Synthetic Studies on Nogarol Anthracyclines. Enantioselective Total Synthesis of an Aminohydroxy Epoxybenzoxocin

Article abstract of DOI:10.1021/jo991483w

A chiral synthesis of the aminohydroxy expoxybenzoxocin 6 is described. Enantioselective Friedel-Crafts coupling using a chiral titanium catalyst was employed to produce the optically active atrolactic ester 16a from the phenol 11 and l-menthyl pyruvate (12). The phenolic group in 16a was protected as the benzyl ether and the t-alcohol functionality as the MEM ether to give 20, which after sequential reduction/oxidation provided the aldehyde 22. Addition of the acetylide anion of propargyl aldehyde diethyl acetal (23) to aldehyde 22, followed by oxidation of the resultant diastereoisomeric carbinols, gave the acetylenic ketone 24. Lindlar reduction of 24 afforded the trans-enone 26. Reaction of 26 with thiophenylate anion furnished 27, which was then cyclized to the α-methyl pyranoside 29. Oxidation of 29 to the sulfoxide and subsequent thermolysis afforded the hexenulose 30. Sequential epoxidation of 30, reduction of the keto epoxide 31, and reaction of the resultant epoxycarbinol 32 with dimethylamine produced the aminohydroxy pyranose 33a. Debenzylation of 33a to the phenol 33b, followed by intramolecular cyclization, completed the fabrication of the optically active aminohydroxy epoxybenzoxocin 6. The 17-step sequence from the phenol 11 to 6 was achieved in 22% overall yield.

Full text of DOI:10.1021/jo991483w

1842
J . Org. Chem. 2000, 65, 1842-1849
Syn th etic Stu d ies on Noga r ol An th r a cyclin es. En a n tioselective
Tota l Syn th esis of a n Am in oh yd r oxy Ep oxyben zoxocin
Frank M. Hauser* and Debashis Ganguly†
Department of Chemistry, State University of New York at Albany, Albany, New York 12222
Received September 20, 1999
A chiral synthesis of the aminohydroxy expoxybenzoxocin 6 is described. Enantioselective Friedel-
Crafts coupling using a chiral titanium catalyst was employed to produce the optically active
atrolactic ester 16a from the phenol 11 and l-menthyl pyruvate (12). The phenolic group in 16a
was protected as the benzyl ether and the t-alcohol functionality as the MEM ether to give 20,
which after sequential reduction/oxidation provided the aldehyde 22. Addition of the acetylide anion
of propargyl aldehyde diethyl acetal (23) to aldehyde 22, followed by oxidation of the resultant
diastereoisomeric carbinols, gave the acetylenic ketone 24. Lindlar reduction of 24 afforded the
trans-enone 26. Reaction of 26 with thiophenylate anion furnished 27, which was then cyclized to
the R-methyl pyranoside 29. Oxidation of 29 to the sulfoxide and subsequent thermolysis afforded
the hexenulose 30. Sequential epoxidation of 30, reduction of the keto epoxide 31, and reaction of
the resultant epoxycarbinol 32 with dimethylamine produced the aminohydroxy pyranose 33a .
Debenzylation of 33a to the phenol 33b, followed by intramolecular cyclization, completed the
fabrication of the optically active aminohydroxy epoxybenzoxocin 6. The 17-step sequence from
the phenol 11 to 6 was achieved in 22% overall yield.
In tr od u ction
Nogalamycin (1), reported in 1968 by Wiley and co-
workers1 at Upjohn, was the first example of an anthra-
cycline antibiotic containing a C-aminosugar residue.
(Figure 1). The antibiotic exhibited strong in vitro activity
against Gram-positive bacteria, L12110 leukemia, and
Kb cell lines. It also demonstrated superior antitumor
activity and reduced cardiotoxicity when compared to the
clinically important anthracycline antibiotics adriamycin,
daunorubicin, and related compounds. The semisynthetic
derivative, 7-con-O-methylnogarol (2), prepared from
nogalamycin (1), exhibited even more substantial anti-
cancer activity.1g Subsequently, other nogarol anthracy-
cline antibiotics, arugomycin,2 decilorubicin,3 and vir-
iplanin,4 were reported, and these likewise showed
significant anticancer activity.
The C-sugar residue in nogarol anthracyclines is
structurally unusual in that it is present as an expoxy-
oxocin fragment. Moreover, in contrast to the usual
attachment of C-sugars to aromatic rings at C-1′, the
sugar residue in these antibiotics is connected through
the C-5′ carbon. An X-ray crystallographic analysis of a
F igu r e 1.
DNA hexamer complexed with nogalamycin (1), reported
by Rich et al.,5 showed that the amine group on the
epoxyoxocin is hydrogen-bonded to two sites on the DNA.
This finding implies both a mechanism of action for
biological activity and suggests that the amino-substi-
tuted epoxyoxocin is essential for biological activity.
The stereochemical complexity, unique structural fea-
tures, and impressive anticancer activity prompted syn-
thetic interest in these compounds. While there have
been no reported preparations of nogalamycin (1), there
have been two syntheses of 7-con-O-methylnogarol (2):
a chiral route by Terashima et al.6 and a racemic
synthesis by us.7 In addition, there have been a number
* Email: FH473@sarah.albany.edu.
† Present address: Eli Lilly & Co., Lilly Research Laboratories,
Indianapolis, IN, 46285.
(1) (a) Wiley, P. F.; Mackellar, F. A.; Caron, E. L.; Kelly, R. B.
Tetrahedron Lett. 1968, 663-668. (b) Wiley, P. F.; Elrod, D. W.;
Marshall, V. P. J . Org. Chem. 1978, 43, 3457. (c) Wiley, P. F. J . Nat.
Prod. 1979, 42, 569. (d) Wiley, P. F.; Eckle, E.; Stezowsky, J . J .
Tetrahedron Lett. 1980, 507. (e) Wiley, P. F.; Elrod, D. J .; Richard, F.
A. J . Med. Chem. 1982, 25, 507. (f) Arora, S. K. J . Am. Chem. Soc.
1983, 105, 1328-1332. (g) Wiley, P. F. Anthracyclin Antibiotics; El
Khadem, H. S., Ed.; Academic Press: New York, NY, 1982; pp 97-
117.
(2) Shimosaka, A.; Kawai, H.; Hayakawa, Y.; Koneshina, N.; Na-
kagawa, M.; Seto, H.; Otake, N. J . Antibiot. 1987, 40, 1283-1291.
(3) Ishii, K.; Kondo, S.; Nishimura, Y.; Hamada, M.; Takeuchi, T.;
Umezawa, H. J . Antibiot. 1983, 36, 451-453.
(4) Huetter, K.; Baader, E.; Frobel, K.; Zeeck, A.; Bauer, K.; Gau,
W.; Kurz, J .; Schroeder, T.; Wuensche, C.; Karl, W.; Wendinsch, D. J .
Antibiot. 1986, 39, 1193-1204.
(5) Rich, A.; Williams, L. D.; Egli, M.; Gao, Q.; Bash, P.; Marel, G.
A. V. D.; Boom, J . H. V.; Fredrick, C. A. Proc. Natl. Acad. Sci. U.S.A.
1990, 87, 2225-2229.
10.1021/jo991483w CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/17/2000

Synthetic Studies on Nogarol Anthracyclines
J . Org. Chem., Vol. 65, No. 6, 2000 1843
Sch em e 1
Sch em e 2
of papers describing various approaches to epoxyben-
zoxocins, which are potentially useful as DEF synthons
to these antibiotics.8 With the exception of the prepara-
tion by Terishma et al. that exploited a sugar starting
material,6 all of the routes to epoxyoxocins have been
racemic. We describe herein a de novo route for optically
active total synthesis of the epoxybenzoxocin 6 from
achiral starting materials.
Resu lts a n d Discu ssion s
Considering the retrosynthetic analysis shown in
Scheme 1, we recognized that our previous racemic
preparation7 of 7-con-O-methylnogarol (2) might be gen-
eralized to encompass an optically active total synthesis.
This asymmetric preparation would be accomplished via
coupling of two chiral subunits, the cyanophthalide 3 and
the 1-(4H)-naphthaleneone 4. We had already established
methodology for brief and efficient optically active prepa-
ration of 1-(4H)-naphthalenones such as 4 and reported
their use as AB-synthons for single enantiomer synthesis
of an anthracyclinone.9 To accomplish an optically active
total synthesis of 2 that would not result in the formation
of diastereoisomers, we needed a route for chiral prepa-
ration of the cyanophthalide 3.
Sch em e 3a
Scheme 2 delineates the retrosynthetic analysis that
led to the exploration of a route to the optically active
epoxybenzoxocin 6, which was to be used as an interme-
diate to the cyanophthalide 3. The epoxybenzoxocin 6 was
chosen as an intermediate since we have previously
reported methodology for the selective oxidative trans-
formation of methyl groups to carboxyl functionality10 (6
to 5) and for the fabrication of phthalide nitriles from
diethylamides (5 to 3).7 The preparation of 6 from the
hexenulose 7 would parallel our earlier racemic prepara-
tion. The hexenulose 7 would be fabricated from the
chiral atrolactaldehyde 9 through the intermediacy of the
acetylenic ketone 8. Planned construction of the atrolac-
taldehyde 9 would be from the optically active ester 10,
which would be prepared through an asymmetric Friedel-
Crafts coupling11 of the phenol 11 with l-menthylpyruvate
(12).12
Synthesis of the phenol 11 needed to initiate the route
was straightforwardly accomplished on a multigram scale
as outlined in Scheme 3. Friedel-Crafts acylation of
commercially available 2-methyl anisole (13) with CH3-
COCl and AlCl3 gave the acetophenone 14, which was
readily purified through distillation, in 88% yield. Fol-
lowing Baeyer-Villiger oxidation of 14 to 15 (85%), the
acetate group was hydrolyzed (THF, 3 N HCl; 84%) to
(6) (a) Motoji, K.; Fuyuhiko, M.; Terashima, S. Tetrahedron 1988,
44, 5695-5711. (b) Motoji, K.; Fuyuhiko, M.; Terashima, S. Tetrahe-
dron 1988, 44, 5727-5743. (c) Motoji, K.; Fuyuhiko, M.; Terashima,
S. Tetrahedron 1988, 44, 5713-5725.
(7) Hauser, F. M.; Chakrapani, S.; Ellenberger, W. P. J . Org. Chem.
1991, 56, 5248-5250.
(8) (a) Bates, M. A.; Sammes, P. G. J . Chem. Soc., Chem. Commun.
1983, 896-898. (b) Hauser, F. M.; Ellenberger, W. P.; Adams, T. C.,
J r. J . Org. Chem. 1984, 49, 1169-1174. (c) Hauser, F. M.; Adams, T.
C., J r. J . Org. Chem. 1984, 49, 2296. (d) Hauser, F. M.; Ellenberger,
W. P. J . Org. Chem. 1988, 53, 1118-1121. (e) DeShong, P.; Li, W.;
Kennington, J . W., J r.; Ammon, H. L.; Leginus, J . M. J . Org. Chem.
1991, 56, 1364-1373. (f) Smith, T. H.; Wu, H. Y. J . Org. Chem. 1987,
52, 3566-3573. (g) Yin, H.; Franck, R. W.; Chen, S. L.; Torado, L. J .
Org. Chem. 1992, 57, 644-651.
(9) Hauser, F. M.; Tommasi, R. A. J . Org. Chem. 1991, 56, 5758-
(11) Casiraghi, G.; Bigi, F.; Casnati, G.; Sartori, G.; Soncini, P.; Fava,
G. G.; Belicchi, F. J . Org. Chem. 1988, 53, 1779-1785.
(12) Matsumoto, K.; Harada, K. J . Org. Chem. 1966, 31, 1956-1958.
5759.
(10) Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 8, 723.

1844 J . Org. Chem., Vol. 65, No. 6, 2000
Hauser and Ganguly
Sch em e 4a
Sch em e 5a
tertiary alcohol would be required to avoid its oxidative
cleavage. Moreover, we were now mindful but not sur-
prised that an electron-withdrawing group R to the
tertiary hydroxyl group (vida infra) was necesssary to
ensure stability.
Various silicon groups were examined for protection
of the tertiary hydroxyl group in 10, but these proved to
be too unstable for subsequent transformations. Ulti-
mately, MEM ether protection provided an appropriate
derivative. Installation of the MEM group in 20 was
achieved in 97% yield through reaction of 10 with NaH
and MEMCl in THF (Scheme 5). Attempted reduction of
20 with commercially available DIBAL in toluene pro-
duced a complex mixture of products that included the
unreduced ester 20, the alcohol 21, the aldehyde 22, and
disturbingly, a substantial amount of MEM ether cleaved
products. This problem was overcome through use of a
freshly prepared solution of DIBAL in toluene. With this
change, reduction of 20 cleanly afforded the alcohol 21
and aldehyde 22, in 54% and 35% yield, respectively,
without coproduction of cleavage products. Swern oxida-
tion of purified 21 quantitatively furnished the aldehyde
22. Alcohol 21 was somewhat unstable, which was not
surprising because of its structural similarity to 17. In
subsequent work, the initially received diol 21/aldehyde
22 mixture was not separated but was directly oxidized
with the Swern reagent to afford an 86% overall yield of
aldehyde 22 from the MEM-protected menthyl ester 20.
Planned introduction of the remaining three carbons
that were needed for elaboration of the pyranose ring was
based on addition of the acetylene 23 to the aldehyde 22
(Scheme 6). The acetylide anion generated from reaction
of n-BuLi with commercially available propargyl alde-
hyde diethylacetal (23) was reacted with the aldehyde
22 to afford a diastereoisomeric mixture of alcohols (70:
30 ratio) in 96% yield. Because conversion of the alcohols
to the ketone 24 would both destroy the newly created
chiral center and enhance stability of the intermediate
by introducing an electron-withdrawing group R to the
labile tertiary hydroxyl group, the mixture was not
separated but was directly oxidized with excess MnO2 to
the ketone 24 in 94% yield.
the phenol 11. The overall yield of phenol 11 for the four-
step sequence was 66%.
The protocol reported by Casiraghi et al.11 (TiCl4 and
l-menthol at -78 °C) was used to effect asymmetric
coupling of phenol 11 with (-)-l-menthyl pyruvate (12),12
(Scheme 4) and afforded the diastereoisomeric atrolactic
esters 16a and 16b in an 86:14 ratio.13 Purification of
the atrolactic esters 16a and 16b proved to be challenging
as a result of the small differences in their Rf values
(<0.08) and streaking caused by the presence of menthol.
Ultimately, the pure diastereoisomers 16a and 16b were
obtained in 48% and 12% yield, respectively. Examina-
tion of the singlet absorptions of the tertiary C-methyl
groups and the C-2 methyl doublet of the menthol ester
group in the 1H NMR readily established that the
enantiomeric purity of the separated diatereoisomers was
>99%.
Since ring closure to the oxocin at a subsequent stage
of the synthesis would require that we be able to
differentiate between the oxygen functionalities on the
aromatic ring, protection of the phenolic group in 16a as
the benzyl ether derivative 10 was performed (K2CO3,
PhCH2Br, acetone, 90%). Attempted direct reduction of
10 to the atrolactaldehyde 18 led instead to diol 17, even
when care was taken to use exactly 1 equiv or less of
DIBAL. While the yield was somewhat modest (56%), a
more serious problem and one which probably contrib-
uted to the low yield was that the diol 17 was unstable.
We felt that this instability was likely due to the presence
of the tertiary benzylic alcohol, coupled with the fact that
the aromatic ring was electron-rich. We expected that
once 17 was oxidized to the atrolactaldehyde 18, stability
would return since formation of a carbocation R to the
aldehyde carbonyl group would be unfavorable. Several
oxidizing agents were screened in unsuccessful attempts
to convert the diol 17 to the R-hydroxy aldehyde 18.
Invariably, the major product was the acetophenone 19.
Even the Swern oxidation,14 which usually does not
cleave 1,2-diols, gave principally the acetophenone 19.
Thus, it was apparent that, minimally, protection of the
The plan was to effect Lindlar hydrogenation of 24 to
the Z-olefinic product 25, because this olefin geometry
would allow direct cyclization to the ethyl glycoside of
the hexenulose 30. Unexpectedly, Lindlar reduction of
24 provided a quantitative yield of the E-olefinic isomer
26, apparently from rapid in situ isomerization of the
Z-isomer 25. Because the olefin geometry in 26 prohibited
direct cyclization, an alternative pathway to the hexenu-
lose 30 would need to be established. Although conjugate
addition of a nucleophile to 26, cyclization of the adduct
to the pyranose, and then elimination of the introduced
nucleophile appeared to be a reasonable solution to this
(13) We repeated the procedure originally reported by Casiraghi et
al.11 and found that the yield (84%) and diastereoselectivity (92%) is
substantially higher when R-naphthol is used in the reaction.
(14) Omura, K.; Sharma, A. K.; Swern, D. J . Org. Chem. 1976, 41,
957-962. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.

Synthetic Studies on Nogarol Anthracyclines
J . Org. Chem., Vol. 65, No. 6, 2000 1845
Sch em e 6a
Sch em e 7a
PPTS, TsOH) were found for selective transformation to
the R-methyl pyranoside 29 (95:5 mixture of anomers)
in nearly quantitatively yield. With further study, it was
found that the three-step sequence used to convert the
diethylacetal 27 to the R-methyl pyranoside 29 could be
accomplished in one pot through reaction with excess
methanol in the presence of TsOH/CF3CO2H. Under these
conditions, a 93:7 ratio of anomeric methyl glycosides was
produced, in which the desired anomer 29 predominated.
The anomeric, diastereoisomeric sulfide mixture 29 was
oxidized with m-CPBA (1 equiv) to the sulfoxide, which
without purification was thermolyzed (toluene, CaCO3,
K2CO3, 48 h) to afford the hexenulose 30 after separation
of the minor anomer (82% yield).17
The sequence employed in our racemic synthesis of
7-con-O-methylnogarol was used to functionalize the
pyranose ring (Scheme 7). Epoxidation18 of the double
bond in 30 with tert-butyl hydroperoxide and Triton-B
produced the epoxide 31 as the sole product of reaction
in 98% yield. Reduction of the epoxyketone 31 with
NaBH4 stereospecifically furnished the alcohol 32 in
quantitative yield, and subsequent reaction of 32 with
dimethylamine19 (sealed tube, 140 °C, 24 h, 75%) regio-
and stereospecifically opened the epoxide to produce the
amino sugar 33a . Debenzylation of 33a with 10% Pd/C
and ammonium formate in ethanol20 gave the phenol 33b,
which without purification was cyclized with acetic acid/
HCl to the aminoexpoxybenzoxocin 6 in 85% overall yield
from 33a .
problem, it would undoubtedly require working with a
mixture of diastereoisomers. A thiolate was chosen as the
nucleophile since the incorporated sulfur-containing group
might be eliminated as either the sulfoxide or sulfone.
As expected, Et3N-catalyzed conjugate addition of PhSH
to 26 produced a diastereoisomeric mixture of sulfides
27 in 98% yield.
An issue that had to be addressed at this point was
formation of the R-glycoside. In earlier work we had found
that this anomer is essential for introduction of func-
tionality on the pyranose ring with the correct regio- and
stereochemistry.15 Although intramolecular cyclization of
27 furnished predominantly the R-ethyl glycoside, prob-
lems were encountered with this derivative,16 which
necessitated that 27 be converted to the R-methyl glyco-
side 30.
Treatment of 27 with TFA in THF/H2O concomitantly
hydrolyzed the acetal and cleaved the MEM ether giving
a quantitative yield of the keto aldehyde 28. It was
apparent from inspection of the 1H NMR spectrum of the
product that it consisted solely of aldehyde diastereoiso-
mers and that none of the pyranose form was present.
Initially, problems were encountered with the conversion
of 28, but ultimately conditions (CHCl3, MeOH, 2:1; TFA,
(17) The undesired â-anomer was recycled to the desired R-anomer
20 in 50% yield through treatment with TFA and MeOH.
(18) Yang, N. C.; Finnegan, R. A. J . Am. Chem. Soc. 1990, 112, 3447.
(19) Ranganaykula, K.; Singh, U. P.; Murray, T. P.; Brown, R. K.
Can. J . Chem. 1974, 52, 988.
(20) (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1977, 81 and
references therein. (b) Bose, A. K.; Mashas, M. S.; Ghose, M.; Shah,
M.; Raju, V. S.; Bari, S. S.; Newaz, S. N.; Banik, B. K.; Chaudhary, A.
G.; Barakat, K. J . J . Org. Chem. 1991, 56, 6968.
(15) Unpublished results, Ph.D. dissertation; Ellenberger, W. P.,
Oregon Graduate Center, 1987.
(16) The ethyl glycoside analogue of the epoxy alcohol 32 unexpect-
edly proved to be unstable to the conditions (sealed tube, 140 °C)
needed to open the epoxide ring with dimethylamine.

1846 J . Org. Chem., Vol. 65, No. 6, 2000
Hauser and Ganguly
mL) solution was added dropwise. The reaction was stirred
initially at -70 °C for 24 h, then subsequently warmed to -40,
-20, and 0 °C, with 24 h of stirring at each interval, and finally
was stirred at room temperature for 48 h. The reaction was
quenched with saturated NH4Cl solution (200 mL), and the
solvent was evaporated under reduced pressure. The residue
was extracted with Et2O (3 × 100 mL). The combined organic
layers were washed with brine, then dried (Na2SO4), filtered,
and concentrated under reduced pressure. Flash chromatog-
raphy of the residue (silica gel, 200 g, 13% EtOAc/hexanes)
provided 14.8 g (48%) of C-2S 16a and 3.70 g (12%) of C-3R
16b as light yellow oils.
Su m m a r y. The developed sequence provides a route
for optically active total synthesis of the epoxybenzoxocin
6 from achiral starting materials in 22% overall yield over
17 steps. Additional studies are in progress to find a more
enantioselective protocol for construction of the tertiary
carbinol and to modify the route to avoid formation of
unstable intermediates.
Exp er im en ta l Section
All reactions were run under N2 or Ar unless otherwise
noted. Glassware for air-sensitive reactions was oven dried,
assembled while hot, and cooled under a nitrogen purge.
Solvents were predried and distilled unless otherwise stated.
THF, PhH, and toluene were distilled from sodium-benzophe-
none ketyl prior to use. CH2Cl2 was distilled from anhydrous
P2O5, and DMF, CH3CN, DMSO, TEA, TMEDA, and hexanes
were distilled from CaH2 and stored over 4 Å molecular sieves.
Pyridine and quinoline were distilled from CaH2 and stored
over KOH. Melting points were taken on a Koffler hot-stage
melting point apparatus and are uncorrected. Flash chroma-
tography was performed according to the literature proce-
dure,21 using Baker flash silica gel 60 (40 mm). Preparative
TLC and TLC utilized EM Kieselgel 60 F-254 (0.25 mm
thickness) precoated plates.
4-Meth oxy-3-m eth yla cetop h en on e (14). To a mechani-
cally stirred mixture of anhydrous AlCl3 (55.98 g, 0.71 mol) in
CH2Cl2 (50 mL) was added slowly a solution of 2-methyl
anisole 3 (79.20 g, 0.65 mol) in CH2Cl2 (40 mL), followed by
acetyl chloride (51 mL, 0.71 mol) in CH2Cl2 (30 mL). The
reaction was heated on a steam bath for 2 h, then cooled to
room temperature, quenched with HCl (3 N, 30 mL), and
extracted with Et2O (125 mL). The organic layer was washed
with brine, then dried (Na2SO4), filtered, and concentrated
under reduced pressure. Vacuum distillation of the residue
afforded 93.65 g (88%) of pure 14 with bp 132-134 °C (7 mm).
1H NMR (CDCl3) δ 2.25 (s, 3 H); 2.55 (s, 3 H); 3.89 (s, 3 H);
6.74 (s, 1 H); 6.89 (s, 1 H); 7.77 (s, 1 H).
16a : [a]23D ) -16.8° (c 16.12, CH2Cl2); IR (film) 3363, 1721,
1627 cm-1; 1H NMR (CDCl3) δ 0.77 (d, J ) 7.2 Hz, 3 H); 0.89-
0.90 (m, 7 H); 0.96-1.15 (m, 2 H); 1.35-1.57 (m, 2 H); 1.60-
1.77 (m, 2 H); 1.79 (s, 3 H); 1.84-1.93 (m, 1 H); 2.01-2.12 (m,
1 H); 2.15 (s, 3 H); 3.75 (s, 3 H); 4.35 (s, 1 H); 4.83 (dt, J )
10.9, 4.5 Hz, 1 H); 6.70 (overlap, 2 H); 8.15 (s, 1 H); 13C NMR
(CDCl3) δ 15.8, 16, 20.7, 21.8, 23.1, 26.2, 26.4, 33.9, 34, 40.5,
47.0, 56.0, 77.3, 78.0, 108.5, 120.1, 122.6, 128.4, 148.8, 150.8,
174.3. Anal. Calcd for C21H32O5: C, 69.20; H, 8.85. Found: C,
69.28; H, 8.82.
16b: [a]23 ) +57.9° (c 3.45, CH2Cl2); IR (film) 3363, 1721,
D
1627 cm-1; 1H NMR (CDCl3) δ 0.62 (d, J ) 7.2 Hz, 3 H); O.74
(d, 3 H); 0.89-0.90 (m, 5 H); 0.96-1.15 (m, 2 H); 1.35-1.57
(m, 2 H); 1.60-1.77 (m, 2 H); 1.82 (s, 3 H); 2.01-2.12 (m, 1
H); 2.17 (s, 3 H); 3.75 (s, 3 H); 4.20 (s, 1 H); 4.72 (dt, J ) 10.8,
4.3 Hz, 1 H); 6.62 (1 H); 6.68 (1 H); 7.92 (s, 1 H); 13C NMR
(CDCl3) δ 15.6, 15.8, 20.5, 21.9, 23.1, 25.7, 26.0, 31.3, 34, 40.4,
47.0, 56.2, 71.3, 77.3, 109.5, 119.6, 122.6, 128.5, 149.0, 151.0,
174.2.
(2S*)-2-H yd r oxy-2-(2′-b en zyloxy-5′-m et h oxy-4′-m et h -
ylp h en yl)-p r op ion ic a cid -(-)-m en th yl Ester (10). To a
magnetically stirred mixture of the R-hydroxy menthyl ester
16a (15.79 g, 43.3 mmol) and anhydrous K2CO3 (24.8 g, 180
mmol) in acetone (400 mL) was added dropwise benzyl bromide
(8.1 mL, 67 mmol). The mixture was heated at reflux for 15 h,
at which point TLC analysis indicated the disappearance of
the starting material. The reaction was cooled to the room
temperature and filtered, and the K2CO3 cake was washed
with excess CH2Cl2 (3 × 70 mL). Evaporation of the solvent
and chromatography of the residue (silica gel, 200 g, 8%
EtOAc/hexanes) provided 17.68 g (90%) of the benzyl ether 10
as a thick brown oil. [a]23D ) -43.5° (c 1.55, CH2Cl2); IR (film)
4-Acetoxy-2-m eth yla n isole (15). To a magnetically stirred
mixture of the acetophenone 14 (66.35 g, 0.40 mol) in CH2Cl2
(150 mL) at 0 °C was added m-CPBA (252.5 g, 0.73 mol). The
mixture was warmed to room temperature and then heated
at reflux for 16 h, at which point TLC analysis indicated
disappearance of the starting material. The reaction was
quenched with saturated Na2S2O3 (70 mL) and extracted with
Et2O (200 mL). The organic layer was washed successively
with a saturated solution of Na2S2O3, Na2CO3, H2O, and brine,
then dried (Na2SO4), filtered, and evaporated under reduced
pressure. Vacuum distillation of the residue gave 61.90 g (85%)
1
3359, 1715, cm-1; H NMR (CDCl3) δ 0.77 (d, J ) 7.2 Hz, 3
H); 0.89-0.90 (m, 7 H); 0.96-1.15 (m, 2 H); 1.35-1.57 (m, 2
H); 1.60-1.77 (m, 2 H); 1.79 (s, 3 H); 1.84-1.93 (m, 1 H); 2.01-
2.12 (m, 1 H); 2.20 (s, 3 H); 3.83 (s, 3 H); 4.21 (s, 1 H); 4.65
(dt, J ) 10.7, 4.5 Hz, 1 H); 5.08 (d, J ) 12.3 Hz, 1 H); 5.04 (d,
J ) 12.3 Hz, 1 H); 6.75 (s, 1 H); 6.96 (s, 1 H); 7.29-7.49 (m, 5
H); 13C NMR (CDCl3) δ 15.9, 16.1, 20.7, 21.9, 23.0, 24.6, 25.8,
25.9, 31.1, 34.1, 39.9, 46.5, 56.1, 70.8, 70.9, 74.3, 75.6, 109.2,
115.3, 126.9, 127.7, 128.5, 136.5, 149.5, 151.5, 174.2. Anal.
Calcd for C28H38O5: C, 73.97; H, 8.42. Found: C, 74.07; H,
8.31.
1
of 15 with bp 136-138 °C (20 mm). H NMR (CDCl3) δ 2.20
(s, 3 H); 2.26 (s, 3 H); 3.81 (s, 3 H); 6.82 (m, 3 H).
4-Hyd r oxy-3-m eth yla n isole (11). A magnetically stirred
solution of 15 (65.0 g, 0.36 mol) in THF (100 mL) and HCl (3
N, 30 mL) was heated at reflux overnight. The reaction was
cooled to room temperature, quenched with saturated Na2CO3
(80 mL) and extracted with Et2O (120 mL). The organic layer
was washed with H2O and brine, then dried (Na2SO4), filtered
and evaporated under reduced pressure. Vacuum distillation
of the residue gave 41.7 g (84%) of 11 with bp 136-138 °C (20
(2S*)-2-(2′-Ben zyloxy-5′-m et h oxy-4′-m et h ylp h en yl)-2-
(m eth oxy eth oxy m eth yloxy)-p r op ion ic a cid -(-)-m en -
th yl Ester (20). A solution of the benzyloxy R-hydroxy
menthyl ester 10 (15.59 g, 34.3 mmol) in THF (30 mL) was
added dropwise to a magnetically stirred suspension of NaH
(11.35 g, 0.28 mol, 60% in mineral oil, prerinsed twice with
dry hexanes) at 0 °C. The reaction was warmed to room
temperature and stirred for 1.5 h, then MEMCl (10.0 mL, 81
mmol) was added, and the reaction was stirred for 24 h. The
reaction was quenched with H2O (20 mL) and extracted with
Et2O (60 mL). The organic layer was washed with brine, then
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. Chromatography of the residue (silica gel, 150 g, 5%,
10%, 15% EtOAc/hexanes) provided 18.02 g (97%) of the MEM
1
mm). IR (film) 3380, 1599 cm-1; H NMR (CDCl3) δ 2.18 (s, 3
H); 3.77 (s, 3 H); 4.70 (s, 3 H); 6.65 (m, 3 H).
(2S*)-2-Hydr oxy-2-(2′-h ydr oxy-5′-m eth oxy-4′-m eth ylph e-
n yl)-p r op ion ic a cid -(-)-m en th yl Ester s (16a ) a n d th e
(2R*)-Isom er (16b). To a precooled (-70 °C) 1-L three-necked
round-bottom flask fitted with an addition funnel were added
successively CH2Cl2 (60 mL), TiCl4 (10 mL, 0.09 mol), and
menthol (14.1 g, 92 mmol) in CH2Cl2 (60 mL). The mixture
was stirred for 50 min, and then a solution of 4-hydroxy-3-
methylanisole 11 (11.7 g, 85 mmol) in CH2Cl2 (70 mL) was
added dropwise. The deep red solution was stirred for 5 h, and
then menthyl pyruvate 12 (20.45 g, 904 mmol) in CH2Cl2 (60
ether 20 as a viscous pale yellow oil. [a]23 ) -57.6° (c 3.87,
D
CH2Cl2); IR (film) 1734 cm-1; H NMR (CDCl3) δ 0.77 (d, J )
1
7.2 Hz, 3 H); 0.89-0.90 (m, 7 H); 0.96-1.15 (m, 2 H); 1.35-
1.57 (m, 2 H); 1.60-1.77 (m, 2 H); 1.85 (s, 3 H); 1.84-1.93 (m,
1 H); 2.01-2.12 (m, 1 H); 2.18 (s, 3 H); 3.31 (s, 3 H); 3.43-
3.57 (m, 2 H); 3.66-3.81 (m, 2 H); 3.80 (s, 3 H); 4.55 (dt, J )
(21) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

Synthetic Studies on Nogarol Anthracyclines
J . Org. Chem., Vol. 65, No. 6, 2000 1847
10.7, 4.5 Hz, 1 H); 4.74-5.04 (m, 4 H); 6.71 (s, 1 H); 7.16 (s, 1
H); 7.20-7.43 (m, 5 H); 13C NMR (CDCl3) δ 15.5, 15.8, 20.5,
21.6, 22.6, 22.8, 25.1, 30.8, 33.8, 39.6, 46.3, 55.5, 58.5, 67, 70.1,
71.4, 74.8, 79.3, 90.8, 109.1, 114.7, 126.2, 126.3, 127.1, 128,
132.8, 148.4, 151.2, 171.2. Anal. Calcd for C32H45O7: C, 70.95;
H, 8.37. Found: C, 71.20; H, 7.92.
diastereomeric alcohols a (1.98 g, 29%) and b (4.63 g, 67%) as
light yellow oils. a : [a]23 ) +20.1° (c 5.51, CH2Cl2); IR (film)
D
3410, 2975, 2930 cm-1; 1H NMR (CDCl3) δ 1.08 (t, J ) 7.1 Hz,
6 H); 1.77 (s, 3 H); 2.21 (s, 3 H); 3.31-3.40 (m, 3 H); 3.42 (s, 3
H); 3.57-3.70 (m, 3 H); 3.80 (s, 3 H); 4.01-4.12 (m, 1 H); 4.24
(d, J ) 9.3 Hz, 1 H); 5.01-5.16 (m, 6 H); 6.77 (s, 1 H); 7.13 (s,
1 H); 7.27-7.43 (m, 5 H); 13C NMR (CDCl3) δ 14.8, 15.9, 20.2,
55.9, 60.4, 60.5, 67.0, 67.9, 70.9, 71.2, 80.3, 83.3, 85.3, 90.6,
91.2, 110.8, 115.6, 126.4, 127.3, 127.9, 128.6, 136.9, 148.9,
151.6.
(2S*)-2-(2′-Ben zyloxy-5′-m et h oxy-4′-m et h ylp h en yl)-2-
(m eth oxy eth oxy m eth yloxy)-p r op ion ic Ald eh yd e (22)
a n d (2S*)-2-(2′-Ben zyloxy-5′-m eth oxy-4′-m eth ylp h en yl)-
2-(m eth oxy eth oxy m eth yloxy)-p r op ion ic Alcoh ol (21).
To a magnetically stirred mixture of the MEM-protected
menthyl ester 20 (14.62 g, 27.0 mmol) and powdered 4 Å
molecular sieves (650 mg) in toluene (50 mL) at -78 °C was
added dropwise neat DIBAL (9.1 mL, 51 mmol). The reaction
was monitored by TLC until the starting material disappeared
and then slowly brought to room temperature. Rochelle salt
(sodium potassium tartrate, 700 mg) was added, followed by
H2O and 10% NaOH solution (7:1 v/v; 14 mL, 2 mL) and stirred
until a solid formed. The mixture was filtered through florisil,
and the residue was washed with excess CH2Cl2. The solvent
was evaporated under reduced pressure, and the residue was
taken up in Et2O (60 mL). The organic phase was washed with
brine, then dried (Na2SO4), filtered, and evaporated under
reduced pressure. Chromatography of the residue (silica gel,
150 g, 15%, 20%, and finally 30% EtOAc/hexanes) provided
3.62 g (35%) of the MEM-protected aldehyde 22 and 5.69 g
(54%) of the MEM-protected alcohol 21 as a thick pale yellow
b: [a]23D ) +8.7° (c 10.38, CH2Cl2); IR (film) 3410, 2973, 2932
1
cm-1; H NMR (CDCl3) δ 1.17 (t, J ) 7.2 Hz, 6 H); 1.85 (s, 3
H); 2.18 (s, 3 H); 3.32 (d, J ) 7.2 Hz, 1 H); 3.37 (s, 3 H); 3.45-
3.65 (m, 7 H); 3.80 (s, 3 H); 3.87-3.95 (m, 1 H); 4.83 (s, 2 H);
5.05 (s, 2 H); 5.20 (d, J ) 7.1 Hz, 1 H); 5.24 (d, J ) 1.1 Hz, 1
H); 6.79 (s, 1 H); 6.99 s, 1 H); 7.27-7.43 (m, 5 H); 13C NMR
(CDCl3) δ 14.9, 15.9, 20.8, 55.8, 58.8, 60.5, 60.6, 67.4, 67.6,
70.7, 71.6, 81.0, 82.9, 84.2, 91.2, 111.6, 116.0, 126.8, 127.0,
127.7, 128.5, 137.0, 149.6, 151.5.
A mixture of the diastereoisomeric alcohols (7.57 g, 14.7
mmol) and MnO2 (28.76 g, 331 mmol) in CH2Cl2 (70 mL) was
stirred at the room temperature for 16 h. The mixture was
filtered, the residue was washed with excess CH2Cl2, and the
filtrate was evaporated under reduced pressure. Chromatog-
raphy of the residue (silica gel, 30 g, 15% EtOAc/hexanes)
provided 7.09 g (94%) of the ketone 24. [a]23D ) -11.9° (c 10.25,
1
CH2Cl2); IR (film) 2929, 2250, 1686 cm-1; H NMR (CDCl3) δ
oil. 21: [a]23 ) -45.6° (c 2.75, CH2Cl2); IR (film) 1724, 1665,
1.08 (t, J ) 7.0 Hz, 6 H); 1.77 (s, 3 H); 2.20 (s, 3 H); 3.35 (s, 3
H); 3.32-3.42 (m, 5 H); 3.49-3.54 (m, 2 H); 3.67-3.75 (m, 1
H); 3.82 (s, 3 H); 4.81 (d, J ) 5.7 Hz, 1 H); 4.89 (d, J ) 5.7 Hz,
1 H); 5.0 (s, 2 H); 5.18 (s, 1 H); 6.71 (s, 1 H); 7.16 (s, 1 H);
7.26-7.37 (m, 5 H); 13C NMR (CDCl3) δ 14.7, 16.0, 20.3, 55.7,
60.8, 60.9, 67.3, 70.7, 71.4, 81.6, 82.2, 85.6, 90.5, 90.7, 109.4,
115.2, 126.9, 127.1, 127.4, 127.6, 128.1, 136.6, 148.6, 151.7,
185.4. Anal. Calcd for C29H38O8: C, 67.69; H, 7.44. Found: C,
67.79; H, 7.44.
D
1608 cm-1; 1H NMR (CDCl3) δ 1.62 (s, 3 H); 2.18 (s, 3H); 2.99
(b s, 1 H); 3.37 (s, 3 H); 3.56 (t, J ) 4.6 Hz, 2 H); 3.79 (s, 3 H);
3.80-3.90 (m, 3 H); 4.04 (d, J ) 3.8 Hz, 1 H); 4.07 (d, J ) 3.8
Hz, 1 H); 4.80 (d, J ) 7.7 Hz, 2 H); 4.91 (d, J ) 7.7 Hz, 2 H);
5.02 (s, 2 H); 6.78 (s, 1 H); 7.03 (s, 1 H); 7.25-7.43 (m, 5H);
13C NMR (CDCl3) δ 15.8, 22.2, 56, 58.8, 66.4, 67.6, 70.9, 71.5,
82.4, 90.6, 110.6, 116.1, 126.4, 127.3, 127.7, 128.5, 129.1, 137.1,
149.3, 151.7. Anal. Calcd for C22H30O6: C, 67.71; H, 7.69.
Found: C, 67.78; H, 7.66.
(5S*)-5-(2′-Ben zyloxy-5′-m et h oxy-4′-m et h ylp h en yl)-5-
(m eth oxy eth oxy m eth yloxy)-4-oxo-h ex-2-en -1-d ieth yl
Aceta l (26). A mixture of the ketone 24 (6.56 g, 12.7 mmol)
in EtOAc (25 mL), Lindlar catalyst (2.35 g), and quinoline (7
mL) was stirred under a hydrogen atmosphere for 24 h. The
reaction mixture was filtered through Celite, and the filtrate
was diluted with Et2O (50 mL). The solution was successively
washed with 10% HCl, H2O, and brine, then dried (Na2SO4),
filtered ,and evaporated under reduced pressure to provide
6.58 g (100%) of the R,â-unsaturated ketone 26. [a]23D ) -23.4°
(c 2.52, CH2Cl2); IR (film) 3053, 2976, 2927, 2304, 1705, 1638
cm-1; 1H NMR (CDCl3) δ 1.06 (t, J ) 7.1 Hz, 3 H); 1.18 (t, J )
7.1 Hz, 3 H); 1.73 (s, 3 H); 2.19 (s, 3 H); 3.17-3.28 (m, 1 H);
3.34 (s, 3 H); 3.46-3.55 (m, 4 H); 3.61-3.76 (m, 3 H); 3.84 (s,
3 H); 4.83 (s, 2 H); 4.83 (d, J ) 12.0 Hz, 1 H); 4.95 (d, J ) 12.0
Hz, 1 H); 5.81 (q, J ) 13.7 Hz, 2 H); 6.29 (d, J ) 18.7 Hz, 1 H);
6.67 (s, 1 H); 7.22 (s, 1 H); 7.25-7.35 (m, 5 H); 13C NMR
(CDCl3) δ 15.2, 15.3, 16.2, 20.3, 55.9, 58.9, 62.4, 62.6, 67.4,
70.4, 71.5, 82.2, 90.3, 96.9, 109.4, 115.0, 124.7, 126.6, 126.7,
127.1, 127.4, 128.3, 136.9, 142.1, 148.4, 151.9, 197.2. Anal.
Calcd for C29H40O8: C, 67.42; H, 7.80 Found: C, 67.42; H, 7.75.
(5S*,2R*)-5-(2′-Ben zyloxy-5′-m eth oxy-4′-m eth ylph en yl)-
5-(m eth oxy eth oxy m eth yloxy)-4-oxo-2-p h en ylth io-h ex-
a n e-1-d ieth yl Aceta l a n d th e (5S*,2S*)-Isom er (27). To a
stirred solution of the R,â-unsaturated ketone 15 (7.44 g, 14.4
mmol) in CHCl3 (25 mL, reagent grade) at 0 °C was added
Et3N (3.7 mL, 21 mmol) followed by PhSH (2.1 mL, 17 mmol).
The reaction was warmed slowly to room temperature for 24
h, at which point TLC analysis indicated disappearance of the
starting material. The reaction was quenched with 10% NaOH
(10 mL) and extracted with Et2O (30 mL). The organic layer
was washed successively with H2O and brine, then dried (Na2-
SO4), filtered, and evaporated under reduced pressure. Chro-
matography of the residue (silica gel, 30 g, 12% EtOAc/
hexanes) provided a diastereomeric mixture of thiophenylated
ketones 27a (3.87 g, 43%) and 27b (5.05 g, 56%).
(2S*)-2-(2′-Ben zyloxy-5′-m et h oxy-4′-m et h ylp h en yl)-2-
(m eth oxy eth oxy m eth yloxy)-p r op ion ic Ald eh yd e (22).
To a stirred solution of (COCl)2, (3.7 mL, 42 mmol) in CH2Cl2
(17 mL) was added DMSO (6.6 mL, 92 mmol) in CH2Cl2 (10
mL), and the pale yellow solution was stirred for 15 min. A
solution of MEM-protected alcohol 11 (3.38 g, 8.7 mmol) in
CH2Cl2 (15 mL) was added dropwise, and the mixture was
stirred for 0.5 h. Trimethylamine (22 mL, 0.16 mmol) in CH2-
Cl2 (15 mL) was added, the cold bath was removed, and the
reaction was stirred for 20 min. TLC analysis indicated the
disappearance of the starting material. The reaction was
quenched with saturated NH4Cl solution (15 mL), warmed to
room temperature, and extracted with Et2O (60 mL). The
organic layer was washed with brine, then dried (Na2SO4),
filtered ,and evaporated under reduced pressure. Chromatog-
raphy of the residue (silica gel, 50 g, 15% EtOAc/CHCl3)
provided 3.27 g (97%) of the MEM-protected aldehyde 22 as a
greenish yellow oil. [a]23D ) +13.5° (c 10.27, CH2Cl2); IR (film)
1
1735, 1608 cm-1; H NMR (CDCl3) δ 1.68 (s, 3 H); 3.83 (s, 3
H); 4.83 (s, 2 H); 4.98 (s, 2 H); 6.77 (s, 1 H); 7.04 (s, 1 H); 7.25-
7.39 (m, 5 H); 13C NMR (CDCl3) δ 16.2, 20, 55.9, 58.8, 67.1,
70.9, 71.2, 81.3, 90.6, 110, 115.7, 126.5, 127.2, 127.7, 127.9,
128.4, 136.5, 148.6, 151.8, 199.5. Anal. Calcd for C22H28O6: C,
68.02; H, 7.27. Found: C, 67.74; H, 8.25.
(5S*)-5-(2′-Ben zyloxy-5′-m et h oxy-4′-m et h ylp h en yl)-5-
(m eth oxy eth oxy m eth yloxy)-4-oxo-h ex-2-yn e-1-d ieth yl
Aceta l (24). To a magnetically stirred solution of the propargyl
aldehyde diethyl acetal (23) (9.4 mL, 65 mmol) at room
temperature was added dropwise n-BuLi (2.15 M in hexanes,
26.6 mL, 57.2 mmol), and the solution was stirred for 1.5 h.
The MEM-protected aldehyde 22 (5.18 g, 13.3 mmol) in THF
(30 mL) was added dropwise, and the reaction was stirred until
disappearance of the starting material was indicated by TLC
(24 h). The reaction was quenched with saturated NH4Cl
solution and extracted with Et2O (50 mL). The organic layer
was washed with brine, then dried (Na2SO4), filtered, and
evaporated under reduced pressure. Chromatography of the
residue (silica gel, 30 g, 20% EtOAc/hexanes) provided the
27a : IR (film) 3418, 1719, 1583 cm-1 1H NMR (CDCl3) δ
;
0.99 (t, J ) 6.9 Hz, 3 H); 1.02 (t, J ) 7.2 Hz, 3 H); 1.70 (s, 3
H); 2.16 (s, 3 H); 2.77-3.12 (m, 2 H); 3.27-3.82 (m, 9 H); 3.33

1848 J . Org. Chem., Vol. 65, No. 6, 2000
Hauser and Ganguly
(s, 3 H); 3.79 (s, 3 H); 4.35 (d, J ) 4.1 Hz, 1 H); 4.68 (d, J )
3.7 Hz, 1 H); 4.78 (d, J ) 3.7 Hz, 1 H); 4.94 (s, 2 H); 6.69 (s, 1
H); 7.11-7.48 (m, 9 H); 7.51 (d, J ) 2.47 Hz, 2 H); 13C NMR
(CDCl3) δ 15.0, 15.1, 16.2, 21.0, 29.6, 37.4, 47.3, 55.9, 58.9,
63.4, 67.2, 70.6, 71.7, 83.1, 90.9, 104.4, 110.4, 115.5, 126.5,
126.8, 127.3, 127.5, 128.4, 128.6, 131.4, 135.8, 136.9, 148.4,
148.7, 206.7.
6.79 (s, 1 H); 6.95 (s, 1 H); 7.29-7.39 (m, 5 H); 13C NMR
(CDCl3) δ 16.2, 24.4, 29.6, 55.6, 55.9, 77.6, 80.6, 94.7, 110.1,
116.7,127.1, 127.8, 128.0, 128.2, 128.3, 136.7, 141.1, 149.7,
151.8, 197.3. Anal. Calcd for C22H24O5: C, 71.72; H, 6.57
Found: C, 71.62; H, 6.63.
30b: mp 123-127 °C; [a]23 ) +15.8° (c 4.05, CH2Cl2); IR
D
(CH2Cl2) 2925, 1693 cm-1
;
1H NMR (CDCl3) δ 1.77 (s, 3 H);
27b: IR (film) 3516, 1721, 1583 cm-1
;
1H NMR (CDCl3) δ
2.18 (s, 3 H); 3.28 (s, 3 H); 3.81 (s, 3 H); 4.81 (d, J ) 11.3 Hz,
1 H); 5.08 (d, J ) 11.3 Hz, 1 H); 5.34 (t, J ) 1.6 Hz, 1 H); 5.89
(dd, J ) 10.4, 1.7 Hz, 1 H); 6.53 (dd, J ) 10.4, 1.7 Hz, 1 H);
6.76 (s, 1 H); 6.92 (s, 1 H); 7.35-7.49 (m, 5 H); 13C NMR
(CDCl3) δ 16.2, 21.6, 54.7, 54.8, 56.1, 71.9, 79.9, 94.1, 94.2,
110.4, 110.7, 116.8, 117.1, 128.2, 128.5, 128.6, 128.8, 136.9,
143.2, 149.7, 151.8, 197.2. Anal. Calcd for C22H24O5: C, 71.72;
H, 6.57 Found: C, 71.79; H, 6.65.
1.10 (t, J ) 6.9 Hz, 3 H); 1.16 (t, J ) 7.2 Hz, 3 H); 1.73 (s, 3
H); 2.16 (s, 3 H); 2.75 (dd, J ) 13.5, 5.7 Hz, 1 H); 3.27-3.45
(m, 1 H); 3.51 (s, 3 H); 3.53-3.80 (m, 9 H); 3.79 (s, 3 H); 4.51
(d, J ) 3.6 Hz, 1 H); 4.67 (d, J ) 3.2 Hz, 1 H); 4.76 (d, J ) 3.2
Hz, 1 H); 4.84 (s, 2 H); 6.61 (s, 1 H); 7.01-7.19 (m, 3 H); 7.20-
7.35 (m, 8 H); 13C NMR (CDCl3) δ 15.0, 15.1, 16.1, 21.2, 29.6,
37.7, 46.2, 55.6, 58.5, 63.4, 63.7, 67.1, 70.3, 71.6, 83.3, 90.5,
103.5, 110.0, 115.1, 126.2, 126.6, 127.3, 127.4, 128.2, 128.5,
130.9, 136.1, 137.1, 148.7, 151.5, 207.4.
(5S*)-Met h yl-6-d eoxy-2,3-a n h yd r o-5-(2′-b en zyloxy-5′-
m eth oxy-4′-m eth ylp h en yl)-h exos-4-u lose (31). To a solu-
tion of the unsaturated ketone 30 (442 mg, 1.16 mmol) in
CH2Cl2 (20 mL) was added t-BuOOH (0.75 mL, 2.3 mmol) and
Triton B (3 mL), and the mixture was stirred overnight at room
temperature. The reaction was quenched with H2O (5 mL) and
extracted with Et2O (50 mL). The organic layer was washed
with brine, then dried (Na2SO4), filtered, and evaporated under
reduced pressure. Chromatography of the residue (silica gel,
10 g, 20% EtOAc/hexanes) provided 458 mg (98%) of the keto
(5S *)-r-Me t h yl-5-(2′-Be n zyloxy-5′-m e t h oxy-4′-m e t h -
ylp h en yl)-2-p h en ylth io-2,3,6-tr id eoxy-h ex-4-u lose (29a )
a n d th e â-An om er (29b). To a magnetically stirred solution
of 27a and 27b (2.52 g, 4.0 mmol) in MeOH/CHCl3 (2:7 v/v; 8
mL, 28 mL) at 0 °C was added TsOH (20 mg) in TFA (4 mL).
The reaction was warmed to room temperature and then
heated at reflux. (The compound at the same Rf of the starting
material 16a and 16b was found to be the transacetalized
MEM-cleaved tertiary alcohol (240 mg, 12% yield), which was
subjected to further cyclization in the same condition to provide
the desired product 19a and 19b). The reaction was cooled to
room temperature, quenched with Na2CO3 solution (30 mL),
and extracted with Et2O (30 mL). The organic layer was
washed with H2O and brine, then dried (Na2SO4), filtered, and
evaporated under reduced pressure. Chromatography of this
residue (silica gel, 15 g, 10% EtOAc/hexanes) provided 1.60 g
(83%) of the diastereomeric cyclized products 29a and 29b.
As a diastereomeric mixture of 29a and 29b: IR (film) 3057,
epoxide 31 as a colorless oil. [a]23 ) -34.0° (c 4.59, CH2Cl2);
D
IR (film) 2931, 1724 cm-1; H NMR (CDCl3) δ 1.72 (s, 3 H);
1
2.17 (s, 3 H); 3.39 (d, J ) 4.0 Hz, 1 H); 3.53 (s, 3 H); 3.58 (m,
1 H); 3.82 (s, 3 H); 4.83 (d, J ) 2.7 Hz, 1 H); 4.89 (d, J ) 2.7
Hz, 1 H); 5.13 (d, J ) 1.1 Hz, 1 H); 6.72 (s, 1 H); 6.99 (s, 1 H);
7.26-7.49 (m, 5 H); 13C NMR (CDCl3) δ 15.9, 26.8, 53.8, 55.9,
56.3, 57.4, 72.0, 80.5, 96.3, 96.4, 109.8, 110.1, 116.8, 117.1,
127.3, 127, 128.0, 128.5, 137.0, 148.3, 152.3, 201.7. Anal. Calcd
for C22H24O6: C, 68.72; H, 6.29. Found: C, 68.69; H, 6.31.
(5S*)-Met h yl-6-d eoxy-2,3-a n h yd r o-5-(2′-b en zyloxy-5′-
m eth oxy-4′-m eth ylp h en yl)-lyxo-h exop yr a n osid e (32). To
a stirred solution of keto epoxide 31 (300 mg, 0.77 mmol) in
2-propanol (20 mL) was added NaBH4 (60 mg, 1.5 mmol) and
the mixture was stirred overnight at room temperature. The
reaction was quenched with H2O (5 mL) and diluted with Et2O
(25 mL), and the layers were separated. The organic layer was
washed with H2O and brine, then dried (Na2SO4), filtered, and
evaporated under reduced pressure. Chromatography of the
residue (silica gel, 10 g, 20% EtOAc/hexanes) gave 302 mg
1
1731, 1583 cm-1; H NMR (CDCl3) δ 1.70 (s, 3 H); 1.85 (s, 3
H); 2.20 (s, 3 H); 2.21 (s, 3 H); 2.32-2.62 (m, 2 H); 2.82 (m, 1
H); 3.32-3.40 (m, 2 H); 3.43 (s, 3 H); 3.54 (s, 3 H); 3.71-3.78
(m, 1 H); 3.85 (s, 6 H); 4.69 (d, J ) 8.2 Hz, 1 H); 4.71-5.09
(m,4 H); 6.81 (s, 2 H); 6.97 (s, 1 H); 7.01 (s, 1 H); 7.18-7.82
(m, 20 H); 13C NMR (CDCl3) δ 16.1, 17.9, 23.3, 24.5, 29.3, 37.0,
38.5, 41.1, 44.7, 45.3, 55.9, 71.4, 72.0, 80.6, 81.2, 99.3, 101.8,
106.3, 109.7, 110.0, 114.9, 116.1, 116.8, 126.6, 126.7, 127.0,
127.5, 127.8, 128.1, 128.2, 128.4, 128.5, 128.6, 128.7, 128.9,
131.3, 131.8, 132.3, 133.1, 133.6, 135.9, 136.1, 148.4, 148.5,
151.8, 152.0, 206.6, 206.8.
(99%) of pure 32 as white crystals with mp 144-146 °C. [a]23
D
) +15.9° (c 0.75, CH2Cl2); IR (CH2Cl2) 3550, 1728 cm-1 1H
;
(5S*)-r-Met h yl-5-(2′-b en zyloxy-5′-m et h oxy-4′-m et h yl-
p h en yl)-6-d eoxyh ex-2-en -4-u lose (30a ) a n d (5S*)-Meth yl-
â-5-(2′-ben zyloxy-5′-m eth oxy-4′-m eth ylph en yl)-6-deoxyh ex-
2-en -4-u lose (30b). To a magnetically stirred solution of the
anomeric methyl pyranosides 29a and 29b (2.01 g, 4.2 mmol)
in CH2Cl2 (15 mL) at 0 °C was added m-CPBA (1.15 g, 6.7
mmol), and the reaction was warmed to room temperature.
The reaction was stirred for 4 h, then quenched with saturated
Na2S2O3 (15 mL) solution, and extracted with Et2O (30 mL).
The organic layer was washed successively with Na2CO3
solution (20 mL), H2O (15 mL), and brine (15 mL), then dried
(Na2SO4), filtered ,and evaporated under reduced pressure to
afford a pale yellow solid. Without further purification, the
diastereomeric sulfoxide mixture was heated at reflux in
toluene (15 mL), in the presence of CaCO3 (30 mg) and K2CO3
(20 mg) for 48 h. The reaction was cooled to room temperature
and filtered, and the filtrate was diluted with Et2O (25 mL).
The organic layer was washed with brine, then dried (Na2-
SO4), filtered, and evaporated under reduced pressure. Chro-
matography of the residue (silica gel, 15 g, 13% EtOAc/
hexanes) provided 1.18 g (93%) of the R-anomer 29a and 0.09
g (7%) of the â-anomer 29b. The â-anomer 29b was converted
to the R-anomer 29a in 50% yield by heating in MeOH (5 mL)
and TFA (2-3 drops) for 24 h.
NMR (CDCl3) δ 1.59 (s, 3 H); 2.20 (s, 3 H); 2.28 (d, J ) 10.6
Hz, 1 H); 3.31 (d, J ) 3.8 Hz, 1 H); 3.54 (s, 3 H); 3.61 (dd, J )
6.5, 3.4 Hz, 1 H); 3.81 (s, 3 H); 4.71 (dd, J ) 10.4, 6.4 Hz, 2 H);
4.96 (d, J ) 11.6 Hz, 1 H); 5.21 (d, J ) 11.6 Hz, 1 H); 6.78 (s,
1 H); 7.29 (s, 1 H); 7.29-7.46 (m, 5 H); 13C NMR (CDCl3) δ
15.7, 23.4, 51.5, 51.8, 55.5, 55.9, 64.6, 71.1, 77.8, 96.4, 109.7,
115.5, 125.8, 127.5, 127.8, 128.6, 129.8, 137.2, 148.1, 151.7.
Anal. Calcd for C22H26O6: C, 68.38; H, 6.78. Found: C, 68.23;
H, 6.79.
(5S*)-Met h yl-r-3-6-d id eoxy-3-(d im et h yla m in o)-5-(2′-
ben zyloxy-5′-m eth oxy-4′-m eth ylp h en yl)-glu co-h exop yr a -
n osid e (33a ). A mixture of 32 (250 mg, 0.65 mmol) and
dimethylamine (6 mL) was heated overnight at 140 °C in a
sealed tube. The reaction mixture was cooled to room temper-
ature, and the excess dimethylamine was evaporated. Chro-
matography of the residue (silica gel, 5 g, 10% MeOH/CH2Cl2)
provided 208 mg of 33 as a yellowish solid in 75% yield with
mp 171-174 °C. [a]23 ) -25.4° (c 1.26, CH2Cl2); IR (CH2Cl2)
D
1
3425, 1625 cm-1; H NMR (CDCl3) δ 1.78 (s, 3 H); 2.22 (s, 3
H); 2.45 (s, 6 H); 2.94 (t, J ) 10.5 Hz, 1 H); 3.35 (s, 3 H); 3.55
(t, J ) 8.4 Hz, 1 H); 3.64 (d, J ) 10.7 Hz, 1 H); 3.79 (s, 3 H);
4.11 (d, J ) 7.4 Hz, 1 H); 5.08 (s, 2 H); 6.85 (s, 1 H); 7.26-7.52
(m, 5 H); 7.59 (s, 1 H); 13C NMR (CDCl3) δ 16.0, 28.1, 41.3,
55.6, 56.9, 65.6, 70.7, 71.1, 75.5, 78.8, 101.4, 111.9, 115.6, 126.7,
126.9, 127.2, 127.9, 128.6, 136.5, 149.3, 151.6. Anal. Calcd for
30a : mp 105-107 °C; [a]23D ) +7.9° (c 6.3, CH2Cl2); IR (CH2-
Cl2) 3053, 1692 cm-1; 1H NMR (CDCl3) δ 1.86 (s, 3 H); 2.20 (s,
3 H); 3.46 (s, 3 H); 3.82 (s, 3 H); 4.79 (d, J ) 11.3 Hz, 1 H);
4.90 (d, J ) 11.3 Hz, 1 H); 5.09 (dd, J ) 2.9, 1.2 Hz, 1 H); 5.87
(dd, J ) 10.4, 2.9 Hz, 1 H); 6.44 (dd, J ) 10.4, 2.9 Hz, 1 H);
C
24H33NO6: C, 66.80; H, 7.71 Found: C, 66.98; H, 7.90.
(5S*)-Meth yl-r-3,6-d id eoxy-3-(d im eth yla m in o)-5-(2′-h y-
d r oxy-5′-m et h oxy-4′-m et h ylp h en yl)-glu co-h exop yr a n o-
sid e (33b). A mixture of 33a (260 mg, 0.6 mmol), 10% Pd/C

Synthetic Studies on Nogarol Anthracyclines
J . Org. Chem., Vol. 65, No. 6, 2000 1849
(261 mg), and ammonium formate (175 mg) in EtOH (15 mL)
was stirred at room temperature for 24 h. The mixture was
filtered through Celite, and the residue was washed with Et2O
(25 mL). The filtrate was evaporated under reduced pressure,
and the residue was chromatographed (silica gel, 5 g, 2%
MeOH/CH2Cl2) to afford 195 mg of the phenol 33b as an oil in
solution (20 mL). The mixture was extracted with Et2O (25
mL), and the organic layer was washed successively with H2O
and brine, then dried (Na2SO4), filtered, and evaporated under
reduced pressure. Chromatography of the residue (silica gel,
5 g, 10% MeOH/CH2Cl2) provided 43 mg of 6 (86%; 94% based
on reclaimed starting material) as white crystals with mp 42-
45 °C; [a]23D ) -34.7° (c 4.29, CH2Cl2); IR (CH2Cl2) 2907, 1601
cm-1; 1H NMR (CDCl3) δ 1.67 (s, 3 H); 2.19 (s, 3 H); 2.64 (s, 6
H); 3.50 (d, J ) 10.3 Hz, 1 H); 3.80 (s, 3 H); 4.03 (m, 2 H); 5,47
(d, J ) 3.7 Hz, 1 H); 6.57 (s, 1 H); 6.70 (s, 1 H); 13C NMR
(CDCl3) δ 15.8, 40.8, 59.8, 65.1, 70.4, 78.8, 80.2, 101.4, 109.8,
120.6, 122.2. 125.6, 128.1, 150.8. Anal. Calcd for C16H23NO5:
C, 62.16; H, 7.49. Found: C, 62.23; H,7.50.
95% yield. [a]23 ) -27.6° (c 7.08, CH2Cl2); IR (CH2Cl2) 2929,
D
1
1654, 1560 cm-1; H NMR (CDCl3) δ 1.69 (s, 3 H); 2.17 (s, 3
H); 2.64 (s, 6 H); 3.02 (t, J ) 11.0 Hz, 1 H); 3.59 (s, 3 H); 3.61-
3.73 (m, 2 H); 3.75 (s, 3 H); 4.29 (d, J ) 7.5 Hz, 1 H); 5.91 (br
s, 1 H); 6.71 (s, 1 H); 7.14 (s, 1 H); 13C NMR (CDCl3) δ 15.8,
41.9, 59.9, 57.6, 65.1, 70.4, 71.8, 78.8, 80.0, 101.4, 109.3, 120.1,
122.0, 128.1, 161.9. Anal. Calcd for C17H27NO6: C, 59.81; H,
7.97. Found: C, 59.69; H, 7.91.
(2S*,3S*,4R*,5R*,6S*)-4-N,N-Dim eth yla m in o-3,5-d ih y-
dr oxy-6,9-dim eth yl-8-m eth oxy-3,4,5,6-tetr a h yd r o-8-m eth -
oxy-2,6-ep oxy-2H-1-ben zoxocin (6). A mixture of 33b (55
mg, 0.16 mmol) in acetic acid (2.6 mL) and 3 N HCl (0.5 mL)
was heated on a steam bath for 3 h. The reaction was cooled
to room temperature and neutralized with saturated Na2CO3
Ack n ow led gm en t. This work was generously sup-
ported by the National Cancer Institute of the National
Institutes of Health under grant CA 18141.
J O991483W