five of the six
stereogenic centers present in the spongian.5 We have
also shown that an angular electrophore6 can readily be
introduced in polycycles via a radical cascade cyclization
of a polyene containing an R,â-unsaturated cyano moiety
and have extended this type of methodology in the
synthesis of a D-homosteroid.7 The combination of these
two strategies (Scheme 1) should provide a stereoselective
entry to spongiatriols 1-5 via the common intermediate
8. Here, intramolecular oxidative radical cyclization of
6 can be effectively utilized to (1) control the desired
6-endo-trig mode in the second radical cyclization step;
(2) stereoselectively introduce, in one step, six key chiral
centers at C-4, 5, 8, 9, 10, and 14 in tricycle 7; (3) provide
an angular 8â-cyano group for further elaboration to a
hydroxymethyl group; (4) introduce appropriate func-
tionality in the A-ring system; and (5) provide a func-
tional group in the termination step that can be used in
the construction of the D-furan ring system. We describe
here the application of this type of radical methodology
in the synthesis of two advanced tetracycle intermediates
that could ultimately be utilized in the total synthesis of
the targeted spongians.
The highly oxygenated tetracyclic diterpenes spongia-
triol (1)1,2 and epispongiatriol (2) were isolated from a
Spongia species off the Great Barrier Reef in the Aus-
tralian waters. The diosphenol 3,3 a sponge metabolite,
was isolated from the nudibranch Casella atromarginata,
at Trincomallee, Sri Lanka. The source of the diterpenes
from the nudibranch is presumed to be obtained indi-
rectly from a sponge in the mollusk’s diet. Two additional
spongian metabolites (4 and 5) possessing an A-ring
lactone system have also been isolated from a Spongia
species from the Great Barrier Reef.2 The latter me-
tabolite (5) was shown to possess moderate cytotoxicity
to P338 murine leukemia cells.
Resu lts a n d Discu ssion
The synthesis of polyene 6 was achieved by using a
similar protocol previously developed by us6 as detailed
in Scheme 2. Horner-Emmons reaction8 of the potas-
sium salt of cyano phosphonate 96 with aldehyde 10 (eq
1) gave an 81:19 mixture of 11 and the corresponding
Recently we4 reported the synthesis of d,l-isospongia-
diol using in part an intramolecular oxidative free-radical
† Duke University Medical Center.
(5) For several approaches to spongians using chiral relay starting
materials, see: Abad, A.; Agullo, C.; Arno, M.; Marin, M. L.; Zaragoza,
R. J . J . Chem. Soc., Perkin Trans. 1 1996, 2193 and references within.
(6) Zoretic, P. A.; Zhang, Y. Tetrahedron Lett. 1996, 37, 1751.
(7) Zoretic, P. A.; Chen, Z.; Zhang, Y. Tetrahedron Lett. 1996, 37,
7909.
‡ P.M. Gross Chemical Laboratories.
(1) Kazlauskas, R.; Murphy, P. T.; Wells, R. J .; Noack, K.; Ober-
hansli, W. E.; Schonholzer, P. Aust. J . Chem. 1979, 32, 867.
(2) Gunasekera, S. P.; Schmitz, F. J . J . Org. Chem. 1991, 56, 1250.
(3) Sheuer, P. J .; de Silva, E. D. Heterocyclics 1982, 17, 167.
(4) Zoretic, P. A.; Wang, M.; Zhang, Y.; Shen, Z.; Riberio, A. A. J .
Org. Chem. 1996, 61, 1806.
(8) Takahashi, T.; Katouda, W.; Sakamoto, Y.; Tomida, S.; Yamada,
H. Tetrahedron Lett. 1995, 36, 2273.
S0022-3263(97)01632-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

Tetracycles in the Synthesis of d,l-Spongiatriols
J . Org. Chem., Vol. 63, No. 4, 1998 1163
Sch em e 1
Sch em e 3a
Sch em e 2a
a
Key: (a) Mn(OAc)3‚2H2O, Cu(OAc)2‚H2O, HOAc, Ar; (b)
n-Bu4NF, THF; (c) m-CPBA, CH2Cl2; (d) CrO3‚2py, CH2Cl2; (e)
p-TsOH‚H2O, DMSO, 50 °C.
desilylated with n-Bu4NF12 to give 7a and 7b in 88%
yield. Subsequent chromatography on silica gel afforded
pure 7a (70%).
a
Key: (a) KN(SiMe3)2, toluene, -78 °C; (b) 10, -78 °C f rt,
overnight; (c) MeOH, p-TsOH‚py; (d) CBr4, Ph3P, CH2Cl2; (e)
LiCH2C(O)CMe(Na)CO2Et, 0 °C, THF; then aqueous HCl.
2E,6E-isomer. The desired 2E,6Z-nitrile 11 was chro-
A series of 2D COSY, HMQC, HMBC, and 1D APT
NMR studies was used to determine the assignment of
each proton and carbon resonance signal in 7a . Using
these assignments, NOE difference spectra (NOEDS) of
7a were used to confirm the stereochemistry derived from
the cyclization process. Irradiation of the C-10 Me (δ
1.21) showed enhancements of the ester methylene
protons (δ 4.15), C-2 axial proton (δ 2.99), C-6 axial
proton (δ 2.26), C-1 equatorial proton (δ 2.13), and the
C-11 axial proton (δ 1.63). Likewise irradiation of the
C-9 axial proton (δ 1.24) gave a strong enhancement of
the C-14 axial proton (δ 2.16), the C-5 axial proton (δ
1.34), and the C-1 axial proton (δ 1.33) and a weaker
enhancement to the C-12 axial proton (δ 2.04), the C-7
axial proton (δ 1.46), and the C-11 equatorial proton (δ
1.94). Irradiation of both of the C-1 axial (δ 1.33) and
the C-5 axial (δ 1.34) protons showed enhancements to
the C-9 axial proton (δ 1.24 ), C-2 equatorial proton (δ
2.43), C-1 equatorial proton (δ 2.13), C-6 equatorial
proton (δ 2.01), and the C-7 axial proton (δ 1.46), thus
confirming the all-trans stereochemistry and the C-4
â-disposition of the carbethoxy group as shown in 7a . It
matographically separated from the isomer to afford pure
11 in 78% yield. Conversion of 11 to polyene 6 (44%
overall yield) in three steps was realized by (1) cleavage
of the THP protecting group in 11 to give alcohol 12; (2)
conversion of alcohol 12 to the corresponding bromide 13;
and (3) alkylation of 13 (inverse addition) with the
dianion9 of ethyl 2-methylacetoacetate.
Intramolecular oxidative free-radical cyclization of 6
(Scheme 3) with a 2:1 ratio of Mn(OAc)3‚2H2O in tandem
with Cu(OAc)2‚H2O10,11 in a 0.1 M solution of deaerated
HOAc afforded an 81:19 ratio of 16a and 16b in 58%
yield, after chromatography. Since it was determined
that the exo and endo products could be separated more
easily at the alcohol stage, the mixture of 16 was directly
(9) Huckin, S. N.; Weiler, L. J . J . Am. Chem. Soc. 1974, 96, 1082.
(10) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J . Am. Chem. Soc.
1990, 112, 2759 and references within.
(11) For recent radical reviews, see: (a) Snider, B. B. Chem. Rev.
1996, 96, 339. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996,
96, 177. (c) Malacria, M. Chem. Rev. (Washington, D.C.) 1996, 96, 289.
(d) Iqbal, J .; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519. (e)
Melikyan, G. G. Synthesis 1993, 833.
(12) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.

1164 J . Org. Chem., Vol. 63, No. 4, 1998
Zoretic et al.
Sch em e 4a
Sch em e 5a
a
Key: (a) NaBH4, EtOH; (b) CF3SO2Cl, 4-DMAP, CH2Cl2, 0 °C;
(c) 4-DMAP, CH2Cl2, ∆; (d) 3.3 equiv of DIBALH, -78 °C, toluene,
then 6% HOAc saturated with NaOAc, -78 °C f rt.
triethylamine to give 21 (72%). Subsequent oxidation of
21 with Collins reagent yielded the targeted ketone 22
(67%).
a
Key: (a) 6.0 equiv of DIBALH, toluene, -78 °C; (b) 6% HOAc,
A second intermediate 25 (Scheme 5) was also targeted,
since it was anticipated that such a derivative should be
suitable for further elaboration to metabolite 4. The
introduction of the ∆2,3-double bond in 25 was acheived
in the following manner. Hydride reduction of 8 gave
alcohol 23 (88%). Treatment of 23 with POCl3 in refuxing
pyridine afforded 24 in only 40% yield. However it was
found that a two-step process produced 24 in excellent
yield. Thus, reaction of alcohol 23 with trifluoromethane-
sulfonyl chloride at 0 °C in the presence of 4-DMAP gave
a mixture of the corresponding sulfonated ester (major
product) and a trace of 24. Heating this mixture with
4-DMAP in refluxing CH2Cl2 yielded 24 (94%, two steps).
The introduction of the desired C-4â-hydroxymethyl
group present in 25 appeared at first to be somewhat
difficult. It is known that LiBH4 in THF can selectively
reduce an ester in the presence of a nitrile. Attempted
LiBH4 reduction of 24 in our case gave only partial
reduction of the ester group. However, it was encourag-
ing to find that reduction of 24 with 3.3 equiv of DIBALH
at -78 °C in toluene followed by hydrolysis of the
intermediate imine with 6% HOAc saturated with NaOAc
gave the targeted hydroxy aldehyde 25 directly in 74%
yield. The stereochemistry shown in 25 was proven to
be correct on the basis of the following NOE study.
Irradition of the 20-Me (δ 0.88) in 25 gave enhancements
of the aldehydic proton (δ 9.86), the vinyl proton (δ 5.63),
one of the hydroxymethyl protons (δ 3.36), the C-1
equatorial proton (δ 2.15), and the C-11 axial proton (δ
2.07). Indirectly this NOE study also confirms the
assigned stereochemistry in tricycle 7a vide supra.
saturated with NaOAc, -78 °C f rt; (c) LAH, THF, ∆; (d) 4.4 equiv
of TBDMSCl, 4-DMAP, CH2Cl2, rt; (e) CrO3‚2py, CH2Cl2, rt.
is also noted that the large deshielding effect of the C-10
Me (δ 1.21) in 7a is comparable to the chemical shift (δ
1.28) observed for an analogue6 possessing an angular
C-8 CN group which is consistent with the C-10 Me in
7a being 1,3-diaxially disposed to the nitrile and in its
deshielding cone. The stereospecificity derived in tetra-
cycles 16 from cyclization of polyene 6 is presumably due
to a stepwise process opposed to a concerted one in which
the most stable ring system is formed at each cyclization
stage in the radical cascade sequence.
The construction of the intact spongian skeleton 8 was
realized from 7a in three steps in 55% overall yield.
Reaction of 7a with m-CPBA gave epoxide 17. The
epoxide stereochemistry in 17 is tentatively assigned in
analogy with that observed in a similar case.4 It is also
noted here that the C-13 center will ultimately be
destroyed during the formation of the D-furan ring
system. Thus, Collins oxidation of 17 followed by treat-
ment of the resulting aldehyde 18 with p-TsOH‚H2O in
DMSO gave tetracycle 8.
With the spongian skeleton secured, our next objective
was to introduce the desired hydroxymethyl group at C-8
and then to modify the A-ring system in an attempt to
obtain two different intermediates that could be used in
separate approaches to the afore-mentioned spongians.
Toward these ends compounds 22 and 25 derivable from
8 were targeted. Reaction of 8 (Scheme 4) with 6.0 equiv
of DIBALH in toluene at -78 °C and subsequent hy-
drolysis of the resulting imine with 6% HOAc saturated
with NaOAc gave ester 19 in 73% yield, after chroma-
tography. Presumably in the reduction of 8 the keto
group is preferentially reduced to form an intermediate
in which the generated C-3 â-diisobutylaluminum alkox-
ide group can chelate with the carbonyl of the ester, thus
blocking complexation with a DIBALH molecule. Hy-
dride reduction of 19 with LAH afforded triol 20 (96%).
Preferential protection of the primary alcohols in the
presence of the secondary alcohol was effected by reaction
of 20 with TBDMSCl12 in the presence of 4-DMAP13 and
Con clu sion
In conclusion, a highly stereoselective radical cascade
cyclization strategy was developed as a facile entry to
various oxygenated spongiatriols. A key factor being the
introduction of a latent angular electrophore at the
cyclization stage which ultimately served as an entry to
the desired angular hydroxymethyl group. In addition,
the synthetic intermediates 22 and 25 can serve as key
compounds en route to spongians 1-5.
(13) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99.

Tetracycles in the Synthesis of d,l-Spongiatriols
J . Org. Chem., Vol. 63, No. 4, 1998 1165
127.6, 125.4, 117.4, 113.8, 60.9, 40.9, 38.0, 33.6, 29.5, 26.8, 19.1,
Exp er im en ta l Section
16.1, 14.8; IR (neat) 2217 cm-1
. Anal. Calcd for C31H40-
Gen er a l P r oced u r es. NMR spectra were obtained at 200,
300, 500, and 600 MHz. C and H microanalyses were obtained
from Galbraith Laboratories. HRMS analyses were obtained
from the Mass Spectroscopy Facility at Duke. All melting
points are uncorrected. Preparative chromatography was
preformed on Merck silica gel G 60 (70-230 mesh) and Merck
silica gel G (230-400 mesh, for pressure chromatography).
TLC was performed with Sybron/Brinkmann silica gel G/UV
254 plates, 0.25 mm (analytical). Compounds on chromatog-
raphy plates were visualized by spraying with 4% phospho-
molybdic acid in isopropyl alcohol followed by heating. THF
was distilled from sodium benzophenone ketyl. Commercial
reagent grade solvents and chemicals were used as obtained
unless otherwise noted.
(2E,6Z,10E)-12-[(ter t-Bu tyld ip h en ylsilyl)oxy]-6-cya n o-
2,10-d im eth yl-1-[(tetr a h yd r o-2H-p yr a n -2-yl)oxy]-2,6,10-
d od eca tr ien e (11). KN(SiMe3)2 (0.5 M in toluene, 31.8 mL,
15.9 mmol) was added dropwise to phosphonate 9 (5.95 g, 16.6
mmol) in dry toluene (60 mL) at -78 °C over 30 min under
N2. Stirring was continued for 1 h, aldehyde 10 (5.06 g, 13.8
mmol) in toluene (50 mL) was added over 1 h, stirring was
continued for 4 h at -78 °C, and then the reaction mixture
was gradually warmed to rt and stirred overnight. The
reaction mixture was diluted with Et2O, and the organic
solution was washed with H2O, brine, dried (Na2SO4), and
concentrated in vacuo to afford an oil. Chromatography on
silica gel (70-230 mesh, 80 g) and elution with 2% and 5%
EtOAc-hexanes gave 6.2 g (78%) of 11 and 450 mg of a
mixture of 11 and the 2E,6E-isomer. For 11: 1H NMR (CDCl3)
δ 7.63-7.74 (m, 4H), 7.32-7.45 (m, 6H), 6.10 (t, 1H, J ) 7.5
Hz), 5.32-5.45 (m, 2H), 4.59 (t, 1H, J ) 3.2 Hz), 4.22 (d, 2H,
J ) 6.2 Hz), 4.10 (d, 1H, J ) 11.8 Hz), 3.84 (d, J ) 11.8 Hz)
and 3.80-3.94 (m) [2H], 3.45-3.56 (m, 1H), 2.44 (m, 2H),
2.20-2.31 (m, 4H), 2.09 (m, 2H), 1.67 (s), 1.46 (s) and 1.41-
1.90 (m) [12H], 1.04 (s, 9H); 13C NMR (CDCl3, 77.0) δ 147.3,
135.5, 135.1, 133.9, 129.5, 127.6, 125.4, 124.8, 117.5, 114.3,
97.5, 72.4, 62.1, 60.9, 38.1, 34.0, 30.6, 29.5, 26.8, 26.3, 25.4,
19.4, 19.1, 16.1, 14.1; IR (neat) 2212 cm-1. Anal. Calcd for
BrNOSi: C, 67.62; H, 7.32; N, 2.54. Found: C, 67.22; H, 7.17;
N, 2.34.
(E)-1-[(ter t-Bu t yld ip h en ylsilyl)oxy]-3,7-d im et h yl-6,7-
oxid o-2-octen e (15). Imidazole (7.89 g, 116.0 mmol), TBDP-
SCl (15.4 mL, 58.0 mmol), and 14 (7.59 g, 44.6 mmol) in DMF
(40 mL) were stirred at rt for 2.5 h. The solvent was removed
in vacuo (50 °C, 0.5 mm), and the residue was diluted with
CH2Cl2. The organic solution was washed with H2O, brine,
dried (Na2SO4), and concentrated in vacuo to afford an oil.
Chromatography on silica gel (70-230 mesh, 100 g) eluting
with 2% EtOAc-hexanes gave 17.9 g (98%) of 15: 1H NMR
(CDCl3) δ 7.63-7.74 (m, 4H), 7.32-7.45 (m, 6H), 5.39-5.50
(m, 1H), 4.23 (d, 2H, J ) 6.2 Hz), 2.70 (t, 1H, J ) 6.2 Hz),
2.02-2.19 (m, 2H), 1.47-1.61 (m, 2H), 1.46 (s, 3H), 1.30 (s,
3H), 1.26 (s, 3H), 1.04 (s, 9H); 13C NMR (CDCl3, 77.0) δ 136.0,
135.5, 133.9, 129.5, 127.5, 124.5, 64.0, 61.0, 58.3, 36.0, 27.1,
26.8, 24.8, 19.1, 18.7, 16.3. The epoxide was not characterized
further but submitted to oxidation.
(E)-6-[(ter t-Bu t yld ip h en ylsilyl)oxy]-4-m et h yl-4-h exe-
n a l (10). HIO4‚2H2O (10.4 g, 45.7 mmol) in THF (100 mL)
was added to a solution of 15 (17.0 g, 41.6 mmol) in Et2O (200
mL) at 0 °C over 1 h, and stirring was continued for an
additional 1 h at 0 °C. The reaction mixture was diluted with
Et2O, washed with H2O, saturated NaHCO3, H2O, and brine,
dried (Na2SO4), and concentrated in vacuo to give an oil.
Chromatography on silica gel (70-230 mesh) eluting with 2%
EtOAc-hexanes gave 11.1 g (73%) of 10: 1H NMR (CDCl3) δ
9.75 (t, 1H, J ) 1.7 Hz), 7.63-7.74 (m, 4H), 7.32-7.45 (m, 6H),
5.34-5.43 (m, 1H), 4.21 (dd, 2H, J ) 0.8, 6.2 Hz), 2.44-2.56
(m, 2H), 2.22-2.36 (m, 2H), 1.44 (s, 3H), 1.04 (s, 9H); 13C NMR
(CDCl3, 77.0) δ 202.2, 135.5, 134.9, 134.7, 133.8, 129.5, 127.63,
127.56, 124.9, 60.9, 41.8, 31.4, 26.8, 26.5, 19.1, 16.4. Anal.
Calcd for C23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.25; H,
8.36.
E t h yl (6E,10Z,14E)-16-[(ter t-Bu t yld ip h en ylsilyl)oxy]-
10-cya n o-2,6,14-t r im e t h yl-3-oxo-6,10,14-h e xa d e ca t r i-
en oa te (6). Ethyl 2-methylacetoacetate (98%, 0.946 g, 6.44
mmol) was added via a syringe to a suspension of NaH (60%
in mineral oil, 257 mg, 6.44 mmol) and HMPA (1 mL) in dry
THF (20 mL) at 0 °C under N2 over 15 min. The reaction
mixture was stirred at 0 °C for 30 min. n-BuLi (2.5 M in
hexanes, 2.57 mL, 6.44 mmol) was added via a syringe over
15 min, and stirring was continued for 30 min. The generated
dianion of ethyl 2-methylacetoacetate was added to bromide
13 (2.95 g, 5.36 mmol) in dry THF (10 mL) at 0 °C over 45
min. The reaction mixture was stirred for 1 h at 0 °C,
quenched with 10% HCl (pH ) 7), and then diluted with CH2-
Cl2 (100 mL). The organic solution was washed with H2O,
brine, dried (Na2SO4), and concentrated in vacuo to give an
oil. Chromatography on silica gel (230-400 mesh, 20 g) and
elution with 5% EtOAc-hexanes gave 2.18 g (66%) of 6: 1H
NMR (CDCl3) δ 7.63-7.74 (m, 4H), 7.32-7.45 (m, 6H), 6.09
(t, 1H, J ) 7.4 Hz), 5.33-5.45 (m, 1H), 5.02-5.13 (m, 1H),
4.12-4.28 (m, 4H), 3.51 (q, 1H, J ) 7.2 Hz), 2.57-2.71 (m,
2H), 2.36-2.53 (m, 2H), 2.04-2.32 (m, 8H), 1.60 (s, 3H), 1.46
(s, 3H), 1.33 (d, J ) 7.2 Hz) and 1.27 (t, J ) 7.2 Hz) [6H], 1.04
(s, 9H); 13C NMR (CDCl3, 77.0) δ 205.4, 170.5, 147.3, 135.5,
135.4, 135.1, 133.9, 129.5, 127.6, 125.4, 122.7, 117.6, 114.4,
61.3, 60.9, 52.9, 39.9, 38.1, 34.2, 33.1, 29.5, 26.8, 26.7, 19.1,
16.1, 14.1, 12.8; IR (neat) 2214, 1743, 1716 cm-1. Anal. Calcd
for C38H51NO4Si: C, 74.35; H, 8.37; N, 2.28. Found: C, 74.19;
H, 8.32; N, 2.59.
C
36H49O3NSi: C, 75.61; H, 8.64; N, 2.45. Found: C, 75.74; H,
8.69; N, 2.53.
(2E,6Z,10E)-12-[(ter t-Bu tyld ip h en ylsilyl)oxy]-6-cya n o-
2,10-d im eth yl-2,6,10-d od eca tr ien -1-ol (12). A solution of
nitrile 11 (1.00 g, 1.75 mmol) and p-TsOH‚py (48 mg, 0.193
mmol) in MeOH (10 mL) was stirred for 10 h at rt. The solvent
was removed in vacuo and the residue diluted with CH2Cl2.
The organic solution was washed with saturated NaHCO3,
brine, dried (Na2SO4), and concentrated in vacuo to afford an
oil. Chromatography on silica gel (230-400 mesh, 20 g) and
elution with 20% EtOAc-hexanes gave 0.70 g (82%) of 12: 1H
NMR (CDCl3) δ 7.65-7.74 (m, 4H), 7.33-7.45 (m, 6H), 6.11
(t, 1H, J ) 7.5 Hz), 5.32-5.44 (m, 2H), 4.21 (d, 2H, J ) 6.2
Hz), 3.99 (br s, 2H), 2.45 (m, 2H), 2.22-2.30 (m, 4H), 2.09 (m,
2H), 1.67 (s, 3H), 1.46 (br s, 4H, CH3 and OH), 1.04 (s, 9H);
13C NMR (CDCl3, 77.0) δ 147.4, 136.5, 135.5, 135.0, 133.7,
129.5, 127.5, 125.3, 122.8, 117.6, 114.2, 68.3, 60.9, 38.0, 33.9,
29.4, 26.7, 26.3, 19.0, 16.0, 13.7; IR (neat) 3447, 2215 cm-1
.
Anal. Calcd for C31H41NO2Si: C, 76.34; H, 8.47; N, 2.87.
Found: C, 75.99; H, 8.26; N, 3.26.
(2E,6Z,10E)-1-Br om o-12-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
6-cya n o-2,10-d im eth yl-2,6,10-d od eca tr ien e (13). Carbon
tetrabromide (2.85 g, 8.58 mmol) was added in several portions
to alcohol 12 (2.79 g, 5.73 mmol) and Ph3P (1.95 g, 7.44 mmol)
in dry CH2Cl2 (30 mL) at rt, and the reaction mixture was
stirred for 1.5 h. The solvent was removed in vacuo. Hexanes
(100 mL) was added to the residue, and the triphenylphosphine
oxide was removed by filtration. Concentration of the filtrate
and subsequent chromatography on silica gel (70-230 mesh,
20 g) eluting with 2% EtOAc-hexanes gave 2.95 g (94%) of
13: 1H NMR (CDCl3) δ 7.63-7.74 (m, 4H), 7.32-7.46 (m, 6H),
6.10 (t, 1H, J ) 7.5 Hz), 5.35-5.57 (m, 2H), 4.21 (d, 2H, J )
6.2 Hz), 3.94 (s, 2H), 2.45 (m, 2H), 2.20-2.34 (m, 4H), 2.10
(m, 2H), 1.77 (s, 3H), 1.46 (s, 3H), 1.04 (s, 9H); 13C NMR
(CDCl3, 77.0) δ 147.8, 135.5, 135.0, 134.0, 133.8, 129.5, 128.4,
d ,l-(1r,4a r,4bâ,8â,8a â,10a â)-Eth yl 8-[(ter t-Bu tyld ip h e-
n ylsilyl)oxy]-8a -cya n o-1,4a -d im eth yl-7-m eth ylen e-2-oxo-
1,4,4a ,4b,5,8,8a ,9,10,10a -d eca h yd r o-1-p h en a n th r en eca r -
b oxyla t e (16a ) a n d d ,l-(1a ,4a r,4b â,8â,8a â,10a â)-E t h yl
8-[(ter t-Bu tyldiph en ylsilyl)oxy]-8a-cyan o-1,4a,7-tr im eth yl-
2-oxo-1,4,4a ,4b,5,8,8a ,9,10,10a -d eca h yd r o-1-p h en a n th r en -
eca r boxyla te (16b). To keto ester 6 (1.54 g, 2.51 mmol) in
deaerated HOAc (25 mL) were added Mn(OAc)3‚2H2O (98%,
1.37 g, 5.02 mmol) and Cu(OAc)2‚H2O (97%, 0.52 g, 2.51 mmol).
The reaction mixture was stirred at rt for 10 h and then passed
through a bed of Celite (salts washed with 100 mL of CH2-

1166 J . Org. Chem., Vol. 63, No. 4, 1998
Zoretic et al.
Cl2). The organic solution was washed with H2O, saturated
NaHCO3, and brine, dried (Na2SO4), and concentrated in vacuo
gave a thick oil. Chromatography on silica gel (270-400 mesh,
20 g) and elution with 10% EtOAc-hexanes gave 887 mg (58%)
of an 81:19 mixture of 16a and 16b. The ratio was determined
by integration of the resonance signals at δ 5.55 (br s) and
4.99 (s) and 4.84 (s). It was found that the isomers could be
more readily separated at the alcohol stage. Thus, the mixture
was submitted directly to a desilylation reaction.
d ,l-(1r,4a r,4b â,7â,8a â,10a â)-E t h yl 8a -Cya n o-7,7-(ep -
o x y m e t h y l e n e ) -8 -f o r m y l -1 , 4 a -d i m e t h y l -2 -o x o -
1,4,4a ,4b ,5,6,7,8,8a ,9,10,10a -d od eca h yd r o-1-p h en a n t h r -
en eca r boxyla te (18). Collins reagent: prepared from dry
CrO3 (308 g, 3.08 mmol) and pyridine (487 mg, 6.17 mmol) in
dry CH2Cl2 (10 mL) under N2 with stirring for 20 min. The
reagent was cooled to 0 °C, alcohol 17 (200 mg, 0.51 mmol) in
CH2Cl2 (5 mL) was added dropwise over 10 min, and stirring
was continued for 45 min. The reaction mixture was passed
through a short bed of Celite-silica gel, and the residue was
washed with CH2Cl2. The solvent was removed in vacuo to
afford crude aldehyde 18: 1H NMR (CDCl3) δ 9.58 (d, 1H, J )
3 Hz), 4.17 (m, 2H), 3.08 (m) and 3.01 (6 line ddd, J ) 6.4,
14.7, 14.7 Hz) [2H], 2.82 (m, 1H), 2.67 (br d, 1H, J ) 2.6 Hz),
1.37 (s), 1.29 (t, 3H, J ) 7.1 Hz), 1.28 (s, 3H). The aldehyde
was not characterized further but was submitted directly to
cyclization.
d,l-(1r,4ar,4bâ,8â,8aâ,10aâ)-Eth yl 8a-Cyan o-8-(h ydr oxy-
m e t h yl)-1,4a -d im e t h yl-7-m e t h yle n e -2-oxo-1,4,4a ,4b ,-
5,8,8a,9,10,10a-decah ydr o-1-ph en an th r en ecar boxylate (7a)
a n d d ,l-(1r,4a r,4bâ,8â,8a â,10a â)-Eth yl 8a -Cya n o-8-(h y-
d r o x y m e t h y l)-1,4a ,7-t r im e t h y l-2-o x o -1,4,4a ,4b ,5,8,-
8a ,9,10,10a -d eca h yd r o-1-p h en a n th r en eca r boxyla te (7b).
n-Bu4NF (1.0 M in THF, 2.9 mL, 2.90 mmol) was added
dropwise via a syringe to an 81:19 mixture of 16a and 16b
(887 mg, 1.45 mmol) in dry THF (10 mL) at rt. The reaction
mixture was stirred for 2 h and then diluted with CH2Cl2 (100
mL). The organic solution was washed with H2O, and brine,
dried (Na2SO4), and concentrated in vacuo to give a solid.
Chromatography on silica gel (230-400 mesh, 20 g) and
elution with 30% EtOAc-hexanes gave 94 mg (17%) of 7b and
381 mg (70%) of 7a . For 7a : mp 176-177.5 °C; 1H NMR
(CDCl3, 600 MHz) δ 5.11 (s, 1H), 4.92 (s, 1H), 4.15 (m, 2H,
d ,l-4â-Ca r beth oxy-8â-cya n o-4r,10â-d im eth yl-3-oxo-13-
n or -16-oxoa n d r osta -13,14-d ien e (8). The crude aldehyde
18 in 5% p-TsOH‚H2O in DMSO (5 mL) was heated at 50 °C
for 20 h with stirring. The solvent was removed in vacuo (50
°C at 0.4 mm); the residue was diluted with CH2Cl2 and the
organic solution was washed with saturated NaHCO3, H2O,
and brine, dried (Na2SO4), and concentrated in vacuo to give
a solid. Chromatography on silica gel (3 g, 270-400 mesh)
eluting with 30% ethyl acetate-hexanes gave 114 mg (60%,
two steps from 17) of 8: mp 182.6-183.8 °C; 1H NMR (CDCl3)
δ 7.38 (d, 1H, J ) 1.3 Hz), 7.16 (s, 1H), 4.19 (m, 2H), 3.05 (6
line ddd, J ) 6.5, 14.8, 14.8 Hz) and 2.90 (br dd, J ) 5.4, 14.3
Hz) [2H], 2.69 (dt, 1H, J ) 3.2, 13.2 Hz), 2.33-2.59 (m, 3H),
2.23 (ddd, 1H, J ) 2.4, 6.5, 13.3 Hz), 1.75-2.13 (m, 3H), 1.63
(6 line ddd, 1H, J ) 3.4, 13.5, 13.5 Hz), 1.39 (s, 3H), 1.30 (s,
3H and t, 3H, J ) 7.2 Hz) and 1.18-1.47 (m) [3H]; 13C NMR
(CDCl3, 77.0) δ 207.4, 173.1, 138.3, 137.8, 125.8, 122.9, 118.8,
61.4, 57.3, 56.7, 54.2, 39.7, 37.8, 37.5, 36.2, 36.1, 21.5, 21.3,
OCH2CH3), 4.02 (m, 2H, CH2OH), 2.99 (6 line ddd, 1H, H2ax
,
J ) 6.5, 14.9, 14.9 Hz), 2.52 (apparent dt, H12eq, J ) ∼3.4,
∼13.1 Hz) and 2.49 (dt, H7eq, J ) 3.4, 13.5 Hz) [overlapping,
2H], 2.43 (dq, 1H, H2eq, J ) 2.4, 15.0 Hz), 2.26 (m, 1H, H6ax),
2.16 (m, H14ax) and 2.13 (ddd, H1eq, J ) 2.4, 6.6, 13.2 Hz)
[overlapping, 2H], 2.04 (6 line ddd, H12ax, J ) 4.6, 13.1, 13.1
Hz) and 2.01 (dq, H6eq, J ) ∼3.4, ∼14.9 Hz) [overlapping, 2H],
1.94 (dp, 1H, H11eq, J ) ∼2.5, ∼13.5 Hz), 1.63 (8 line dddd,
1H, H11ax, J ) 4.1, 13.0, 13.0, 13.0 Hz), 1.57 (dd, OH, J ) 4.2,
7.2 Hz, slow exchange), 1.46 (6-line ddd, 1H, H7ax, J ) 3.6,
13.6, 13.6 Hz), 1.37 (s, 3H, C4-Me), 1.34 (dd, H5ax, J ) 2.4,
12.5 Hz) and 1.33 (6-line ddd, H1ax, J ) ∼4.6, ∼13.6, ∼13.6
Hz) [overlapping, 2H], 1.27 (t, 3H, J ) 7.1 Hz), 1.24 (dd, 1H,
H9ax, J ) 2.8, 12.4 Hz), 1.21 (s, 3H, C10-Me); 13C NMR (CDCl3,
166 MHz) δ 207.6 (C3), 173.1 (ester CO), 144.0 (C13), 121.4
(CN), 110.0 (dCH2), 61.4 (ethyl CH2), 59.5 (CH2OH), 57.2 (C4),
56.7 (C5), 56.3 (C9), 54.6 (C14), 43.6 (C8), 39.9 (C1), 38.2 (C10),
36.6 (C7), 36.4 (C2 and C12), 25.5 (C11), 21.6 (C6), 20.8 (C4-
Me), 13.9 (ethyl CH3), 12.7 (C10-Me); IR (KBr) 3446, 2223,
1746, 1701. Anal. Calcd for C22H31NO4: C, 70.75; H, 8.37;
N, 3.75. Found: C, 70.35; H, 8.44; N, 3.62. For 7b: mp 148-
20.8, 20.3, 13.9, 12.2; IR (KBr) 2225, 1721, 1707 (sh) cm-1
.
Anal. Calcd for C22H27NO4: C, 71.52; H, 7.37; N, 3.79.
Found: C, 71.21; H, 7.67; N, 3.43.
d ,l-4â-Ca r b e t h oxy-8â-for m yl-3â-h yd r oxy-4r,10â-d i-
m eth yl-13-n or -16-oxoa n d r osta -13,14-d ien e (19). DIBALH
(1.0 M in toluene, 0.94 mL, 0.94 mmol) was added via a syringe
to cyano ketone 8 (58.0 mg, 0.157 mmol) in dry toluene (6 mL)
at -78 °C over a 25 min period under N2. The reaction
mixture was stirred at -78 °C for 25 min and then quenched
with 6% HOAc saturated with NaOAc at -78 °C. The
heterogeneous mixture was allowed to come to rt, stirred for
15 min, and then extracted with CHCl3 (3 × 10 mL). The
combined organic solution was washed with water (10 mL),
saturated NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4),
and concentrated in vacuo to give a solid. Chromatography
on silica gel (5 g, 230-400 mesh) eluting with ethyl acetate-
hexanes gave 43 mg (73%) of 19: mp 131.8-132.5 °C (EtOAc-
hexanes 1:2); 1H NMR (CDCl3) δ 9.84 (d, 1H, J ) 1.4 Hz), 7.18
(s, 1H), 7.15 (d, 1H, J ) 1.3 Hz), 4.11 (q, 1H, J ) 7.1 Hz), 3.45
(d, 1H, J ) 12 Hz), 3.08 (6-line ddd, 1H, J ) 4.3, 11.8, 11.8
Hz), 2.89 (m, 1H), 2.73 (dt, 1H, J ) 3.3, 13.0 Hz), 2.52 (m,
1H), 1.41 (s, 3H), 1.28 (t, 3H, J ) 7.1 Hz), 1.10 (dd, 1H, J )
4.2, 11.4 Hz), 0.70 (s, 3H); 13C NMR (CDCl3) δ 199.36, 177.60,
139.56, 138.09, 123.60, 120.40, 78.00, 60.49, 56.01, 55.60,
48.88, 48.21, 38.08, 37.79, 33.61, 28.15, 23.49, 20.72, 20.57,
17.73, 13.95, 13.25. HRMS calcd for C22 H30O5 (M+) 374.2093,
found 374.2093. Anal. Calcd for C22H30O5: C, 70.43, H, 8.05.
Found: C, 70.56; H, 8.07.
d,l-3â-Hydr oxy-4,8-bis(h ydr oxym eth yl)-4r,10â-dim eth yl-
13-n or -16-oxoa n d r osta -13,14-d ien e (20). Aldehyde 19 (34.1
mg, 0.0912 mmol) in dry THF (1.5 mL) was added dropwise
to a suspension of LAH (10.4 mg, 0.274 mmol) in dry THF
(1.5 mL). The reaction mixture was refluxed for 2 h, cooled
to 0 °C, carefully quenched with saturated Na2SO4 (10 mL),
and then extracted with CHCl3 (3 × 10 mL). The combined
organic solution was washed with brine (10 mL), dried (Na2-
SO4), and concentrated in vacuo to afford a solid. Chroma-
tography on silica gel (5 g, 230-400 mesh) eluting with 50%
and then 70% ethyl acetate-hexanes followed by ethyl acetate
gave 29.2 mg (96%) of 20: mp 185.0-186.1 °C (MeOH-
1
149 °C; H NMR (CDCl3, 300 MHz) δ 5.65 (br s, 1H), 3.99-
4.22 (m, 3H), 2.75 (dt, 1H, J ) 3.3, 13.7 Hz), 2.42 (dq, 1H, J )
2.3, 14.9 Hz), 3.96 (dd, 1H, J ) 4.7, 12.2 Hz), 2.98 (6 line ddd,
1H, J ) 6.3, 14.7 Hz), 1.85-2.38 (m, 7H), 1.78 (br s, 3H), 1.38
(s), 1.28 (t, J ) 7.0 Hz), 1.25 (s) and 1.17-1.41 (m) [13H]; 13
C
NMR (CDCl3, 77.0) δ 207.7, 173.2, 130.9, 123.9, 123.1, 61.4,
60.6, 57.2, 56.8, 53.7, 51.2, 39.8, 38.4, 38.0, 37.6, 36.3, 23.3,
21.3, 21.2, 20.9, 13.9, 12.6; IR (KBr) 3500, 2229, 1740 (sh),
1709 cm-1. Anal. Calcd for C22H31NO4: C, 70.75; H, 8.37; N,
3.75. Found: C, 70.66; H, 8.50; N, 3.64.
d ,l-(1r,4a r,4b â,7â,8a â,10a â)-E t h yl 8a -Cya n o-7,7-(ep -
oxym eth ylen e)-8-(h yd r oxym eth yl)-1,4a -d im eth yl-2-oxo-
1,4, 4a,4b,5,6,7,8,8a,9,10,10a-dodecah ydr o-1-ph en an th r en -
eca r boxyla te (17). m-CPBA (80%, 295 mg, 1.36 mmol) was
added to 7a (254 mg, 0.68 mmol) in CH2Cl2 (8 mL). The
reaction mixture was stirred at rt for 1.5 h, diluted with CH2-
Cl2 (80 mL), washed with 0.1 N NaOH (2 × 30 mL), H2O (30
mL), and brine (30 mL), dried (Na2SO4), and concentrated in
vacuo to afford a solid. The solid was recrystallized from
EtOAc-hexanes to give 240 mg (91%) of 17: 1H NMR (CDCl3)
δ 4.16 (m, 2H), 3.69 (m, 2H), 3.34 (dd, 1H, J ) 1.4, 3.1 Hz),
3.00 (6 line ddd, J ) 6.4, 14.7 Hz), 2.80 (d, 1H, J ) 3.4 Hz),
1.38 (s, 3H), 1.28 (t, 3H, J ) 7.1 Hz), 1.23 (s, 3H); 13C NMR
(CDCl3, 77.0) δ 207.3, 173.0, 121.3, 61.4, 60.3, 58.5, 57.0, 56.3,
55.6, 51.1, 50.6, 41.6, 39.7, 38.0, 36.4, 36.2, 35.0, 22.8, 21.2,
20.8, 13.9, 12.5; IR (KBr) 3504, 2226, 1741, 1702 cm-1. Anal.
Calcd for C22H31NO5: C, 67.84; H, 8.02; N, 3.60. Found: C,
68.06; H, 8.29; N, 3.55.

Tetracycles in the Synthesis of d,l-Spongiatriols
J . Org. Chem., Vol. 63, No. 4, 1998 1167
hexanes); 1H NMR (CDCl3) δ 7.17 (s, 2H), 4.20 (d, 1H, J )
11.4 Hz), 3.80 (overlapping d, J ) 11.1 Hz) and 3.74 (overlap-
ping d, J ) 10.9 Hz) [2H], 3.44 (m, 3H), 2.75 (m, 2H), 2.49 (m,
3H), 1.59 (s, 3H), 1.24 (s, 3H), 0.85 (s, 3H); 13C NMR (CDCl3,
77.00) δ 138.13, 137.20, 129.76, 119.74, 80.46, 64.17, 61.98,
56.28, 56.05, 42.83, 40.22, 38.07, 36.91, 34.69, 27.67, 22.42,
20.14, 18.05, 17.60, 17.24; HRMS calcd for C20H30O4 (M+)
334.2150, found 334.2144.
mg, 1.13 mmol) in dry CH2Cl2 (5 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 4 h and then diluted with CH2-
Cl2. The organic solution was washed with saturated NaHCO3
and brine, dried (Na2SO4), and concentrated in vacuo afforded
a mixture of the corresponding sulfonate ester, a trace amount
of 24, and 4-DMAP. 4-DMAP (50 mg) was then added to the
three-component mixture in CH2Cl2 (5 mL). The reaction
mixture was refluxed overnight and then diluted with CH2-
Cl2. The organic solution was washed with 10% HCl, satu-
rated NaHCO3, and brine, dried (Na2SO4), and concentrated
in vacuo to give a solid. Chromatography on a silica gel sep-
pack and elution with 5% EtOAc-hexanes gave 63 mg (94%)
d ,l-4â,8â-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-3â-
h ydr oxy-4r,10â-dim eth yl-13-n or -16-oxoan dr ostan e-13,14-
d ien e (21). TBDMSCl (46.0 mg, 0.305 mmol) was added in
one portion to triol 21 (23.2 mg, 0.0695 mmol) and 4-DMAP
(18.7 mg, 0.153 mmol) in dry CH2Cl2 (3 mL) under N2. The
reaction mixture was stirred at rt for 48 h. Water (3 mL) was
added, and the mixture was extracted with CH2Cl2 (3 × 5 mL).
The combined organic solution was dried (Na2SO4) and con-
centrated in vacuo. Chromatography of the residue on silica
gel (5 g, 230-400 mesh) eluting with ethyl acetate-hexanes
gave 28 mg (72%) of 21: mp 116.5-117.2 °C (from column);
1H NMR (CDCl3) δ 7.06 (s, 2Η), 4.27 (d, 1H, J ) 6.8 Hz), 4.20
(d, 1H, J ) 10.1 Hz), 3.77 (d, 1H, J ) 9.5 Hz), 3.47 (apparent
t, 1H, J ) 9.5 Hz), 3.21-3.34 (m, 1H), 2.68-2.82 (m, 1H),
2.36-2.57 (m, 2H), 1.20 (s), 0.91 (s), 0.84 (s), 0.87 (s), 0.095
(s), -0.15 (s), -0.18 (s); 13C NMR (CDCl3, 77.00) δ 137.92,
136.30, 130.83, 119.89, 80.18, 65.22, 64.30, 56.74, 56.34, 42.60,
39.63, 38.47, 37.06, 35.51, 28.11, 25.92, 25.79, 25.70, 20.48,
18.51, 18.06, 17.97, 17.80, 17.55, -3.60, -5.72, -5.77, -5.94;
HRMS calcd for C32H58O4Si2 (M+) 562.3875, found 562.3874.
d ,l-4â,8â-Bis[[(t er t -b u t yld im e t h ylsilyl)oxy]m e t h yl]-
4r,10â-d im et h yl-3-oxo-13-n or -16-oxoa n d r ost a -13,14-d i-
en e (22). J ones reagent was prepared from pyridine (63 mg,
0.80 mmol) and dry CrO3 (40.0 mg, 40.0 mmol) in dry CH2Cl2
(1 mL). Alcohol 21 (28 mg, 0.05 mmol) in dry CH2Cl2 (1 mL)
was added dropwise to the J ones reagent at rt. The reaction
mixture was stirred for 2.5 h and then filtered through a pad
of Celite and silica gel eluting with CH2Cl2. Concentration of
the organic solution in vacuo and subsequent chromatography
on silica gel (5 g, 230-400 mesh) eluting with ethyl acetate-
hexanes gave 18.6 mg (67%) of 22: mp 119.1-120.8 °C; 1H
NMR (CDCl3) δ 7.10 (s, 2H), 3.91 (d, 1H, J ) 9.5 Hz), 3.82 (d,
1H, J ) 10 Hz), 3.74 (d, 1H, J ) 10 Hz), 3.56 (d, 1H, J ) 9.5
Hz), 2.73-2.86 (m, 1H), 2.33-2.71 (m, 4H), 1.33-1.56 (m, 1H),
2.13 (ddd, 1H, J ) 3.1, 7.0, 13.1 Hz), 1.11 (s, 6H, 2-Me), 0.89
(s) and 0.86 (s) [18H], 0.046 (s, 6H), -0.11 (s) and -0.13 (s)
[6H]; 13C NMR (CDCl3, 77.00) δ 214.44, 138.07, 136.39, 130.57,
119.79, 65.68, 64.12, 57.06, 55.96, 53.91, 39.75, 39.65, 36.95,
35.24, 35.05, 25.90, 25.85, 21.57, 20.60, 19.91, 18.24, 16.82,
-5.58, -5.66, -5.66, -5.91; HRMS calcd for C32H56O4Si2 (M+)
560.3722, found 560.3717.
d ,l-4â-Ca r b e t h oxy-8â-cya n o-3â-h yd r oxy-4r,10â-d i-
m eth yl-13-n or -16-oxo-a n d r osta -13, 14-d ien e (23). NaBH4
(100 mg, 2.63 mmol) was added in several portions to keto
ester 8 (90 mg, 0.24 mmol) in a 1:2 mixture of CH2Cl2 to EtOH
(12 mL) at 0 °C. The reaction mixture was stirred for 1 h and
then quenched with acetone. The solvent was removed in
vacuo, and the residue was diluted with CH2Cl2 (40 mL). The
organic solution was washed with H2O (20 mL) and brine (20
mL), dried (Na2SO4), and concentrated in vacuo to give a solid.
The solid was triturated with hexanes and then recrystallized
with CH2Cl2-hexanes to give 80 mg (88%) of 23: 1H NMR
(CDCl3) δ 7.36 (d, 1H, J ) 1.3 Hz), 7.15 (d, 1H, J ) 1.1 Hz),
4.18 (q, 2H, J ) 7.2 Hz), 3.53 (d, 1H, J ) 12.0 Hz), 3.08 (6-line
ddd, 1H, J ) 4.3, 12.0, 12.0 Hz), 2.87 (br dd, 1H, J ) 5.5, 16.3
Hz), 2.65 (dt, 1H, J ) 3.2, 13.3 Hz), 1.71-2.57 (m, 9H), 1.61
(6 line ddd, 1H, J ) 3.6, 13.3, 13.3 Hz), 1.44 (s, 3H), 1.34 (t,
3H, J ) 7.2 Hz), 1.17 (dd, 1H, J ) 1.4, 11.5 Hz), ∼1.08 (m)
and 1.04 (s) [4H]; 13C NMR (CDCl3, 77.00) δ 177.47, 138.20,
137.81, 126.06, 123.18, 119.05, 78.01, 60.76, 55.43, 54.70,
48.71, 38.40, 37.84, 37.81, 36.18, 27.85, 23.54, 21.38, 21.03,
20.38, 14.02, 12.58; IR (KBr) 3450, 2226, 1735 cm-1. HRMS
calcd for C22H29NO4 (M+) 371.2096, found 371.2094.
1
of 24: mp 126.5-128 °C; H NMR (CDCl3) δ 7.38 (d, 1H, J )
1.3 Hz), 7.16 (d, 1H, J ) 1.3 Hz), 5.65 (m, 2H), 4.14 (q, 2H, J
) 7.1 Hz), 2.88 (br dd, 1H, J ) 5.1, 16.1 Hz), 2.64 (dq, 1H, J
) 3.2, 13.2 Hz), 1.32 (s, 3H), 1.27 (t, 3H, J ) 7.1 Hz), 1.09 (s,
3H); 13C NMR (CDCl3, 77.0) δ 175.0, 138.1, 137.9, 131.5, 126.0,
123.0, 122.9, 119.0, 60.7, 53.9, 52.4, 45.0, 40.4, 37.2, 36.3, 36.1,
27.7, 21.4, 21.2, 20.4, 14.1, 13.5; IR (KBr) 2225, 1734 cm-1
.
Anal. Calcd for C22H27NO3: C, 74.76; H, 7.70; N, 3.96.
Found: C, 74.53; H, 7.84; N, 3.79.
d,l-For m yl-4â-(h ydr oxym eth yl)-4r,10â-dim eth yl-13-n or -
16-oxoa n d r osta -2,13,14-tr ien e (25). DIBALH (1.0 M in
toluene, 0.47 mL, 0.47 mmol) was added via a syringe over 5
min to cyano ester 24 (50 mg, 0.14 mmol) in dry toluene (1.5
mL) at -78 °C under N2, and stirring was continued for 1 h
at -78 °C. The reaction mixture was quenched with 6% HOAc
saturated with NaOAc, allowed to warm to rt, and then stirred
for an additional 15 min. The reaction mixture was diluted
with CH2Cl2, and the organic solution was washed with H2O,
saturated NaHCO3, and brine, dried (Na2SO4), and concen-
trated in vacuo to give a solid. Chromatography on a silica
gel sep-pak and elution with 10% EtOAc-hexanes gave 33 mg
(74%) of 25: 1H NMR (CDCl3, 500 MHz) δ 9.86 (d, 1H, CHO,
J ) 1.5 Hz), 7.18 (s, 1H, H16), 7.15 (d, 1H, H15, J ) 1.0 Hz),
5.63 (m, 2H, H2 and H3), 3.63 (d, 1H, CHHOH, J ) 11.0 Hz),
3.47 (d, 1H, CHHOH, J ) 10.7 Hz), 2.90 (dd, 1H, H12eq, J )
5.0, 16.0 Hz), 2.73 (6-line ddd, 1H, H7eq, J ) 3.1, 3.1, 12.8 Hz),
2.54 (m, 1H, H12ax), 2.15 (dd, 1H, H1eq, J ) 4.3, 16.8 Hz), 2.07
(8-line dddd, 1H, H1ax, J ) 5.4, 12.5, 12.5, 12.5 Hz), 1.92 (m,
1H, H11eq), 1.76 (m, 2H, H1ax, H6eq), 1.59 (dd, H9ax, J ) 1.8, 12.5
Hz) and 1.53 (partially resolved 8-line dddd, H6ax, J ) 3.1, 13.1,
13.1, 13.1 Hz) [2H], 1.44 (dd, 1H, H5ax, J ) 2.7, 13.1 Hz), 1.36
(m, 1H, H7ax), 1.09 (s, 3H, C-4 Me), 0.88 (s, 3H, C-10 Me); 13
C
NMR (CDCl3, 126 MHz) δ 199.5 (CHO), 139.7 (C16), 138.1
(C15), 132.9 (C3), 123.7 (C14), 123.5 (C2), 120.5 (C13), 66.8
(CH2OH), 55.4 (C9), 52.2 (C5), 48.6 (C8), 39.9 (C1), 39.5 (C4),
36.4 (C10), 33.4 (C7), 25.7 (C-4 Me), 20.7 (C12), 19.7 (C6), 17.9
(C11), 16.0 (C10).
Ack n ow led gm en t. We are indebted to the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research, and H.F. thanks the Burroughs Wellcome
Foundation for a research fellowship. The Duke Uni-
versity NMR Spectroscopy Center was established with
grants from the NIH, the NSF, and the North Caro-
lina Biotechnology Center, which are gratefully acknowl-
edged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 15, 20, 21, 22, 23, 24, and 25 and 2D COSY,
HMQC, HMBC, and 1D APT spectra for 7a (6 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
d ,l-4â-Ca r b et h oxy-8â-cya n o-4r,10â-d im et h yl-13-n or -
16-oxoa n d r osta -2, 13, 14-tr ien e (24). Trifluoromethane-
sulfonyl chloride (51 µL, 79.5 mg, 0.47 mmol) was added via a
syringe to alcohol 23 (70 mg, 0.19 mmol) and 4-DMAP (138
J O971632F