Syntheses of strychnan- and aspidospermatan-type alkaloids. 11. Total syntheses of (-)-lochneridine and (-)- and racemic 20-epi-lochneridine

Article abstract of DOI:10.1021/jo981401o

Enantioselective syntheses of (-)-lochneridine (1) and (-)-epi- lochneridine (2) were obtained by two alternative C-20 diastereoselective syntheses of the respective pentacyclic (3aS,5S,11bR)-methyl 12-oxo-3,5- ethanol-2,3,3a,4,5,7-hexahydro-3H-pyrrolo[2,3-d]carbazole-6-carboxylate ((- )-8) and tetracyclic methyl (2S,3aS,5R,11bR))-3-benzyl-2,3,3a,4,5,7- hexahydro-5-(2-(1-butenyl))-1H-pyrrolo[2,3-d]carbazole-6-carboxylate ((-)- 12b) precursors from tryptophan derived 2-[(methoxycarbonyl)methyl]-3-[2(S)- (methoxy or benzyloxycarbonyl)-2-(N(b)-benzyl)aminoethyl]indole (15 or 16). While a modified Grignard reaction of the ketone (-)-8 provided (-)- lochneridine (1), dihydroxylation and cyclization of the olefin ()-12b gave its C-20 epimer (2).

Full text of DOI:10.1021/jo981401o

9434
J . Org. Chem. 1998, 63, 9434-9439
Syn th eses of Str ych n a n - a n d Asp id osp er m a ta n -Typ e Alk a loid s. 11.
Tota l Syn th eses of (-)-Loch n er id in e a n d (-)- a n d Ra cem ic
20-epi-Loch n er id in e
Martin E. Kuehne* and Feng Xu
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received J uly 17, 1998
Enantioselective syntheses of (-)-lochneridine (1) and (-)-epi-lochneridine (2) were obtained by
two alternative C-20 diastereoselective syntheses of the respective pentacyclic (3aS,5S,11bR)-methyl
12-oxo-3,5-ethano-2,3,3a,4,5,7-hexahydro-3H-pyrrolo[2,3-d]carbazole-6-carboxylate ((-)-8) and tet-
racyclic methyl (2S,3aS,5R,11bR))-3-benzyl-2,3,3a,4,5,7-hexahydro-5-(2-(1-butenyl))-1H-pyrrolo[2,3-
d]carbazole-6-carboxylate ((-)-12b) precursors from tryptophan derived 2-[(methoxycarbonyl)methyl]-
3-[2(S)-(methoxy or benzyloxycarbonyl)-2-(Nb-benzyl)aminoethyl]indole (15 or 16). While a modified
Grignard reaction of the ketone (-)-8 provided (-)-lochneridine (1), dihydroxylation and cyclization
of the olefin (-)-12b gave its C-20 epimer (2).
The alkaloid (-)-lochneridine (1)1 was isolated from
Catharanthus roseus2 and its 20-hydroxy epimer (2) has
been obtained by oxidation of the C-19,20 double bond
in akuammicine (3).3 The enantiomer of that oxidation
product, (+)-20-epi-lochneridine (3,7,15-epi-lochneridine,
4), an alkaloid isolated from Tabernaemontana panda-
caqui,4 represents an interesting example of a natural
skeletal enantiomerism in strychnan-type alkaloids that
has been synthetically achieved in analogous examples
by their thermal isomerization.5,6 The present paper
describes enantioselective total syntheses of (-)-lochne-
ridine (1) and (-)-20-epi-lochneridine (2), and since the
former (easily)1 and the latter (sparingly)3 have been
shown to undergo dehydration to akuammicine (3), these
syntheses also provide enantioselective routes to that
alkaloid (Scheme 1).
Sch em e 1
Synthetic access to (-)-lochneridine (1) and its C-20
epimer (2) seemed relatively simple by extension of
transformations of the tetracyclic aldehyde 57 to an ethyl
ketone 6, i.e., by its reaction with a sulfur ylide and
cyclization of a resulting epoxide followed by Nb-deben-
zylation. An analogous construction of a ring D C-20
alcohol had been obtained directly from the aldehyde 5
in our first synthesis of racemic strychnine.7 However,
the ring D annelation starting from the ketone 6 could
not be realized, and we were also not able to cyclize an
Nb-(phenylthio)methyl ketone 7 (Scheme 2).
bromide led only to destruction of the starting material,
and no substantial amounts of characterizable products
were obtained. However, softening of the Grignard
reagent by addition of ceric chloride, with a reaction at
-78 °C, resulted in a 73% yield of a tertiary alcohol with
complete diastereoselection for the formation of (-)-
lochneridine (1). 1H NMR NOE interaction of a C-14
methylene bridge hydrogen at δ 2.10 with the C-19
methylene hydrogens of the ethyl substituent at δ 1.80
established the stereochemistry of the C-20 alcohol.
To obtain the relative stereochemistry of 20-epi-loch-
neridine (2), a new synthetic pathway was required. This
was established in reaction sequences leading to racemic
and to (-)-20-epi-lochneridine (Scheme 4).
Consequently, we turned to the sensitive pentacyclic
ketone intermediate (-)-8 (Scheme 2) of our second
strychnine synthesis.8 Its reaction with ethylmagnesium
From the foregoing results, it seemed desirable to
generate a tetracyclic intermediate that incorporates all
carbon atoms of the final alkaloid skeleton and that
would allow stereoselective introduction of the C-20
hydroxyl function. To that end, 2-ethylacrolein was
converted by a Horner-Emmons condensation (Scheme
3) to 1-(ethoxycarbonyl)-3-ethylbutadiene (9).9 Its reduc-
tion to the corresponding allylic alcohol and a PCC
oxidation provided the diene aldehyde 10. A condensation
(1) (a) Nakagawa, Y.; Wilson, J . M.; Budzikiewicz, H.; Djerassi, C.
Chem. Ind. 1962, 1986. (b) Djerassi, C.; Nakagawa, Y.; Wilson, J . M.;
Budzikiewicz, H.; Gilbert, B.; Antonaccio, L. D. Experientia 1963, 19,
467.
(2) Svoboda, G, H.; Gorman, M.; Neuss, N.; Barnes, A. J ., J r. J .
Pharm. Sci. 1961, 50, 409.
(3) Mirand, C.; Massiot, G.; Le Men-Olivier, L.; Le´vy, J . Tetrahedron
Lett. 1982, 23, 1257.
(4) Lathuillere, P.; Olivier, L.; Le´vy, J .; Le Men, J . Ann. Pharm. Fr.
1966, 24, 547.
(5) For C-3,7,15-epimerization of 19,20-dihydroakuammicine, see:
Scott, A. I.; Yeh, C. L. J . Am. Chem. Soc. 1974, 96, 2273.
(6) Kuehne, M. E.; Frasier, D. A.; Spitzer, T. D. J . Org. Chem. 1991,
56, 6, 2696.
(8) Kuehne, M. E.; Xu, F. J . Org. Chem. 1998, 63, 9427.
(9) Sundberg, R. J .; Bukowick, P. A.; Holcombe, F. O. J . Org. Chem.
1967, 32, 2938.
(7) Kuehne, M. E.; Xu, F. J . Org. Chem. 1993, 58, 7490.
10.1021/jo981401o CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/12/1998

Syntheses of Lochneridines
Sch em e 2
J . Org. Chem., Vol. 63, No. 25, 1998 9435
Sch em e 4a
Sch em e 3a
a
Key: (a,b) benzoic acid, benzene, reflux 10 h/18 h, 79%/70%;
(c) MeOH, NH3, rt, 5 d, 75%; (d) TFAA, CH2Cl2, 0 °C to rt, 40
min; (e) KBH4, EtOH, 75-80 °C, 4 h, 74% for d + e; (f) H2/Pd,
HOAc, 91%; (g) HCO2NH4, Pd/C, MeOH, EtOAc, reflux 2 h; (h)
(t-Boc)2O, THF, aqueous K2CO3, 92%; (i) OsO4, pyridine, 0 °C,
NaHSO3, Ts2O, Et3N, rt, 3 h, 62%; (j) TMSOTf, Et3N, rt, 1 h,
MeOH, 50-60 °C, 2 h, 85%; (k) n-Bu4NF, THF, 2 h, rt, 94%.
a
Key: (a) LAH, 90%; (b) PCC, 80%; (c) benzene, benzoic acid,
75 °C, 18 h, 57%.
19, its dehydration to a nitrile 20, and final reduction
with potassium borohydride, furnished the tetracyclic
urethane (-)-12b. The tetracyclic products 17 and 18
were obtained without evidence of alternative stereoiso-
mers. Their relative stereochemistry was evident from
an NOE interaction of a vinyl hydrogen with the meth-
ylene â-hydrogen on the pyrrolidine ring, confirming the
cis configuration of these structural moieties.12
of this aldehyde 10 with 2-(methoxycarbonylmethyl)-Nb-
benzyltryptamine (11),10 catalyzed by benzoic acid, pro-
vided a 10:1 mixture of racemic tetracyclic vinylogous
urethanes 12a and 13a . Formation of the minor isomer
13a appears to be the result of epimerization through
the imonium salt 14a since the minor epimer 13a was
formed, in the same relative ratio, on subjecting the
major tetracyclic product 12a to the initial acidic reaction
conditions.
For an enantioselective synthesis of this tetracyclic
urethane (-)-12b, the aldehyde 10 was condensed with
tryptophan derived 2-[(methoxycarbonyl)methyl]-3-[2(S)-
(methoxy or benzyloxycarbonyl)-2-(Nb-benzyl)aminoeth-
yl]indole (Scheme 4, 15 or 16).8,11 Conversion of the
product tetracyclic urethane esters 17 or 18 to an amide
Hydrogenolysis of the tetracyclic Nb-benzylamines (()-
12a or (-)-12b with Pd/C in acetic acid gave a secondary
amine product without reduction of the terminal double
bond. However, under these acidic conditions, epimer-
ization arose through the imonium salt 21, and the
respective secondary amines (()-22a or (-)-22b and (()-
23a or (+)-23b were formed formed in equal amounts.
(11) Kuehne, M. E.; Xu, F. J . Org. Chem. 1997, 62, 7950.
(12) For 1H NMR signal assignments see supplemental spectra, 17,
and ref 11.
(10) Parsons, R. L.; Berk, J . D.; Kuehne, M. E. J . Org. Chem. 1993,
58, 7482.

9436 J . Org. Chem., Vol. 63, No. 25, 1998
Kuehne and Xu
However, hydrogenolysis of the Nb-benzyl substituent
with Pd/C and ammonium formate in methanol and ethyl
acetate furnished the secondary amines (()-22a or (-)-
22b, respectively, without epimerization.
g (53.6 mmol) of pyridinium chlorochromate in 50 mL of
dichloromethane. After warming to room temperature and
continued stirring for 30 min, the reaction mixture was diluted
with ether and filtered through Florisil. Concentration and
chromatography on a silica gel column, eluting with ether/
hexane, 5:95, provided 2.4 g (80% yield) of 4-ethyl-2,4-penta-
dienal (10) with Rf ) 0.35 (silica gel, ether/hexane, 5:95,
detection UV), which was used directly in the following
condensation.
Protection of the secondary amine function in (()-22a
or (-)-22b with (t-Boc)2O and oxidation of the resulting
olefinic urethane (()-24a or (-)-24b with osmium tetrox-
ide led to the stereoselective formation of a diol (()-25a
or (-)-25b. Its monotosylation at the primary hydroxyl
group ((()-26a or (-)-26b), silylation of the tertiary
alcohol and cyclization on heating, provided the penta-
cyclic TMS ether (()-27a or (-)-27b. Cleavage of the silyl
ether function with fluoride completed the syntheses of
racemic (2a ) and (-)-20-epi-lochneridine ((-)-2b). 1H
NMR NOE interactions of the C-19 methylene hydrogen
of the ethyl substituent at δ 1.39 with a C-5 hydrogen of
the pyrrolidine ring at δ 3.18 established the C-20
tertiary alcohol stereochemistry.
A solution of 2-[(methoxycarbonyl)methyl]]-3-[2-(S)-(meth-
oxycarbonyl)-2-(Nb-benzylamino)ethyl]indole (15,8 1.2 g, 3.15
mmol), 4-ethyl-penta-(2,4)-dienal (10, 382 mg, 3.47 mmol),
benzoic acid (385 mg, 3.154 mmol), and 10 mg of dihydro-
quinone in 25 mL of benzene was heated at reflux with a
Dean-Stark trap. After 5 h, 181 mg of the aldehyde 10 (1.78
mmol) was introduced again. The reaction mixture was cooled
to room temperature after a total of 10 h. The organic phase
was washed with 5% sodium carbonate. The residue, obtained
on drying and concentration, was purified on a silica gel
column, eluted with Et2O/Hex (3:7), to give 1.18 g of the title
product 17 (79% yield): Rf ) 0.39 (Et2O/Hex, 3:7, CAS blue);
An elegant, very different synthesis of racemic 20-epi-
[R]25 -195 (c ) 1.0, MeOH); UV λmax (EtOH) 200, 228, 298,
lochneridine (2a ) was recently reported.13
D
328 nm; IR (KBr) νmax 3363, 1748, 1673, 1607 cm-1; H NMR
1
δ 9.25 (s, 1 H), 7.36 (m, 5 H), 7.11 (t, J ) 7.6 Hz, 1 H), 6.79 (d,
J ) 7.7 Hz, 1 H), 6.74 (t, J ) 7.4 Hz, 1 H), 6.46 (d, J ) 7.4 Hz,
1 H), 4.79 (s, 1 H), 4.71 (s, 1 H), 4.80 (d, J ) 15.2 Hz, 1 H),
4.70 (d, J ) 15.2 Hz, 1 H), 3.74 (s, 3 H), 3.73 (m, 2 H), 3.58 (s,
3 H), 3.53 (d, J ) 5.7 Hz, 1 H), 2.74 (dd, J ) 11.6, 11.6 Hz, 1
H), 2.57 (qd, J ) 7.4, 14.8 Hz, 1 H), 2.21 (m, 2 H), 1.72 (dd, J
) 5.5, 11.6 Hz, 1 H), 1.27 (ddd, J ) 6.1, 6.1, 14.1, Hz, 1 H),
1.14 (t, J ) 7.4 Hz, 3 H); 13C NMR δ 172.7, 168.8, 164.2, 153.7,
142.8, 137.2, 136.2, 130.3, 128.2, 127.9, 127.4, 121.7, 120.5,
109.2, 108.4, 97.4, 65.2, 63.2, 56.5, 54.3, 51.5, 51.0, 45.2, 39.17,
3.4, 27.3, 12.0; MS m/z 473 (4), 472 (M+, 12),414 (11), 381 (15),
268 (34), 236 (18), 212 (11), 208 (25), 202 (10), 194 (12), 180
(14), 167 (11), 91 (100).
Exp er im en ta l Section
(-)-Loch n er id in e (1). To anhydrous CeCl3 (148 mg, 0.58
mmol) in 1 mL of THF at -78 °C was added EtMgBr (129 µL,
0.388 mmol, 3.0 M in Et2O) dropwise. The mixture was stirred
for 30 min. A solution of (3aS,5S,11bR)-methyl 12-oxo-3,5-
ethano-2,3,3a,4,5,7-hexahydro-3H-pyrrolo[2,3-d]carbazole-6-
carboxylate ((-)-8,8 30 mg, 0.097 mmol) in 1 mL of THF was
cannulated into the above mixture. The mixture was stirred
for another 30 min at -78 °C and then warmed to room
temperature. The reaction was quenched by adding 5%
NH4OH. The aqueous phase was extracted with dichlo-
romethane several times. The residue, obtained on drying and
concentration, was chromatographed on a silica gel column,
eluting with CH2Cl2/MeOH (9:1) to afford 24 mg (73% yield)
of (-)-lochneridine: Rf ) 0.29 (CH2Cl2/MeOH, 9:1, CAS blue);
The benzyl ester 18 could be prepared by the same proce-
dure from 2-[(methoxycarbonyl)methyl]-3-[2-(S)-(benzyloxy-
carbonyl)-2-(Nb-benzylamino)ethyl]indole (16)11 in 70% yield
after 18 h of reflux in benzene and purification on a silica gel
column (EtOAc/Hex, 1:9): Rf ) 0.33 (Et2O/Hex, 1:4, CAS blue);
UV λmax (EtOH) 202, 226, 298, 328 nm; IR (KBr) νmax 3364,
1734, 1672, 1608 cm-1; 1H NMR δ 9.22 (s, 1 H), 7.36-7.23 (m,
10 H), 7.09 (t, J ) 7.3 Hz, 1 H), 6.77 (d, J ) 7.6 Hz, 1 H), 6.71
(t, J ) 7.3 Hz, 1 H), 6.43 (d, J ) 7.3 Hz, 1 H), 5.06 (d, J ) 12.1
Hz, 1 H), 4.98 (d, J ) 12.1 Hz, 1 H), 4.65 (s, 2 H), 4.04 (d, J )
13.4 Hz, 1 H), 3.95 (d, J ) 13.4 Hz, 1 H), 3.74 (m, 2 H), 3.71
(s, 3 H), 3.53 (m, 1 H), 2.73 (dd, J ) 11.6, 11.6 Hz, 1 H), 2.42
(m, 1 H), 2.16 (m, 1 H), 2.12 (m, 1 H), 1.74 (dd, J ) 5.5, 11.6
Hz, 1 H), 1.24 (m, 1 H), 1.04 (t, J ) 7.4 Hz, 3 H); MS m/z 473
(4), 472 (M+, 1).
mp 209-211 °C (lit.4 mp 211-214 °C); [R]24 -614 (c ) 0.09,
D
CHCl3), (lit.4 [R]D -608); UV λmax (EtOH) 206, 230, 298, 328
1
nm; IR (KBr) νmax 3365, 1671, 1599 cm-1; H NMR δ 8.82 (s,
1 H), 7.19 (d, J ) 7.4 Hz, 1 H), 7.15 (t, J ) 7.7 Hz, 1 H), 6.92
(t, J ) 7.4 Hz, 1 H), 6.84 (d, J ) 7.8 Hz, 1 H), 3.93 (s, 1 H),
3.82 (s, 3 H), 3.12 (ddd, J ) 6.8, 6.8, 10.5 Hz, 1 H), 3.06 (s, 1
H), 2.99 (m, 1 H), 2.85 (d, J ) 12.1 Hz, 1 H), 2.84 (m, 1 H),
2.64 (s, br, 1 H, OH), 2.44 (d, J ) 12.1 Hz, 1 H), 2.10 (ddd, J
) 3.1, 3.1, 13.6 Hz, 1 H), 1.88 (ddd, J ) 2.2, 6.8, 13.2 Hz, 1 H),
1.80 (m, 2 H), 1.30 (ddd, J ) 1.0, 1.0, 13.6 Hz, 1 H), 1.03 (t, J
) 7.4 Hz, 3 H); 13C NMR δ 169.0, 144.1, 135.1, 127.8, 121.3,
120.1, 109.8, 98.3, 71.2, 59.7, 57.8, 55.8, 53.9, 51.5, 43.7, 37.5,
31.9, 27.6, 7.0; MS m/z 341 (46), 340 (M+, 100), 283 (56), 241
(27), 226 (72), 208 (33), 194 (84), 184 (26), 180 (40), 167 (88),
156 (18), 154 (30), 149 (30), 139 (19), 126 (19), 115 (25), 111
(21). Anal. Calcd for C20H24N2O3: C, 70.57; H, 7.11; N, 8.23.
Found: C, 70.30; H, 7.14; N, 8.22.
Racem ic Meth yl (3aS*,5R*,11bR*)-3-Ben zyl-2,3,3a,4,5,7-
h exa h yd r o-5-(2-(1-bu ten yl))-1H-p yr r olo[2,3-d ]ca r ba zole-
6-ca r b oxyla t e (12a ) a n d Met h yl (3a R*,5R*,11b S*)-3-
Ben zyl-2,3,3a ,4,5,7-h exa h yd r o-5-(2-(1-b u t en yl))-1H -p yr -
r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (13a ). A solution of
2-[(methoxycarbonyl)methyl]]-3-[2-(Nb-benzylamino)ethyl]in-
dole (11, 1.1 g, 3.42 mmol),10 4-ethylpenta-(2,4)-dienal (10, 451
mg, 4.1 mmol), benzoic acid (42 mg, 0.34 mmol), MgSO4 (2 g),
and 10 mg of dihydroquinone, in 25 mL of benzene, was heated
in a 75 °C oil bath. After 5 h, 451 mg of additional aldehyde
(4.1 mmol) was introduced. The reaction mixture was cooled
to room temperature after a total of 18 h. The organic phase
was then washed with 5% sodium carbonate. The residue,
obtained on drying and concentration, was purified on a silica
gel column, eluted with Et2O/Hex (7:93), to give 720 mg of the
title product (12a , 51% yield) and 80 mg of its epimer (13a ,
6% yield).
Meth yl (2S,3a S,5R,11bR)-2-(Meth oxyca r bon yl)-3-ben -
zyl-2,3,3a,4,5,7-h exah ydr o-5-(2-(1-bu ten yl))-1H-pyr r olo[2,3-
d ]ca r ba zole-6-ca r boxyla te a n d Meth yl (2S,3a S,5R,11bR)-
2-(Ben zyloxyca r bon yl)-3-ben zyl-2,3,3a ,4,5,7-h exa h yd r o-
5-(2-(1-b u t en yl))-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r b ox-
yla te (17 a n d 18). A solution of 4.8 g (0.12 mmol) of lithium
aluminum hydride in 15 mL of ether was added to 15.5 g (0.10
mmol) of ethyl 4-ethyl-2,4-pentadienoate,9 in 20 mL of ether,
with stirring at 0 °C. After the reaction was warmed to room
temperature, 10% aqueous sodium hydroxide was added, and
the resulting solution was extracted with ether and concen-
trated, 10.0 g (90% yield) of 4-ethyl-2,4-pentadienol was
obtained.
The crude alcohol (3.00 g, 26.8 mmol) in 25 mL of dichlo-
romethane was added dropwise, with stirring at 0 °C, to 11.5
For the major isomer 12a : Rf ) 0.22 (Et2O/Hex, 3:97, CAS
blue); UV λmax (EtOH) 204, 226, 300, 326 nm; IR (KBr) νmax
3366, 1674, 1609 cm-1; 1H NMR δ 9.28 (s, 1 H), 7.34 (m, 4 H),
7.26 (m, 1 H), 7.14 (m, 2 H), 6.86 (t, J ) 7.5 Hz, 1 H), 6.82 (d,
J ) 7.9 Hz, 1 H), 4.81 (s, 1 H), 4.76 (s, 1 H), 4.17 (d, J ) 13.5
(13) Bonjoch, J .; Sole´, D.; Garcia-Rubio, S.; Bosch, J . J . Am. Chem.
Soc. 1997, 119, 7230.

Syntheses of Lochneridines
J . Org. Chem., Vol. 63, No. 25, 1998 9437
Hz, 1 H), 3.74 (s, 3 H), 3.61 (m, 1 H), 3.60 (d, J ) 13.5 Hz, 1
H), 3.28(d, J ) 3.8 Hz, 1 H), 2.82 (dd, J ) 6.5, 8.5 Hz, 1 H),
2.55-2.41 (m, 3 H), 2.28 (m, 1 H), 2.21 (dq, J ) 15.0, 7.4 Hz,
1 H), 1.54 (m, 1 H), 1.42 (ddd, J ) 5.6, 5.6, 11.7 Hz, 1 H), 1.14
(t, J ) 7.4 Hz, 3 H); 13C NMR δ 169.0, 166.0, 154.1, 143.2,
139.3, 138.4, 128.5, 128.3, 127.7, 126.8, 121.9, 120.3, 109.1,
107.7, 96.9, 66.5, 58.4, 55.6, 51.0, 50.7, 42.6, 39.5, 29.2, 27.6,
12.16; MS m/z 415 (M+ + 1, 15), 146 (32), 143 (8), 91 (100).
Anal. Calcd for C27H30N2O2‚0.33 H2O: C, 77.11; H, 7.35; N,
6.66. Found: C, 77.62; H, 7.19; N, 6.46.
80 °C bath for 4 h. The solvent was evaporated under vacuum.
The residue was dissolved in dichloromethane, and the solu-
tion washed with 5% NH4OH. Concentration and chromatog-
raphy on a silica gel column, eluted with Hex/EtOAc (5:95),
afforded 308 mg (74% yield) of the tetracyclic amine (-)-12b
as a white solid: [R]23 -230 (c ) 0.8, CHCl3); mp 104-6 °C
D
(from EtOAc/Hex). Anal. Calcd for C27H30N2O2‚0.2 H2O: C,
77.58; H, 7.26; N, 6.70. Found: C, 77.62; H, 7.19; N, 6.46.
(()-Meth yl (2S*,3a S*,5R*,11bR*)-2,3,3a ,4,5,7-Hexa h y-
d r o-5-(2-(1-b u t en yl))-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r -
boxyla te (22a ) a n d Its 2,3,11-Ep im er (23a ). A mixture of
the Nb-benzyl tetracyclic amine 12a (100 mg, 0.24 mmol) and
10% Pd-C (26 mg, 0.024 mmol), in 5 mL of HOAc, was stirred
under an atmosphere of hydrogen for 1.5 h. The solid was
removed by filtration, and the filtrate was basified with
concentrated NH4OH at 0 °C. The aqueous phase was ex-
tracted with dichloromethane. The residue, obtained on con-
centration, was purified on a silica gel column that was eluted
with MeOH/CH2Cl2 (5:95) to give 36 mg of the title product
(()-22a (46% yield) and 35 mg of its C-2,3,11-epimer (()-23a
(45% yield). For 22a : Rf ) 0.31 (MeOH/CH2Cl2, 5:95, CAS
blue); mp 102 °C; UV λmax (EtOH) 204, 228, 298, 326 nm; IR
For the minor isomer 13a : Rf ) 0.16 (Et2O/Hex, 3:97, CAS
blue); UV λmax (EtOH) 204, 226, 298, 328 nm; IR (KBr) νmax
3368, 1676, 1609 cm-1; 1H NMR δ 9.05 (s, 1 H), 7.41 (m, 2 H),
7.35 (m, 3 H), 7.27 (m, 1 H), 7.15 (t, J ) 7.5 Hz, 1 H), 6.89 (t,
J ) 7.5 Hz, 1 H), 6.82 (d, J ) 7.7 Hz, 1 H), 4.69 (s, 1 H), 4.58
(s, 1 H), 3.95 (d, J ) 13.2 Hz, 1 H), 3.84 (d, J ) 13.2 Hz, 1 H),
3.68 (s, 3 H), 3.42 (dd, J ) 5.5, 5.5 Hz, 1 H), 3.32 (dd, J ) 5.4,
5.4 Hz, 1 H), 2.82 (m, 2 H), 2.22 (m, 1 H), 2.08 (q, J ) 7.3 Hz,
2 H), 1.88 (ddd, J ) 5.4, 5.5, 11.3 Hz, 1 H), 1.80 (m, 1 H), 1.62
(ddd, J ) 5.4, 5.5, 11.3 Hz, 1 H), 1.08 (t, J ) 7.3 Hz, 3 H); 13
C
NMR δ 169.1 165.8, 155.7, 143.7, 139.6, 137.5, 128.6, 128.2,
127.6, 126.9, 122.4, 120.5, 109.2, 107.3, 97.3, 61.2, 56.7, 55.2,
50.42, 49.2, 43.4, 38.8, 31.8, 28.1, 12.5; MS m/z 415 (M++1,
42), 146 (53), 143 (16), 91 (100).
(KBr) νmax 3360, 1674, 1607 cm-1 1H NMR δ 9.30 (s, 1 H),
;
7.23 (d, J ) 7.4 Hz, 1 H), 7.15 (t, J ) 7.2 Hz, 1 H), 6.88 (t, J
) 7.5 Hz, 1 H), 6.84 (d, J ) 7.7 Hz,1 H), 4.87 (s, 1 H), 4.85 (s,
1 H), 3.77 (s, 1 H), 3.72 (s, 1 H), 3.59 (s, 1 H), 3.09 (dd, J )
6.3, 11.6 Hz, 1 H), 2.96 (ddd, J ) 5.3, 11.6, 11.6 Hz, 1 H), 2.31
(qd, J ) 7.4, 14.7 Hz, 1 H), 2.25 (m, 2 H), 2.14 (ddd, J ) 3.1,
0.31, 14.5 Hz, 1 H), 1.77 (dd, J ) 5.3, 12.2 Hz, 1 H), 1.66 (ddd,
J ) 6.4, 6.4, 14.7 Hz, 1 H), 1.14 (t, J ) 7.4, 3 H); 13C NMR δ
168.8, 166.7, 154.0, 143.2, 137.9, 127.9, 121.3, 120.7, 109.5,
109.2, 96.2, 63.0, 51.0, 46.3, 45.9, 39.5, 30.9, 27.6, 12.6; MS
m/z 326 (23), 325 (M+, 100), 324 (90), 280 (10), 268 (34), 265
(38), 254 (27), 242 (76), 236 (29), 226 (13), 222 (27), 210 (49),
208 (55), 194 (33), 180 (33), 167 (30), 159 (34), 154 (16), 144
(8). Anal. Calcd for C20H24N2O2‚0.5H2O: C, 72.05; H, 7.56; N,
8.12. Found: C, 71.93; H, 7.32; N, 8.40.
Isomerization of the C-15 epimers 12a and 13a : A solution
of epimer 12a (50 mg, 0.12 mmol) and benzoic acid (1.5 mg,
0.012 mmol) in 5 mL of benzene was heated in a 75 °C oil bath
for 6 h. Workup and purification, as above, gave 35 mg of the
epimer 12a (70% yield) and 4 mg of epimer 13a (8% yield).
Meth yl (2S,3a S,5R,11bR)-2-(Am in oca r bon yl)-3-ben zyl-
2,3,3a ,4,5,7-h exa h yd r o-5-(2-(1-b u t en yl))-1H -p yr r olo[2,3-
d ]ca r ba zole-6-ca r boxyla te (19). Meth od a : A solution of
1.00 g (2.12 mmol) of the dimethyl ester 17 in 30 mL of of dry
methanol, at 0 °C, was saturated with dry NH3(g). The solution
was stirred at room temperature for 5 days and then the
solvent was evaporated under vacuum. The residue was
chromatographed on a silica gel column, eluted with Hex/
EtOAc (1:1), to afford 725 mg (75% yield) of amide 19 as a
white solid.
For the C-2,3,11-epimer (()-23a : Rf ) 0.19 (MeOH/CH2Cl2,
5:95, CAS blue); UV λmax (EtOH) 202, 226, 294, 328 nm; IR
Meth od b: A solution of the ester 17 in methanol was
saturated with with dry NH3(g) and heated in a sealed tube
for 17 h at 110 °C. Concentration and purification as above
gave a 52% yield of the amide 19.
(KBr) νmax 3364, 1682, 1609 cm-1 1H NMR δ 9.15 (s, 1 H),
;
7.32 (d, J ) 7.3 Hz, 1 H), 7.16 (t, J ) 7.6 Hz, 1 H), 6.88 (t, J
) 7.4 Hz, 1 H), 6.84 (d, J ) 7.8 Hz, 1 H), 5.62 (s, br, 1 H), 4.67
(s, 1 H), 4.39 (s, 1 H), 3.66 (s, 3 H), 3.64 (m, 1 H), 3.34 (m, 2
H), 3.22 (m, 1 H), 2.34 (m, 1 H), 2.10 (m, 2 H), 1.91 (m, 2 H),
1.84 (m, 1 H), 1.06 (t, J ) 7.4 Hz, 3 H); 13C NMR δ 168.8,
163.7, 155.4, 144.0, 135.7, 128.1, 121.9, 120.7, 109.6, 107.9,
96.4, 55.5, 50.7, 42.9, 42.7, 39.3, 33.6, 29.7, 28.8, 12.5; MS m/z
325 (M+, 63), 324 (13), 242 (29), 236 (12), 210 (11), 208 (32),
194 (16), 180 (27), 167 (25), 91 (55).
The benzyl ester 18 was converted into amide 19 by the
same procedure. Data for 19: Rf ) 0.33 (EtOAc/Hex, 1:1, CAS
blue); [R]24 -211 (c ) 1.0, CHCl3); UV λmax (EtOH) 206, 228,
D
298, 328 nm; IR (KBr) νmax 3440, 3369, 1683, 1608 cm-1; H
1
NMR δ 9.17 (s, 1 H), 7.39 (m, 3 H), 7.28 (m, 2 H), 7.08 (t, J )
7.6 Hz, 1 H), 6.77 (d, J ) 7.7 Hz, 1 H), 6.68 (t, J ) 7.5 Hz, 1
H), 6.61 (d, br, J ) 3.8 Hz, 1 H), 6.28 (d, J ) 7.3 Hz, 1 H), 5.44
(d, br, J ) 3.8 Hz, 1 H), 4.84 (s, 1 H), 4.79 (s, 1 H), 3.99 (d, J
) 13.5 Hz, 1 H), 3.85 (d, J ) 13.5 Hz, 1 H), 3.72 (s, 3 H), 3.60
(m, 2 H), 3.57 (dd, J ) 5.3, 11.7 Hz, 1 H), 2.43 (dd, J ) 11.7,
11.7 Hz, 1 H), 2.40 (qd, J ) 7.4, 14.9 Hz, 1 H), 2.23 (qd, J )
7.4, 14.9 Hz, 1 H), 2.15 (d, J ) 14.5 Hz, 1 H), 1.83 (dd, J )
5.3, 11.7 Hz, 1 H), 1.29 (ddd, J ) 5.9, 5.9, 14.5 Hz, 1 H), 1.12
(t, J ) 7.4 Hz, 3 H); 13C NMR δ 175.4, 168.6, 165.2, 153.0,
142.6, 136.8, 134.5, 130.7, 128.5, 128.0, 127.9, 121.5, 120.7,
109.7, 109.3, 96.4, 65.7, 64.3, 55.7, 54.5, 51.1, 47.3, 39.1, 29.7,
27.7, 12.3; MS m/z 458 (2), 457 (M+, 5), 413 (27), 268 (20), 236
(11), 208 (15), 194 (12), 167 (14), 91 (100). Anal. Calcd for
Meth yl (2S,3a S,5R,11bR)-3-(ter t-Bu toxyca r bon yl)-2,3,-
3a,4,5,7-h exah ydr o-5-(2-(1-bu ten yl))-1H-pyr r olo[2,3-d]car -
ba zole-6-ca r boxyla te ((-)-24b) a n d Its Ra cem a te (24a ).
A mixture of the tetracyclic Nb-benzylamine (-)-12b (370 mg,
0.893 mmol), ammonium formate (281 mg, 4.46 mmol), and
10% Pd-C (95 mg, 0.089 mmol), in 8 mL of MeOH and 2 mL
of EtOAc, was heated at reflux for 2 h. The solid was removed
by filtration, and the solvents were evaporated under vacuum.
The residue was dissolved in dichloromethane, and the solu-
tion was washed with saturated NaHCO3. The product 22b,
obtained on drying and concentration, was pure enough for
the next reaction but it also could be purified on a column
eluted with MeOH/CH2Cl2 (5:95) to afford the amine as a white
solid.
C
28H31N3O3: C, 73.50; H, 6.83; N, 9.18. Found: C, 73.47; H,
6.44; N, 9.38.
Meth yl (2S,3a S,5R,11bR)-3-Ben zyl-2,3,3a ,4,5,7-h exa h y-
d r o-5-(2-(1-b u t en yl))-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r -
boxyla te ((-)-12b). To a solution of the amide 19 (460 mg,
1.005 mmol) and Et3N (697 µL, 5.0 mmol) in 10 mL of
dichloromethane, at 0 °C, was added TFAA (282 µL, 2.0 mmol),
dropwise. The solution was stirred at room temperature for
40 min, and saturated sodium bicarbonate was added to
quench the reaction. The organic phase was extracted with
dichloromethane. The nitrile 20, obtained on drying and
concentration, was dissolved in 10 mL of dry EtOH. KBH4 (271
mg, 5.03 mmol) was added in several portions at room
temperature. The reaction mixture was then heated in a 75-
The above crude product 22b was dissolved in 6 mL of THF
and 3 mL of water, and 247 mg of potassium carbonate (1.79
mmol) was added, followed by (t-Boc)2O (234 mg, 1.07 mmol),
in several portions. The solution was stirred at room temper-
ature for 1 h, and then the aqueous layer was extracted with
dichloromethane. The residue, obtained on drying and con-
centration, was purified on a silica gel column, eluted with
EtOAc/Hex (1:9), to afford 350 mg (92% yield) of urethane (-)-
24b as a white solid: Rf ) 0.24 (EtOAc/Hex, 1:9, CAS blue);
mp 150-151 °C (MeOH); [R]24 -259 (c ) 0.35, CHCl3); UV
D
λmax (EtOH) 204, 226, 298, 326 nm; IR (KBr) νmax 3361, 1697,
1
1683, 1609 cm-1; H NMR δ 9.29 (s, 1 H), 7.15 (t, br, J ) 7.1

9438 J . Org. Chem., Vol. 63, No. 25, 1998
Kuehne and Xu
Hz, 1 H), 7.07 (d, J ) 7.1 Hz, 1 H), 6.87 (t, J ) 7.1 Hz, 1 H),
6.83 (d, J ) 7.8 Hz, 1 H), 4.79 (s, 1 H), 4.78 (s, 1 H), 4.26 (s,
br, 0.5 H), 4.13 (s, br, 0.5 H), 3.72 (s, 3 H), 3.58 (m, 1 H), 3.50
(s, br, 1 H), 2.48 (m, 1 H), 2.30 (m, br, 0.5 H), 2.16 (qd, J )
7.3, 14.5, Hz, 1 H), 2.12 (qd, J ) 7.3, 14.5 Hz, 1 H), 2.0 (m, br,
0.5 H), 1.77 (s, br, 1 H), 1.60 (m, 1 H), 1.52 (s, 9 H), 1.09 (t, J
) 7.3 Hz, 2.5 H), 0.89 (t, J ) 7.3 Hz, 0.5 H); 13C NMR (more
peaks observed due to the rotameres) δ 168.9, 155.0, 154.9,
154.1, 143.0, 138.5, 136.3, 136.1, 128.1, 121.4, 120.77, 109.2,
109.2, 107.3, 79.6, 59.8, 50.9, 50.8, 44.1, 43.6, 40.0, 39.7, 39.6,
38.7, 32.1, 31.1, 28.5, 27.3, 14.8, 13.4, 12.3; MS m/z: 425 (M+
+ 1, 19), 370 (46314 (74), 287 (100), 269 (11), 254 (11), 242
(11), 237 (19), 226 (16), 222 (12), 209 (19), 202 (10), 194 (43),
180 (16), 167 (20), 155 (18), 91 (23). Anal. Calcd for C25H32N2O4‚
0.5H2O: C, 69.26; H, 7.67; N, 6.46. Found: C, 69.66; H, 7.55;
N, 6.35.
1H NMR δ 9.02 (s, 1 H), 7.16 (d, J ) 7.3 Hz, 1 H), 7.03 (t, J )
7.5 Hz, 1 H), 6.88 (t, J ) 7.4 Hz, 1 H), 6.79 (d, J ) 7.7 Hz, 1
H), 3.86 (s, 1 H), 3.76 (s, 3 H), 3.05 (m, 1 H), 3.04 (s, 1 H), 2.86
(m, 2 H), 2.74 (dd, J ) 7.1, 11.7 Hz, 1 H), 2.61 (ddd, J ) 3.0,
3.0, 12.8 Hz, 1 H), 2.15 (d, J ) 12.5 Hz, 1 H), 1.79 (dd, J )
6.7, 13.3 Hz, 1 H), 1.69 (qd, J ) 7.5, 15.0 Hz, 1 H), 1.39 (qd, J
) 7.5, 15.0 Hz, 1 H), 1.08 (ddd, J ) 2.9, 2.9, 12.8 Hz, 1 H),
0.91 (t, J ) 7.5 Hz, 3 H), 0.23 (s, 9 H); 13C NMR δ 171.7, 168.7,
144.3, 136.1, 127.4, 121.0, 119.8, 109.5, 101.0, 75.8, 60.7, 56.9,
54.6, 54.2, 51.0, 43.1, 37.6, 32.7, 26.1, 7.2, 2.5; MS m/z 413
(M+ + 1, 30), 314 (25), 268 (100), 240 (8), 238 (10), 236 (21),
226 (34), 209 (59), 194 (23), 180 (25), 167 (38), 97 (13).
The racemate 27a was prepared by the same procedure from
the racemic tosylate 26a . It matched the above compound in
spectroscopic data.
(-)-20-epi-Loch n er id in e (2b) a n d Its Ra cem a te 2a . A
solution of the silyl ether (-)-27b (18 mg, 0.0436 mmol) and
n-Bu4NF (87 µL, 1.0 M in THF, 0.087 mmol) in 2 mL of THF
was stirred at room temperature for 2 h. Concentration and
chromatography on a silica gel column (MeOH/CH2Cl2/Et3N,
5:95:1) afforded 14 mg (94% yield) of (-)-20-epi-lochneridine
(2b): Rf ) 0.31 (MeOH/CH2Cl2, 5:95, SiO2 plate was deacti-
vated with Et3N, CAS blue); mp 205-6 °C (lit.3 mp 205-6 °C);
The racemate 24a , obtained by the same procedure from
racemic 12a , had a mp of 145 °C (MeOH) and the same
spectroscopic data.
Meth yl (2S,3a S,5R,11bR)-3-(ter t-Bu toxyca r bon yl)-2,3,-
3a,4,5,7-h exah ydr o-5-(2-((1-tosyloxy-2-h ydr oxy)bu ten yl))-
1H-p yr r olo[2,3-d ]ca r b a zole-6-ca r boxyla t e ((-)-26b a n d
its Ra cem a te 26a ). To a solution of the urethane (-)-24b (230
mg, 0.542 mmol) in 8 mL of pyridine, at 0 °C, was added OsO4
(145 mg, 0.569 mmol) in one portion. The solvent was
evaporated in a vacuum after 4 h at 0 °C. The residue was
dissolved in 20 mL of dichloromethane, and 10 mL of 10%
NaHSO3 solution was added. The mixture was stirred for 30
min and basified with saturated NaHCO3. The aqueous layer
was extracted with dichloromethane. The residue, obtained on
drying and concentration, was passed through a short silica
gel column, eluted with MeOH/CH2Cl2 (2:98), to afforded the
crude diol (-)-25b, which was dissolved in 10 mL of CH2Cl2.
Triethylamine (91 uL, 0.65 mmol) and Ts2O (194 mg, 0.596
mmol) were added at 0 °C, and the solution was stirred at 0
°C for 3 h. The solvent was evaporated in a vacuum, and the
residue was purified on a silica gel column, eluted with Hex/
EtOAc (7:3), to afford 205 mg (62% yield) of the tosylate (-)-
26b as a white solid: Rf ) 0.26 (EtOAc/Hex, 3:7, CAS blue);
[R]24 -716 (c ) 0.2, MeOH); UV λmax (EtOH) 204, 234, 296,
D
328 nm; IR (KBr) νmax 3353, 1666, 1596 cm-1; 1H NMR δ 9.04
(s, 1 H), 7.18 (d, J ) 7.3 Hz, 1 H), 7.12 (ddd, J ) 1.0, 7.7, 7.7
Hz, 1 H), 6.90 (ddd, J ) 0.8, 7.6, 7.6 Hz, 1 H), 6.80 (d, J ) 7.7
Hz, 1 H), 3.99 (s, 1 H), 3.76 (s, 3 H), 3.18 (m, 1H), 3.05 (s, 1
H), 2.86 (m, 3 H), 2.73 (ddd, J ) 3.1, 3.1, 13.5 Hz, 1 H), 2.40
(d, J ) 12.6 Hz, 1 H), 1.91 (m, 1 H), 1.61 (qd, J ) 7.5, 15.0 Hz,
1 H), 1.39 (qd, J ) 7.5, 15.0 Hz, 1 H), 1.19 (ddd, J ) 2.8, 2.8,
13.5 Hz, 1 H), 0.98 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 170.9,
168.5, 144.3, 135.1, 127.8, 121.3, 119.8, 109.8, 101.5, 70.8, 60.6,
6.16, 54.5, 53.8, 51.1, 42.4, 36.5, 32.4, 25.7, 6.7; MS m/z 341
(45), 340 (M+, 17), 283 (79), 241 (38), 226 (69), 209 (31), 194
(69), 184 (20), 182 (32), 180 (37), 167 (100), 156 (10), 154 (29),
149 (60), 138 (36), 130 (12), 126 (14), 115 (41).
The racemate 2a was prepared by the same procedure from
the racemic silyl ether 27a . It matched the above compound
in spectroscopic data.
[R]24 -166 (c ) 0.8, CHCl3); UV λmax (EtOH) 204, 228, 296,
D
326 nm; IR (KBr) νmax 3358, 1683, 1607 cm-1; 1H NMR δ 9.51
(s, 1 H), 7.78 (d, J ) 8.1 Hz, 2 H), 7.33 (d, J ) 8.1 Hz, 2 H),
7.16 (t, J ) 7.6 Hz, 1 H), 7.05 (d, J ) 7.4 Hz, 1 H), 6.88 (t, J
) 7.4 Hz, 1 H), 6.83 (d, J ) 7.7 Hz, 1 H), 4.21 (d, J ) 9.9 Hz,
1 H), 4.10 (dd, J ) 6.1, 6.1 Hz, 1 H), 3.88 (d, J ) 9.9 Hz, 1 H),
3.70 (s, 3 H), 3.56 (dd, J ) 3.6, 9.6 Hz, 2 H), 3.31 (dd, J ) 4.4,
8.4 Hz, 1 H), 2.75 (m, 1 H), 2.43 (s, 3 H), 2.27 (s, 1 H, OH),
2.04 (m, 1 H), 1.90 (m, 1 H), 1.69 (m, 2 H), 1.59 (m, 1 H), 1.50
(s, 9 H), 0.83 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 168.8, 154.6,
144.8, 142.3, 136.7, 132.9, 129.8, 128.1, 128.0, 121.4, 121.2,
109.4, 92.5, 80.0, 75.8, 73.5, 60.2, 54.0, 51.1, 44.8, 44.6, 37.7,
29.6, 28.7, 28.5, 28.4, 26.5, 21.6, 8.5; MS m/z 441 (M+ - TsOH,
3), 427 (12), 370 (21), 314 (28), 299 (32), 281 (12), 269 (6), 226
(10), 194 (42), 186 (50), 182 (11), 180 (13), 167 (14), 155 (50),
107 (16), 91 (100).
(()-Meth yl (2S,3aS,5R,11bR)-3-ben zyl-2,3,3a ,4,5,7-h exa -
h yd r o-5-(1-p r op ion yl)-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r -
boxylate (6). To a solution of (()-methyl (2S*,3aS*,5R*,11bR*)-
3-benzyl-2,3,3a,4,5,7-hexahydro-5-formyl-1H-pyrrolo[2,3-d]-
carbazole-6-carboxylate (5)7 (1.4 g, 3.6 mmol) in 30 mL of THF
at -20 °C was added EtMgBr (3.0 M in Et2O, 2.64 mL, 7.93
mmol), dropwise. The reaction solution was stirred for 30 min
at -20 °C and then 30 min at 0 °C. The reaction was quenched
by adding water, and the aqueous phase was extracted with
dichloromethane. Purification on a silica gel column, eluted
with EtOAc/Hex (1:4), gave 1.3 g (86% yield) of an inseparable
mixture (6:4 in favor of isomer A) of two alcohols. For the major
isomer A: Rf ) 0.4 (EtOAc/Hex, 3:7, CAS blue fades fast); UV
λmax (EtOH) 206, 236, 296, 326 nm; IR (KBr) νmax 3360, 1670,
1
1606 cm-1; H NMR (250 MHz) δ 9.31 (s, 1 H), 7.37 (m, 5 H),
The racemate 26a was prepared by the same procedure from
racemic urethane 24a . It matched the above compound in
spectroscopic data.
7.14 (t, J ) 7.1 Hz, 1 H), 7.05 (d, J ) 7.8 Hz, 1 H), 6.84 (t, J
) 7.6 Hz, 1 H), 6.80 (d, J ) 7.7 Hz, 1 H), 5.78 (s, br, 1 H), 4.22
(d, J ) 13.0 Hz, 1 H), 3.78 (m, 1 H), 3.76 (s, 3 H), 3.61 (d, J )
13.0 Hz, 1 H), 3.31 (d, J ) 4.8 Hz, 1 H), 3.19 (m, 1 H), 2.96 (m,
1 H), 2.62 (m, 2 H), 1.95 (d, J ) 14.8 Hz, 1 H), 1.75 (m, 1 H),
1.63 (m, 2 H), 1.43 (m, 1 H), 1.05 (t, J ) 7.4 Hz, 3 H); 13C
NMR δ 169.2, 150.8, 142.8, 129.2, 128.6, 127.9, 120.6, 120.3,
109.3, 95.6, 76.3, 65.6, 58.6, 51.6, 50.9, 43.8, 40.1, 32.4, 28.6,
11.1; MS m/z 419 (M+ + 1, 1), 361 (23), 228 (68), 194 (13), 180
(12), 167 (22), 146 (66), 134 (22), 117 (12), 91 (100).
(-)-20-epi-Loch n er id in e Tr im eth ylsilyl Eth er (-)-(27b)
a n d Its Ra cem a te 27a . To a solution of 65 mg of the tosylate
alcohol (-)-26b (0.11 mmol) and 59 µL of Et3N (0.42 mmol) in
1.5 mL of dichloromethane at 0 °C was added 61 µL of TMSOTf
(0.32 mmol), dropwise. After the solution was stirred at room
temperature for 1 h, the reaction was quenched by adding
saturated sodium bicarbonate. The aqueous phase was ex-
tracted with dichloromethane. The residue, obtained on drying
and concentration, was dissolved in 10 mL of dry MeOH, and
the solution was heated in a 50-60 °C oil bath for 2 h.
Concentration and dissolution of the residue in dichlo-
romethane, washing with 10% sodium carbonate, and concen-
tration gave the cyclized product (-)-27b, which could be
purified on a silica gel column, eluted with EtOAc/Hex (4:1),
to afford 37 mg (85% yield) of product: Rf ) 0.5 (EtOAc/Hex,
4:1, CAS blue); [R]24D - 586 (c ) 0.25, CHCl3); UV λmax (EtOH)
For the minor isomer B: selected data of 1H NMR (250 MHz)
spectrum δ 9.18 (s, 1 H), 4.26 (d, J ) 12.9 Hz, 1 H), 3.77 (s, 3
H), 3.55 (d, J ) 12.9 Hz, 1 H), 3.09 (m, 1 H), 2.94 (m, 1 H),
2.58 (m, 2 H), 2.30 (d, J ) 14.8 Hz, 1 H), 1.07 (t, J ) 7.5 Hz,
3 H).
To a stirred mixture of N-chlorosuccinimide (1.92 g, 14.4
mmol) in 15 mL of toluene, at 0 °C, was added Me2S (1.5 mL,
20 mmol), dropwise. The mixture was stirred for an additional
10 min and cooled to -20 °C. A solution of the above mixture
of alcohols A and B (1.20 g, 2.87 mmol) in 5 mL of toluene
204, 230, 296, 328 nm; IR (KBr) νmax 3351, 1669, 1592 cm-1
;

Syntheses of Lochneridines
J . Org. Chem., Vol. 63, No. 25, 1998 9439
was introduced. The reaction solution was stirred at -25 °C
for 3 h. Et3N (2.4 mL, 17 mmol) was added, and after 10 min,
the solution was allowed to warm to room temperature and
stirred for 30 min. Saturated sodium bicarbonate was added,
and the aqueous phase was extracted with dichloromethane.
The residue, obtained on drying and concentration, was
purified on a silica gel column, eluting with EtOAc/Hex (1:4)
to give 1.1 g (92% yield) of the title ketone 6: Rf ) 0.32 (EtOAc/
Hex, 1:4, CAS blue); mp 103-105 °C; UV λmax (EtOH) 208,
To 40 mg (0.123 mmol) of the secondary amine, dissolved
in 2 mL of dichloromethane, were added NaI (110 mg, 0.74
mmol), Na2CO3 (260 mg, 2.46 mmol), and ClCH2SPH (100 µL,
0.738 mmol). The reaction mixture was stirred at room
temperature overnight. Water was then added, and the
mixture was extracted with dichloromethane. The residue,
obtained on drying and concentration, was purified on a silica
gel column, eluting with EtOAc/Hex (1:4), to give 45 mg (80%
yield) of the title product 7: Rf ) 0.24 (EtOAc/Hex, 1:4; CAS
blue); UV λmax (EtOH) 206, 226, 296, 324 nm; 1H NMR δ 9.06
(s, 1 H), 7.51 (m, 3 H), 7.28 (m, 2 H), 7.19 (m, 2 H), 6.94 (t, J
) 7.6 Hz 1 H), 6.84 (d, J ) 7.8 Hz, 1 H), 7.75 (d, J ) 13.2 Hz,
1 H), 4.68 (d, J ) 13.2 Hz, 1 H), 4.73 (m, 1 H), 4.72 (s, 3 H),
3.19 (m, 1 H), 2.68 (dd, J ) 7.0, 8.7 Hz, 1 H), 2.47 (m, 1 H),
2.45 (m, 1 H), 2.43 (d, J ) 14.4 Hz, 1 H), 2.19 (m, 1H), 1.58
(dd, J ) 5.2, 11.9 Hz, 1 H), 1.42 (dd, J ) 5.4, 5.4, 14.4 Hz, 1
H), 1.05 (t, J ) 7.3 Hz, 3 H); 13C NMR δ 211.5, 167.8, 142.5,
131.5, 129.2, 127.9, 126.7, 121.9, 120.9, 109.4, 60.9, 60.8, 51.1,
49.3, 46.7, 43.2, 32.7, 29.8, 8.4.
To a solution of the phenylthiomethylamine 7 (200 mg, 0.446
mmol) in 8 mL of benzene, at 80 °C, was added a solution of
nBu3SnH (600 µL, 2.23 mmol) and AIBN (8 mg) in 2 mL of
benzene, via a syringe pump, in 1 h. The reaction mixture was
then heated at reflux for 1 h. The residue, obtained on
concentration, was purified on a silica gel column, eluting with
EtOAc/Hex (3:7), to obtain 130 mg (72% yield) of the Nb-
methylamine, contaminated with tin compounds: Rf ) 0.36
(EtOAc/Hex, 3:7, CAS blue); UV λmax (EtOH) 206, 298, 326 nm;
IR (KBr) νmax 3371, 1710, 1682, 1610 cm-1; 1H NMR δ 9.06 (s,
br, 1 H), 7.15 (m, 2 H), 6.87 (t, J ) 7.3 Hz, 1 H), 6.83 (d, J )
8.0 Hz, 1 H), 3.73 (s, 3 H), 3.69 (dd, J ) 2.4, 5.5 Hz, 1 H), 2.93
(d, J ) 3.0 Hz, 1 H), 2.83 (dd, J ) 6.7, 8.6 Hz, 1 H), 2.65 (m,
1 H), 2.49 (m, 3 H), 2.43 (s, 3 H), 2.22 (m, 1 H), 1.57 (dd, J )
4.9, 11.8 Hz, 1 H), 1.49 (ddd, J ) 4.4, 4.4, 14.2 Hz, 1 H), 1.07
(t, J ) 7.3 Hz, 3 H).
1
298, 326 nm; IR (KBr) νmax 3373, 1701, 1683, 1610 cm-1; H
NMR δ 9.11 (s, br, 1 H), 7.35-7.25 (m, 5 H), 7.15 (t, J ) 7.6
Hz, 1 H), 7.05 (d, J ) 7.4 Hz, 1 H), 6.84 (m, 2 H), 4.13 (d, J )
13.3 Hz, 1 H), 3.77 (dd, J ) 2.2, 5.9 Hz, 1 H), 3.74 (s, 3 H),
3.57 (d, J ) 13.3 Hz, 1 H), 3.26 (d, J ) 4.1 Hz, 1 H), 2.81 (m,
1 H), 2.76 (m, 1 H), 2.61 (m, 1 H), 2.55 (m, 1 H), 2.49 (m, 1 H),
2.23 (ddd, J ) 6.5, 6.5, 12.0 Hz, 1 H), 1.58 (m, 2 H), 1.10 (t, J
) 7.3 Hz, 3 H); 13C NMR δ 211.9, 142.1, 138.2, 137.7, 128.9,
128.3, 127.8, 127.1, 121.5, 120.6, 109.4, 65.6, 58.2, 55.9, 51.1,
50.9, 46.8, 43.7, 33.2, 30.6, 8.2; MS m/z 417 (4), 416 (M+, 10),
359 (49), 327 (12), 226 (12), 194 (13), 180 (9), 167 (12), 146
(30), 134 (21), 91 (100). Anal. Calcd for C26H28N2O3‚1H2O: C,
71.87; H, 6.96; N, 6.45. Found: C, 71.50; H, 6.75; N, 6.22.
To a solution of the title ketone 6 (700 mg, 1.68 mmol) in
15 mL of MeOH, at 0 °C, was added NaBH4 (127 mg, 3.36
mmol) in several portions. The solution was stirred for another
30 min, the solvent was evaporated in a vacuum, and 5%
NH4OH was added. The aqueous mixture was extracted with
dichloromethane. The residue, obtained on concentration, was
purified on a silica gel column, eluted with EtOAc/Hex (1:4),
to give 695 mg (99% yield) of the above alcohol as a single
isomer A.
R a cem ic Met h yl (3a S*,5R*,11bR*)-3-((P h en ylt h io)-
m eth yl)-2,3,3a ,4,5,7-h exa h yd r o-5-(p r op ion yl))-1H-p yr r o-
lo[2,3-d ]ca r ba zole-6-ca r boxyla te (7) a n d Meth yl (3a S*,-
5R*,11bR*))-3-Meth yl-2,3,3a ,4,5,7-h exa h yd r o-5-(p r op ion -
yl))-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te. A mixture
of methyl (3aS*,5R*,11bR*)-3-benzyl-2,3,3a,4,5,7-hexahydro-
5-(propionyl)-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (6, 200
mg, 0.48 mmol), HCO2NH4 (152 mg, 2.4 mmol), and 10% Pd-C
(50 mg, 0.05 mmol) in 8 mL of MeOH was heated at reflux for
3 h. The solid was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was taken
into dichloromethane and washed with saturated sodium
bicarbonate. The residue, obtained on drying and concentra-
tion, was purified on a silica gel column, eluting with CH2Cl2/
MeOH (9:1), to give 105 mg (67% yield) of the corresponding
secondary amine product: Rf ) 0.31 (MeOH/CH2Cl2, 1:9, CAS
blue); UV λmax (EtOH) 204, 228, 296, 328 nm; 1H NMR δ 9.33
(s, 1 H), 7.26 (d, J ) 7.4, 1 H), 7.17 (t, J ) 7.6 Hz, 1 H), 6.90
(t, J ) 7.5 Hz, 1 H), 6.86 (d, J ) 7.8 Hz, 1 H), 3.87 (dd, J )
2.4, 5.6 Hz, 1 H), 3.81 (s, 4 H), 3.07 (m, 2 H), 2.70 (m, 1 H),
2.60 (m, 1 H), 2.42 (d, J ) 14.4 Hz, 1 H), 1.69 (m, 2 H), 1.56
Ack n ow led gm en t. This work was supported by the
Cancer Institute of the National Institutes of Health
with grant RO1 CA 12010. We are indebted to Robert
Bennett and Patrick J okiel of our group for low-
resolution mass spectra.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra, compounds marked with an asterisk include COSY
spectra and compounds marked with a dagger (†) include
NOESY spectra, for compounds 1*†, 2b*†, pre 6 isomer A*, 6,
pre 7, 7, 12b*, 17*†, 19*, 23b*, 24b*, 26b*, 27b*†, and 1H NMR
spectra for compounds 13a *†, 22b*† (46 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.
(ddd, J ) 6.4, 6.4, 14.4 Hz, 1 H), 1.05 (t, J ) 7.3 Hz, 3 H); 13
C
NMR δ 213.9, 168.2, 167.2, 142.7, 137.6, 127.9, 121.8, 121.1,
109.4, 93.5, 61.2, 56.9, 51.3, 47.2, 45.2, 33.4, 30.9, 29.7, 8.0.
J O981401O