Synthesis of an azasteroid using an acyl iminium ion-initiated tandem cyclization

Article abstract of DOI:10.1021/jo960673t

An acyl iminium ion-initiated tandem cyclization gave an unexpected dienone product, a secoazasteroid (2). The factors governing the formation of 2 were investigated in an attempt to optimize its formation. The reaction was applied to a more elaborate system, resulting in the synthesis of the full steroid skeleton of 13-azaandrosta-1,4-diene-3,17-dione (3), which contains the unusual substitution of a chlorine atom for the axial 19-methyl.

Full text of DOI:10.1021/jo960673t

6974
J . Org. Chem. 1996, 61, 6974-6979
Syn th esis of a n Aza ster oid Usin g a n Acyl Im in iu m Ion -In itia ted
Ta n d em Cycliza tion
Arthur G. Romero,* J effrey A. Leiby, and Stephen A. Mizsak
Structural, Analytical, and Medicinal Chemistry, Pharmacia & Upjohn, Kalamazoo, Michigan, 49001
Received April 12, 1996X
An acyl iminium ion-initiated tandem cyclization gave an unexpected dienone product, a seco-
azasteroid (2). The factors governing the formation of 2 were investigated in an attempt to optimize
its formation. The reaction was applied to a more elaborate system, resulting in the synthesis of
the full steroid skeleton of 13-azaandrosta-1,4-diene-3,17-dione (3), which contains the unusual
substitution of a chlorine atom for the axial 19-methyl.
Heterocyclic azasteroids are of continuing interest,
particularly due to their diverse range of biological
activities. Many of these activities are thought to be due
to the formation of stable substrate-enzyme complexes,
facilitated by the presence of the nitrogen atom. These
activities include inhibition of steroid biosynthesis, which
includes the use of A-ring azasteroids to inhibit the
enzyme 5R-reductase in the conversion of testosterone
to 5R-dihydrotestosterone, leading to a treatment for
benign prostatic hypertrophy1 and possibly acne and male
pattern baldness.2 Other 4-azasteroids have been shown
to inhibit the 3â-hydroxy-∆5-steroid dehydrogenase and/
or 3-keto-∆5-steroid isomerase conversion of pregnenolone
to progesterone.3 Similarly, azasteroid antimycotic4 ac-
tivity is postulated to be a consequence of the inhibition
of fungal 14,15-sterol reductase. Further antifungal,5
antibacterial,4,6 hypochlosterolemic,4 hypotensive,4 and
neuromuscular blocking7 activities have also been at-
tributed to azasteroids.
F igu r e 1.
(1) for further conversion into compounds of biological
interest, we obtained an unexpected product (2), which
can be described as a seco-azasteroid adduct (Figure 1).
This came about during the treatment of 4 with paraform-
aldehyde in formic acid at 55 °C, where, in addition to
the anticipated tandem cyclization to the site ortho to to
the methoxy group leading to 1 (path a, Figure 2), we
observed a competing cyclization occurring to the chlorine
substituted position to give 2 (path b), via loss of the
methyl on the para-substituted oxonium group contained
in indermediate 6. The yield of 2 (34%) is remarkable
considering the number of chemical bonds both broken
and formed, as well as the other reaction manifolds
available, leading to 1 and 16.9
In the course of an investigation into the utility of using
N-acyl iminium ion8-initiated tandem cyclizations to
afford substituted octahydrobenz[f]isoquinoline adducts
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; J obson, R. B.;
Primka, R. L.; Berman, C.; Brooks, J . R. Azasteroids as inhibitors of
rat prostatic 5R-reductase. J . Med. Chem. 1984, 27, 1690-1701.
Rasmusson, G. H.; Reynolds, G.; Steinberg, N. G.; Walton, E.; Patel,
G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J . R.; Berman,
C. Azasteroids: structure activity relationships for inhibition of 5R-
reductase and of androgen receptor binding. J . Med. Chem. 1986, 29,
2298-2315.
(2) Brooks, J . R.; Berman, C.; Primka, R. L.; Reynolds, G. F.;
Rasmusson, G. H. 5R-Reductase inhibitory and anti-androgenic activi-
ties of some 4-azasteroids in the rat. Steroids 1986, 47, 1-19. Brooks,
J . R.; Berman, C.; Garnes, D.; Giltinan, D.; Gordon, L. R.; Malatesta,
P. F.; Primka, R. L.; Reynolds, G. F.; Rasmusson, G. H. Prostatic effects
induced in dogs by chronic or acute oral administration of 5R-reductase
inhibitors. Prostate 1986, 9, 65-75.
Herein are reported the details of this reaction and the
subsequent elaboration of this methodology to obtain the
complete ring skeleton of androsta-1,4-diene-3,17-dione,
with the bioisostere substitution of a nitrogen in place
of C-13, and a chlorine replacing the axial 19-methyl (3).10
It is noteworthy that besides the possibility for enzyme
deactivation resulting from substitution with the aza
group, the A-ring of this compound can serve as a mildly
electrophilic chlorinating group, another possible mech-
anism for enzyme inhibition which has received atten-
tion.11
(3) Brandt, M.; Levy, M. A. 3â-Hydroxy-∆5-steroid dehydrogenase/
3-keto-∆5-steroid isomerase from bovine adrenals: mechanism of
inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the
dehydrogenase. Biochemistry 1989, 28, 140-148.
(4) Dolle, R. E.; Allaudeen, H. S.; Kruse, L. I. Design and synthesis
of 14R-methyl-15-aza-D-homosterols as novel antimycotics. J . Med.
Chem. 1990, 33, 877-880.
(5) Solomons, W. E.; Doorenbos, N. J . Synthesis and antimicrobial
properties of 17â-amino-4-aza-5R-androstane and derivatives. J . Pharm.
Sci. 1974, 63, 19-23. Doorenbos, N. J .; Solomons, W. E. Synthesis and
antimicrobial properties of 17â-isopentyloxy-4-aza-5R-androstane and
the 4-methyl derivative. J . Pharm. Sci. 1973, 62, 638-640.
(6) Chesnut, R. W.; Durham, N. N.; Brown, R. A.; Mawdsley, E. A.;
Berlin, R. A. Antibacterial activity of 15-azasteroids alone and in
combination with antibiotics. Steroids 1976, 525-541.
The cyclization substrates were easily obtained (Scheme
1). 4-Chloro-3-methylphenol (7) was protected as the tert-
(8) Review of intramolecular cyclizations of N-acyliminium ions:
Speckamp, W. N.; Heimstra, H. Intramolecular reactions of N-
acyliminium intermediates. Tetrahedron 1985, 41, 4367-4416.
(9) Compound 16 arises from formic acid serving as a nucleophile,
intercepting 5 after the first cyclization. This is probably a synchronous
mechanism since only trans-substituted 16 is obtained.
(10) Steroid numbering system.
(7) Singh, H.; Paul, D.; Parashar, V. V. J . Chem. Soc., Perkin Trans.
1 1973, 1204. Singh, H.; Paul, D. Ibid. 1974, 1475. Singh, H.; Bhardwaj,
T. R.; Ahuja, N. K.; Paul, D. Steroids and related studies. Part 44.
17a-Methyl-3â-(N-pyrrolidinyl)-17a-aza-D-homo-5R-androstane bis-
(methiodide) (Dihydrochandonium iodide) and certain other analogues
of chandonium iodide. Ibid. 1979, 305-307.
S0022-3263(96)00673-1 CCC: $12.00 © 1996 American Chemical Society

Synthesis of an Azasteroid
J . Org. Chem., Vol. 61, No. 20, 1996 6975
Sch em e 1. Syn th esis of Seco-Ster oid P r ecu r sor s (4, 14, a n d 15) a n d Su bsequ en t Acyl Im in iu m
Ion -In itia ted Ta n d em Cycliza tion of 4.
butyldimethylsilyl ether (8) in order to provide flexibility
to examine how varying the aryl ether substituent would
affect the cyclization product ratios. Benzylic bromina-
tion of 8 with NBS, followed by enolate alkylation
afforded ester 10 in good yield. LAH reduction followed
by Swern oxidation gave aldehyde 11. Treatment with
vinylmagnesium bromide afforded allylic alcohol 12
which underwent a Claisen rearrangement when treated
with triethylorthoacetate. Saponification of the ester
followed by a diphenyl phosphorazidate-mediated Curtius
rearrangement12 gave the isocyanate which was con-
densed with ethanol to provide the carbamate 14. At this
stage the silyl ether could be converted into either methyl
ether 4 or MOM ether 15, using a one-pot procedure with
potassium fluoride/methyl iodide or chloromethyl methyl
ether, respectively.13 Methyl ether 4 was cyclized with
1.1 equiv of paraformaldehyde in formic acid at 55 °C
for 2 h to afford 1, 2, and 16 (41%, 34%, and 20% isolated
yields, respectively).
attempt to demonstrate whether enhancing the ability
of the oxonium ion to be neutralized would increase the
amount of 2 obtained. Interestingly, these variations had
no effect on the product ratios. In a separate experiment,
compound 4 was treated with boron trifluoride etherate
to observe the effect of acid catalysis without the nucleo-
philic component present in formic acid.14 Under the
influence of this Lewis acid, 1 was the only product
obtained, in excellent yield.
For a more elaborate demonstration of this unusual
cyclization, the full ring skeleton of 13-aza-androsta-1,4-
diene-3,17-dione (3) was synthesized, where the D-ring
portion of the azasteroid skeleton was obtained by
proceeding through a Speckamp cyclization8 of the cyclic
imide (Scheme 2). To carry this out, 4 was saponified to
the primary amine (17) and acylated with succinic
anhydride, followed by cyclization with acetyl chloride
to obtain imide 18. Selective reduction of the imide with
sodium borohydride in ethanol afforded cyclization pre-
cursor 19. Subjecting 19 to N-acyl iminium ion cycliza-
tion conditions, formic acid, and paraformaldehyde at 25
°C, afforded 3 in 30% yield, with four contiguous stereo-
centers.15 The remainder of the mass balance was
accounted for by cyclization ortho to the methoxy group
and by formic acid trapping the partially cyclized product,
analogously to 4.
Several variables were examined in an effort to opti-
mize the formation of 2 as well as to gain mechanistic
information. Silyl ether 14 and MOM ether 15 were
subjected to the cyclization conditions used for 4 in an
(11) Steroidal N-chloro amides have been synthesized for this
purpose: Back, T. G.; Lai, E. K. Y.; Morzycki, J . W. A convenient new
synthesis of 17-azasteroids. Preparation of some novel N-chloro-17-
aza- and N-chloro-17A-aza-17A-homosteroids as potential affinity
labels and enzyme inhibitors. Heterocycles 1991, 32, 481-488.
(12) Ninomiya, K.; Shioiri, T.; Yamada, S., Phosphorus in organic
synthesis-VII. Diphenyl phosphorazidate (DPPA). A new convenient
reagent for a modified Curtius reaction. Tetrahedron 1974, 30, 2151-
2157.
(13) Sinhababu, A. S.; Kawase, M.; Borchardt, R. T. tert-Butyldi-
methylsilyl ethers of phenols: their one step conversion to benzyl or
methyl ethers and utility in regioselective ortho lithiation. Tetrahedron
Lett. 1987, 4139-4142.
The trans-anti-trans ring fusions of compound 3 were
proven by examining several NMR proton-proton cou-
(14) One equivalent of boron trifluoride etherate was added to a
slurry of 4 and 1.1 equivalent of paraformaldehyde in methylene
chloride at 25 °C. The reaction was complete in several minutes. Other
Lewis acids, such as titanium tetrachloride, were much inferior.
(15) Repeating this procedure with a MOM ether substituted for
the methyl ether afforded a similar yield and product mixture.

6976 J . Org. Chem., Vol. 61, No. 20, 1996
Romero et al.
Sch em e 2. Syn th esis of Sp eck a m p -Typ e Acyl
Im in iu m Ion In itia tor 19 a n d Cycliza tion to
Aza ster oid 3.
F igu r e 2. Cyclization by pathways a and b to give 1 and 2,
pling constants. The indicated trans-diaxial relationship
between the chlorine and the C-9 proton results in the
“B”-ring assuming a pseudo-chair conformation; the C-6
proton resonances support this with axial C-6/axial C-7,
equatorial C-6/axial C-7, and equatorial C-6/equatorial
C-7 couplings of 13.7, 4.4, and 2.5 Hz, respectively.16 The
relative stereochemistry of the remaining ring fusions are
supported by the axial proton on C-9 exhibiting a 10.9
Hz coupling to the axial C-8 proton and a 11.0 Hz
coupling to the axial C-11 proton, the axial C-7 proton
exhibiting a 12.0 Hz coupling to the axial C-8 proton, and
the pseudo-axial C-14 proton exhibiting a 9.8 Hz coupling
to the axial C-8 proton. Similar arguments support the
stereochemical assignment of 2.17
respectively.
F igu r e 3. Alternate explanation for the formation of 1 from
6, by fragmentation of oxonium intermediate 20. This mech-
anism is less likely than a direct partitioning of 5 to 1 and 2.
tandem cyclization mechanism which directly partitions
5 between the observed products via paths a and b. At
first it would appear that the role of the acid catalyst is
solely to catalyze the condensation of paraformaldehyde
with the carbamate nitrogen to generate the highly
reactive acyl iminium species which immediately cyclizes
to give the product(s). However, this explanation does
not account for the dramatic difference in product ratios
observed upon going from formic acid to boron trifluoride
etherate as the catalyst. An alternative mechanism can
be considered, although less likely than irreversible direct
partitioning. This would require the kinetically gener-
ated oxonium species 6 to either lose a methyl to give 2
or undergo fragmentation to give 20, which could then
recyclize to the unsubstituted ortho position to provide
1 (Figure 3). In this instance the ratio of 1 to 2 would
be a reflection of the relative rate of demethylation of 6
versus the overall rate of fragmentation of 6 to 20 and
subsequent cyclization of 20 to give 1. Thus, assuming
a kinetic cyclization to 6 occurred first, regardless of the
acid catalyst, the inability of boron trifluoride etherate
to demethylate 6 would eventually result in fragmenta-
tion to 20.
Discu ssion
While Friedel-Crafts cyclization of p-methoxy-substi-
tuted benzene rings to give geminally disubstituted
dienones is not uncommon, these are usually systems
which for steric reasons are constrained to cyclize to the
ipso position giving spirocycles.18 These specialized
systems contrast with the ability of 4 to undergo “normal”
cyclization to an unsubstituted ortho-position (path a,
Figure 2), leading to 1. The question arises as to whether
1 and 2 are generated as a result of a synchronous
(16) Examination of a model of the alternative pseudo-boat confor-
mation indicates that it would result in both of the C-6 protons
eclipsing a vicinal C-7 proton, resulting in syn-periplanar coupling
constants for both of the C-6 protons. This is not supported by the 1H
NMR. Furthermore, a cis-ring fusion between C-9 and C-10 would
require the chlorine to eclipse the C-9 proton, resulting in an upfield
shielding of this proton. However, the resonance of this proton (1.55
ppm) shows it is not undergoing shielding, again supporting the trans-
fusion of these rings.
(17) A full tabulation of proton resonances for compounds 2 and 3,
including assignments and coupling partners, as well as 13C reso-
nances, including assignments and multiplicities, are included in the
supporting information. Copies of the spectra used to assign the
resonances, including HETCOR, DEPT, and COSY studies, are also
included.
(18) Some recent examples: Boyle, F. T.; Matusiak, Z. S.; Hares,
O.; Whiting, D. A. Synthesis of tricyclospirodienones via spiroannu-
lation: methodology for synthesis of aromatase inhibitors. J . Chem.
Soc., Chem. Commun. 1990, 518-519. Haack, R. A.; Beck, K. R.
Synthesis of substituted spiro[4.5]deca-3,6,9-triene-2,8-diones: an
expeditious route to the spiro[4.5]decane terpene skeleton. Tetrahedron
Lett. 1989, 1605-1608.
However, several pieces of evidence argue against the
intermediacy of 20. Only trans-fused (1 and 2) or
substituted (16) products are obtained with either acid
catalyst; it is unlikely that 20 could exhibit this high level
of stereospecificity, requiring exclusive pseudo-equatorial
attack on the secondary carbocation. Furthermore, the

Synthesis of an Azasteroid
J . Org. Chem., Vol. 61, No. 20, 1996 6977
and the solvent was removed under vacuum. The residue was
flash chromatographed on a 19.5 × 7 cm silica gel column and
eluted with hexane to yield 7.74 g (66%) of a pale oil. MS (EI)
m/z: 334, 277. High resolution calculated: 334.0156.
Found: 334.0153. IR (thin film): 2957, 1597, 1574, 1479,
inability to influence the ratio of products 1, 2, and 16
by varying the ability of cationic oxonium intermediates
such as 6 to be neutralized, by substituting a silyl (14)
or MOM (15) ether in place of the methyl ether (4) in
the formic acid-catalyzed reaction, suggests that the
reaction is proceeding through an early transition state,
leading to direct partitioning to the observed products.
This is in agreement with prior work where results from
biomimetic cationic polyene cyclizations19 and biomimetic
tandem heterocyclizations20 suggest a very high degree
of synchronicity in the tandem cyclizations.
Therefore it is likely that the change in catalyst from
formic acid to boron trifluoride etherate results in dif-
ferent rates for path a versus path b and that intermedi-
ate 6 is not being generated in the presence of boron
trifluoride etherate. Implicit in this explanation is that
the acid catalysts are performing more of a role than
simply catalyzing the formation of the acyl iminium ion
5.
In conclusion, this unusual selectivity allows for the
synthesis of a full azasteroid skeleton, wherein four
contiguous asymmetric centers are generated in one step.
With the ability to substitute a chlorine for the C-19 axial
methyl, resulting in a mildly electrophilic oxidizing
species, this approach may prove useful in the rapidly
developing field of drug inhibition of steroid biosynthesis
pathways.
1464, 1410 cm-1
.
1H NMR (300 MHz, CDCl3): 7.22 (d, 1H, J
) 8.6), 6.90 (d, 1H, J ) 2.9), 6.72 (dd, 1H, J ) 8.7, 2.9), 4.51
(s, 2H), 0.97 (s, 9H), 0.19 (s, 6H). Anal. Calcd for C13H20
-
BrClOSi: C: 46.51, H: 6.00, Cl: 10.56, Br: 23.80. Found:
C: 46.15, H: 6.11, Cl: 10.24, Br: 23.92.
Eth yl 3-[5-(ter t-Bu tyld im eth ylsiloxy)-2-ch lor op h en yl]-
p r op ion a te (10). Ethyl acetate (8.4 mL, 86 mmol) was added
to LDA (1 equiv) in THF (100 mL) at -78 °C. After 10 min,
9 (29 g, 86 mmol) in THF (50 mL) was added. The solution
was allowed to warm to -35 °C and stir for 3 h. The reaction
was quenched with aqueous HCl and extracted with diethyl
ether. The organic layer was washed successively with water,
aqueous sodium bicarbonate, and brine and was dried over
sodium sulfate. The product was flash chromatographed on
a 22 × 7 cm silica gel column and eluted with 5% methylene
chloride in hexane to yield 21 g (72%) of an oil. MS (EI) m/z:
342, 297, 239. High resolution calculated: 242.1418; found:
342.1417. IR (thin film): 1738, 1598, 1574, 1477 cm-1
;
1H
NMR (300 MHz, CDCl3): 7.00 (d, 1H, J ) 8.6), 6.55 (d, 1H, J
) 2.9), 6.46 (dd, 1H, J ) 8.6, 2.9), 3.96 (q, 2H, J ) 7.2), 2.81
(t, 2H, J ) 7.8), 2.43 (t, 2H, J ) 7.8), 1.07 (t, 3H, J ) 7.1),
0.79 (s, 9H), 0.00 (s, 6H). Anal. Calcd for C17H27ClO3Si: C:
59.45, H: 7.94. Found: C: 59.51, H: 8.03.
3-[5-(ter t-Bu tyld im eth ylsiloxy)-2-ch lor oben zen e]p r o-
p ion a ld eh yd e (11). Ester 10 (28.7 g, 83.71 mmol) in diethyl
ether (100 mL) was added to lithium aluminum hydride (3.34
g, 83.71 mmol) in diethyl ether (50 mL) at 0 °C. The ice bath
was removed, and after 90 min, it was reapplied. Water (3
mL), 15% aqueous sodium hydroxide (3 mL), and water (10
mL) were added and the slurry stirred at 25 °C for 10 min.
The slurry was filtered and dried over sodium sulfate, and the
solvent was removed under vacuum to yield 23.7 g (94%) of
the alcohol as a clear oil. 1H NMR (300 MHz, CDCl3): 6.99
(d, 1H, J ) 8.6), 6.54 (d, 1H, J ) 2.9), 6.44 (dd, 1H, J ) 8.6,
2.9), 3.51 (m, 2H), 2.57 (m, 2H), 1.69 (m, 2H), 1.21 (s, 1H),
0.80 (s, 9H), 0.00 (s, 6H). Oxalyl chloride (7.6 g, 86.64 mmol)
was added to DMSO (12.3 mL, 173.3 mmol) in methylene
chloride in a -78 °C bath. After 15 min, the alcohol (23.7 g,
78.8 mmol) was added, followed by triethylamine (54.9 mL,
393.9 mmol), and the slurry was allowed to warm to 25 °C.
The solution was partitioned between water and diethyl ether.
The organic layer was washed with 2 N hydrochloric acid,
water, aqueous sodium bicarbonate, and brine. It was dried
over sodium sulfate, and the solvent was removed under
vacuum to yield 23.6 g (100% crude) of a pale yellow oil. High
resolution calculated: 300.1312; found: 300.1312. IR (thin
Exp er im en ta l Section
Gen er a l. Analytical TLC was performed on Analtech 10
× 20 cm (250 µm) silica gel prescored glass plates. Flash
column chromatography was performed with silica gel 60
(230-400 mesh) from EM Science. THF and dioxane were
distilled from benzophenone ketyl prior to use. All reactions
were performed under nitrogen atmosphere. Melting points
are uncorrected. Elemental analyses reported for the tandem
cyclization products are within 0.4% of the calculated values,
except for compound 3 which degraded upon storing. The
structures of compounds 2 and 3 were determined using 1H
NMR, carbon-hydrogen correlation (HETCOR), carbon mul-
tiplicity (DEPT), and hydrogen-hydrogen correlation (COSY)
experiments. Copies of these experimental spectra and tabu-
lated NMR assignments are included in the supporting
information.
4-Ch lor o-3-m eth ylph en yl ter t-Bu tyldim eth ylsilyl Eth er
(8). tert-Butyldimethylchlorosilane (5.9 g, 38.2 mmol) was
added to 4-chloro-3-methylphenol (5.0 g, 34.71 mmol) and
imidazole (5.2 g, 76.4 mmol) in DMF (70 mL, 0 °C). The ice
bath was removed and the solution stirred overnight. After
cooling to 0 °C, the solution was quenched with water and
extracted with ether. The ether layer was washed with
hydrochloric acid (2 N), water, aqueous sodium bicarbonate,
and brine and then dried over sodium sulfate, removing the
solvent under vacuum to yield 8.92 g (100%) of a clear oil. MS
(EI) m/z: 256, 199. High resolution calculated: 256.1050;
found: 256.1052. IR (thin film): 2958, 1598, 1577, 1480, 1464
film): 3346, 2931, 1597, 1573, 1477, 1448 cm-1
.
1H NMR (300
MHz, CDCl3): 9.64 (s, 1H), 7.00 (d, 1H, J ) 8.6), 6.54 (d, 1H,
J ) 2.9), 6.46 (dd, 1H, J ) 8.6, 2.9), 2.80 (t, 2H, J ) 7.5), 2.60
(t, 2H, J ) 7.4), 0.79 (s, 9H), 0.00 (s, 6H). Anal. Calcd for
C15H25ClO2Si: C: 59.88, H: 8.37. Found: C: 59.84, H: 8.53.
5-(ter t-Bu tyld im eth ylsilyloxy)-2-ch lor o-r-eth en ylben -
zen ep r op a n ol (12). Aldehyde 11 (23.6 g, 78.8 mmol) in THF
(25 mL) was added to vinylmagnesium bromide (168 mL, 118.1
mmol, 0.70 M in THF) at 0 °C. The ice bath was removed
and after 2 h replaced, and aqueous ammonium chloride was
added. The mixture was partitioned between diethyl ether
and 2 N hydrochloric acid. The organic layer was washed with
water, aqueous sodium bicarbonate, and brine. It was dried
over sodium sulfate, and the solvent was removed under
vacuum to yield 24.4 g (95%) of a dark yellow oil. MS (EI)
m/z: 326, 291, 269. IR (thin film): 3363, 1597, 1573, 1477
cm-1
.
1H NMR (300 MHz, CDCl3): 6.98 (d, 1H, J ) 8.6), 6.53
(d, 1H, J ) 2.8), 6.42 (dd, 1H, J ) 8.6, 2.8), 2.12 (s, 3H), 0.79
(s, 9H), 0.00 (s, 6H). Anal. Calcd for C13H21ClOSi C: 60.79,
H: 8.24. Found: C: 60.99, H: 8.07.
3-(Br om om eth yl)-4-ch lor op h en yl ter t-Bu tyld im eth yl-
silyl Eth er (9). Benzoyl peroxide (0.43 g, 1.74 mmol) was
added to 8 (8.9 g, 34.71 mmol) and N-bromosuccinimide (6.9
g, 38.18 mmol) in carbon tetrachloride (25 mL) and refluxed
for 2 h. The mixture was filtered through diatomaceous earth,
cm-1
.
1H NMR (300 MHz, CDCl3): 6.99 (d, 1H, J ) 8.6), 6.55
(d, 1H, J ) 2.9), 6.44 (dd, 1H, J ) 8.6, 2.9), 5.74 (ddd, 1H, J )
17.0, 10.4, 6.1), 5.12 (dt, 1H, J ) 17.1, 0.7), 4.97 (dt, 1H, J )
10.4, 0.6), 3.98 (q, 1H, J ) 6.2), 2.58 (m, 2H), 1.64 (m, 2H),
1.48 (s, 1H), 0.79 (s, 9H), 0.00 (s, 6H).
(19) Bartlett, P. A.; Brauman, J . I.; J ohnson, W. S.; Volkman, R. A.
Concerning the mechanism of nonenzymatic biogenetic-like olefin
cyclizations. J . Am. Chem. Soc. 1973, 95, 7502-7504.
(20) Dijkink, J .; Speckamp, W. N. Biomimetic heterocyclization of
aryl olefins one step formation of two carbon-carbon bonds. Tetrahedron
1987, 34, 173-178.
(E)-6-[5-(ter t-Bu tyld im eth ylsilyloxy)-2-ch lor op h en yl]-
h ex-3-en eca r boxylic Acid (13). Triethyl orthoacetate (44.6
mL, 235.8 mmol), propionic acid (0.35 mL, 4.72 mmol), and
12 (25.7 g, 78.6 mmol) were heated for 1 h while ethanol was

6978 J . Org. Chem., Vol. 61, No. 20, 1996
Romero et al.
distilled off. The solution was heated at 160 °C for another 1
h. The reaction was partitioned between ether and water, the
ether layer was washed with saturated aqueous sodium
bicarbonate and brine, and dried over sodium sulfate, and the
solvent was removed under vacuum to yield 30 g (96%) of the
ester as a yellow oil. MS (EI) m/z: 396, 351, 339; IR (thin
film): 1738, 1597, 1573 cm-1; 1H NMR (300 MHz, CDCl3): 6.98
(d, 1H, J ) 8.5), 6.49 (d, 1H, J ) 2.9), 6.43 (dd, 1H, J ) 8.6,
2.9), 5.30 (m, 2H), 3.95 (q, 2H, J ) 7.1), 2.51 (m, 2H), 2.15 (m,
4H), 1.08 (t, 3H, J ) 7.1), 0.79 (s, 9H), 0.00 (s, 6H). Potassium
hydroxide (14.6 g, 226.7 mmol), methanol (150 mL), water (15
mL), THF (35 mL), and the ester (30.0 g, 75.6 mmol) were
stirred at room temp for 4 h, and the solvents were removed
under vacuum. The residue was partitioned between water
and diethyl ether. The water layer was acidified with hydro-
chloric acid to pH 2 at 0 °C and extracted with diethyl ether.
The ether layer was washed with water and brine and dried
over sodium sulfate. The solvent was removed under vacuum
to yield a yellow solid. 1H-NMR analysis of the crude material
indicated that a significant amount of the tert-butyldimeth-
ylsilyl protecting group had come off. The crude product was
combined with imidazole (22.8 g, 332.4 mmol) and DMF (150
mL), and tert-butyldimethylsilyl chloride (25.8 g, 166.2 mmol)
was added at 0 °C, the ice bath was removed, and the reaction
was stirred overnight at 25 °C. Ice was then added, followed
by water and diethyl ether. The ether layer was washed with
2 N hydrochloric acid, water, and brine. It was dried over
sodium sulfate, and the solvent was removed under vacuum.
Methanol (150 mL) was added and stirred 2 days. The solvent
was removed under vacuum to yield 25.2 g (90%) of an amber
oil. MS (FAB) m/z: 369, 353, 351. IR (thin film): 3001, 1712,
were stirred for 45 min, and then chloromethyl methyl ether
(1.36 mL, 17.91 mmol) was slowly added (0 °C) to the mixture.
After 10 min, the ice bath was removed and after 21.5 h,
diethyl ether, and water were added. The ether layer was
washed with water and brine and dried over sodium sulfate
to yield an amber oil, 6.01 g. The oil was flash chromato-
graphed on a 20 × 2.0 cm silica gel column, eluting with 12%
ethyl acetate in hexane to yield 3.57 g (61%) of a pale oil. MS
(EI) m/z: 341, 309, 274. IR (thin film): 3419, 3345, 1707, 1478
cm-1
.
1H NMR (300 MHz, CDCl3): 7.24 (d, 1H, J ) 8.7), 6.89
(d, 1H, J ) 2.9), 6.83 (dd, 1H, J ) 8.7, 2.9), 5.52 (m, 1H), 5.40
(m, 1H), 5.14 (s, 2H), 4.67 (br, 1H), 4.10 (m, 2H), 3.47 (s, 3H),
3.19 (m, 2H), 2.75 (m, 2H), 2.32 (m, 2H), 2.18 (m, 2H), 1.24 (t,
3H, J ) 7.1).
Acyl Im in iu m Ion Cycliza tion of (E)-[6-(2-Ch lor o-5-
m eth oxyp h en yl)-3-h exen yl]ca r ba m ic Acid , Eth yl Ester
(4). Paraformaldehyde (0.095 g, 3.2 mmol) was added to a
solution of 4 (0.90 g, 2.89 mmol) in formic acid (6 mL). The
solution was heated to 55 °C and stirred for 2 h. Most of the
formic acid was removed in vacuo, and the residue was flash
chromatographed on a 22 × 2 cm silica gel column, eluting
with 10% and then 15% ethyl acetate in hexane to afford 0.37
g (41%) of 1, 0.32 g (34%) of 2, and 0.21 g (20%) of 16.
(4a r,10bâ)-7-Ch lor o-10-m eth oxy-1,2,3,4,4a ,5,6,10b-octa h y-
d r ob en z[f]isoq u in olin e-3-ca r b a m ic a cid , et h yl est er
(1): MS (EI) m/z: 323, 294, 288, 250. High resolution
calculated: 323.1288; found: 323.1288. IR (Nujol): 1693,
1441, 1431 cm-1
.
1H NMR (300 MHz, CDCl3): 7.18 (d, 1H, J
) 8.7), 6.65 (d, 1H, J ) 8.7), 4.22 (m, 4H), 3.79 (s, 3H), 2.96
(m, 3H), 2.62 (m, 3H), 1.83 (m, 1H), 1.50 (m, 1H), 1.27 (m,
4H), 1.09 (m, 1H). 13C NMR DEPT (75 MHz, CDCl3): 157.33
C, 155.53 C, 136.74 C, 129.26 C, 126.90 CH, 126.20 C, 109.03
CH, 61.08 CH2, 55.06 CH3, 50.08 CH2, 44.80 CH2, 41.82 CH,
40.84 CH, 30.27 CH2, 28.94 CH2, 25.67 CH2, 14.63 CH3.
Anal. Calcd for C17H22ClNO3 C: 63.06, H: 6.85, N: 4.33, Cl:
10.95. Found: C: 62.97, H: 6.93, N: 4.28, Cl: 10.99.
(4ar,10ar,10bâ)-10a-Ch lor o-1,4,4a,5,6,8,10a,10b-octah ydr o-
8-oxoben zo[f]isoqu in olin e-3(2H)-ca r ba m ic a cid , eth yl
ester (2): MS (EI) m/z: 309, 274, 263. IR (Nujol): 1683, 1670,
1
1597, 1573, cm-1; H NMR (300 MHz, CDCl3): 6.98 (d, 1H, J
) 8.6), 6.49 (d, 1H, J ) 2.9), 6.43 (dd, 1H, J ) 8.6, 2.9), 5.30
(m, 2H), 2.52 (m, 2H), 2.23 (m, 2H), 2.14 (m, 4H), 0.79 (s, 9H),
0.00 (s, 6H).
(E)-[6-[5-(ter t-Bu tyld im eth ylsilyloxy)-2-ch lor op h en yl]-
3-h exen yl]ca r ba m ic Acid , Eth yl Ester (14). Triethylamine
(9.5 mL, 68.2 mmol) was added to 13 (25.2 g, 68.2 mmol) and
diphenyl phosphorazidate (15.0 mL, 68.2 mmol) in 1,4-dioxane
(225 mL). After 30 min at room temp, it was refluxed for 40
min, and ethanol (40 mL, 682 mmol) was added. Refluxing
continued overnight after which the solvent was removed
under vacuum. The residual oil was partitioned between
diethyl ether and water. The ether layer was washed with
water, 2 N hydrochloric acid, aqueous sodium bicarbonate, and
brine. It was dried over sodium sulfate, and the solvent was
removed under vacuum. The residue was flash chromato-
graphed on a 20 × 4.7 cm silica gel column and eluted with
10% ethyl acetate in hexane to yield a light amber oil, 13.45
g (48%). MS (EI) m/z: 411, 383, 354. IR (thin film): 3429,
1663, 1449, 1439 cm-1
.
1H NMR (300 MHz, CDCl3, 50 °C):
7.08 (d, 1H, J ) 10.1), 6.23 (dd, 1H, J ) 10.1, 2.0), 6.10 (d,
1H, J ) 2.0), 4.30 (br, 2H), 4.15 (q, 2H, J ) 7.1), 2.91 (m, 1H),
2.72 (br, 1H), 2.45 (m, 1H), 2.37 (br, 1H), 1.82-2.08 (m, 4H),
1.46 (m, 1H), 1.28 (t, 3H, J ) 7.1), 1.19 (m, 1H). 13C NMR
DEPT (75 MHz, CDCl3): 184.6 C, 159.8 C, 155.1 C, 146.4 CH,
127.1 CH, 124.3 CH, 66.2 C, 61.4 CH2, 50.9 CH, 48.75 CH2,
43.2 CH2, 35.4 CH, 31.4 CH2, 31.0 CH2, 26.3 CH2, 14.6 CH3.
Anal. Calcd for C16H20ClNO3: C: 62.03, H: 6.51, Cl: 11.44,
N: 4.52. Found: C: 61.72, H: 6.45, Cl: 11.52, N: 4.62.
tr a n s-4-(F or m yloxy)-3-[(2-ch lor o-5-m eth oxyp h en yl)eth -
yl]p ip er id in e-1-ca r ba m ic a cid , eth yl ester (16): MS (EI)
m/z: 334, 324, 288, 250. High resolution calculated: 369.1343;
3343, 1710, 1596, 1573 cm-1
.
1H NMR (300 MHz, CDCl3): 6.99
(d, 1H, J ) 8.6), 6.50 (d, 1H, J ) 2.9), 6.44 (dd, 1H, J ) 8.5,
2.9), 5.34 (m, 1H), 5.21 (M, 1H), 4.44 (br, 1H), 3.93 (q, 2H, J )
7.1), 3.00 (q, 2H, J ) 6.2), 2.53 (m, 2H), 2.12 (q, 2H, J ) 7.7),
2.00 (q, 2H, J ) 6.7), 1.06 (t, 3H, J ) 7.1), 0.79 (s, 9H), 0.00 (s,
6H).
found: 369.1350. IR (thin film): 1723, 1698, 1478, 1435 cm-1
.
1H NMR (300 MHz, CDCl3): 8.09 (s, 1H), 7.23 (d, 1H, J ) 8.7),
6.75 (d, 1H, J ) 2.9), 6.69 (dd, 1H, J ) 8.7, 3.0), 4.87 (m, 1H),
4.15 (q, 2H, J ) 7.1), 3.88 (m, 1H), 3.78 (s, 3H), 3.20 (br, 1H),
3.02 (br, 1H), 2.78 (m, 1H), 2.69 (m, 1H), 1.99 (m, 1H), 1.77
(m, 2H), 1.52 (m, 2H), 1.28 (t, 3H, J ) 7.1). Anal. Calcd for
C18H24ClNO5: C: 58.57, H: 6.55, N: 3.79, Cl: 9.60. Found:
C: 58.48, H: 6.73, N: 3.82, Cl: 9.56.
(E)-[6-(2-Ch lor o-5-m eth oxyp h en yl)-3-h exen yl]ca r ba m -
ic Acid , Eth yl Ester (4). Iodomethane (0.84 mL, 13.35 mmol)
was added to potassium fluoride (1.42 g, 24.27 mmol), 14 (5.0
g, 12.13 mmol), and DMF (25 mL) at 0 °C. After 15 min, the
ice bath was removed and after 27 h, diethyl ether and water
were added. The ether layer was washed with water and brine
and dried over sodium sulfate to yield a yellow oil, 3.65 g. The
oil was flash chromatographed on a 19 × 2.0 cm silica gel
column, eluting successively with 10%, 15%, and 20% ethyl
acetate in hexane to yield 2.39 g (63%) of a pale oil. 1H NMR
(300 MHz, CDCl3): 7.24 (d, 1H, J ) 8.7), 6.74 (d, 1H, J ) 3.0),
6.69 (dd, 1H, J ) 8.7, 3.0), 5.55 (m, 1H), 5.39 (m, 1H), 4.62
(br, 1H), 4.11 (m, 2H), 3.78 (s, 3H), 3.19 (m, 2H), 2.75 (m, 2H),
2.32 (m, 2H), 2.21 (m, 2H), 1.24 (t, 3H, J ) 7.1). IR (thin
film): 3341, 1719, 1597 cm-1. MS (EI) m/z: 311, 276. Anal.
Calcd for C16H22NO3Cl C: 61.63, H: 7.11, N: 4.49. Found:
C: 61.97, H: 7.35, N: 4.17.
(E)-[6-(2-Ch lor o-5-m et h oxyp h en yl)-3-h exen yl]a m in e
(17). Carbamate 4 (2.4 g, 7.66 mmol) was refluxed with
potassium hydroxide (2.97 g, 46.0 mmol), ethanol (20 mL), and
water (2 mL) for 48 h. The solvent was removed under vacuum
and the residue partitioned between diethyl ether and water.
The ether layer was washed with water and brine and dried
over sodium sulfate to yield 1.85 g (100%, crude) of a yellow
oil. 1H NMR (300 MHz, CDCl3): 7.23 (d, 1H, J ) 8.7), 6.74
(d, 1H, J ) 3.0), 6.68 (dd, 1H, J ) 8.7, 3.0), 5.53 (m, 1H), 5.40
(m, 1H), 3.77 (s, 3H), 2.72 (m, 4H), 2.34 (q, 2H, J ) 7.3), 2.12
(q, 2H, J ) 6.6), 1.18 (br, 2H).
(E)-1-[6-(2-Ch lor o-5-m et h oxyp h en yl)-3-h exen yl]-2,5-
p yr r olid in ed ion e (18). Succinic anhydride (0.87 g, 8.43
mmol) was added to 17 (1.84 g, 7.66 mmol) in THF (20 mL) at
0 °C. After the succinic anhydride was fully dissolved, the ice
bath was removed and after 2.75 h, 1,3-dicyclohexylcarbodi-
(E)-[6-[2-Ch lor o-5-(m eth oxym eth yloxy)p h en yl]-3-h ex-
en yl]ca r ba m ic Acid , Eth yl Ester (15). Potassium fluoride
(2.0 g, 34.12 mmol), 14 (7.0 g, 17.06 mmol), and DMF (35 mL)

Synthesis of an Azasteroid
J . Org. Chem., Vol. 61, No. 20, 1996 6979
imide (1.60 g, 7.66 mmol) was added. The mixture was stirred
overnight and then was filtered through diatomaceous earth,
and the solvent was removed under vacuum to yield an amber
semisolid. This was flash chromatographed through a 23 ×
2.2 cm silica gel column and eluted with 66% ethyl acetate in
hexane followed by 90% methylene chloride in methanol. The
seco-imide was obtained as a solid, 1.69 g (65%), mp 86.0-
87.0 °C. MS (EI) m/z: 339, 222, 155. IR (Nujol): 3300, 1695,
(q, 2H, J ) 7.0), 3.08 (m, 1H), 2.73 (m, 2H), 2.49 (m, 1H), 2.4-
2.0 (m, 6H), 1.96 (m, 1H), 1.23 (t, 3H, J ) 7.0).
(4a r,4bâ,10a â,10br)-4a -Ch lor o-4a ,4b,5,6,9,10,10a ,10b,-
11,12-d eca h yd r oben zo[f]p yr r olo[2,1-a ]isoqu in olin e-2,8-
d ion e (3). Formic acid (7 mL) was added to 19 (0.46 g, 1.3
mmol) at 25 °C. After 18 h, solvents were removed under
vacuum and the residue was partitioned between diethyl ether
and saturated aqueous sodium bicarbonate. The organic layer
was washed with brine and dried over sodium sulfate to yield
0.40 g of white foam. This was flash chromatographed on a
22 × 1.2 cm silica gel column, eluting with 10% methanol
(saturated with ammonia) in methylene chloride to yield 0.11
g (30% yield) of the title compound as a white foam, mp 112
°C dec. MS (FAB) m/z: 294, 292, 258. High resolution
calculated: 292.1104; found: 292.1090. IR (Nujol): 1686,
1639, 1555, 1478 cm-1
.
1H NMR (300 MHz, CDCl3) 7.24 (d,
1H, J ) 8.7), 6.75 (d, 1H, J ) 3.0), 6.69 (dd, 1H, J ) 8.7, 3.0),
5.82 (br, 1H), 5.54 (m, 1H), 5.35 (m, 1H), 3.78 (s, 3H), 3.26 (q,
2H, 6.3), 2.75 (t, 2H, 7.6), 2.69 (t, 2H, 6.6), 2.47 (t, 2H, 6.5),
2.34 (q, 2H, 7.5), 2.19 (t, 2H, 6.5). Anal. Calcd for C17H22
-
ClNO4: C, 60.09; H, 6.53; N, 4.12. Found: C, 60.26; H, 6.68;
N, 4.20. To effect cyclization to the imide, acetyl chloride (40
mL), and the seco-imide (1.18 g, 3.47 mmol) were refluxed 20
h. Another 40 mL portion of acetyl chloride was added and
the solution refluxed an additional 4 h. Solvents were removed
under vacuum, and the residue was flash chromatographed
on a 23 × 2.2 cm silica gel column, eluting with 33% ethyl
acetate in hexane to yield 0.78 g (70%) of the imide. MS (EI)
m/z: 321, 286, 222, 207. 1H NMR (300 MHz, CDCl3): 7.23 (d,
1H, J ) 8.6), 6.73 (d, 1H, J ) 2.9), 6.68 (dd, 1H, J ) 8.7, 2.9),
5.52 (m, 1H), 5.40 (m, 1H), 3.78 (s, 3H), 3.54 (t, 2H, J ) 7.2),
2.70 (m, 2H), 2.68 (s, 4H), 2.28 (q, 4H, J ) 7.0). Anal. Calcd
for C17H20NO3: C: 71.31, H: 7.04, N: 4.89. Found: C: 71.72,
H: 7.43, N: 4.66.
1666, 1633, 1609 cm-1
.
1H NMR (300 MHz, CDCl3): 7.10 (d,
1H, J ) 10.1), 6.24 (dd, 1H, J ) 10.1, 1.9), 6.12 (dd, 1H, J )
1.8, 1.8), 4.26 (ddd, 1H, J ) 13.4, 5.0, 2.0), 3.07 (dt, 1H, J )
9.8, 7.3), 2.89 (dddd, 1H, J ) 13.7, 13.7, 5.2, 1.7), 2.67 (ddd,
1H, J ) 13.3, 13.3, 3.7), 2.49 (ddd, 1H, J ) 13.5, 4.4, 2.5), 2.43
(m, 1H), 2.37 (ddd, 1H, J ) 17.0, 9.1, 1.5), 2.28 (dddd, 1H, J )
9.0, 7.3, 7.3, 3.8), 2.07 (dddd, 1H, J ) 13.0, 5.4, 3.7, 2.6), 1.95
(dddd, 1H, J ) 13.0, 3.4, 3.4, 2.0), 1.83 (dddd, 1H, J ) 12.9,
12.9, 11.0, 5.0), 1.76-1.66 (m, 2H), 1.58 (ddd, 1H, J ) 11.0,
10.9, 3.3), 1.20 (dddd, 1H, J ) 13.3, 13.3, 12.0, 4.4). 13C NMR
DEPT (75 MHz, CDCl3): 184.38 C, 173.20 C, 159.21 C, 146.32
CH, 127.22 CH, 124.37 CH, 66.06 C, 60.64 CH, 49.98 CH, 42.52
CH, 38.43 CH2, 31.13 CH2, 30.19 CH2, 29.39 CH2, 25.37 CH2,
23.85 CH2.
(E)-1-[6-(2-Ch lor o-5-m eth oxyp h en yl)-3-h exen yl]-5-h y-
d r oxy-2-p yr r olid in on e (19). Sodium borohydride (0.55 g,
14.14 mmol) was added to 18 (0.65 g, 2.02 mmol) in ethanol
(50 mL) at 0 °C followed by chlorotrimethylsilane (2.6 mL in
7.4 mL ethanol, five drops every 15 min over a period of 4 h).
The remaining amount of the chlorotrimethylsilane in ethanol
was then added and stirred 75 min. The white slurry was
poured into aqueous sodium bicarbonate and extracted with
chloroform (4 × 400 mL). The organic layer was washed with
water and brine and then dried over sodium sulfate to yield
0.65 g of pale amber oil. This oil was flash chromatographed
on a 1.2 × 22 cm silica gel column, eluted with 33% and 50%
ethyl acetate in hexane to yield 0.46 g (65%) of a clear oil. MS
(EI) m/z: 351, 306, 222, 196. IR (thin film): 1699, 1597, 1576
Su p p or tin g In for m a tion Ava ila ble: Two charts contain-
ing the assignment of all of the proton chemical shifts, J
values, coupling assignments, and 13C NMR assignments of
compounds 2 and 3, as well as reproductions of the spectra
from the NMR experiments (1H, 13C, HETCOR, and COSY
NMR) used in this determination. Reproductions of the 1H
NMR spectra for compounds 1, 4, 16, 18, and 19 are also
included (18 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
cm-1
.
1H NMR (300 MHz, CDCl3): 7.23 (d, 1H, J ) 8.7), 6.74
(d, 1H, J ) 3.0), 6.68 (dd, 1H, J ) 8.7, 3.0), 5.54 (m, 1H), 5.43
(m, 1H), 4.96 (d, 1H, J ) 5.0), 3.78 (s, 3H), 3.56 (m, 1H), 3.46
J O960673T