An efficient enantioselective synthesis of the D1 agonist (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopenta[c] phenanthrene-9,10-diol (A-86929)

Article abstract of DOI:10.1021/jo970066l

(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopenta[c] phenanthrene-9,10-diol (A86929, 1), a potent selective dopamine D1 agonist, was synthesized enantioselectively from D-aspartic acid. Key features of the 10-step synthesis are the follo

Full text of DOI:10.1021/jo970066l

2782
J . Org. Chem. 1997, 62, 2782-2785
An Efficien t En a n tioselective Syn th esis of th e D1 Agon ist
(5a R,11bS)-4,5,5a ,6,7,11b-Hexa h yd r o-2-p r op yl-3-th ia -
5-a za cyclop en ta [c]p h en a n th r en e-9,10-d iol (A-86929)
Paul P. Ehrlich,* J effrey W. Ralston, and Michael R. Michaelides
Neuroscience Research Division, Pharmaceutical Product Discovery, Department 47C,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500
Received J anuary 13, 1997X
(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopenta[c]phenanthrene-9,10-diol (A-
86929, 1), a potent selective dopamine D1 agonist, was synthesized enantioselectively from D-aspartic
acid. Key features of the 10-step synthesis are the following: (1) there is no chromatography
required; (2) formation of 15 occurs in >99% ee; (3) the electrophilic cyclization to provide the
desired trans stereochemisry in 18 is achieved with no loss of enantiomeric integrity.
Sch em e 1
In tr od u ction
We have recently described a new class of dopa-
minergic compounds, of which (5aR,11bS)-4,5,5a,6,7,11b-
hexahydro-2-propyl-3-thia-5-azacyclopenta[c]phenan-
threne-9,10-diol, (A-86929, 1) has been identified as a D1
selective agonist that maintains efficacy upon repeated
administration in both rodent and primate models.1,2
ABT-431, (2), the diacetyl prodrug of A-86929, has
increased solid state stability and is currently being
evaluated in man as therapy for Parkinson’s disease.
Herein, we report a highly efficient enantioselective
synthesis of A-86929.
Sch em e 2
Ch em istr y
In our initial synthesis of 1, the racemic 5a and 11b
trans stereochemistry was set with the Michael addition
of 5-allyl-N-tert-butylthiophenecarboxamide, 3, into the
nitroolefin 4 (Scheme 1). This was followed by conversion
of 5 to 6 and the subsequent resolution of 6 to provide
enantiomerically pure 1.2 We had initially attempted to
induce enantioselectivity in this sequence by introducing
a chiral auxiliary on the carboxamide of 3. Unfortu-
nately, this approach was not successful. Reaction
conversions were minimal and any 5 which was isolated
showed no enhanced enantiomeric excess.
Direction then turned to redesigning the entire syn-
thetic approach to 1. We decided to employ (R)-N-
(trifluoroacetyl)aspartic anhydride, 7, as a chiral synthon3
(Scheme 2). The Friedel-Crafts acylation of veratrole
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Shiosaki, K.; J enner, P.; Asin, K. E.; Britton, D.; Lin, C. W.;
Michaelides, M. R.; Smith, L.; Bianchi, B.; DiDomenico, S., J r.; Hodges,
L.; Hong, Y.; Mahan, L.; Mikusa, J .; Miller, T.; Nikkel, A.; Stashko,
M.; Witte, D.; Williams, M. J . Pharmacol. Exp. Ther. 1996, 276, 150-
160.
with 7 was performed as previously described by Nor-
lander and co-workers.4 Hydrogenation of the ketone 8
proceeded well in 1 M HCl/iPA with catalytic palladium
to furnish the butanoic acid 9, which was then converted
(2) Michaelides, M. R.; Hong, Y.; DiDomenico, S., J r; Asin, K. E.;
Britton, D. R.; Lin, C. W.; Williams, M.; Shiosaki, K. J . Med. Chem.
1995, 38, 3445-3447.
(4) Norlander, E. J .; Payne, M. J .; Njoroge, F. G.; Vishwanath, V.
M.; Han, G. R.; Laikos, G. D.; Balk, M. A. J . Org. Chem. 1985, 50,
3619-3622.
(3) Lapidus, M.; Sweeney, M. J . J . Med Chem. 1973, 16, 163.
S0022-3263(97)00066-2 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Synthesis of a D1 Agonist
J . Org. Chem., Vol. 62, No. 9, 1997 2783
Ta ble 1. Solven t Effects on th e Con ver sion of 16a a n d
16b to 17
Sch em e 3
reaction time,
temp
product ratio (trans:cis),
yield, %
solvent
CH2Cl2
THF
Et2O
10 min, room temp
>3 days, room temp
10 h, room temp
4:1, 95%
trans only (20% conversion)
3:2, 90%
EtOAc
15 h, room temp
10:1, 97%
Sch em e 4
Halogen-metal exchange with n-butyllithium on 12,
followed by the addition of 10, afforded the corresponding
condensation product 15 in excellent yield (Scheme 4).
None of the crude product showed any racemization (ee
> 99%),6 nor was any further addition of the 4-lithio-2-
propylthiophene to 15 observed. Reduction of 15 was
initially carried out on the crude reaction product, for fear
that the R-amino ketone would not maintain its enan-
tiomeric integrity. It has since been determined that 15
can be chromatographed with no detectable racemization
taking place.6
Reduction of 15 with NaBH4 resulted in a 4:1 ratio of
diastereomeric alcohols 16a and 16b. The major isomer
16a could be selectively crystallized; however, this was
not necessary as the ratio of 16a to 16b had no bearing
on the outcome of the following critical cyclization step.
We found that upon treatment of pure 16a or a mixture
of 16a and 16b with 1 M SnCl4/CH2Cl2 with methylene
chloride as solvent the product was a 4:1 ratio of the
desired trans 17 and cis 18 with the reaction time being
approximately 10 min. In the interest of improving the
trans/ cis product ratio, we performed the conversion at
different temperatures ranging from -70 °C to 0 °C in
10° increments. We found that at -10 °C the reaction
showed evidence of product formation after 1 h and
proceeded at a reasonable pace (monitored by TLC).
After a total of 8 h, the reaction was complete and, after
workup, showed a 5:1 ratio of 17 to 18. We saw this as
a minimal improvement and decided to look at the effects
of different solvents, as shown in Table 1.
When tetrahydrofuran was employed as the solvent,
only 17 could be detected, but the reaction times were
too prolonged to make this an alternative. Diethyl ether
resulted in decreased reaction times, but also decreased
trans selectivity. Ethyl acetate gave the best results with
a reasonable reaction time and significantly improved
product ratio. As with 16a and 16b, the desired trans
diastereomer 17 could be selectively crystallized away
from 18. Deprotection of the amide with K2CO3 in
methanol followed by Pictet-Spengler cyclization then
furnished the tetracycle 19 (ee > 99%), as the hydrochlo-
ride salt, in 75% overall yield from 12 (Scheme 5).
The demethylation of 19 proceeded smoothly with the
agency of BBr3 to quantitatively furnish 1. In the
formation of 1 it is of interest to note that if performed
on the base of 19, under the same reaction conditions,
the product was contaminated with up to 5% of the
oxidized byproduct 20.
to the Weinreb amide 10, in 55% overall yield from 7.5
In our initial studies of the formation of 10, it was found
that short reaction times were crucial to eliminate the
formation of an azalactone byproduct, (11). The azalac-
tone, which provided a mechanism by which racemization
of 10 was facilitated, would constitute up to 15% of the
reaction product if the reaction times were 10 min or
longer. Fortunately, we discovered that if any of 10 did
racemize, it merely required trituration of the crude
product with ether; the racemate would then precipitate
while the enantiomerically pure amide would remain in
solution.6
With 10 in hand, we then required 4-bromo-2-propyl-
thiophene (12), for the introduction of the D ring (Scheme
3). This was produced via the bromination of 1-(2-thi-
enyl)-1-propanone (13),7 utilizing Br2 and AlCl3 followed
by Wolff-Kishner reduction of ketone 14 in a 65% overall
yield.8
Con clu sion
(5) Angelastro, M. R.; Peet, Norton, P. P.; Bey, P. J . Org. Chem.
1989, 54, 3913- 3916.
(6) Enantiomeric excess was determined utilizing an analytical
Chiracel OD column purchased from Chiral Technologies Inc., 730
Springdale Dr., Exton, PA. The mobile phase was 9:1 hexanes:iPA,
detection ) 254 nm, flow ) 1mL/min.
(7) Purchased from Aldrich Chemical Company, Inc., Milwaukee,
WI 53233.
(8) Alvarez-Insua, A. S.; Conde, S.; Corral, C. J . Heterocycl. Chem.
1982, 19, 713-716.
We have described an efficient unambiguous asym-
metric synthesis of A-86929 (1), that requires 10 inter-
conversions with no chromatography required and an
overall yield of >30%. The key steps in the synthesis
are the formation of 15 in >99% ee and the subsequent
cyclization to trans 18 with no loss of enantiomeric
integrity.

2784 J . Org. Chem., Vol. 62, No. 9, 1997
Ehrlich et al.
1H), 2.63 (m, 2H), 3.21 (s, 3H), 3.65 (s, 3H), 3.86 (s, 3H), 3.89
(s, 3H), 5.01 (m, 1H), 6.70-6.85 (m, 3H), 7.11 (s, 1H). Anal.
Calcd for C16H21F3N2O5 C, 50.79; H, 5.59; N, 7.40. Found: C,
50.44; H, 5.45; N, 7.34. [R]D ) -8.87° (c ) 1.42, CH2Cl2).
Sch em e 5
1-(4-Br om o-2-th ien yl)-1-p r op a n on e (14). To a solution
of 13 (47.3 g, 338 mmol, Aldrich), in 225 mL of CHCl3 was
added AlCl3 (101.3 g, 760 mmol) with stirring. To this mixture
was added a solution of bromine (57.5 g, 360 mmol) in 375
mL of CHCl3. The mixture was stirred at rt for 18 h and then
poured into 500 mL of ice-water. The organic layer was
separated, washed with water (2 × 200 mL), dried over MgSO4,
and evaporated to yield 81 g of the crude title compound, which
was taken directly to the next step: mp 40-41°C; MS m/ z
158 (M+ + H), 236 (M+ + NH4); 1H NMR (CDCl3) δ 1.22 (t,
3H, J ) 7.5 Hz), 2.91 (q, 2H, J ) 7.5Hz), 7.51 (d, 1H, J )
2Hz), 7.60 (d, 1H, J ) 2Hz); IR (KBr) 2960, 1670, 1400, 1220
•
cm-1
.
4-Br om o-2-p r op ylth iop h en e (12). To a solution of crude
14 (53 g, 242 mmol) in 210 mL of ethylene glycol was added
hydrazine monohydrate (30 mL, 617 mmol). The resulting
solution was then heated to 160 °C with stirring for 45 min.
The solution was cooled to 35 °C, and KOH (42 g, 750 mmol)
was added. The mixture was heated to 160 °C and stirred for
1.5 h. The reaction was cooled to rt, and 450 mL of water was
added. The mixture was then acidified with concd HCl, and
the product was extracted with pentane (3 × 200 mL). The
pentane was dried over MgSO4 and evaporated to yield 39.7 g
of crude product as a free-flowing oil. The material was
purified by flash chromatography on silica gel, eluting with
pentane, to afford 33 g, (65% yield) of the title product.
Alternatively, the product can be purified by distillation: bp
120-125 °C 7 mmHg; 1H NMR (CDCl3) δ 0.97 (t, 3H, J ) 7.5
Hz), 1.69 (sextet, 2H, J ) 7.5 Hz), 2.75 (t, 2H, J ) 7.5 Hz),
6.70 (d, 1H, J ) 2 Hz), 7.00 (d, 1H, J ) 2 Hz). Anal. Calcd
for C7H9 BrS: C, 40.99; H, 4.42. Found: C, 41.04; H, 4.40.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. All spectral and
analytical data were obtained through the Abbott analytical
department. All reactions were conducted in oven-dried or
flame-dried glassware under a nitrogen atmosphere. Anhy-
drous solvents were purchased from Aldrich Chemical Co.
Analytical TLC was performed by using 2.5 cm ×10 cm plates
coated with a 0.25 mm thickness of silica gel containing PF
254 indicator (Analtech). Flash chromatography was per-
formed with silica gel 60 (E. Merck 9285, 230-400 mesh).
(R)-(-)-4-(3,4-Dim et h oxyp h en yl)-2-((t r iflu or oa cet yl)-
a m in o)bu ta n oic Acid (9). A mixture of 8 (237 g, 678.6
mmol), 10% Pd/C (23.7 g), and concentrated HCl (115 mL) in
900 mL of isopropyl alcohol was hydrogenated under 4 atm of
hydrogen at rt for 14 h. After filtration of the catalyst over
Celite, ether (2 L) was added to the filtrate and the resultant
solution was washed with water (4 × 1.5 L). The organic
solution was evaporated under reduced pressure to leave an
oily residue, which was redissolved in ether (700 mL) and
treated with saturated aqueous NaHCO3 until pH 8 was
reached. The aqueous solution was separated and washed
with ether (2 × 500 mL). After careful acidification to pH 2
by addition of 6 N HCl, the mixture was extracted with ether
(2 × 1 L). The organic layers were combined, dried (MgSO4),
and concentrated under reduced pressure to give a light brown
solid which was recrystallized from hexane/EtOAc. The title
compound was obtained as a white crystalline solid (193 g,
85% yield): mp 159-160 °C; 1H NMR (CDCl3) δ 2.05-2.35
(m, 2H), 2.65 (t, 2H, J ) 7.5 Hz), 3.70 (s, 3H), 3.80 (s, 3H),
4.60 (br q, 1H, J ) 7.5 Hz), 6.70-6.81 (m, 3H), 7.19 (br d, 1H,
J ) 7.5 Hz). Anal. Calcd for C14 H16F3O5: C, 50.15; H, 4.81;
N, 4.18. Found: C, 49.97; H, 4.65; N, 4.15. [R]D -6.44 (c 1.35,
MeOH).
(2R)-4-(3,4-Dim eth oxyp h en yl)-1-(2-p r op yl-4-th ien yl)-2-
((tr iflu or oa cetyl)a m in o)-1-bu ta n on e (15). To a solution of
12 (17.4 g, 85 mmol) dissolved in 200 mL of ether and cooled
to -78 °C was added 38 mL of 2.5 M nBuLi in hexanes
(Aldrich), maintaining the reaction temperature at less than
-70 °C. The reaction was stirred at -78 °C for 30 min, and
a precooled (-78 °C) solution of 10 (10.7 g, 28.3 mmol) in 50
mL of THF was added at such a rate to maintain the reaction
temperature at less than -70 °C. The reaction was quenched
with saturated NH4Cl, stirred at rt, and diluted with 300 mL
of ethyl acetate. The organic layer was separated and washed
with 1 N HCl and saturated NaCl, dried over MgSO4, and
evaporated to yield the crude product as an oil (12.5 g, 100%),
which was taken directly to the next step: MS m/ z 444 (M+
+ H), 461 (M+ + NH4); 1H NMR (CDCl3) δ 0.98 (t, 3H, J ) 7.5
Hz), 1.68 (m, 2H), 2.04 (m, 1H), 2.30 (m, 1H), 2.63 (dt, 2H, J
) 2.4, 7.5 Hz), 2.75 (t, 2H, J ) 7.5 Hz), 3.87 (s, 3H), 3.88 (s,
3H), 5.37 (dt, 1H, J ) 3, 7.5 Hz), 6.74 (m, 2H), 6.81 (d, 1H, J
) 2 Hz), 7.05 (bs, 1H), 7.31 (bd, 1H, J ) 9 Hz), 7.72 (d, 1H, J
) 2 Hz). Anal. Calcd for C21H24F3NO4S:C, 56.88; H, 5.46; N,
3.16. Found: C, 56.64; H, 5.45; N, 3.28. [R]D ) -38° (c )
0.75, CHCl3).
(2R)-N-Meth oxy-N-m eth yl-4-(3,4-d im eth oxyp h en yl)-2-
((tr iflu or oa cetyl)a m in o)bu ta n a m id e (10). To a solution
of 9 (8 g, 24 mmol) in 65 mL of THF was added N-methyl-
morpholine, (2.6 mL, 24 mmol), and the solution was cooled
to -25 °C and stirred for 30 min. Isobutyl chloroformate (3.1
mL, 24 mmol) was then added, and the solution was stirred
for 1.5 min. To this solution was added a solution of N,O-
dimethylhydroxylamine (prepared by adding N,O-dimethyl-
hydroxylamine hydrochloride (3.5 g, 36 mmol) to a solution of
24 mL of THF and 1 mL of water, adding K2CO3, (7 g, 216
mmol), stirring for 30 min, and then filtering), and the reaction
mixture was stirred for 30 min at -25 °C. The mixture was
diluted with ethyl acetate (200 mL), and the organic layer was
separated and washed with 50 mL each of water, 1 N NaOH,
1 N HCl, water, and saturated NaCl. The organic layer was
then dried over MgSO4 and evaporated to yield a colorless oil.
The oil was crystallized from ether/hexanes to yield 7 g of the
title compound (77%): mp 70-72 °C; MS m/ z 379 (M+ + H),
396 (M+ + NH4); 1H NMR (CDCl3) δ 2.02 (m, 1H), 2.15 (m,
(2R)-4-(3,4-Dim eth oxyp h en yl)-1-(2-p r op yl-4-th ien yl)-2-
((tr iflu or oa cetyl)a m in o-1-bu ta n ol (16a a n d 16b). To a
solution of 15, (12.5 g, 28.8 mmol) in 300 mL of absolute
ethanol cooled to 0 °C was added 1.4 g (36 mmol) of NaBH4,
and the reaction was stirred at rt for 2 h. The reaction was
carefully quenched with 1 N HCl and diluted with ethyl
acetate. The organic layer was separated and washed with
water (2 × 100 mL), and saturated NaCl, dried over MgSO4
and then evaporated to a solid. The solid was triturated with
5:1 hexanes/ethyl acetate to yield pure title product as a 4:1
mixture of trans:cis product (12.1 g, 95%: 1H NMR (CDCl3) δ
3
0.95 (t, /5 H, J ) 7.5Hz), 0.97 (t, 3H, J ) 7.5 Hz), 1.52-1.92
(m, 44/5H), 2.42-2.70 (m, 22/5H), 2.74 (t, 2/5H, J ) 7.5 Hz), 2.75
1
(t, 2H, J ) 7.5 Hz), 3.75 (m, 1H), 3.77 (m, /5H), 3.84 (s, 3H),
3.85 (s, 3H), 3.87 (s, 3/5H), 3.88 (s, 3/5H), 4.85 (d, 1/5H, J ) 3
Hz), 4.90 (d, 1H, J ) 3 Hz), 6.42 (bd, 1H, J ) 9 Hz), 6.51 (bd,
1/5H, J ) 9 Hz), 6.63 (m, 33/5H), 6.70-6.82 (m, 11/5H), 6.95 (s,
1/5H), 6.97 (s, 1H); MS m/ z 445 (M+ + H), 463 (M+ + NH4).

Enantioselective Synthesis of a D1 Agonist
J . Org. Chem., Vol. 62, No. 9, 1997 2785
Anal. Calcd for C21H26F3NO4S: C, 56.62; H, 5.88; N, 3.14.
Found: C, 56.50; H, 5.38; N, 3.14.
for 15 min, 3.7 mL of concd HCl was added, and the reaction
was heated at reflux for 4 h. The reaction was then cooled,
and the suspension was diluted with 200 mL of ether and
stirred at rt for 1 h. The mixture was filtered, and the product
was dried to yield 4.7 g (95%) of a white crystalline solid: mp
tr a n s-(1S,2R)-N-(Tr iflu or oacetyl)-6,7-dim eth oxy-1,2,3,4-
tetr a h yd r o-1-(2-p r op yl-4-th ien yl)-2-n a p h th yla m in e (17).
To a solution of the alcohols 16a and 16b above (7.65 g, 17
mmol) in 200 mL of ethyl acetate cooled to 0 °C was added 17
mL of 1 M SnCl4 in CH2Cl2. The reaction was stirred at rt for
16 h and then quenched with water, and the organic layer was
separated, washed with water and saturated NaCl, dried over
MgSO4, and evaporated to a solid (6.9 g, 97%). The solid was
recrystallized from one part ethyl acetate and five parts
hexanes to yield the trans title product as a white crystalline
1
284-286 °C dec; H NMR (CDCl3) δ 1.00 (t, 3H, J ) 7.5 Hz),
1.69 (m, 3H), 2.39 (m, 1H), 2.62 (m, 1H), 2.79 (t, 2H, J ) 7.5
Hz), 2.84-3.09 (m, 2H), 3.18 (m, 1H), 3.83 (s, 3H), 3.88 (s, 3H),
4.30 (d, 1H, J ) 10.5 Hz), 4.37 (d, 1H, J ) 16.5 Hz), 4.54 (d,
1H, J ) 15 Hz), 6.70 (s, 1H), 6.92 (s, 1H), 7.01 (s, 1H); MS
m/ z 344 (M+ + H), 361 (M+ + NH4). Anal. Calcd for C20H26
-
ClNO2S: C, 63.23; H, 6.90; N, 3.69; Found: C, 62.85; H, 6.83;
1
N, 3.70. [R]D ) -263.14° (c ) 3.31, methanol). Base: [R]D
-343° (c ) 0.52, methanol).
)
solid (5.9 g, 83% yield): mp 157-158 °C; H NMR (CDCl3) δ
0.95 (t, 3H, J ) 7.5 Hz), 1.66 (m, 2H), 1.88 (m, 1H), 2.10 (m,
1H), 2.72 (t, 2H, J ) 7.5 Hz), 2.81 (t, 1H), 2.92 (m, 1H), 3.74
(s, 3H), 3.89 (s, 3H), 4.01 (d, 1H, J ) 6 Hz), 4.39 (dt, 1H, J )
3, 7.5 Hz), 6.28 (bd, 1H, J ) 7.5 Hz), 6.45 (s, 1H), 6.53 (s, 1H),
tr a n s-(5a R,11bS)-4,5,5a ,6,7,11b-Hexa h yd r o-2-p r op yl-3-
th ia -5-a za cyclop en ta [c]p h en a n th r en e-9,10-d iol Hyd r o-
br om id e (1). A three-neck flask equipped with a mechanical
stirrer and a thermometer was charged with a suspension of
19 (19.22 g, 50.6 mmol) in CH2Cl2 (750 mL) and then placed
in a dry ice bath. BBr3 (210 mL, 1.0 M solution in CH2Cl2,
210 mmol) was added via syringe over a period of 20 min,
resulting in a clear light brown solution. The reaction mixture
was stirred at -70 °C for 45 min and then placed in an ice
bath and stirred for an additional 2 h. The reaction mixture
was recooled to -78 °C and carefully quenched with 180 mL
of MeOH. The cooling bath was removed, and the reaction
was stirred at rt for 1.5 h. The reaction mixture was
concentrated in vacuo, and the product was triturated from
methanol-CH2Cl2-ether to afford the title product as a tan
solid. The product was dried under high vacuum for 16 h to
afford 20.1 g (100%) of 1. The product was >99% pure by
HPLC on a reverse phase C-60 Dynamax column using a 1:1
mixture of methanol and 0.1% trifluoroacetic acid as the mobile
phase (UV detector at 254 nm): mp 155-162 °C dec; MS m/ z
316 (M+ + H); 1H NMR (CDCl3) δ 1.03 (t, 3H, J ) 8 Hz), 1.75
(sx, 2H, J ) 8 Hz), 1.9-2.0 (m, 1H), 2.28-2.41 (m, 1H), 2.87
(t, 2H, J ) 8 Hz), 2.88-3.05 (m, 2H), 3.15-3.27 (m, 1H), 4.02
(d, 1H, J ) 11 Hz), 4.46 (s, 2H), 6.67 (s, 1H), 6.90 (s, 1H), 7.02
(s, 1H). Anal. Calcd for C18H22BrNO2S‚0.7H2O: C, 52.87; H,
5.77; N, 3.43. Found: C, 52.87; H, 5.45; N, 3.34. [R]D ) -167°
(c 1.03, methanol).
6.59 (s, 1H), 6.65 (s, 1H); MS m/ z 428 (M+ + H), 445 (M+
+
NH4). Anal. Calcd for C21H24F3NO3S: C, 59.00; H, 5.66; N,
3.28. Found: C, 56.64; H, 5.45; N, 3.28. [R]D ) -18.6° (c 0.05,
CH2Cl2).
tr a n s-(1S,2R)-6,7-Dim et h oxy-1,2,3,4-t et r a h yd r o-1-(2-
p r op yl-4-th ien yl)-2-n a p h th yla m in e (17a ). To a solution of
17 (5.9 g, 13.3 mmol) in 200 mL of 10% aqueous methanol was
added 11.8 g of K2CO3 (80 mmol). The resulting suspension
was heated at reflux for 2 h, cooled to rt, and diluted with
ethyl acetate. The organic layer was washed with water (2 ×
100 mL) and saturated NaCl, dried over MgSO4, and evapo-
rated to yield the title compound as an amorphous solid (4.4
g, 100% yield). The compound was taken to the next step
without further purification. MS m/ z 332 (M+ + H) 349 (M+
+ NH4). 1H NMR (CDCl3) δ 0.93 (t, 3H, J ) 7.5 Hz), 1.59-
1.79 (m, 3H), 2.06 (m, 1H), 2.73 (t, 2H, J ) 7.5 Hz), 2.89 (m,
2H), 3.15 (m, 1H), 3.64 (s, 3H), 3.70 (d, 1H, J ) 9 Hz), 3.86 (s,
3H), 6.32 (s, 1H), 6.48 (s, 1H), 6.60 (s, 1H), 6.88 (d, 1H, J ) 2
Hz). Anal. Calcd for C19H25NO2S: C, 68.85; H, 7.60; N, 4.22.
Found: C, 68.63; H, 7.45; N, 4.28.
tr a n s-(5aR,11bS)-9,10-Dim eth oxy-4,5,5a,6,7,11b-h exah y-
dr o-2-pr opyl-3-th ia-5-azacyclopen ta[c]ph en an th r en e Hy-
d r och lor id e (19). To a solution of 17a , (4.4 g, 13.3 mmol) in
100 mL of absolute ethanol was added 37% formaldehyde in
water (10.3 mL, 133 mmol). The reaction was stirred at rt
J O970066L