Asymmetric synthesis of two new conformationally constrained lysine derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00450-7

The asymmetric synthesis of the conformationally constrained L- and D-lysine derivatives methyl (1S,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7, 8-octahydroanthracene-1-carboxylate (4) and methyl (1R,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7, 8-octahydroanthracene-1-carboxylate (5), respectively are described. Application of the Bucherer hydantoin synthesis to the carbonyl group of 2′,3′,4′,5′,6′,7′-hexahydrospiro[1, 3-ethylenedithiole-2,1′-anthracen]-8′-one (18), which was prepared from 1,8-dichloroanthraquinone (14) in nine steps and the deprotection of the masked second ketone of 18 yields rac-21. The latter is the precursor for a novel asymmetric reductive amination protocol using (R)-phenylglycinol as a chiral amino auxiliary and NaBH(OAc)₃ as a reducing agent. Using this procedure, the asymmetric reductive amination of α-tetralone derivatives and indanone proceeds with >95% de. Lower diastereomeric excesses are observed for benzosuberone (16.7% de) and acetophenone (27.3% de). rac-21 gave (1′S,8′S,1(R)-25a (38% yield) and (1′R,8′S,1(R)-25b (44.5% yield) with greater than 52 and 78% de, respectively. Cleavage of the amino auxiliary of (1′S,8′S,1(R)-25a and of (1′R,8′S,1(R)-25b with lead(IV) tetraacetate and hydrolysis of the hydantoin ring yields the unprotected analogs of 4 and 5. The latter are transformed into the selectively protected target molecules 4 and 5 through standard protection procedures. The overall yield of the 17- and 18-step synthesis starting from 13 was 0.3% yield for each constrained lysine derivative.

Full text of DOI:10.1016/S0040-4020(02)00450-7

TETRAHEDRON
Pergamon
Tetrahedron 58 /2002) 4837±4849
Asymmetric synthesis of two new conformationally constrained
lysine derivatives
p
Robert A. Stalker, Tamara E. Munsch, Jacquelyn D. Tran, Xiaoping Nie, RalfWarmuth,
È
²
Alicia Beatty and Christer B. Aakeroy
Department of Chemistry, Kansas State University, Manhattan, KS 66506-3701, USA
Received 8 November 2001; revised 18 April 2002; accepted 22 April 2002
AbstractÐThe asymmetric synthesis ofthe conofrmationally constrained l- and d-lysine derivatives methyl /1S,8S)-1-amino-8-tert-
butoxycarbonylamino-1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxylate /4) and methyl /1R,8S)-1-amino-8-tert-butoxycarbonylamino-
1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxylate /5), respectively are described. Application ofthe Bucherer hydantoin synthesis to the
0
carbonyl group of2 ,30,40,50,60,70-hexahydrospiro[1,3-ethylenedithiole-2,10-anthracen]-80-one /18), which was prepared from 1,8-dichloro-
anthraquinone /14) in nine steps and the deprotection ofthe masked second ketone of 18 yields rac-21. The latter is the precursor for a novel
asymmetric reductive amination protocol using /R)-phenylglycinol as a chiral amino auxiliary and NaBH/OAc)3 as a reducing agent. Using
this procedure, the asymmetric reductive amination of a-tetralone derivatives and indanone proceeds with .95% de. Lower diastereomeric
excesses are observed for benzosuberone /16.7% de) and acetophenone /27.3% de). rac-21 gave /10S,80S,1/R)-25a /38% yield) and
/10R,080S,1/R)-25b /44.5% yield) with greater than 52 and 78% de, respectively. Cleavage ofthe amino auxiliary of/1 0S,80S,1/R)-25a and
of/1 R,80S,1/R)-25b with lead/IV) tetraacetate and hydrolysis ofthe hydantoin ring yields the unprotected analogs of 4 and 5. The latter are
transformed into the selectively protected target molecules 4 and 5 through standard protection procedures. The overall yield ofthe 17- and
18-step synthesis starting from 13 was 0.3% yield for each constrained lysine derivative. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
that mimic parts ofpeptide oflds and induce an increased
conformational stability have mainly focused on the a-helix
and b-hairpin.1,2,4,6,7
The design and synthesis ofconofrmationally constrained
amino acids1 and peptidomimetics2 is ofspecial interest for
medicinal and bio-organic chemistry in view oftheir pos-
sible application as potency-enhanced ligands for biological
receptors,3 as probes for mimicry of peptide secondary
structures,4 and as novel structural elements ofrelevance
to bio-materials.5 Efforts to design and synthesize scaffolds
In particular constrained di- and tripeptides have been used
to mimic turn structures, which are parts ofthese motifs. In
addition, the incorporation of a,a-disubstituted glycines
into the peptide backbone has led to stabilized helices.8,9
We have designed the conformationally constrained amino
Figure 1. Stereoview ofenergy-minimized structure ofhelix-nucleation site 3 /OPLS-AAp,31 GB/SA water solvation model25c); atom coloring: C grey; H
white; N dotted; O black.
Keywords: asymmetric reductive amination; constrained amino acid; lysine.
Corresponding author. Tel.: 11-785-532-6684; fax: 11-785-532-6666; e-mail: warmuth@ksu.edu
Present address: Department ofChemistry and Biochemistry; University ofNotre Dame, Notre Dame, IN, USA.
p
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/02)00450-7

4838
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
acids 1 and 2, which belong to the family of a,a-disubsti-
tuted glycines. Our motivation for the design and synthesis
of 1 and 2 was twofold. /1) Both 1 and 2 are conformation-
ally constrained l- and d-lysines, respectively,10 with a
completely constrained side chain in the /1)g, t, t, /2)g
conformation for 1 and /2)g, t, t, /2)g conformation for
2. In lieu ofthe importance ofthe lysine side chain for the
stability ofthe a-helix11 both amino acids are interesting
targets for extended studies related to this aspect. For
example, model studies show that the protonated e-amino
group of 1 can undergo an /i, i23)-electrostatic interaction
with a backbone carbonyl group ofan a-helix. /2) Both
constrained lysines are interesting rigid building blocks
for the design of novel C- and N-terminal peptide helix
nucleation sites.7,11 For example, linking both amino groups
of 1 with a Gly-/l)-Pro-/l)-Asn tripeptide leads to a macro-
cycle 3 that mimics the ®rst turn ofan a-helix /Fig. 1) and
could strongly stabilize the a-helical conformation of a
covalently attached peptide.
Chart 1.
In this report, we describe the asymmetric synthesis of 4 and
Scheme 1. Synthetic strategy towards the conformationally constrained lysines 1 and 2.
Scheme 2. Model studies on the reductive amination of a-tetralone 12. Conditions: /a) NaBH4, EtOH, toluene, 2108C; /b) Pd/C/H2, MeOH, HCl /1N)
/c) /R)-phenylglycinol, p-TsOH, xylenes, re¯ux; /d) NaBH/OAc)3 THF, 08C; /e) 1.Pb/OAc)4, MeOH, 08C; 2. HCl /6N), EtOH, re¯ux.

R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
Table 1. Asymmetric reductive amination ofketones 12a±e
4839
Entry
Ketone
Ratioa,b 10:13
Reducing agent/solvent
Temperature /8C)
Ratioc /1S,10R)-
11//1R,10R)-11
/de)
Yieldd 11 /%)
1
2
3
4
5
6
7
8
12a
12b
12b
12b
12b
12c
12d
12e
.40:1e
86:14e,f
86:14e,f
86:14e,f
86:14e,f
NaBH/OAc)3/THF
NaBH4/EtOH
NaBH4/EtOH
0
24
0
210
0
24
24
0
.40:1 /.95%)
9.5:1 /80.7%)
9.95:1 /81.7%)
9.85:1 /81.6%)
40:1 /95.1%)
.40:1 /.95%)
1.4:1 /16.7%)
7:4 /27.3%)
84
85
83
85
87
48
84
90
NaBH4/EtOH
NaBH/OAc)3/THF
NaBH/OAc)3/THF
NaBH/OAc)3/THF
NaBH/OAc)3/THF
89:11e,g
h
22:78d,i
a
Determined from the integrals of the 10 methine proton signals ofthe products in the 1H NMR spectrum ofthe reaction mixture.
See Ref. 24d,e.
Determined by HPLC.
Yield ofisolated product /mixture).
Only E-imine was detected.
b
c
d
e
f
10:4 Ratio ofdiastereomeric 1,3-oxazolidines 13b.
7:4 Ratio ofdiastereomeric 1,3-oxazolidines 13c.
Complex mixture of E-10, Z-10, and two diastereomeric 1,3-oxazolidines /1S,10R)-13 and /1R,10R)-13.
2.1:1 Ratio ofdiastereomeric 1,3-oxazolidines 13e.
g
h
i
5, which are selectively protected derivatives of 1 and 2 and
which are suitable to be incorporated into short host
peptides for such model studies /Chart 1).
derived imine 7 by Gutman et al. caught our attention
/Scheme 2).23
Under optimal conditions, the reduction proceeded with
excellent 97:3 diastereofacial selectivity. Unfortunately,
the subsequent debenzylation using catalytic hydrogenation
showed a marginally regioselectivity of3.5:1 in afvor of
cleaving the C10 ±N bond of 7. Nevertheless, the high facial
selectivity ofthis reduction lured us to investigate the
related reduction ofthe / R)-a-phenylglycinol derived
imine 10b. The use of/ R)-a-phenylglycinol as the chiral
amino auxiliary is very attractive since the C10 ±N bond of
the expected product 11b is selectively cleaved with lead
/IV) tetraacetate.24 Imine 10b was prepared as an equi-
librium mixture with the two diastereomeric 1,3-oxazo-
lidines 13b in greater 90±95% yield by re¯uxing tetralone
and /R)-a-phenylglycinol in xylenes in the presence of
catalytic amounts of p-tolylsulfonic acid.24e The reduction
ofthis mixture with NaBH 4 in ethanol at room temperature
gave in greater than 85% yield a 9.5:1-mixture ofdiastereo-
meric amines /1S,10R)-11b and /1R,10R)-11b /80.7% de)
/Table 1, entry 2). The diastereomeric excess /de) showed
little temperature dependence /Table 1, entries 3±4). We
reckoned that an increased bulkiness ofthe reducing agent
would improve the facial selectivity. Indeed, reduction of
the 10b/13b mixture with freshly prepared NaBH/OAc)3 in
THF at 08C strongly increased the diastereomeric ratio /dr)
of/1 S,10R)-11b//1R,10R)-11b to 40:1 /95.1 de; 87% isolated
yield) /Table 1, entry 5). The subsequent oxidative cleavage
of/1 S,10R)-11b using Pb/OAc)4 gave /S)-9 in 63% yield.
Thus, this method proved to be a suitable alternative to
Gutman's method as well as other asymmetric reductive
amination protocols. The stereochemical outcome ofthe
reduction was determined by X-ray crystallography. The
use of/ R)-a-phenylglycinol gives /S)-stereochemistry at
the new stereogenic center ofthe major product diastereo-
mer 11b. This outcome is consistent with the lowest energy
conformation of 10b obtained from a Monte Carlo confor-
mational search /MM2; GB/SA CHCl3 solvent model),25
which shows a better accessibility ofthe imine bond from
the re-face of 10b to give /S)-9b.
2. Results and discussion
2.1. Synthetic strategy
Our strategy for the synthesis of 1 and 2 involves the regio-
selective conversion ofthe carbonyl groups of1,2,3,4,
5,6,7,8-tetrahydroanthracene-1,8-dione 6,12 into an amino
acid group and an amine, respectively /Scheme 1). For the
®rst key transformation, we choose the Bucherer hydantoin
synthesis followed by the hydrolysis of the hydantoin ring.
Even though no asymmetric protocol has been developed
for the Bucherer reaction, it has been proven highly reliable
and high yielding for the synthesis of benzocyclic aryl- and
alkyl-amino acids.13 The subsequent enantioselective reduc-
tive amination ofthe second ketone group of 7 would yield
both diastereomeric 1 and 2, which would have to be
separated chromatographically or through crystallization.
2.2. Model study of the asymmetric reductive amination
Based on our outlined synthetic strategy, the reductive
amination is a very important step in the reaction sequence.
We undertook an investigation using a-tetralone as model
compound /Scheme 2). Several methods for the asymmetric
reductive amination ofketones had been developed
earlier.14 These include the reduction ofimines, oximes,
or enamines in the presence ofa chiral reducing reagent, 15,16
a chiral hydrogenation catalyst,17,18 or a hydrosilylation
catalyst,19 asymmetric transaminations,20 enzymatic
methods,21 and the selective reduction ofchiral imines
formed from chiral amino auxiliaries and the ketone.22,23
The latter method has the advantage to yield diastereomeric
product mixtures. Often, these mixtures can be separated
through column chromatography or crystallization to yield
enantiopure amines after cleavage of the auxiliary. A recent
investigation ofthe reduction of/ R)-a-methylbenzylamine

4840
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
Scheme 3. Synthesis of1,2,3,4,5,6,7,8-tetrahydroanthracene-1,8-dione 6. Conditions: /a) 1. Li/NH3 liq.; 2. NH4Cl; /b) EtOH; Pd/C/H2 67% yield over 2 steps.
We further tested this approach for the asymmetric reduc-
tive amination ofother arylketones 12a and 12c±e /Table 1,
entries 1, 6±8). In each case, the major product diastereomer
had /S)-stereochemistry at the new stereogenic center, as
determined by comparing the optical rotation ofthe amines
9 after cleavage of the auxiliary with Pb/OAc)4 /47±75%
yield) with those reported in the literature.23 For ®ve and
six-membered benzocycloalkanones, we obtained excellent
diastereomeric excesses .95%. These high diastereomeric
excesses clearly show that the two diastereomeric
1,3-oxazolidines 13 have no negative in¯uence on the
diastereofacial selectivity of the reduction. Poor diastereo-
meric ratios were obtained for benzosuberone 12d and
acetophenone 12e, which is consistent with similar results
for the TMSCN addition to these imines.24d,e Whereas the
condensation of 12d with /R)-a-phenylglycinol 12a±c and
12e yields only the corresponding /E)-imine, the formation
ofboth / E)-13d and /Z)-13d might contribute to the lower
de observed in the reductive amination of 12d. Both
isomeric imines 13d will have different and most likely
opposite diastereofacial selectivities in their reaction with
NaBH/OAc)3.
2.3. Synthesis of constrained lysines derivatives
As brie¯y discussed in Section 1, our strategy for the syn-
thesis ofthe constrained lysine derivatives 1 and 2 involved
the conversion ofone carbonyl group of 6 into a racemic
fully protected amino acid moiety. Subsequently, appli-
cation ofour asymmetric reductive amination would result
in a pair ofdiastereomers, which we would try to separate
chromatographically. For the synthesis ofdione 6, we chose
a literature procedure,12a which we slightly modi®ed during
the course ofour investigations /Scheme 3). 1,8-Dichloro-
anthraquinone 14 was converted in three steps into anthra-
cene-1,8-dicarboxylic acid 15.26 We experienced major
dif®culties in converting 15 into 17 according to the
reported three-step literature procedure.12a In particular,
the Birch reduction of 15 under the published conditions
gave very unreliable results in our laboratory. Thus, we
modi®ed the conditions ofthis step.
27
Quenching the
Birch reduction with excess solid ammonium chloride
gave 1,4,5,8-tetrahydroanthracene-1,8-dicarboxylic acid
16, which was immediately subjected to a catalytic hydro-
genation on Pd/C to afford17 as a mixture ofdiastereomers.
Scheme 4. Conditions: /a) HSCH2CH2SH; BF3´Et2O; CH2Cl2. /b) KCN; /NH4)2CO3; EtOH; H2O; 1308C. /c) AgNO3; EtOH; THF; H2O. /d) /BOC)2O; DMAP
cat.; THF; rt. /e) /R)-phenylglycinol; xylenes; p-TsOH cat.; re¯ux. /f) NaBH/OAc)3; THF; 08C.

R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
4841
group of 21 into an amino group would render the molecule
stable enough. For the reductive amination of 21, we applied
our protocol described above. Heating a solution of 21 and
1.5 equiv. of/ R)-phenylglycinol in xylenes in the presence
ofcatalytic amounts of p-tolylsulfonic acid under constant
removal ofcondensation water aoffrded a 1:1 mixture of
diastereomeric imines 24a and 24b in about 80±85%
1
yield as determined from the H NMR spectrum ofthe
crude reaction mixture. Reduction ofboth imines with
NaBH/OAc)3 in THF yielded a 1:1-mixture oftwo major
products. Both products were isolated in 38 and 44.5% yield
using normal phase gravity chromatography followed by
reversed phase HPLC. Their spectroscopic properties are
consistent with those ofthe diastereomeric amines 25a
and 25b, which are the expected stereoisomers according
to our model investigation. The other two possible dia-
stereomers 25c and 25d could not be isolated and must be
formed, if at all, in very low yields.
Figure 2. X-Ray crystal structure ofdiastereomer 26b.
The total yield ofconverting 15 to 17 was very reproducible
and is comparable to the yield ofthe reported three-step
synthesis. Diacid 17 was further converted into 6 in three
steps as described by Caluwe and Pepper.12a
The assignment ofthe stereochemical relationship between
the hydantoin ring at C10 and the amino group at C80 of 25a
and 25b was determined after the cleavage of the chiral
auxiliary using lead /IV) acetate. N-BOC protection ofthe
generated amino group gave 26a from 25a and 26b from
25b in 65 and 62% yield, respectively. Fortunately, we were
able to grow crystals of 26b that were suitable for X-ray
crystal structure analysis. The crystal structure of 26b
is illustrated in Fig. 2 and shows R-con®guration at the
stereogenic carbon C10.
Monoprotection ofone carbonyl group of 6 using one
equivalent ofethane-1,2-dithiol in the presence ofthe
Lewis acid BF3´Et2O gave 18 together with small amounts
ofthe diprotected bis-dithiane 19 which could be easily
separated by chromatography /Schemes 3 and 4).
Subjection of 18 to typical conditions ofa Bucherer
hydantoin synthesis /KCN, /NH4)2CO3, EtOH, water,
1308C)13 gave almost quantitatively the racemic hydantoin
20. The protected carbonyl group of 20 was unmasked using
AgNO3 in an ethanol/water/THF /5:3:1) mixture /65%
yield). Unfortunately, the arylketone group of 21 was too
unstable under the harsh conditions /Ba/OH)2/1208C)
required for the hydrolysis of the hydantoin moiety. Thus,
we tested a mild hydantoin hydrolysis procedure reported
by Rebek and co-workers in which they successfully hydro-
lyzed a N,N-bis-BOC-protected hydantoin at room tempera-
ture with aqueous LiOH.28 The BOC protection of 21 using
/BOC)2O in the presence ofcatalytic amounts ofDMAP
afforded 22 in 79% yield. However, treatment of 22 at
room temperature with 2N LiOH in THF/water reverted
22 back to 21 rather than forming the desired amino acid 23.
In order to complete the synthesis of 4 /Scheme 5), the
hydantoin ring of 26a was hydrolyzed with aqueous
Ba/OH)2 at 1258C. Subsequent heating ofcrude 1 in metha-
nol in the presence ofSOCl for 24 h afforded the methyl
2
ester 27a in 40.5% yield. Selective BOC-protection ofthe
more reactive secondary amine of 27a under standard con-
ditions gave the desired constrained l-lysine derivative 4,
which is suitably protected to allow its incorporation into a
short peptide. The yield ofthe esteri®cation ofcrude 1 was
disappointingly low. This might result from an acid cata-
lyzed deamination of 1 or 27a during the esteri®cation as a
consequence ofthe stability ofcarbocation 28.
Thus, for the synthesis of the constrained d-lysine derivative
5 /Scheme 5), we choose a slightly different route in the
hope to improve the overall yield. After hydrolysis of
After the failure to hydrolyze the hydantoin on this stage of
the synthesis, we decided that the conversion ofthe carbonyl

4842
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
Scheme 5. Final steps ofthe synthesis of 4 and 5. Conditions: /a) 1. Pb/OAc)4; CH2Cl2/MeOH /2:1); 08C; 2. HCl /2N) re¯ux; 3. Na2CO3, /BOC)2O; dioxane/
water /1:1); 26a: 62% yield, 26b: 65% yield. /b) 1. Ba/OH)2; water; 1258C; 2. H2SO4; 3. SOCl2; MeOH; re¯ux; 4. Na2CO3; 40.5% yield. /c) /BOC)2O;
dioxane; 78% yield. /d) 1. Ba/OH)2; water; 1258C; 2. H2SO4; 3. /BOC)2O; Na2CO3; dioxane/water /1:1); 45% yield. /e) CH2N2; ether; quantitative. /f) 1. TFA;
08C; 2. Na2CO3 3. /BOC)2O; dioxane; 65% yield.
hydantoin 26b, both amino groups of 2 were ®rst protected
with a BOC group through the reaction ofcrude 2 with
excess /BOC)2O. The subsequent reaction of 29 with diazo-
methane afforded 30 quantitatively. Deprotection ofboth
amino groups with tri¯uoroacetic acid and subsequent
selective BOC-protection ofthe secondary amine of 27b
gave 5 in 65% yield. Unfortunately, the total yield of this
sequence did not lead to an improved yield as compared to
the shorter sequence used for the preparation of 4 from 26a.
test the important role ofthe lysine side chain in the confor-
mational stability ofsecondary peptide structures. They are
also useful building blocks for the design and synthesis of
novel C- and N-terminal a-helix nucleation sites. Such
studies are currently underway in our laboratories.
4. Experimental
4.1. General
3. Conclusions
1-Indanone, 1-tetralone, and 1-benzosuberone were
obtained from Aldrich Chemical Company, and were
distilled under reduced pressure prior to use when neces-
sary. 7-Fluoro-a-tetralone was synthesized from ¯uoro-
benzene and succinnic anhydride in three steps.29,30
Dichloromethane, methanol and tetrahydrofuran were
freshly distilled from calcium hydride, magnesium methox-
ide or benzophenone ketyl respectively, under an inert
atmosphere. All other reagents were used without further
puri®cation. All reactions were conducted under an argon
atmosphere unless otherwise stated. 1H and 13C NMR
spectra were obtained using a 400 MHz Varian FT NMR
spectrometer or a Varian 200 MHz FT NMR spectrometer.
In summary, we have developed a new asymmetric
reductive amination protocol for arylalkylketones in
which a-phenylglycinol is used as chiral auxiliary and
NaBH/OAc)3 as reducing agent. Particularly high diastereo-
meric excesses are obtained for indanone and tetralone
derivatives. This reductive amination protocol was a key
step in our synthesis ofthe new coonrfmationally
constrained l-lysine and d-lysine derivatives 4 and 5,
which were prepared starting from 1,8-dichloroanthra-
quinone 14 through a 17- and 18-step reaction sequence.
Both amino acids derivatives are interesting scaffolds to

R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
4843
1H NMR spectra were referenced to the residual CHCl3,
CHD2OD, CHCl2CDCl2, C6D5CD2H or HDO, signals at d
7.26, 3.31, 5.91, 2.09 or 4.81, respectively. 13C NMR spectra
were referenced to the residual CDCl3, CDCl2CDCl2, or
CD3OD signals at d 77.3, 74.2, or 49.5, respectively.
MALDI-TOF mass spectra were obtained on an IonSpec
HiRes MALDI mass spectrometer. High resolution
FAB-MS were determined on a ZAB SE instrument with
3-nitrobenzyl alcohol /NOBA) matrix from the mass
spectrometry laboratory at the University ofKansas,
Lawrence, Kansas. CHN analyses were obtained from
Desert Analytics, Tucson, Arizona. Gravity chroma-
tography was performed on Bodman silica gel /70±230
mesh). HPLC was performed on Rainin Varian Dual
Pump System. Melting points are uncorrected.
solution was stirred until all imine and oxazolidines had
been reduced /TLC control) and was worked up as
described above. The diastereomeric ratio ofeach reaction
was determined by reversed phase HPLC ofthe crude reac-
tion products /Higgins TARGA C18 column, 4,6£250 mm,
100 mM phosphate buffer pH 2.74/MeOH /55:45), 1 mL/
min ¯ow rate, detection at 270 nm). Retention time of
major isomer: 26.5 min; retention time ofminor isomer:
31.2 min. Both diastereomers were separated by preparative
reversed phase HPLC on a TARGA C18 column /250£
20 mm) /Higgins Analytical) using 40 mM phosphate buffer
pH 2.85/MeOH /60:40) as the mobile phase /15 mL/min
¯ow rate, detection at 285 nm). The product fractions
were concentrated, basi®ed with saturated Na2CO3 and
extracted twice with ether. The combined organic layers
were washed with water and with brine, dried over
MgSO4 and concentrated to yield the pure diastereomers.
4.2. X-Ray crystallography
4.3.1. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-amino-
1,2,3,4,-tetrahydronaphthalene .1S,10R)-11b .major dia-
Crystalline samples of/1 S,10R)-11b and 26b were placed in
inert oil, mounted on a glass pin, and transferred to the cold
gas stream ofthe difractometer. Crystal data were collected
and integrated using a Bruker SMART 1000 system, with
24
stereomer). Colorless solid; mp 84±868C; [a]D ˆ295.28
/c 3.14, MeOH); 1H NMR /400 MHz, CDCl3) d 7.40±7.27
/m, 6H), 7.2±7.14 /m, 2H), 7.12±7.07 /m, 1H), 3.98 /dd,
Jˆ4.6, 7.9 Hz, 1H), 3.80 /t, Jˆ4.5 Hz, 1H), 3.72 /dd, Jˆ4.6,
10.7 Hz, 1H), 3.51 /dd, Jˆ7.9, 10.7 Hz, 1H), 2.86±2.64
/m, 2H), 1.94±1.60 /m, 4H) 2.4±1.7 /svb, 2H); 13C NMR
/50.29 MHz, CDCl3) d 142.2, 139.3, 137.4, 129.3, 129.2,
128.8, 127.7, 127.4, 127.0, 125.8, 66.9, 63.2, 54.3, 30.2,
29.1, 18.8; HR-MALDI MS m/z /M1Na1) 290.154
/calcd for C18H21NONa, 290.152). Anal. calcd for
C18H21NO: C, 81.16; H, 7.57; N, 5.26. Found: C, 81.17;
H, 7.89; N, 5.33.
Ê
graphite monochromated Mo Ka /lˆ0.71073 A) radiation
at 173 K. The structures were solved by direct methods
using SHELXS-97 and re®ned using SHELXL-97
È
/Sheldrick, G. M., University ofGo ttingen). Non-hydrogen
atoms were found by successive full matrix least squares
re®nement on F2 and re®ned with anisotropic thermal para-
meters. Hydrogen atom positions were located from differ-
ence Fourier maps, and a riding model with ®xed thermal
parameters /uijˆ1.2Uij/eq) for the atom to which they are
bonded), was used for subsequent re®nements.
4.3.2. N-[.R)-20-Hydroxy-10-phenylethyl]-.R)-1-amino-
1,2,3,4,-tetrahydronaphthalene .1R,10R)-11b .minor dia-
4.3. Asymmetric reductive amination of a-tetralone
using .R)-2-phenylglycinol .procedure A)
24
stereomer). Colorless oil; [a]D ˆ13.58 /c 0.34, MeOH);
1H NMR /400 MHz, CDCl3) d 7.44±7.30 /m, 5H), 7.16±
7.06 /m, 4H), 3.99 /dd, Jˆ4.6, 9.0 Hz, 1H), 3.71±3.66 /m,
2H), 3.51 /dd, Jˆ9.0, 10.8 Hz, 1H), 2.88±2.79 /m, 1H),
2.74±2.60 /m, 1H), 2.4±1.7 /svb, 2H), 2.15±1.9 /m, 2H),
1.77±1.65 /m, 2H); 13C NMR /50.29 MHz, CDCl3) d
141.0, 139.2, 137.9, 129.4, 129.14, 129.07, 128.1, 127.7,
127.2, 126.2, 67.1, 62.2, 51.7, 29.6, 27.4, 18.5; HR-MALDI
MS m/z /M1Na1) 290.153 /calcd for C18H21NONa1,
290.152).
To a stirred solution of a-tetralone 12b /15 mmol) in
xylenes /30 mL) was added /R)-2-phenylglycinol /16.5
mmol) and p-tolylsulfonic acid monohydrate /0.5 mol%).
The resulting mixture was heated to re¯ux and maintained
there until 1H NMR spectroscopy showed less than 5% 12b
/3±8 h). The reaction mixture is diluted with 15 mL toluene,
washed with 10% NaHCO3 /2£10 mL), water /5£10 mL),
and brine /10 mL) and is dried over MgSO4. Solvent was
removed in vacuo to give a mixture ofimine 10b, oxazo-
lidines 13b and unreacted 12b /86:10:4:5 ratio).24e For the
reduction with NaBH/OAc)3, the crude imine/oxazolidine
mixture /1.3 g, 4.8 mmol) was taken up in anhydrous THF
/10 mL) and cooled to 08C under argon. NaBH4 /2.1 g,
5.5 mmol) and glacial acetic acid /0.95 mL, 16.5 mmol)
were added and the reaction mixture was stir at 08C f or
2 h. Dichloromethane /10 mL) and saturated NaHCO3
/2 mL) was added. The organic phase was separated and
washed with saturated NaHCO3 /4£2 mL), dried over
MgSO4 and concentrated to yield 1.3 g ofthe crude product.
The crude diastereomeric mixtures ofamines were puri®ed
by column chromatography /Silica gel, CH2Cl2) to give a
mixture ofdiastereomeric amines /1 S,10R)-11b//1R,10R)-
11b /1.16 g, 87%). For the reduction with NaBH4, the
imine/oxazolidine mixture /100 mg, 0.38 mmol) was
dissolved in absolute ethanol /10 mL). The solution was
thermally equilibrated at the desired reaction temperature
/24, 0, or 2108C) and NaBH4 /3 equiv.) was added. The
4.3.3. N-[.R)-20-Hydroxy-10-phenylethyl]-.R)-1-amino-8-
¯uoro-1,2,3,4,-tetrahydronaphthalene .1S,10R)-11c. Appli-
cation ofprocedure A to 8-¯uoro-1,2,3,4-tetrahydro-1-
naphthalone 12c and /R)-phenylglycinol gave crude
/1S,10R)-11c, which was puri®ed by column chroma-
tography /SiO2, CH2Cl2/MeOH /50:1)) to afford /1S,10R)-
11c as a single diastereomer by 1H NMR in 48% yield. Pale
24
yellow oil; [a]D ˆ251.88 /c 0.79, CHCl3); 1H NMR
/400 MHz, CDCl3) d 7.4±7.28 /m, 5H), 7.08 /dd, Jˆ2.4,
9.6 Hz, 1H), 7.03 /dd, Jˆ6.0, 7.6 Hz, 1H), 6.86 /dt, Jˆ2.4,
8.4 Hz, 1H), 3.97 /dd, Jˆ4.1, 8.0 Hz, 1H), 3.78±3.70 /m,
2H), 3.52 /dd, Jˆ8.0, 10.8 Hz, 1H), 2.80±2.60 /m, 2H), 2.5
/svb, 2H), 1.90±1.77 /m, 2H), 1.74±1.58 /m, 2H); 13C NMR
1
/100.56 MHz, CDCl3) d 161.1 /d, JCFˆ242 Hz), 142.0,
3
4
141.3 /d, JCFˆ6.1 Hz), 132.8 /d, JCFˆ3.1 Hz), 130.5 /d,
3JCFˆ7.6 Hz), 128.9, 127.8, 127.6, 115.2 /d, 2JCFˆ20.9 Hz),
114.0 /d, 2JCFˆ21.2 Hz), 67.0, 65.2, 54.3 /d, 4JCFˆ1.2 Hz),

4844
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
30.1, 28.4, 19.0; HR-FAB MS m/z /M1H1) 285.1606
MS m/z /M1H1) 282.1858 /calcd for C19H24NO1,
282.1858).
/calcd for C18H21NOF1, 285.1607).
4.3.4. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-amino-
benzocyclopentane .1S,10R)-11a. Application ofpro-
cedure A to 1-indanone 12a and /R)-phenylglycinol gave
crude /1S,10R)-11a, which was puri®ed by column chroma-
tography /SiO2, CH2Cl2/EtOAc /1:1)) to afford /1S,10R)-11a
as a single diastereomer by 1H NMR in 84% yield.
Yellowish oil; [a]D ˆ253.28 /c 0.37, CHCl3); H NMR
/400 MHz, CDCl3) d 7.43±7.28 /m, 6H), 7.22±7.18 /m,
3H), 4.21 /t, Jˆ6.8 Hz, 1H, CHNH), 4.03 /dd, Jˆ4.4,
8.4 Hz, 1H), 3.73 /dd, Jˆ4.4, 10.4 Hz, 1H), 3.54 /dd, Jˆ
10.4, 8.4 Hz, 1H), 3.5±1.4 /svb, 2H, NH, OH), 2.91 /ddd,
Jˆ4.8, 8.4, 11.6 Hz, 1H), 2.76±2.66 /m, 1H), 2.26±2.15 /m,
1H), 1.66±1.63 /m, 1H); 13C NMR /100.56 MHz, CDCl3) d
145.8, 143.7, 142.1, 128.9 127.7, 127.5, 126.4, 125.0, 124.5,
66.8, 63.7, 36.0, 30.6; HR-FAB-MS m/z /M1H1) 254.1544
/calcd for C17H20NO1, 254.1545).
4.4.3. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-phenyl-
1-ethylamine ..1S,10R)-11e) and N-[.R)-20-hydroxy-10-
phenylethyl]-.R)-1-phenyl-1-ethylamine ..1R,10R)-11e).
Application ofprocedure A to acetophenone 12e and
/R)-phenylglycinol gave crude 11e, which was puri®ed by
column chromatography /SiO2, CH2Cl2/EtOAc /2:3) to
afford a /4:7)-mixture of diastereomers /1R,10R)-11e and
24
1
1
/1S,10R)-11e /determined by H NMR) as a colorless oil
24
1
in 90% yield. [a]D ˆ2112.48 /c 1.31 MeOH); H NMR
/400 MHz, CDCl3) d 7.4±7.2 /m, 10H major, 10H minor),
3.90 /dd, Jˆ4.4, 7.8 Hz, 1H minor), 3.77 /q, Jˆ6.4 Hz, 1H,
CHCH3 minor), 3.74 /dd, Jˆ4.8, 10.4 Hz, 1H minor), 3.77
/qt, Jˆ6.4 Hz, 1H, CHCH3 major), 3.58±3.46 /m, 1H
minor, 3H major), 2.44 /svb, 2H, NH, OH minor and
major), 1.38 /d, Jˆ6.4 Hz, 3H, CHCH3 minor), 1.33 /d,
Jˆ6.4 Hz, 3H, CHCH3 major); 13C NMR /100.56 MHz,
CDCl3): major diastereomer d 145.3, 141.2, 128.8, 128.7,
127.7, 127.5, 127.3, 127.0, 67.2, 61.8, 55.1, 25.3; minor
diastereomer d 146.0, 141.4, 128.8, 128.7, 127.7, 127.4,
127.3, 126.8, 66.4, 61.8, 55.0, 22.7; HR-FAB-MS m/z
/M1H1) 242.1544 /calcd for C16H20NO1, 242.1545).
4.4. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-amino-
benzocycloheptane .1S,10R)-11d and N-[.R)-20-hydroxy-
10-phenylethyl]-.S)-1-amino-benzocycloheptane
.1R,10R)-11d
4.4.4. .S)-1,2,3,4-Tetrahydro-1-naphthylamine ..S)-8b)
.procedure B). Lead /IV) acetate 95% /2.43 g, 5.2 mmol)
was dissolved at 08C in dry methanol /55 mL). To this
solution was drop wise added over 30 min a solution of
/1S,10R)-11b /1.07 mg, 4 mmol) in dry methanol /30 mL)
under argon. The solution was stirred at 08C for further
10 min before it was diluted with dichloromethane
Application ofprocedure A to 1-benzosuberone 12d and
/R)-phenylglycinol gave crude 11d, which was puri®ed by
column chromatography /SiO2, CH2Cl2/EtOAc /1:1) to
afford a /1:1.4)-mixture of diastereomers /1R,10R)-11d
and /1S,10R)-11d as determined by HPLC /Higgins Ana-
lytical TARGA C18 column, 4,6£250 mm, 0.1% TFA in
H2O/MeOH /65:35), 2 mL/min ¯ow rate, detection at
254 nm; retention time ofminor isomer: 16.7 min; retention
time ofmajor isomer: 19.8 min) in 84% yield. A small
portion /40 mg) was separated via preparative HPLC
/TARGA C18 column /250£20 mm) /Higgins Analytical);
0.1% TFA in H2O/MeOH /65:35); 20 mL/min ¯ow rate,
detection at 254 nm) to afford the pure diastereomers.
/105 mL) and quenched by the addition of10% Na CO3
2
/35 mL). The organic layer was separated and the aqueous
layer extracted with CH2Cl2 /3£30 mL). The combined
organic layers were washed with brine /30 mL) and dried
over magnesium sulfate, ®ltered and concentrated in vacuo.
The remaining yellowish oil was taken up in ethanol
/135 mL) and conc. HCl /3 mL) and heated to re¯ux for
22 h. After cooling to room temperature, the reaction
mixture was concentrated and partitioned between water
/100 mL) and ether /15 mL). The aqueous layer was sepa-
rated, basi®ed with solid K2CO3 to pH 9.1 and extracted
with ether /3£40 mL). The combined ether extracts were
dried over MgSO4 and concentrated in vacuo to leave a
brown oil /0.5 g). This oil was taken up in the minimum
volume ofethyl acetate and puri®ed by silica gel column
chromatography /SiO2, ethyl acetate/MeOH /9:1)) to yield
4.4.1. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-amino-
benzocycloheptane ..1S,10R)-11d) .major diastereomer).
24
1
Colorless oil; [a]D ˆ2151.48 /c 0.99, CHCl3); H NMR
/400 MHz, CDCl3) d 7.4±7.0 /m, 9H), 7.22±7.18 /m, 3H),
3.76 /d, Jˆ7.2 Hz, 1H), 3.68±3.53 /m, 3H), 3.13 /t,
Jˆ7.8 Hz, 1H), 2.8±2.1 /svb, 2H, NH, OH), 2.70 /dd,
Jˆ7.8, 14.2 Hz, 1H), 2.1±1.7 /m, 5H), 1.58±1.43 /m,
1H); 13C NMR /100.56 MHz, CDCl3) d 142.8, 141.9,
140.6, 130.6, 129.0, 127.9, 127.8, 127.6, 126.3, 67.4, 61.9,
59.7, 36.1, 34.7, 28.3, 26.9; HR-FAB-MS m/z /M1H1)
282.1846 /calcd for C19H24NO1, 282.1858).
24
/S)-9b /370 mg, 63% yield) as a yellowish oil. [a]D ˆ1278
/c 1.7 MeOH); //R)-9b: [a]D ˆ2268 /c 1.32 MeOH));23 dH
24
/400 MHz, CDCl3) 7.41 /d, Jˆ7.2 Hz, 1H), 7.23±7.02 /m,
3H), 3.99 /t, Jˆ5.8 Hz, 1H), 2.90±2.70 /m, 2H), 2.14±1.90
/m, 2H), 1.88±1.64 /m, 2H), 1.55 /sb, 2H); dC /100.6 MHz,
CDCL3) 141.0, 137.0, 129.2, 128.3, 126.8, 126.3, 49.6, 33.6,
29.8, 19.8; MALDI MS m/z /M1H1) 148.1 /calcd for
C10H14N, 148.1).
4.4.2. N-[.R)-20-Hydroxy-10-phenylethyl]-.S)-1-amino-
benzocycloheptane ..1R,10R)-11d) .minor diastereomer).
24
1
Colorless oil; [a]D ˆ215.28 /c 0.51, CHCl3); H NMR
/400 MHz, CDCl3) d 7.38±7.22 /m, 5H), 7.16±7.05 /m,
4H), 3.93 /dd, Jˆ4.8, 8.8 Hz, 1H), 3.81 /d, Jˆ7.2 Hz,
1H), 3.76 /dd, Jˆ4.4, 11.0 Hz, 1H), 3.56 /dd, Jˆ8.8,
11.0 Hz, 1H), 3.14±3.03 /m, 1H), 2.7±2.1 /svb, 2H, NH,
OH), 2.67 /dd, Jˆ8.0, 13.6 Hz, 1H), 2.12±1.7 /m, 5H),
1.58±1.50 /m, 1H); 13C NMR /100.56 MHz, CDCl3) d
143.8, 142.8, 140.5, 130.4, 129.0, 128.0, 127.4, 127.2,
126.4, 66.9, 61.4, 59.6, 36.3, 31.7, 28.3, 26.7; HR-FAB-
4.4.5. .S)-8-Fluoro-1,2,3,4-tetrahydro-1-naphthylamine
..S)-9c). Application ofprocedure B to /1 S,10R)-11c
24
afforded /S)-8c as a colorless oil in 70% yield. [a]D
ˆ
131.38 /c 0.48 CHCl3); dH/400 MHz, CDCl3) 7.12 /dd,
Jˆ2.4, 9.6 Hz, 1H), 7.02 /dd, Jˆ6.0, 8.4 Hz, 1H), 6.84
/td, Jˆ2.4, 8.4 Hz, 1H), 3.94 /t, Jˆ5.4 Hz, 1H), 2.80±2.64

R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
4845
/m, 2H), 2.12 /sb, 2H), 2.1±1.6 /m, 4H); dC /100.56 MHz,
Ice-cold aqueous HCl /6N) was added until pH,1. The
precipitated crude 1,4,5,8-tetrahydroanthracene-1,8-dicar-
boxylic acid 15 was ®ltered off, washed with water until
the ®ltrate was pH neutral, sucked dry and was used for
the next step without further puri®cation. The crude 15
/1.2 g) was dissolved in ethanol /150 mL). Hydrogenation
catalyst, 5% Pd on activated charcoal, /1.2 g) was added and
the solution degassed twice and purged with hydrogen gas.
The solution was shaken under a hydrogen atmosphere
/70 psi) for 12 h. After completion of the hydrogenation,
the solution was degassed and ®ltered through a pad of
celite. The ethanol was removed in vacuo to leave 17 as a
white solid, which was 90 to 95% pure by 1H NMR spectro-
scopy. It was further puri®ed by crystallization from boiling
xylenes to give 1712a as colorless solid /0.83 g, 66.2% yield).
1
3
CDCl3) d 161.1 /d, JCFˆ243 Hz), 142.8 /d, JCFˆ6.1 Hz),
4
3
132.5 /d, JCFˆ3.0 Hz), 130.5 /d, JCFˆ7.7 Hz), 114.4 /d,
2
4
2JCFˆ21.0 Hz), 114.0 /d, JCFˆ21.3 Hz), 49.9 /d, JCFˆ
1.1 Hz), 33.5, 29.0, 20.0; HR-FAB MS m/z /M1H1)
166.1027 /calcd for C10H13FN, 166.1032).
4.4.6. .S)-1-Indanamine ..S)-9a). Application ofprocedure
B to /1S,10R)-11a afforded /S)-9a as a colorless oil in 47%
24
20
yield. [a]D ˆ116.48 /c 1.4, MeOH) //R)-9a: [a]D ˆ217
/c 1.5, MeOH));23 dH/400 MHz, CDCl3) 7.33 /d, Jˆ7.6 Hz,
1H), 7.26±7.18 /m, 3H), 4.36 /t, Jˆ7.4 Hz, 1H), 3.00±2.86
/m, 1H), 2.83±2.76 /m, 1H), 2.58±2.44 /m, 1H), 1.63 /s,
2H), 1.74±1.65 /m, 1H); dC /100.56 MHz, CDCl3) d 147.7,
143.3, 127.4, 126.7, 124.9, 123.5, 57.5, 37.6, 30.3; HR-FAB
MS m/z /M1H1) 134.0988 /calcd for C9H12N, 134.0988).
4.5.1.
20,30,40,50,60,70-Hexahydrospiro[1,3-ethylene-
dithiole-2,10-anthracen]-80-one .18) and 20,30,40,50,60,70-
hexahydrodispiro[1,3-dithiolane-2,10-anthracen-80,200-
[1,3]dithiolane] .19). 3,4,5,6-Tetrahydro-1/2H),8/7H)-
anthracenedione 6 /365 mg, 1.7 mmol) was dissolved in
50 mL dry dichloromethane under argon and cooled to
08C. Ethane-1,2-dithiol /90%, 0.14 mL, 1.7 mmol) was
added via syringe followed by the addition of BF3´Et2O
/86 mL, mmol). The solution was stirred at room tempera-
ture under argon. After 24 h, the reaction solution was
washed with 5% Na2CO3 solution /10 mL), dried over
MgSO4, ®ltered, and concentrated. The residual solid was
dissolved in the minimum amount ofdichloromethane and
was puri®ed by ¯ash-column chromatography on silica gel.
The diprotected anthracenedione 19 was eluted with CH2Cl2
/192 mg, 37% based on consumed 6) followed by the
monoprotected anthracenedione 17 /214 mg, 52% based
on consumed 6). Unreacted 6 /56 mg) was eluted with
CH2Cl2/MeOH /9:1). 18: colorless solid mp 1388C; 1H
NMR /400 MHz, CDCl3) d 8.59 /s, 1H), 6.89 /s, 1H),
3.7±3.42 /m, 4H), 2.88 /t, Jˆ6.1 Hz, 2H), 2.81 /t, Jˆ
6.4 Hz, 2H), 2.62 /dd, Jˆ6.2, 6.9 Hz, 2H), 2.42±2.37 /m,
2H), 2.14±1.98 /m, 4H); 13C NMR /100.56 MHz, CDCl3) d
197.8, 143.1, 142.9, 139.0, 131.4, 130.4, 128.9, 68.3, 43.8,
41.2, 39.4, 30.0, 29.5, 23.4, 22.9; HR-MALDI MS m/z
/M1Na1) 313.070 /calcd for C16H18S2ONa1, 313.069).
Anal. calcd for C16H18OS2: C, 66.16; H, 6.25. Found: C,
66.12; H, 6.19. 19: colorless solid mp 236±2388C; 1H
NMR /400 MHz, CDCl3) d 8.50 /s, 1H), 6.65 /s, 1H),
3.7±3.42 /m, 8H), 2.73 /t, Jˆ6.2 Hz, 4H), 2.40±2.37 /m,
4H), 2.01±1.95 /m, 4H); 13C NMR /100.56 MHz, CDCl3) d
137.4, 136.6, 133.7, 128.7, 68.9, 43.8, 41.0, 29.3, 23.2;
HR-MALDI MS m/z /M1Na1) 389.051 /calcd for
C18H22S4Na1, 389.050). Anal. calcd for C18H22S4: C,
58.96; H, 6.05. Found: C, 58.37; H, 6.02.
4.4.7. 1-Aminobenzocycloheptane .9d). Application of
procedure B to /1S,10R)-11d//1R,10R)-11d /1.4:1) afforded
24
9d as a colorless oil in 61% yield. [a]D ˆ21.48 /c 1.5,
20
MeOH) //R)-9d: [a]D ˆ126 /c 1.125, MeOH));23
dH/400 MHz, CDCl3) 7.42 /d, Jˆ7.6 Hz, 1H), 7.21 /dt,
Jˆ1.6, 5.7 Hz, 1H), 7.15±7.05 /m, 2H), 4.22 /d, Jˆ
8.8 Hz, 1H), 2.86±2.78 /m, 2H), 2.04±1.93 /m, 1H),
1.91±1.75 /m, 3H), 1.70±1.38 /m, 4H); dC /100.56 MHz,
CDCl3) d 146.0, 141.7, 129.7, 126.6, 126.4, 124.4, 55.0,
37.5, 36.1, 29.1, 27.8.
4.4.8. 1-Phenyl-1-ethylamine .9e). Application ofpro-
cedure B to /1S,10R)-11e//1R,10R)-11e /7:4) afforded
/S)-8e /23% ee) as
a colorless oil /75% yield).
24
[a]D ˆ28.08 /c 2.36, MeOH) //R)-9e /Aldrich Chemical
20
Company, 99%ee): [a]D ˆ134.4 /c 3.52, MeOH));
dH/400 MHz, CDCl3) 7.37±7.22 /m, 5H), 4.12 /q, Jˆ
6.6 Hz, 1H, CHCH3), 1.48 /sb, 2H), 1.39 /d, Jˆ6.6 Hz,
3H, CHCH3); dC /100.56 MHz, CDCl3) d 148.0, 128.7,
127.0, 125.9, 51.5, 25.9.
4.5. 1,2,3,4,5,6,7,8-Octahydroanthracene-1,8-
dicarboxylic acid .17)
Dry tetrahydrofuran /20 mL) was added under argon into a
3-necked, 250 mL ¯ask ®tted with a dry ice condenser, gas
inlet and low temperature thermometer and was cooled to
2708C using an acetone/dry ice bath. The dry ice condenser
was charged with a acetone/dry ice slurry and dry ammonia
gas was passed through the cold tetrahydrofuran until the
¯ask was approximately half-full. To this solution, solid
anthracene-1,8-dicarboxylic acid26 /1.21 g, 4.55 mmol)
was added under stirring in one portion. The acetone/dry
ice bath was removed. Lithium wire /190 mg, 27 mmol)
was added in eight portions. Caution: exothermic reaction.
Enough time was given to allow each lithium piece to
dissolve before the next portion was added. After the addi-
tion was complete, the reaction mixture was re¯uxed for 1 h
and was quenched by the addition ofsolid ammonium chlo-
ride /3 g). Caution: the addition ofammonium chloride is
very exothermic. The ammonium chloride should be added
carefully in small portions. After the addition, the reaction
mixture was further stirred at room temperature until all of
the ammonia had been evaporated. The tetrahydrofuran was
removed under vacuum. The residual solid was suspended
in water /20 mL) and was cooled with an ice bath to 08C.
4.5.2.
rac-20,30,40,50,60,70-Hexahydrodispiro[imidazol-
idine-4,10-anthracene-80,200-[1,3]dithiolane]-2,5-dione
.20). A suspension of 18 /2 g, 6.85 mmol), KCN /2.5 g,
mmol) and /NH4)2CO3 /13.6 g, mmol) in ethanol/water
/4:1) /100 mL) was placed in a steel reactor ®tted with a
glass liner. The reactor was sealed and the content heated to
130±1408C for 48 h with stirring. After the reactor had
cooled to room temperature it was carefully vented in a
fume hood and opened. The content was poured into
water /400 mL). The precipitated product was ®ltered off
and washed with water /200 mL). The precipitate was dried

4846
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
and suspended in boiling dichloromethane /100 mL). After
cooling and standing for 1 h, the suspension was ®ltered to
give 1.8 g ofpure 20 as a white solid. The ®ltrate contained
some unreacted 18, 20 and an unidenti®ed byproduct. All
three compounds were separated by silica gel column
chromatography. Unreacted 18 /252 mg) was eluted ®rst
with CH2Cl2, followed by the byproduct /50 mg) with
CH2Cl2/EtOAc /9:1), followed by 20 /420 mg) with
CH2Cl2/EtOAc /6:4). The total yield of 20 was 97% based
MS m/z 407.159 /M2CO22CH2vC/CH3)21Na1) /calcd
for C21H24N2O5Na1, 407.158).
4.5.5. .10S,80S,100R)-N-[200-Hydroxy-100-phenylethyl]-80-
amino-20,30,40,50,60,70,80-heptahydrospiro[imidazolidine-
4,10-anthracene]-2,5-dione .25a) and .10R,80S,100R)-N-
[200-hydroxy-100-phenylethyl]-80-amino-20,30,40,50,60,70,
80-heptahydrospiro[imidazolidine-4,10-anthracene]-2,5-
dione .25b). Application ofprocedure A using 21 /300 mg,
1.06 mmol), /R)-phenylglycinol /299 mg, 1.7 mmol), and
p-tolylsulfonic acid monohydrate /28 mg, 0.13 mmol)
to form the intermediate imines /10S,100R)-24a and
/10R,100R)-24b, and NaBH/OAc)3 as reducing agents
afforded the crude amines 25a and 25b. Column chroma-
tography /silica gel; eluant: CHCl3/ethyl acetate) afforded
unreacted 21 /50 mg) and a 1:1-mixture ofthe diastereo-
meric amines /336 mg). Both diastereomers were further
separated by preparative reversed phase HPLC on a
TARGA C18 column /250£20 mm; Higgins Analytical)
using water/methanol /20:35) containing 0.1% TFA as the
mobile phase /20 mL/min ¯ow rate, detection at 254 nm;
retention time of 25a: 19.6 min, retention time of 25b:
17.3 min). The product fractions were concentrated by
rotavaporation. The residual TFA salts of 25a and of 25b
were partitioned between saturated aqueous Na2CO3
/20 mL) and ethyl acetate /20 mL). The organic layers
were separated off. The aqueous layers were extracted
with ethyl acetate /4£25 mL each). The combined organic
layers were dried over MgSO4, concentrated to give 25a and
25b, respectively as white solids. Both diastereomers were
recrystallized from ethyl acetate. 25a: /136 mg, 38% yield)
1
on reacted 18. Mp 2518C; H NMR /400 MHz, CDCl3) d
7.79 /s, 1H), 7.49 /sb, 1H), 6.8 /s, 1H), 5.6 /s, 1H), 3.6±3.38
/m, 4H), 2.86±2.7 /m, 4H), 2.4±2.25 /m, 4H), 2.08±1.94
/m, 3H), 1.84±1.74 /m, 1H); 13C NMR /100.56 MHz,
CD3OD/CDCl3 /1:2)) d 178.5, 157.7, 137.7, 137.6 136.8,
130.8, 129.3, 128.8, 68.3, 64.1, 43.4, 40.5, 34.0, 29.0, 28.2,
22.5, 18.7; HR-FABMS m/z /M1H1) 361.1033 /calcd for
C18H21N2O2S2, 361.1044). Anal. calcd for C18H20N2O2S2: C,
59.97; H, 5.59; N, 7.77. Found: C, 60.01; H, 5.53; N, 7.78.
4.5.3. rac-20,30,40,50,6070-Hexahydrospiro[imidazolidine-
4,10-anthracen-80-one]-2,5-dione .21). Compound 20
/569 mg, 1.58 mmol) was dissolved in ethanol/water/THF
/5:3:1) /90 mL) under gentle warming. To this solution was
added a solution ofsilver/I) nitrate /1.07 g, 6.3 mmol) in
ethanol/water/THF /5:3:1) /30 mL). Immediately after the
addition, a yellowish precipitate forms. The suspension was
stirred in the dark at 458C for 1 h. Brine /10 mL) was added.
The precipitate was ®ltered off and washed with hot ethanol
/30 mL). The ®ltrate was concentrated to 20 mL and
extracted with ethyl acetate /4£30 mL). The combined
extracts were dried over MgSO4 and concentrated to give
the crude product as a slightly yellowish solid. The crude
product was puri®ed by crystallization from boiling ethanol/
ethyl acetate to give 21 as a colorless solid /305 mg, 68%
24
colorless needles; mp 224±2268C; [a]D ˆ2528 /c 0.31
1
CHCl3); H NMR /400 MHz, CDCl3) d 7.4±7.16 /m, 5H),
7.10 /s, 1H), 7.03 /sb, 1H), 6.81 /s, 1H), 5.4±3.9 /svb, 3H),
3.86 /dd, Jˆ3.8, 9.0 Hz, 1H), 3.58±3.51 /m, 1H), 3.52
/dd, Jˆ3.8, 11.2 Hz, 1H), 3.33 /m, 1H), 2.8±2.5 /m, 4H),
2.3±2.14 /m, 2H), 1.95±1.5 /m, 6H); 13C NMR /100.56
MHz, CDCl3; 608C) d 177.27, 157.05, 142.14, 138.8,
138.51, 136.55, 130.53, 130.28, 128.96, 127.8, 127.75,
126.95, 67.55, 64.87, 64.2, 54.03, 34.57, 30.8, 28.93,
28.76, 19.5, 19.17; HR-FABMS m/z /M1H1) 406.2125
/calcd for C24H28N3O3, 406.2131). Anal. calcd for
C24H27N3O3: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.54; H, 6.50; N, 10.20. 25b: /159 mg, 44.5% yield) color-
1
yield): mp 2748C; H NMR /400 MHz, CD3OD) d 7.78 /s,
1H), 7.15 /s, 1H), 2.95 /t, Jˆ6.4 Hz, 2H), 2.88 /t, Jˆ6.0 Hz,
2H), 2.61 /t, Jˆ6.0 Hz, 2H), 2.3±2.0 /m, 5H), 1.94±1.82 /m,
1
1H); H NMR /400 MHz, CDCl3) d 7.91 /s, 1H), 7.38 /sb,
1H), 7.07 /s, 1H), 5.54 /sb, 1H), 2.95±2.81 /m, 4H), 2.62 /t,
Jˆ6.4 Hz, 2H), 2.40±2.30 /m, 2H), 2.15±2.0 /m, 3H),
1.88±1.77 /m, 1H); 13C NMR /100.56 MHz, CD3OD/
DMFd7 /1:1)) d 199.1, 179.5, 158.7, 146.0, 145.7, 134.4,
132.5, 131.1, 126.4, 65.0, 40.0, 35.0, 30.3, 30.2, 24.4,
19.8; HR-FABMS m/z /M1H1) 285.1223 /calcd for
C16H17N2O3, 285.1239). Anal. calcd for C16H16N2O3: C,
67.59; H, 5.67; N, 9.85. Found: C, 67.49; H, 5.64; N, 9.88.
24
less needles; mp 2088C; [a]D ˆ239.18 /c 1.39, CHCl3); 1H
NMR /400 MHz, CDCl3) d 7.38±7.16 /m, 5H), 7.18 /s, 1H),
6.83 /s, 1H), 6.66 /sb, 1H), 6.4±3.0 /svb, 3H), 3.80 /dd,
Jˆ3.6, 8.8 Hz, 1H), 3.60±3.55 /m, 1H), 3.51 /dd, Jˆ3.6,
11.0 Hz, 1H), 3.33 /dd, Jˆ8.8, 11.0 Hz, 1H), 2.8±2.5 /m,
4H), 2.3±2.18 /m, 2H), 2.0±1.9 /m, 1H), 1.86±1.64 /m,
2H), 1.64±1.50 /m, 3H); 13C NMR /100.56 MHz, CDCl3)
d 178.2, 157.6, 142.0, 136.6, 138.3, 136.4, 130.4, 130.1,
128.8, 127.6, 127.2, 67.2, 64.6, 64.3, 54.2, 34.2, 30.5,
28.8, 28.7, 19.5, 18.9; HR-FABMS m/z /M1H1)
406.2131 /calcd for C24H28N3O3, 406.2131). Anal. calcd
for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.28; H, 6.49; N, 10.40.
4.5.4. rac-N,N0-bis[tert-Butyloxycarbonyl]-20,30,40,50,60,70-
hexahydrospiro[imidazolidine-4,10-anthracen-80-one]-
2,5-dione .22). Ketone 21 /50 mg, 0.176 mmol) was
dissolved in dry THF /7 mL) under argon. /BOC)2O
/150 mg, 0.69 mmol) was added and the solution was
re¯uxed for 3 h. The solvent was removed in vacuo. The
residual crude product was puri®ed by column chromato-
graphy on silica gel /eluant: dichloromethane/ethyl acetate
1
/9:1)) to give 22 as a colorless oil /67 mg, 79% yield) H
NMR /400 MHz, CDCl3) d 7.76 /s, 1H), 7.09 /s, 1H),
295±2.78 /m, 3H), 2.66±2.55 /m, 2H), 2.61 /t, Jˆ6.0 Hz,
2H), 2.3±2.0 /m, 5H), 1.94±1.82 /m, 1H), 1.63 /s, 9H),
1.29 /s, 9H); 13C NMR /100.56 MHz, CDCl3 /1:1)) d
197.5, 168.3, 147.8, 147.7, 145.4, 144.8, 144.5,
131.6, 31.1, 130.4, 123.9, 87.0, 84.8, 65.5, 39.2,
32.1, 29.5, 29.3, 27.94, 27.92 23.3, 19.3; HR-MALDI
4.5.6. .10,80S)-N-[tert-Butyloxycarbonyl]-80-amino-20,30,
40,50,60,70,80-heptahydrospiro[imidazolidine-4,10-anthra-
cene]-2,5-dione .26b). Application ofprocedure B to 25b
/133 mg, 0.32 mmol) using dichloromethane/methanol
/2:1) as solvent mixture instead ofpure methanol, aforded

R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
4847
the crude amine 31, which was N-BOC protected without
puri®cation. Thus, crude 31 was dissolved in THF /6 mL),
methanol /3 mL) and triethylamine /0.5 mL). Solid
/BOC)2O /110 mg, mmol) was added and the solution was
stirred at room temperature for 13 h. The solvent was evapo-
rated in vacuo. The residual solid was participated between
water /10 mL) and ethyl acetate /10 mL). The organic layer
was separated off. The aqueous layer was extracted with
ethyl acetate /3£10 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The
residual solid was puri®ed by column chromatography
/SiO2, ethyl acetate/dichloromethane /1:2)) to yield pure
26b /82 mg, 65% yield), which was further recrystallized
trated. The residual oil was puri®ed by reversed phase
HPLC /TARGA C18 20£250 mm /Higgins Analytical);
MeOH/water /6:4); ¯ow 20 mL/min, detection at 254 nm;
retention time of 27aˆ4.5 min) to yield 27a as a yellowish
24
1
oil /50 mg, 40.5% yield). [a]D ˆ1608 /c 0.1, MeOH); H
NMR /400 MHz, C6D5CD3) d 7.38 /s, 1H), 6.60 /s, 1H),
3.66 /t, Jˆ5.6 Hz, 1H), 3.34 /s, 3H), 2.64±2.4 /m, 4H),
2.24±2.16 /m, 1H), 2.05±1.95 /m, 1H), 1.88±1.63 /m,
4H), 1.56±1.43 /m, 1H), 1.4±1.3 /m, 1H), 1.0 /ssb, 4H
/NH2), 4H /H2O)); 13C NMR /100.56 MHz, CDCl3) d
178.12, 139.24, 136.51, 136.36, 135.23, 129.91, 126.55,
59.84, 52.85, 49.29, 36.66, 33.35, 29.40, 29.33, 19.80,
19.34; HR-MALDI-MS m/z 297.159 /M1Na1) /calcd for
C16H22N2O2Na1, 297.157).
24
from chloroform/hexane /1:3). Mp 2248C; [a]D ˆ223.48
/c 1.49, MeOH); 1H NMR /400 MHz, CDCl2CDCl2; 353 K)
d 8.2 /svb, 1H), 7.12 /s, 1H), 6.83 /s, 1H), 6.1 /svb, 1H), 5.0
/svb, 1H), 4.66 /sb, 1H), 2.8±2.6 /m, 4H), 2.25±2.10 /m,
2H), 2.0±1.85 /m, 2H), 1.82±1.71 /m, 4H), 1.38 /s, 9H); 13C
NMR /100.56 MHz, CDCl2CDCl2, 353 K) d 176.88,
156.50, 155.92, 138.50, 137.00, 136.69, 131.14, 130.15,
126.83, 80.03, 64.54, 49.45 /sb), 34.54, 30.59, 29.17,
28.72, 28.66, 20.1, 19.24; HR-FABMS m/z /M1H1)
386.2056 /calcd for C21H28N3O4, 386.2080).
4.5.9. Methyl .1S,8S)-1-amino-8-tert-butoxycarbonyl-
amino-1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxyl-
ate .4). /BOC)2O /34 mg, 0.156 mmol) was added at room
temperature to a solution of 27a /48 mg, 0.134 mmol) in dry
THF /3 mL). The solution was stirred for 10 h at room tempera-
ture under argon. The solvent was evaporated in vacuo. The
remaining solid was washed with hexanes /2£2 mL) to
leave 4 as a slightly yellowish solid /49 mg, 78% yield).
24
4.5.7. .10S,80S)-N-[tert-Butyloxycarbonyl]-80-amino-20,30,
40,50,60,70,80-heptahydrospiro[imidazolidine-4,10-anthra-
cene]-2,5-dione .26a). This compound was prepared from
25a in 62% yield as described for the synthesis of 26b from
Mp 1708C; [a]D ˆ214.48 /c 0.23, MeOH); 1H NMR
/400 MHz, CDCl3; 608C) d 7.15 /s, 1H), 6.83 /s, 1H),
4.76 /sb, 1H), 4.62 /sb, 1H), 3.71 /s, 3H), 2.82±2.62 /m,
4H), 2.3±2.2 /m, 1H), 2.08±1.74 /m, 9H), 1.49 /s, 9H); 13C
NMR /100.56 MHz, CDCl3, 608C) d 177.91, 155.73,
137.28, 136.88, 136.22, 135.89, 129.96, 127.33, 79.60,
60.10, 52.58, 48.99, 36.73, 31.00, 29.51, 29.23, 28.82,
20.32, 19.41; HR-MALDI-MS m/z 397.212 /M1Na1)
/calcd for C21H30N2O4Na1, 397.210).
24
25b. Colorless solid; mp 2488C; [a]D ˆ217.08 /c 0.84,
1
MeOH); H NMR /400 MHz, CDCl3) d 7.35 /sb, 1H),
7.15 /s, 1H), 6.88 /s, 1H), 5.78 /sb, 1H), 4.75±4.55 /m,
2H), 2.9±2.2 /m, 4H), 2.38±2.2 /m, 2H), 2.1±1.1 /m, 6H),
1.47 /s, 9H); 13C NMR /100.56 MHz, CDCl3/CD3OD /5:1))
d 178.7, 157.3, 156.3, 138.0, 136.8, 136.0, 130.9, 130.0,
126.3, 79.7, 64.3, 48.7, 34.3, 30.4, 28.9, 28.5, 28.3, 20.1,
18.9, 18.9; HR-FABMS m/z /M1H1) 386.2061 /calcd for
C21H28N3O4, 386.2080).
4.5.10.
1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxylic acid
.29). Application ofprocedure C to 26b /141 mg,
.1R,8S)-1,8-bis.tert-Butyloxycarbonylamino)-
0.37 mmol) gave crude 2´nH2SO4: 1H NMR /400 MHz,
D2O) d 7.27 /s, 1H), 7.16 /s, 1H), 4.56 /sb, 1H), 3.0±2.75
/m, 4H), 2.5±2.4 /m, 1H), 2.35±1.8 /m, 7H). Crude
2´nH2SO4, was dissolved in dioxane/1N NaOH /1:1,
10 mL). This solution was cooled to 08C. /BOC)2O
/600 mg, 2.75 mmol) was added and the solution stirred at
room temperature for 20 h. The solution was concentrated to
halfofits initial volume. Ethyl acetate /20 mL) was added
and the aqueous layer cooled to 08C and acidi®ed to pH 3
with aqueous citric acid /10%). The organic layer was sepa-
rated off and the aqueous layer extracted with ethyl acetate
/5£25 mL). The combined organic layers were washed with
brine /10 mL), dried over MgSO4 and concentrated. The
crude product was puri®ed by column chromatography
/SiO2, CH2Cl2/ethyl acetate 2:1 to 0:1). The product
fractions were concentrated. The remaining solid was
crystallized form dichloromethane/hexanes /1:10) to yield
29 as colorless crystals /76 mg, 45% yield). mp 1858C;
4.5.8. Methyl .1S,8S)-1,8-diamino-1,2,3,4,5,6,7,8-octa-
hydroanthracene-1-carboxylate .27a) .Procedure C).
Hydantoin 26a /173 mg, 0.61 mmol) and Ba/OH)2´8H2O
/5.85 g, 18.5) were suspended in water /14 mL) and were
heated to 1208C for 24 h in a Te¯on-lined steel-reactor.
After cooling the reactor to room temperature, it was vented,
opened and the content was poured into 50 mL ofwater. The
solution is carefully acidi®ed with 1.4 M H2SO4 aq. The
precipitated BaSO4 was ®ltered off and washed with
water. The ®ltrate was concentrated. The partially solidi®ed
crude 1. nH2SO4 was taken up in the minimum amount of
methanol and was precipitated with ether, ®ltered off,
1
washed with ether and dried at high vacuum: H NMR
/400 MHz, D2O) d 7.27 /s, 1H), 7.16 /s, 1H), 4.56 /sb,
1H), 3.0±2.75 /m, 4H), 2.5±2.4 /m, 1H), 2.35±1.8 /m,
7H). The crude 1´H2SO4 was dissolved in dry methanol
/20 mL) and was cooled to 08C under argon. Thionyl
chloride /4 mL, mmol) was dropwise added to this stirred
solution. After the addition was complete, the reaction solu-
tion was re¯uxed for 24 h. The solvent was evaporated in
vacuo. The remaining solid was participated between ethyl
acetate and 10% aqueous Na2CO3. The organic layer was
separated off. The aqueous layer was extracted with ethyl
acetate /4£20 mL). The combined organic layers were
washed with 10 mL brine, dried over MgSO4 and concen-
[a]D ˆ255.38 /c 1.36, MeOH); 1H NMR /400 MHz,
24
CDCl3; 608C) d 7.37 /s, 1H), 6.83 /s, 1H), 5.7 /sb, 1H),
5.9±3.8 /svb, 1H), 4.9±4.6 /m, 2H), 2.82±2.5 /m, 4H),
2.4±2.32 /m, 1H), 2.12±2.02 /m, 1H), 1.92±1.7 /m, 4H),
1.48 /s, 9H), 1.41 /s, 9H); 13C NMR /100.56 MHz, CDCl3;
608C) d 176.14, 156.06, 154.68, 137.69, 137.28, 135.53,
133.93, 130.07, 127.19, 80.14, 60.85, 49.12, 32.89,
30.44, 29.33, 29.18, 28.98, 28.79, 28.69, 20.34, 19.71;

4848
R. A. Stalker et al. / Tetrahedron 58 (2002) 4837±4849
HR-MALDI-MS m/z 483.247 /M1Na1) /calcd for
C25H36N2O6Na1, 483.247). Anal. calcd for C25H36N2O6:
C, 65.20; H, 7.88; N, 6.08. Found: C, 65.43; H, 7.77; N, 6.03.
Cancer Research for an Undergraduate Student Cancer
Research Fellowship. R. W. warmly thanks the National
Institute ofHealth ofr a FIRST AWARD /Grant R01
GM57934-01, NIGMS)
4.5.11. Methyl .1R,8S)-1,8-bis.tert-butyloxycarbonyl-
amino)-1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxyl-
ate 30). Carboxylic acid 29 /75 mg, 0.163 mmol) was
dissolved in diethyl ether /6 mL) and was cooled to 08C.
Into this solution was condensed an approximately 0.4 M
solution ofdiazomethane in diethyl ether /9 mL), which was
prepared from diazald /1 g, 4.6 mmol) using a commercially
available Mini-Diazald Kit /Aldrich Chemical Company).
The reaction ¯ask was sealed with a rubber septum and was
left standing inside a metal can in the back of a well-venti-
lated fume hood. After 12 h, excess diazomethane was
decomposed via the drop-wise addition ofglacial acetic
acid /100 mL). The solvent was removed under high
vacuum to yield 30 as a colorless oil /77 mg, quantitative).
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4.75±4.65 /m, 1H), 4.58 /sb, 1H), 3.72 /s, 3H), 2.82±2.5 /m,
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ate .5). Ice-cold tri¯uoroacetic acid /0.5 mL) was added to
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The remaining 27b´2CF3COOH was taken up in aqueous
saturated Na2CO3 /2 mL) and was extracted with ethyl
acetate /2£5 mL). The combined organic layers were
dried over MgSO4 and concentrated. The remaining crude
27b was redissolved in dioxane /1 mL). A solution of
/BOC)2O /12.5 mg, 0.057 mmol) dissolved in dioxane
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been consumed /TLC control: SiO2; mobile phase: ethyl
acetate/n-butanol/acetic acid/water /2:1:1:1; RF/27b)ˆ0.3;
RF/5)ˆ0.8). The solution was concentrated in vacuo. The
residual crude product was puri®ed by reversed phase
HPLC /TARGA C18 20£250 mm /Higgins Analytical);
MeOH/water /7:3); ¯ow 20 mL/min, detection at 254 nm;
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È
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24
1
/13 mg, 61% yield). [a]D ˆ2218 /c 0.32, MeOH); H
NMR /400 MHz, CDCl3; 608C) d 7.13 /s, 1H), 6.83 /s,
1H), 4.73 /sb, 1H), 4.64 /sb, 1H), 3.71 /s, 3H), 2.8±2.62
/m, 4H), 2.3±2.21 /m, 1H), 2.03±1.75 /m, 9 H), 1.49 /s,
9H); 13C NMR /100.56 MHz, CDCl3; 608C) d 179.07,
155.79, 137.16, 137.02, 136.07, 135.96, 130.04, 127.07,
79.73, 60.09, 52.82, 49.17, 36.79, 30.86, 29.59, 29.27,
28.83, 20.22, 19.47; HR-MALDI-MS m/z 397.212
/M1Na1) /calcd for C21H30N2O4Na1, 397.210).
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