Enantiodivergent synthesis of pyrrolo[2,1-α]isoquinolines based on diastereoselective parham cyclization and α-amidoalkylation reactions

Article abstract of DOI:10.1021/jo049672o

Enantiodivergent synthesis of C-10b-substituted pyrrolo[2,1-α ]isoquinolines starting from an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide 3a, with a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral auxiliary, has been developed. The key transformations are derived from diastereoselective intramolecular cyclization of aryllithiums and α-amidoalkylation reactions, with the ethylidene bridge of the norbornene moiety dictating the stereochemical outcome in both types of reactions. Thus, the organolithium addition-intramolecular α-amidoalkylation sequence on imide 3a afforded stereoselectively the R configuration at C-12b, whereas the tandem Parham cyclization-intermolecular α-amidoalkylation reactions on the corresponding iodinated imide 3b occurred with complete control of stereoselectivity, leading to the epimer at C-12b. Subsequent reductive removal of the chiral auxiliary and retro-Diels-Alder reaction afforded (10bS)-and (10bR)-pyrroloisoquinolines 1 in high yields and optical purities (>99% ee).

Full text of DOI:10.1021/jo049672o

En a n tiod iver gen t Syn th esis of P yr r olo[2,1-a ]isoqu in olin es Ba sed
on Dia ster eoselective P a r h a m Cycliza tion a n d r-Am id oa lk yla tion
Rea ction s
Ine´s Gonza´lez-Temprano, In˜aki Osante, Esther Lete,* and Nuria Sotomayor
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa,
Universidad del Pa´ıs Vasco/ Euskal Herriko Unibertsitatea, Apdo 644, 48080 Bilbao, Spain
qopleexe@lg.ehu.es
Received February 26, 2004
Enantiodivergent synthesis of C-10b-substituted pyrrolo[2,1-a]isoquinolines starting from an
enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide 3a , with a 2-exo-hydroxy-
10-bornylsulfinyl group as a chiral auxiliary, has been developed. The key transformations are
derived from diastereoselective intramolecular cyclization of aryllithiums and R-amidoalkylation
reactions, with the ethylidene bridge of the norbornene moiety dictating the stereochemical outcome
in both types of reactions. Thus, the organolithium addition-intramolecular R-amidoalkylation
sequence on imide 3a afforded stereoselectively the R configuration at C-12b, whereas the tandem
Parham cyclization-intermolecular R-amidoalkylation reactions on the corresponding iodinated
imide 3b occurred with complete control of stereoselectivity, leading to the epimer at C-12b.
Subsequent reductive removal of the chiral auxiliary and retro-Diels-Alder reaction afforded (10bS)-
and (10bR)-pyrroloisoquinolines 1 in high yields and optical purities (>99% ee).
In tr od u ction
mediate precursors of bicyclic N-acyliminium ions,5 which
can be transformed into a variety of derivatives via
intermolecular R-amidoalkylation with different nucleo-
philes. This has been illustrated in the synthesis of the
isoindolo[1,2-a]isoquinoline skeleton of nuevamine-type
alkaloids.6 This approach is complementary to the tan-
dem organolithium addition-N-acyliminium ion cycliza-
tion sequence with N-phenethylimides, which also con-
stitutes an effective route to several types of isoquinoline
alkaloids. Although intramolecular R-amidoalkylation
Aryl and heteroaryllithium compounds1 are interesting
building blocks in synthetic organic chemistry because
by reaction with carbon electrophiles they produce,
together with the formation of a carbon-carbon bond,
the transfer of functionality to the electrophilic reagent,
and as a result, polyfunctionalized molecules are pre-
pared in one step. Thus, the aromatic metalation-
cyclization sequence has become a valuable protocol for
the regioselective construction of carbocyclic and hetero-
cyclic systems. However, certain electrophilic groups,
such as ketones and imides, do not remain passive during
the metalation process, and competitive nucleophilic
attack by organolithium base may occur. In these cases,
one can take advantage of the very fast rate of metal-
halogen exchange2 compared with nucleophilic addition
to carbonyl groups to allow aromatic metalation and
subsequent intramolecular cyclization reactions, which
are known as Parham cyclizations.3
(3) For reviews, see: (a) Parham, W. E.; Bradsher, C. K. Acc. Chem.
Res. 1982, 15, 300-305. (b) Gray, M.; Tinkl, M.; Snieckus, V. In
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., Eds.; Pergamon Press: Exeter, 1995; Vol. 11, pp
66-92. (c) Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J .; Sotomayor,
N.; Lete, E. In Targets in Heterocyclic Systems; Atanassi, O., Spinelli,
D., Eds.; Italian Society of Chemistry: Rome, 2001; Vol. 5, pp 393-
418. (d) Mealy, M. J .; Bailey, W. F. J . Organomet. Chem. 2002, 646,
59-67. (e) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275-
300. (e) Na´jera, C.; Sansano, J . M.; Yus, M. Tetrahedron 2003, 59,
9255-9303. See also ref 1.
(4) (a) Lete, E.; Egiarte, A.; Sotomayor, N.; Vicente, T.; Villa, M. J .
Synlett 1993, 41-42. (b) Collado, M. I.; Lete, E.; Sotomayor, N.; Villa,
M. J . Tetrahedron 1995, 51, 4701-4710. (c) Collado, M. I.; Sotomayor,
N.; Villa, M. J .; Lete, E. Tetrahedron Lett. 1996, 37, 6193-6196. (d)
Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M. J .; Lete, E. J . Org.
Chem. 1997, 62, 2080-2092.
Our work in this field has demonstrated that iodinated
N-phenethylimides tolerate iodine-lithium exchange,
giving rise to the isoquinoline nucleus via a Parham-type
cyclization.4 Since the thus obtained fused isoquinolones
possess a R-hydroxylactam function, they represent im-
(5) For reviews on N-acyliminium ion chemistry, see: (a) Speckamp,
W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (b) Hiemstra,
H.; Speckamp, W. N. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1988; Vol. 32, pp 271-339. (c) Hiemstra, H.;
Speckamp, W. N. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1047-
1082. (d) de Koning, H.; Speckamp, W. N. In Stereoselective Synthesis
[Houben-Weyl], Workbench ed. E21; Helmchen, G., Hoffmann, R. W.,
Muzler, J ., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3, pp
1952-2010. (e) Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000,
56, 3817-3856.
* Phone: 34 94 6012576. Fax: 34 94 6012748.
(1) (a) Wakefield, B. J . The Chemistry of Organolithium Compounds,
2nd ed., Pergamon Press: New York, 1990. (b) Clayden, J . Organo-
lithiums: Selectivity for Synthesis; Pergamon Press: New York, 2002.
(2) (a) Beak, P.; Musick, T. J .; Chen, C.-W. J . Am. Chem. Soc. 1988,
110, 3538-3542. (b) Narasimhan, N. S.; Sunder, N. M.; Ammana-
manchi, R.; Bonde, B. D. J . Am. Chem. Soc. 1990, 112, 4431-4435. (c)
Gallagher, D. J .; Beak, P. J . Am. Chem. Soc. 1991, 113, 7984-7987.
(d) Beak, P.; Liu, C. Tetrahedron 1994, 50, 5999-6004.
(6) Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004, 45,
1253-1256.
10.1021/jo049672o CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004
J . Org. Chem. 2004, 69, 3875-3885
3875

Gonza´lez-Temprano et al.
reaction7 has been widely used in the stereocontrolled
synthesis of nitrogen heterocycles, relatively minor effort
has been dedicated to stereoselective Parham cyclization.
However, its potential as a useful stereoselective cycliza-
tion procedure has proven to be extremely interesting.8
In this context, we have developed a diastereodivergent
synthesis of 1,10b-cis- and 1,10b-trans-thiazolo[4,3-a]-
isoquinoline systems, based on both types of cyclizations.9
On the other hand, pyrrolo[2,1-a]isoquinolones10 have
attracted considerable interest because they possess
antidepressant,11 muscarinic agonist,12 antiplatelet,13 and
anticancer14 activity. Moreover, they can be used as PET
radiotracers for imaging serotonin uptake sites.15 The
importance of these nitrogen heterocycles is further
enhanced by their utility as advanced intermediates for
the synthesis of alkaloids.16 In connection with our
interest in aromatic lithiation and R-amidoalkylation
reactions, our next challenge was to achieve the asym-
metric synthesis of the C-10b substituted pyrrolo[2,1-a]-
isoquinolones 1.17 In fact, we have previously reported
that N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide
could be considered as a synthetic equivalent of N-
phenethylmaleimide in the organolithium addition-N-
acyliminium ion cyclization sequence, as it carries a
masked R,â-unsaturated imide moiety, that could be
released by a retro-Diels-Alder reaction.18 Therefore, in
contrast to previous approaches,19 we reasoned that if a
chiral auxiliary is appended to the norbornene moiety,
enantiomerically pure isoindoloisoquinolines 2 could be
obtained. For this purpose, we chose the 2-exo-hydroxy-
10-bornylsulfinyl group as chiral auxiliary.20 Thus, our
imide precursor would be (2-exo-hydroxy-10-bornyl)sul-
finylnorbornenedicarboximide 3a (Figure 1). Organo-
lithium addition would generate a hydroxylactam, whose
intramolecular R-amidoalkylation reaction would lead to
C-10b-substituted dihydropyrrolisoquinolines (10bR)-1,
after removal of the chiral auxiliary and retro Diels-
Alder reaction. The stereochemistry of the stereogenic
center on C-10b would be determined in the R-amido-
alkylation reaction, in which attack of the aromatic ring
onto the N-acyliminium ion would occur from the less
hindered side. Alternatively, a Parham cyclization on
iodinated imide 3b would afford a 12b-hydroxy iso-
indoloisoquinoline, precursor of a bicyclic N-acyliminium
ion. The subsequent intermolecular R-amidoalkylation
reaction21 would occur with complete inversion of con-
figuration at C-12b, which finally would lead to dihydro-
pyrrolisoquinolines (10bS)-1. We now wish to report the
complete details of our investigations,22 which have
culminated in enantiodivergent approaches to the target
dihydropyrrolo[2,1-a]isoquinolinones 1.
(7) For reviews, see refs 5d,e. For some recent examples of dia-
stereoselective intramolecular R-amidoalkylation reactions of cyclic
N-acyliminium ions, see the following: Steric control by the substit-
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T.; Hiemstra, H. Eur. J . Org. Chem. 2000, 115-124. (b) Consonni, A.;
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Org. Chem. 2001, 1377-1383. (c) Hwang, D. J .; Kang, S. S.; Lee, J .
Y.; Choi, J . H.; Park, H.; Lee, Y. S. Synth. Commun. 2002, 32, 2499-
2505. (d) Padwa, A. Pure Appl. Chem. 2003, 75, 47-62. (e) Kaluza, Z.;
Mostowicz, D. Tetrahedron: Asymmetry 2003, 14, 225-232. Steric
control by the substituents along the chain connecting the π-nucleo-
philes and the nitrogen atom: (f) Garc´ıa, E.; Ardeo, A.; Arrasate, S.;
Lete, E.; Sotomayor, N. Tetrahedron Lett. 2001, 42, 1511-1513. (g)
Allin, S. M.; J ames, S. L.; Martin, W. P.; Smith, T. A. D. Tetrahedron
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12249. (f) Nishiyama, H.; Sakata, N.; Motoyama, Y.; Wakita, H.;
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Sugimoto, H.; Motoyama, Y.; Wakita, H.; Nagase, H. Synlett 1998,
930-932. (h) Pedrosa, R.; Andre´s, C.; Iglesias, J . M.; Pe´rez-Encabo,
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M. J .; Wiberg, K. B. Org. Lett. 2002, 4, 791-794. (j) Barluenga, J .;
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Org. Chem. 2001, 1267-1277.
(10) For a general review on properties, synthesis, and reactivity of
pyrrolo[2,1-a]isoquinolines, see: Mikhailovskii, A. G.; Shklyaev, V. S.
Chem. Heterocycl. Comp. (Translation of Khimiya Geterotsiklicheskikh
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(11) (a) Elwan, N. M.; Abelhadi, H. A.; Abdallah, T. A.; Hassaneen,
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(16) For a review, see, for instance: (a) Bentley, K. Nat. Prod. Rep.
2003, 20, 342-365. For some selected examples of pyrroloisoquinolones
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the C-10b position plays an important role in the biological activity of
the pyrrolo[2,1-a]isoquinolines, see for instance: Maryanoff, B. E.;
McComsey, D. F.; Gardocki, J . F.; Shank, R. P.; Costanzo, M. J .; Nortey,
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(19) Although chiral pyrroloisoquinoline derivatives are particularly
valuable both as synthetic intermediates and as medicinally important
compounds, relatively few asymmetric syntheses of these heterocycles
have been reported. Most of these approaches are based on diastereo-
selective N-acyliminium ions cyclizations of chiral substrates with
stereogenic centers along the chain connecting the π-nucleophiles and
the nitrogen atom or adjacent to the iminium carbon (see refs 5 and
7).
(20) (a) Arai, Y.; Matsui, M.; Koizumi, T.; Shiro, M. J . Org. Chem.
1991, 56, 1983-1985. (b) Arai, Y.; Matsui, M.; Fujii, A.; Kontani, T.;
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15-23. (c) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Gianneto, P
J . Org. Chem. 1997, 62, 4376-4384.
3876 J . Org. Chem., Vol. 69, No. 11, 2004

Enantiodivergent Synthesis of Pyrroloisoquinolines
SCHEME 1
phenethylmaleimide 7. As shown in Scheme 1, addition
of 10-mercaptoisoborneol24 to maleimide 418b afforded
succinimide 5 in good yield and excellent diastereoselec-
tivity (>95:5 dr). Subsequent treatment with NCS af-
forded maleimide 6, which was oxidized with MCPBA to
yield sulfinylmaleimide 7 as a single diastereoisomer in
quantitative yield. The stereochemical outcome of this
type of oxidation has been widely studied.25 The most
accepted proposal is that the oxidation preference is
determined by the hydroxyl group of the auxiliary, which
participates in a hydrogen bond with the reactive peracid,
determining the preferential attack on one of the dia-
stereotopic electron pairs on sulfur. In fact, it has been
reported that on similar substrates, oxidation occurs on
the same side of the hydroxyl group of the auxiliary, in
the preferred conformation.26 Therefore, in our case, the
absolute configuration of the sulfur atom could be as-
signed as R.27
F IGURE 1.
Resu lts a n d Discu ssion
In tr a m olecu la r R-Am id oa lk yla tion . Preparation of
imide 3a was carried out using the procedure developed
by Arai20 for related substrates, which relies on an
asymmetric Diels-Alder reaction23 of a sulfinylmale-
imide. Thus, our first task was the synthesis of N-
Once the sulfoxide was efficiently installed, it con-
trolled the stereochemistry of an asymmetric Diels-Alder
reaction. Thus, reaction of sulfinylmaleimide 7 with
cyclopentadiene in the presence of ZnCl2 afforded sulfinyl
norbornenedicarboximide 3a in excellent yield (93%), as
a single diastereoisomer (Scheme 2). In addition, we have
observed that when the cycloaddition reaction was car-
ried out in the absence of a Lewis acid, a diastereo-
isomeric mixture of 3a and 8 was obtained in a 33:67
ratio (90%). From the stereochemical standpoint, these
(21) Intermolecular R-amidoalkylation reactions of bicyclic N-
acyliminium ions with different types of nucleophiles (silyl enol ethers,
allylsilanes, organocuprates, etc.) usually occur with complete stereo-
selectivity, as a result of stereoelectronically favored axial attack at
the least hindered face. For reviews, see refs 5d,e. For some examples,
see: (a) Agami, C.; Amiot, F.; Couty, F.; Dechoux, L.; Kaminsky, C.;
Venier, O. Tetrahedron: Asymmetry 1998, 9, 3955-3958. (b) Dhimane,
H.; Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur. J . Org. Chem.
1998, 1955-1963. (c) Potts, D.; Stevenson, P. J .; Thompson, N.
Tetrahedron Lett. 2000, 41, 275-278. (d) David, M.; Dhimane, H.;
Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Heterocycles 2001, 55,
941-949.
(22) For a preliminary communication, see: Gonza´lez-Temprano,
I.; Lete, E.; Sotomayor, N. Synlett 2002, 593-597.
(24) Mercaptoisoborneol was prepared by LiAlH4 reduction of com-
mercial (1S)-(+)-10-camphorsulfonyl chloride according to literature
procedure: Eliel, E. L.; Frazee, W. J . J . Org. Chem. 1979, 44, 3598-
3599.
(23) For reviews on Diels-Alder reaction, see: (a) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Ox-
ford, 1990. (b) Corey, E. J . Angew. Chem., Int. Ed. 2002, 41, 1650-
1667. (c) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668-1698. For reviews
on stereoselective Diels-Alder reactions of sulfinyl dienophiles, see:
(d) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717-1760. (e) Garc´ıa Ruano,
J . L.; Carretero, J . C.; Carren˜o, M. C.; Mart´ın Cabrejas, L. M.; Urbano,
A. Pure Appl. Chem. 1996, 68, 925-930. (f) Garc´ıa Ruano, J . L.; Mart´ın
Castro, A. M.; Rodr´ıguez Ramos, J . H. Heteroat. Chem. 2002, 13, 453-
462. For some recent examples, see, for instance: (g) Takayashi, T.;
Yamakoshi, Y.; Okayama, K.; Yamada, J .; Ge, W.-Y.; Koizumi, T.
Heterocycles 2002, 56, 209-220. (h) Bayer, A.; Hansen, L. K.; Gautun,
O. R. Tetrahedron: Asymmetry 2002, 13, 2407-2415. (i) Aucagne, V.;
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.; Rollin, P.;
Tatiboueet, A. J . Org. Chem. 2002, 67, 6925-6930. (j) Carren˜o, M. C.;
Garc´ıa-Cerrada, S.; Urbano, A. Chem. Eur. J . 2003, 9, 4118-4131.
(25) For a review on the synthesis and utilization of chiral sulfoxides,
see: Ferna´ndez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651-3705.
(26) (a) Glass, R. S.; Setzer, W. N.; Prahbu, U. D. G.; Wilson, G. S.
Tetrahedron Lett. 1982, 23, 2335-2338. (b) de Lucchi, O.; Lucchini,
V.; Marchioro, C.; Valle, G.; Modena, G. J . Org. Chem. 1986, 51, 1457-
1466. (c) de Lucchi, O.; Lucchini, V.; Marchioro, C.; Valle, G.; Modena,
G. J . Org. Chem. 1989, 54, 3245-3246. The stereochemical outcome
of this kind of oxidation has also been explained through the formation
of an intramolecular hydrogen bond; see: (d) Annunziata, R.; Cinquini,
M.; Cozzi, F.; Farina, S.; Montanari, V. Tetrahedron 1987, 43, 1013-
1018.
(27) Absolute configuration of the sulfoxide was established by
correlation with related structures. Arai, Y.; Matsui, M.; Koizumi, T.
Synthesis 1990, 320-323. See also ref 20b.
J . Org. Chem, Vol. 69, No. 11, 2004 3877

Gonza´lez-Temprano et al.
SCHEME 2
SCHEME 3a
results may be explained as shown in Figure 2. In the
presence of ZnCl2, formation of a zinc chelate with
sulfinyl and carbonyl oxygen atoms would direct the
attack of cyclopentadiene from the less hindered side to
afford the endo product 3a . In the absence of ZnCl2, a
more stable conformer, due to dipole-dipole repulsion,
would lead to the formation of endo product 8.
Once the chiral nonracemic imide precursor 3a had
been prepared, we studied the stereoselectivity of the
intramolecular R-amidoalkylation route to pyrroloiso-
quinolines (10bR)-1. Thus, addition of MeLi or BuLi (2.3
equiv) afforded R-hydroxylactams 9a ,b in quantitative
yields as single diastereoisomers (Scheme 3). As expected,
attack of the organolithium took place regioselectively
at the less hindered carbonyl group. Similarly, reduction
of imide 3a was carried out with excess NaBH4 at 0 °C
to afford hydroxylactam 9c. It was not necessary to
determine the stereochemistry of R-hydroxylactams 9a -
c, as a planar N-acyliminium ion was going to be
generated in the subsequent cyclization. The next step
was the intramolecular R-amidoalkylation reaction. As
depicted in Scheme 3, treatment of R-hydroxylactams
9a -c with an excess of TFA at room temperature
furnished the expected methaneisoindoloisoquinolines
(12bR)-2a -c, together with their derivatives 10a ,b, in
which trifluoroacetylation of the hydroxyl group of the
auxiliary had occurred. Although these products were
separated and characterized independently, this side
reaction had no relevance in the following steps. Thus,
considering the combined yield of both isoquinolines 2
and 10, the intramolecular R-amidoalkylation reaction
a
Reagents: (a) R2Li (2.3 equiv), THF, -78 °C (for a ,b); NaBH4,
EtOH, 0 °C (for c). (b) TFA, CH2Cl2, rt.
SCHEME 4
efficiently afforded the isoquinoline system with complete
stereocontrol, as isoindoloisoquinolines 2 and 10 were
isolated as single diastereoisomers.
Among the methods described in the literature for the
reductive desulfinylation, SmI2 in the presence of HMPA
and t-BuOH was chosen for the removal of the chiral
auxiliary.28 Thus, (12bR)-2a ,b and their O-trifluoroacetyl
derivatives 10a ,b were converted separately into the
same isoindoloisoquinolines (12bR)-11a ,b in high yields
and excellent (>99%) enantiomeric excesses (Scheme 4,
Table 1). However, (12bR)-11c (entry 5) was obtained by
desulfinylation of the crude mixture of (12bR)-2c and 10c,
without purification, due to their instability under chro-
matographic conditions. It is interesting to point out that
(28) (a) For a general review on applications of samarium diiodide
in organic chemistry, see: Kagan, H. B. Tetrahedron 2003, 59, 10351-
10372. (b) For a review on reductions with samarium diiodide, see:
Molander, G. A. Org. React. 1994, 46, 211-305. For related examples
of desulfinylation, see refs 20a,b.
F IGURE 2.
3878 J . Org. Chem., Vol. 69, No. 11, 2004

Enantiodivergent Synthesis of Pyrroloisoquinolines
SCHEME 5a
TABLE 1. Rem ova l of Ch ir a l Au xilia r y: P r ep a r a tion of
(12bR)-11
entry substrate
product
[R]
ee (%) yield (%)
1
2
3
4
5
2a
10a
2b
10b
2c, 10c
(12bR)-11a
(12bR)-11a
(12bR)-11b
(12bR)-11b
(12bR)-11c
+202.8
>99
>99
>99
>99
>99
83
83
96
86
39a
+200.7
+176.4
a
Overall yield of two steps, starting from 9c.
the reaction is strongly influenced by the amount of
HMPA used. Thus, the best results were obtained using
an excess of SmI2 (10 equiv) and HMPA (70 equiv). The
yield obtained decreased drastically (from 83 to 47% for
2a ) when less HMPA was used (24 equiv). Spectroscopic
data of 11a -c were in agreement with those of the
corresponding racemates prepared through an analogous
route,18b which confirms, on one hand, the endo stereo-
chemistry of the norbornene moiety, and on the other,
the relative stereochemistry of the substituent on C-12b.
Finally, retro-Diels-Alder reaction29 of 11a ,b using a
FVP technique produced the R,â-unsaturated pyrrolo-
isoquinolines (10bR)-1a ,b in high yield and enantio-
meric purity, without racemization. Unfortunately, under
the conditions tested, 11c gave only decomposition
products.
a
Reagents: (a) I2, CF3CO2Ag, CHCl3, rt. (b) t-BuLi, THF, -78
°C. (c) BF3‚Et2O or TiCl4. (d) R22CuLi or NaBH4/TFA. (e) o-DCB,
reflux.
TABLE 2. In ter m olecu la r r-Am id oa lk yla tion of 14
Lewis acid
conditions
product
yield (%)
Ta n d em P a r h a m Cycliza tion -In ter m olecu la r R-
Am idoalkylation . Once the pyrroloisoquinolines (10bR)-1
had been efficiently prepared, our next concern was the
synthesis of enantiomerically pure (10bS)-1 through
combined Parham cyclization-intermolecular R-amido-
alkylation methodology, followed by retro-Diels Alder
reaction. A preliminary study with racemic compounds
was carried out to check the diastereoselectivity of this
sequence (Scheme 5).
Thus, iodinated imide 13, obtained regioselectively
from 12,18b was submitted to Parham cyclization condi-
tions (t-BuLi, -78 °C, 6 h), affording hydroxylactam 14
in excellent yield and with complete diastereoselectivity.30
Intermolecular R-amidoalkylation reaction was achieved
by prior formation of a bicyclic N-acyliminium ion by
treatment of 14 with BF3‚OEt2, followed by alkylation
with the corresponding cuprates. Thus, C-12b-substituted
isoindoloisoquinolines (12bSR)-11a ,b were obtained in
good yields as single diastereomers, with complete inver-
sion of configuration at C-12b (Table 2, Scheme 5). In
addition, reduction of 14 efficiently furnished (12bSR)-
11c in a stereoselective fashion using NaBH4/TFA, a
reagent that has proven to be synthetically valuable for
the reduction of hydroxy groups.31 Other nucleophiles
such as allylsilane could also be introduced using this
procedure, though in this case it was necessary to use
TiCl4 as a Lewis acid (entry 4).32 Therefore, this approach
could be considered as diastereocomplementary to the
BF3‚Et2O
BF3‚Et2O
MeLi/CuI, -78 °C
BuLi/CuI, -78 °C
NaBH4/TFA, 0 °C to
room temperature
(allyl)TMS,-78 °C to
room temperature
(12bSR)-11a
(12bSR)-11b
(12bSR)-11c
69
52
99
TiCl4
(12bSR)-11d
89
organolithium addition-intramolecular R-amidoalkyl-
ation sequence, as methanoisoindoloisoquinolines (12bSR)-
11 are epimers at C-12b of those previously reported by
us.18b To complete the synthesis of racemic pyrroloiso-
quinolines 1, retro-Diels-Alder reaction was carried out.
However, the application of the FVP procedure described
above to (12bSR)-11 only led to decomposition products,
and it was necessary to carry out the reaction at reflux
of o-DCB to obtain the pyrroloisoquinolines; even working
under these conditions, only good yields of pyrroloiso-
quinolines 1a ,b were achieved.
Having established that the Parham cyclization-
intermolecular R-amidoalkylation sequence was com-
pletely stereoselective, we applied this strategy to the
enantiomerically pure precursor 3b, obtained by regio-
selective iodination of 3a (Scheme 6). Thus, Parham
cyclization of 3b provided hydroxylactam (12bS)-15 as a
single diastereomer, which was submitted to inter-
molecular R-amidoalkylation with different nucleophiles
to afford isoindoloisoquinolines (12bS)-2a -d with com-
plete inversion of configuration at C-12b. Removal of the
chiral auxiliary under the previously tested conditions
(SmI2, HMPA, t-BuOH) furnished isoindoloisoquinolines
(12bS)-11 in good yield and high enantiomeric purity,
determined by CSP HPLC (Table 3). Finally, the use of
refluxing o-DCB to carry out the retro-Diels-Alder
(29) For
a review on the concept of transient chirality in the
stereoselective synthesis via Retro-Diels-Alder reaction, see: Klunder,
A. J . H.; Zhu, J .; Zwanenburg, B. Chem. Rev. 2000, 99, 1163-1190.
(30) Hydroxylactam 14 turned out to be unstable under chromato-
graphic purification conditions on silicagel, suffering partial epimer-
ization at C-12b to give the (12bRS)-14′ epimer (see stereochemical
discussion and Supporting Information). However, it could be efficiently
purified using neutral alumina.
(31) For a review on reduction of alcohols and other functional
groups with this reagent, see: Gribble, G. W. Chem. Soc. Rev. 1998,
27, 395. For related examples, see ref 9.
(32) When BF3‚OEt2 was used, no R-amidoalkylation reaction was
observed. Instead, epimeric hydroxylactam (12bRS)-14′ was recovered
as result of water attack to the intermediate N-acyliminium ion with
inversion of configuration during workup.
J . Org. Chem, Vol. 69, No. 11, 2004 3879

Gonza´lez-Temprano et al.
SCHEME 6a
F IGURE 3.
SCHEME 7a
a
Reagents: (a) I2, CF3CO2Ag, CHCl3, rt. (b) t-BuLi, THF, -78
°C. (c) BF3‚Et2O (d) R22CuLi or NaBH4/TFA. (e) SmI2, HMPA,
t-BuOH. (f) o-DCB, reflux.
TABLE 3. Rem ova l of Ch ir a l Au xilia r y: P r ep a r a tion of
(12bS)-11
entry
product
[R]
ee (%)
yield (%)
1
2
3
4
(12bS)-11a
(12bS)-11b
(12bS)-11c
(12bS)-11d
-192.7
-220.0
-182.4
-149.7
>99
>99
>99
>99
79
60
56
60
a
Reagents: (a) MeLi, THF, -78 °C. (b) SmI2, HMPA, t-BuOH.
(c) TFA, CH2Cl2.
C-12b. In this case, the C10-C11 ethylidene bridge of
the endo-norbornene moiety would block the Re side
(Figure 3).
reaction provided enantiomerically pure pyrroloisoquino-
lines (10bS)-11a ,b. As in the racemic series, under the
conditions tested (12bS)-11c,d , gave only decomposition
products.
To verify that it is the ethylidene bridge that controls
the stereochemistry of the cyclization, the chiral auxiliary
was removed prior to the cyclization step. Thus, using
the organolithium addition conditions (MeLi, THF, -78
°C) on imide 3a followed by treatment with SmI2 gave
enamide 16, since the intermediate hydroxylactam de-
hydrated under reductive desulfinylation conditions.
Without further purification, 16 was treated with TFA
to provide the isoindoloisoquinoline (12bR)-11a in good
yield and >99% ee, thus confirming our hypothesis.
In a similar fashion, the C10-C11 ethylidene bridge
controls the stereochemical outcome of the Parham
cyclization-intermolecular R-amidoalkylation sequence.
Thus, as depicted in Figure 4, the attack of the aryl-
lithium intermediate would occur from the less hindered
Si side of the carbonyl group, resulting in an S configu-
ration for C-12b. Hydroxylactam 15 is subsequently
treated with a Lewis acid, resulting in the formation of
a bicyclic N-acyliminium intermediate. The attack of the
incoming nucleophile would occur from the face opposite
Ster eoch em ica l Con sid er a tion s. Throughout the
methodology described above, different types of stereo-
chemical control have been used to achieve the asym-
metric synthesis of the targeted pyrroloisoquinolines 1.
Thus, it has been shown that the hydroxyl group in the
isoborneol moiety of maleimide 6 controlled the config-
uration of the sulfoxide of maleimide 7 in the oxidation
reaction. Conversely, the sulfinyl group determined the
formation of the endo adduct 3a in a chelation-controlled
Diels-Alder reaction of 7 with cyclopentadiene. Finally,
the ethylidene bridge of the norbornene (and not the
chiral auxiliary) moiety controlled the stereochemical
outcome of the N-acyliminium cyclization of 9a -c to give
(12bR)-2a -c as single diastereomers. Thus, the observed
stereochemistry is consistent with the aromatic ring
approaching the intermediate N-acyliminium ion from
the less hindered Si side, which resulted in an R
configuration for the newly created stereogenic center at
3880 J . Org. Chem., Vol. 69, No. 11, 2004

Enantiodivergent Synthesis of Pyrroloisoquinolines
out were fully consistent with the proposed stereochem-
istry in each case.
In summary, we have developed a stereodivergent
route to enantiomerically pure C-10b-substituted 5,6-
dihydropyrrolo[2,1-a]isoquinolines of R and S absolute
configuration via diastereoselective intra- or inter-
molecular R-amidoalkylation reactions of R-hydroxyl-
actams. The strategy has as a starting point the prepara-
tion of an enantiomerically pure N-phenethylnorborn-5-
en-endo-2,3-dicarboxyimide, with a 2-exo-hydroxy-10-
bornylsulfinyl group as a chiral auxiliary. Thus, the chiral
auxiliary controls the configuration at sulfur, which, in
turn, determines the formation of the endo adduct in a
chelation-controlled Diels-Alder reaction. The applica-
tion of the organolithium addition-intramolecular R-
amidoalkylation sequence on this imide give isoindolo-
isoquinolines of R configuration on C-12b, while (12bS)-
epimers are obtained via a Parham cyclization-inter-
molecular R-amidoalkylation sequence. In both sequences,
the ethylidene bridge of the norbornene moiety is re-
sponsible for the stereochemical control. After reductive
elimination of the chiral auxiliary and retro-Diels-Alder
reaction (10bS)- and (10bR)-pyrroloisoquinolines are
obtained in high yields and optical purities (>99% ee).
F IGURE 4.
Exp er im en ta l Section
In tr a m olecu la r r-Am id oa lk yla tion . Syn th esis of Iso-
in d oloisoqu in olin es (12R)-2a -c. (8a R,9S,12R,12a S,12bR)-
(+)-8a -[(1S,2R,4R,SR)-(2-H yd r oxy-7,7-d im et h ylb icyclo-
[2.2.1]h ep t a n -1-yl)m et h ylsu lfin yl]-2,3-d im et h oxy-12b -
m e t h y l-5,6,8a ,9,12,12a -h e x a h y d r o -9,12-m e t h a n e is o -
in d olin [2,3-a ]isoqu in olin -8-on e [(12bR)-2a ]. To a solution
of compound 3a (1.15 g, 2.2 mmol) in dry THF (45 mL) was
added MeLi (7.6 mL of a 0.66 M solution in pentane, 5 mmol)
at -78 °C. The resulting mixture was stirred at this temper-
ature for 6 h, quenched by the addition of saturated NH4Cl
(20 mL), and allowed to warm to room temperature. The
organic layer was separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo to
afford hydroxy lactam 9a (1.18 g, 99%), which was used
without further purification. To a solution of the thus obtained
hydroxy lactam 9a (203 mg, 0.4 mmol) in CH2Cl2 (10 mL) was
added TFA (2.5 mL, 32.4 mmol), and the resulting solution
was stirred at room temperature for 3 days. The reaction
mixture was treated with saturated aqueous NaHCO3; the
organic layer was decanted, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were washed with brine (2 × 10 mL), dried (Na2SO4),
and concentrated in vacuo. The resulting crude reaction
mixture was purified by flash column chromatography (sili-
cagel, 60% hexane/ethyl acetate), yielding two fractions. 2a
F IGURE 5. Selected NOE enhancements.
to the C10-C11 ethylidene bridge, resulting in an S
configuration for the stereogenic center at C-12b.
Nuclear Overhauser effect difference spectroscopy and
1H-1H decoupling experiments confirmed the stereo-
chemistry of all the isoquinoline derivatives. The most
significant results obtained with epimeric isoindoloiso-
quinolines (12bS)-2a and (12bR)-2a are shown in Figure
5. For instance, isoindoloisoquinoline (12bR)-2a demon-
strated an enhancement of the H-11, H-12, and H-6ax
signals upon irradiation on C-12b methyl hydrogens and
vice versa. This fact, together with the absence of NOE
between C-12b methyl hydrogens and the protons H-12a,
confirms an R configuration for C-12b. On the other hand,
epimeric (12bR)-2a showed an enhancement of H-12a and
H-6ax upon irradiation of C-12b methyl hydrogens,
confirming an S configuration for C-12b. Analogous
results were obtained with the epimeric hydroxylactams
14 and 14′.30 Thus, an enhancement of the signals of endo
protons H-8a and H-12a was observed upon irradiation
on the hydroxyl proton of (12bRS)-14′, whereas on
(12bSR)-14, the signal of hydroxyl proton showed a NOE
enhancement upon irradiation on H-11 and H-12 protons,
and vice versa. The rest of the NOE experiments carried
(101 mg, 51%): [R]23 + 117.9 (0.5, CHCl3); mp (Et2O) 93-94
D
°C; IR (CHCl3) 3400, 1673 cm-1; H NMR (CDCl3) δ 0.60 (s,
1
3H), 1.04 (s, 3H), 1.23-1.25 (m, 2H), 1.48 (s, 3H), 1.60-1.72
(m, 6H), 2.1 (d, J ) 8.3 Hz, 1H), 2.54 (dd, J ) 16.2, 4.4 Hz,
1H), 2.75 (d, J ) 13.1 Hz, 1H), 2.81-2.92 (m, 1H), 3.07 (ddd,
J ) 13.1, 12.3, 4.8 Hz, 1H), 3.21 (d, J ) 13.1 Hz, 1H), 3.32 (d,
J ) 3.6 Hz, 1H), 3.37 (s, 1H), 3.74-3.78 (m, 2H), 3.81-3.89
(m, 1H)*, 3.82 (s, 3H)*, 3.89 (s, 3H)*, 4.18 (dd, J ) 13.1, 6.3
Hz, 1H), 6.33-6.37 (m, 1H), 6.45-6.48 (m, 2H), 6.60 (s, 1H)
(* designates partially overlapped signals); 13C NMR (CDCl3)
δ 19.9, 20.4, 26.5, 27.0, 27.6, 30.5, 35.4, 38.3, 44.9, 45.8, 46.5,
48.1, 48.7, 50.2, 51.0, 52.5, 55.7, 56.2, 60.6, 75.4, 76.8, 107.4,
112.0, 124.1, 135.3, 135.8, 139.2, 147.9, 148.0, 168.4; MS (EI)
m/z (rel intensity) 526 (M+ + 1, 2), 525 (M+, 1), 373 (47), 325
(19), 324 (23), 310 (16), 308 (25), 307 (100), 292 (21), 290 (27),
258 (26), 206 (16), 164 (8), 119 (35), 91 (26). Anal. Calcd for
J . Org. Chem, Vol. 69, No. 11, 2004 3881

Gonza´lez-Temprano et al.
C
30H39NO5S: C, 68.54; H, 7.47; N, 2.66. Found: C, 68.81; H,
su lfin yl]-2,3-d im et h oxy-5,6,8a ,9,12,12a -h exa h yd r o-9,12-
m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-on e [(12bR)-2c].
To a solution of the imide 3a (160 mg, 0.3 mmol) in dry EtOH
(12 mL) was added NaBH4 (214 mg, 5.6 mmol) in portions at
0 °C. The resulting mixture was stirred at this temperature
for 1 h and allowed to warm to room temperature. After 4 h,
the reaction was quenched by the addition of saturated NH4Cl
(10 mL). The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in
vacuo to afford hydroxy lactam 9c (148 mg, 92%), which was
used without further purification. To a solution of the thus
obtained hydroxy lactam 9c (148 mg, 0.28 mmol) in CH2Cl2
(15 mL) was added TFA (4 mL, 52 mmol), and the resulting
solution was stirred at room temperature for 3 days. The
reaction mixture was treated with saturated aqueous NaHCO3;
the organic layer was decanted, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were washed with brine (2 × 10 mL), dried (Na2SO4),
and concentrated in vacuo. The resulting crude reaction
mixture was purified by flash column chromatography (sili-
cagel, ethyl acetate), yielding two fractions: 2c (45 mg, 26%)
and 10c (24.6 mg, 17%). These isoindoloisoquinolines were too
unstable to be fully characterized and in subsequent experi-
ments were submitted to reductive desulfinylation without
purification.
7.42; N, 2.70. 10a (38 mg, 16%): [R]23 + 95.7 (1, CHCl3); IR
D
(CHCl3) 1780, 1673 cm -1; 1H NMR (CDCl3) δ 0.86 (s, 3H), 1.04
(s, 3H), 1.48 (s, 3H), 1.23-1.25 (m, 2H), 1.58-1.92 (m, 5H),
2.1 (d, J ) 8.3 Hz, 1H), 2.47 (dd, J ) 16.0, 3.8 Hz, 1H), 2.79
(ddd, J ) 16.0, 12.3, 6.5 Hz, 1H), 3.03 (td, J ) 12.6, 4.4 Hz,
1H), 3.12-3.23 (m, 2H), 3.28 (s, 1 H), 3.52 (d, J ) 3.6 Hz, 1H),
3.59 (s, 1H), 3.82-3.88 (m, 1H)*, 3.82 (s, 3H)*, 3.89 (s, 3H)*,
4.10 (dd, J ) 13.1, 6.1 Hz, 1H), 5.05 (dd, J ) 7.4, 2.8 Hz, 1H),
6.31-6.34 (m, 1H), 6.45-6.49 (m, 2H), 6.60 (s, 1H) (* desig-
nates partially overlapped signals); 13C NMR (CDCl3) δ 19.6,
20.0, 26.3, 26.7, 27.6, 29.9, 35.7, 38.5, 44.8, 45.3, 45.6, 46.7,
49.2, 50.2, 50.4, 52.6, 55.7, 56.2, 60.7, 75.7, 82.0, 107.6, 111.7,
110.7, 124.0, 135.4, 136.2, 139.7, 147.8, 147.9, 155.6, 169.2;
MS (EI) m/z (rel intensity) 621 (M+, 6), 325 (5), 324 (100), 308
(17), 307 (18), 290 (12), 258 (15), 206 (15), 164 (13), 135 (10),
119 (52), 93 (11), 91 (20).
(8a R,9S,12R,12a S,12b R)-(+)-12b -Bu t yl-8a -[(1S,2R,4R,
SR)-(2-h yd r oxy-7,7-d im et h ylb icyclo[2.2.1]h ep t a n -1-yl)-
m e t h y ls u lfin y l]-2,3-d im e t h o x y -5,6,8a ,9,12,12a -h e x a -
h yd r o-9,12-m et h a n eisoin d olin [2,3-a ]isoq u in olin -8-on e
[(12bR)-2b]. To a solution of compound 3a (969 mg, 1.7 mmol)
in dry THF (37 mL) was added n-BuLi (3.1 mL of a 1.44 M
solution in hexane, 4.3 mmol) at -78 °C. The resulting mixture
was stirred at this temperature for 6 h, quenched by the
addition of saturated NH4Cl (15 mL), and allowed to warm to
room temperature. The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to afford hydroxy lactam 9b (1.05 g, 99%),
which was used without further purification. To a solution of
the thus obtained hydroxy lactam 9b (844 mg, 1.14 mmol) in
CH2Cl2 (40 mL) was added TFA (10 mL, 130 mmol), and the
resulting solution was stirred at room temperature for 3 days.
The reaction mixture was treated with saturated aqueous
NaHCO3; the organic layer was decanted, and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were washed with brine (2 × 10 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting crude
reaction mixture was purified by flash column chromatography
(silicagel, 60% hexane/ethyl acetate), yielding two fractions.
2b (187 mg, 21%): [R]23D + 660 (0.05, CHCl3); IR (CHCl3) 3408,
P a r h a m Cycliza tion of Iod in a ted Im id e 3b. Syn th e-
sis of (8a R,9S,12R,12a S,12bS)-(+)-8a -[(1S,2R,4R,SR)-(2-
Hyd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -1-yl)m eth yl-
su lfin yl]-12b -h yd r oxy-2,3-d im e t h oxy-5,6,8a ,9,12,12a -
h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-
on e (15). To a solution of the imide 3b (121 mg, 0.18 mmol)
in dry THF (15 mL) was added t-BuLi (0.63 mL of a 1.17 M
solution in pentane, 0.74 mmol) at -78 °C. The resulting
mixture was stirred at this temperature for 5 h, quenched by
the addition of saturated NH4Cl (5 mL), and allowed to warm
to room temperature. The organic layer was separated, and
the aqueous phase was extracted with Et2O (2 × 5 mL) and
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to afford hydroxylactam
15, which was crystallized from Et2O (66 mg, 67%): [R]23
+
D
203.3 (0.4, CHCl3); mp (Et2O) 198-200 °C; IR (CHCl3) 3667,
1676 cm-1; 1H NMR (CDCl3) δ 0.41 (s, 3H), 0.98 (s, 3H), 1.15-
1.28 (m, 3H), 1.58-1.73 (m, 5H), 2.10 (d, J ) 9.1 Hz, 1H), 2.31
(d, J ) 12.7 Hz, 1H), 2.60 (dd, J ) 16.4, 4.2 Hz, 1H), 2.75-
2.88 (m, 2H), 3.12-3.27 (m, 3H), 3.41-3.47 (m, 1H), 3.70-
3.77 (m, 2H), 3.82 (s, 3H)*, 3.91 (s, 3H)*, 3.82-3.90 (m, 1H)*,
4.16 (dd, J ) 13.3, 5.7 Hz, 1H), 6.27-6.29 (m, 1H), 6.30-6.56
(m, 2H), 6.84 (s, 1H) (* designates partially overlapped signals);
13C NMR (CDCl3) δ 20.0, 20.1, 27.0, 28.0, 30.6, 34.5, 38.3, 44.7,
46.3, 46.7, 47.9, 48.1, 49.1, 51.0, 52.8, 55.8, 56.2, 75.4, 76.7,
84.9, 107.8, 111.7, 125.9, 130.8, 133.9, 140.2, 148.6, 149.5,
166.5; MS (EI) m/z (rel intensity) 528 (M+ + 1, 1), 527 (M+, 1),
309 (100), 375 (47), 376 (10), 327 (26), 325 (73), 292 (19), 291
(31). Anal. Calcd for C29H37NO6S: C, 66.01; H, 7.07; N, 2.65.
Found: C, 66.07; H, 7.01; N, 2.40.
1675 cm-1 1H NMR (CDCl3) δ 0.63 (s, 3H), 0.87 (t, J ) 6.5
;
Hz, 3H), 1.05 (s, 3H), 1.19-1.41 (m, 8H), 1.66-1.75 (m, 6H),
2.08 (d, J ) 8.7 Hz, 1H), 2.61 (dd, J ) 17.2, 5.3 Hz, 1H), 2.76-
2.94 (m, 2H), 3.19-3.37 (m, 2H), 3.41-3.47 (m, 2H), 3.73 (m,
1H), 3.82 (s, 3H)*, 3.88 (s, 3H)*, 3.83-3.85 (m, 2H)*, 4.18 (dd,
J ) 13.5, 7.9 Hz, 1H), 6.34-6.36 (m, 1H), 6.45-6.47 (m, 1H),
6.51 (s, 1H), 6.68 (s, 1H) (* designates partially overlapped
signals); 13C NMR (CDCl3) δ 13.9, 19.9, 20.4, 23.3, 26.9, 27.0,
28.0, 30.5, 35.4, 37.9, 38.3, 44.9, 45.6, 46.3, 48.1, 48.9, 50.3,
51.0, 51.5, 55.6, 56.3, 63.2, 75.4, 76.8, 108.7, 112.0, 125.3, 132.3,
135.9, 138.9, 147.9, 149.9, 168.7; MS (EI) m/z (rel intensity)
510 (M+ - Bu, 5), 416 (20), 415 (75), 366 (45), 350 (21), 349
(94), 310 (33), 309 (25), 301 (27), 292 (100), 164 (35), 119 (52),
93 (26), 55 (25). 10b (604 mg, 57%): [R]23 +100.9 (0.03,
D
CHCl3); IR (CHCl3) 1783, 1672 cm-1; 1H NMR (CDCl3) δ 0.86-
0.98 (m, 6H), 1.05 (s, 3H), 1.11-1.42 (m, 6H), 1.57-1.93 (m,
7H), 2.07 (d, J ) 8.3 Hz, 1H), 2.5 (dd, J ) 16.8, 5.3 Hz, 1H),
2.76-2.90 (m, 1H), 3.10-3.27 (m, 4H), 3.57-3.58 (m, 2H), 3.84
(s, 3H)*, 3.90 (s, 3H)*, 3.84-3.90 (m, 1H)*, 4.10 (dd, J ) 13.5,
7.3 Hz, 1H), 5.05 (dd, J ) 7.5, 2.7 Hz, 1H), 6.30-6.33 (m, 1H),
6.45-6.48 (m, 2H), 6.70 (s, 1H) (* designates partially over-
lapped signals); 13C NMR (CDCl3) δ 13.8, 19.6, 20.1, 23.3, 26.6,
26.8, 27.9, 29.8, 35.6, 37.6, 38.5, 44.7, 45.1, 45.5, 46.6, 49.2,
50.2, 50.3, 51.3, 55.6, 56.1, 63.3, 75.6, 82.1, 108.8, 111.7, 111.0,
125.1, 132.4, 136.3, 139.3, 146.9, 147.8, 155.9, 169.4; MS (EI)
m/z (rel intensity) 663 (M+, <1), 569 (14), 568 (36), 415 (84),
366 (84), 350 (23), 349 (100), 309 (40), 308 (75), 292 (98), 276
(20), 248 (33), 244 (24), 119 (52), 91 (47), 57 (10), 55 (24).
In ter m olecu la r R-Am id oa lk yla tion Rea ction s of 15.
Syn th esis of Isoin d oloisoqu in olin es (12S)-2a -d . (8a R,
9S ,12R ,12a S ,12b S )-(-)-8a -[(1S ,2R ,4R ,SR )-(2-H yd r oxy-
7,7-d im e t h ylb ic yc lo[2.2.1]h e p t a n -1-yl)m e t h ylsu lfin -
yl]-2,3-d im eth oxy-12b-m eth yl-5,6,8a ,9,12,12a -h exa h yd r o-
9,12-m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-on e [(12b S)-
2a ]. MeLi (1.42 mL of a 1.6 M solution in pentane, 2.28 mmol)
was added at 0 °C to suspension of CuI (217 mg, 1.14 mmol)
in dry THF (10 mL), and the solution was stirred at this
temperature for 1 h. A solution of the hydroxylactam 15 (100
mg, 0.19 mmol) in dry THF (10 mL) at 0 °C was treated with
BF3‚Et20 (0.07 mL, 0.57 mmol), and after 30 min, the reaction
mixture was added via cannula over the organocuprate previ-
ously formed at 0 °C. The resulting mixture was stirred at
this temperature for 3 days, quenched by the addition of NH3
(12% aq, 10 mL), and allowed to warm to room temperature.
(8a R ,9S ,12R ,12a S ,12b R )-(+)-8a -[(1S ,2R ,4R ,S R )-(2-
Hyd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -1-yl)m eth yl-
3882 J . Org. Chem., Vol. 69, No. 11, 2004

Enantiodivergent Synthesis of Pyrroloisoquinolines
The organic layer was separated, and the aqueous phase was
extracted with Et2O (2 × 15 mL) and CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The resulting crude reaction mixture
was purified by flash column chromatography (silicagel, ethyl
1H), 2.49-2.70 (m, 2H), 2.84 (ddd, J ) 12.7, 11.5, 4.7 Hz, 1H),
2.98 (s, 1H), 3.31 (d, J ) 13.1 Hz, 1H), 3.42 (d, J ) 13.1 Hz,
1H), 3.61-3.66 (m, 2H), 3.86 (s, 3H)*, 3.90 (s, 3H)*, 3.86-
3.90 (m, 1H)*, 4.04-4.22 (m, 2H), 4.97 (d, J ) 8.7 Hz, 1H),
5.23-5.26 (m, 1H), 6.07 (dd, J ) 4.8, 3.2 Hz, 1H), 6.55 (s, 1H),
6.63 (s, 1H) (* designates partially overlapped signals); 13C
NMR (CDCl3) δ 19.9, 20.5, 27.1, 28.2, 30.9, 38.0, 38.5, 45.0,
45.4, 45.9, 46.5, 48.2, 48.6, 49.2, 51.0, 55.7, 55.8, 56.0, 76.0,
77.1, 108.6, 111.4, 125.5, 126.5, 135.2, 138.0, 147.8, 147.9,
167.3; MS (EI) m/z (rel intensity) 512 (M+ + 1, 6), 359 (22),
311 (22), 310 (88), 309 (100), 294 (25), 293 (90), 277 (12), 276
(33), 245 (12), 244 (32), 192 (4). Anal. Calcd for C29H37NO5S:
C, 68.07; H, 7.29; N, 2.74. Found: C, 67.98; H, 7.27; N, 2.69.
acetate) to afford (12bS)-2a (85 mg, 84%): [R]23 -101.6 (1.1,
D
CHCl3); mp (pentane) 114-115 °C; IR (CHCl3) 3421, 1677
cm-1; 1H NMR (CDCl3) δ 0.92 (s, 3H), 1.17-1.27 (m, 4H), 1.38-
1.85 (m, 10H), 2.04 (d, J ) 8.3 Hz, 1H), 2.49-2.71 (m, 2H),
2.89-3.01 (m, 2H), 3.39-3.56 (m, 4H), 3.86 (s, 3H)*, 3.91 (s,
3H)*, 3.86-3.94 (m, 1H)*, 4.04-4.15 (m, 2H), 5.14 (dd, J )
5.1, 2.6 Hz, 1H), 6.04 (dd, J ) 5.1, 3.2 Hz, 1H), 6.51 (s, 1H),
6.64 (s, 1H) (* designates partially overlapped signals); 13C
NMR (CDCl3) δ 19.9, 20.5, 27.1, 28.5, 30.8, 32.4, 35.3, 38.5,
45.0, 46.3, 46.5, 48.3, 48.6, 49.5, 51.0, 53.7, 55.8, 56.1, 61.2,
75.6, 77.2, 109.4, 111.0, 125.8, 130.7, 135.3, 138.3, 147.5, 147.9,
166.5; MS (EI) m/z (rel intensity) 526 (M+ + 1, 5), 373 (31),
325 (28), 324 (28), 310 (44), 309 (14), 308 (26), 307 (100), 292
(11), 290 (44), 258 (21), 164 (6). Anal. Calcd for C30H39NO5S:
C, 68.54; H, 7.48; N, 2.66. Found: C, 68.49; H, 7.42; N, 2.41.
(8a R ,9S ,12R ,12a S ,12b S )-(-)-8a -[(1S ,2R ,4R ,SR )-12b -
Allyl-(2-h yd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -1-yl)-
m eth ylsu lfin yl]-2,3-dim eth oxy-5,6,8a,9,12,12a-h exah ydr o-
9,12-m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-on e [(12b S)-
2d ]. Allylmagnesium chloride (1.1 mL of a 2 M solution in
THF, 2.2 mmol) was added at -20 °C to a suspension of CuI
(207 mg, 1.09 mmol) in dry THF (10 mL), and the solution
was stirred at this temperature for 20 min. A solution of the
hydroxylactam 15 (41 mg, 0.08 mmol) in dry THF (5 mL) was
treated with BF3‚Et20 (0.03 mL, 0.23 mmol), and after 30 min,
the reaction mixture was added via cannula over the organo-
cuprate previously formed at -20 °C. The resulting mixture
was stirred at this temperature for 30 min and then at 0 °C
for 5 days. The reaction was quenched by the addition of NH3
(12% aq, 10 mL) and allowed to warm to room temperature.
The organic layer was separated, and the aqueous phase was
extracted with Et2O (2 × 10 mL) and CH2Cl2 (3 × 15 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The resulting crude reaction mixture
was purified by flash column chromatography (silicagel, ethyl
(8aR,9S,12R,12aS,12bS)-(-)-12b-Bu tyl-8a-[(1S,2R,4R,SR)-
(2-h yd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -1-yl)m eth -
ylsu lfin yl]-2,3-d im eth oxy-5,6,8a ,9,12,12a -h exa h yd r o-9,12-
m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-on e [(12bS)-2b].
n-BuLi (1.42 mL of a 1.18 M solution in hexane, 3.51 mmol)
was added at 0 °C to suspension of CuI (333 mg, 1.75 mmol)
in dry THF (10 mL), and the solution was stirred at this
temperature for 1 h. A solution of the hydroxylactam 15 (154
mg, 0.29 mmol) in dry THF (10 mL) at 0 °C was treated with
BF3‚Et20 (0.11 mL, 0.88 mmol), and after 30 min, the reaction
mixture was added via cannula over the organocuprate previ-
ously formed at 0 °C. The resulting mixture was stirred at
this temperature for 3 days, quenched by the addition of NH3
(12% aq, 15 mL), and allowed to warm to room temperature.
The organic layer was separated, and the aqueous phase was
extracted with Et2O (2 × 15 mL) and CH2Cl2 (3 × 15 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The resulting crude reaction mixture
was purified by flash column chromatography (silicagel, ethyl
acetate) to afford (12bS)-2c as an oil (36 mg, 85%): [R]23
D
-134.4 (0.68, CHCl3); IR (CHCl3) 3400, 1676 cm-1; H NMR
1
(CDCl3) δ 0.90 (s, 3H), 1.16 (s, 3H), 1.22-2.05 (m, 8H), 2.03
(d, J ) 8.3 Hz, 1H), 2.48-3.20 (m, 6H), 3.37-3.54 (m, 3H),
3.64 (s, 1H), 3.85 (s, 3H)*, 3.90 (s, 3H)*, 3.85-3.90 (m, 1H)*,
4.04-4.11 (m, 2H), 5.04-5.15 (m, 3H), 5.57-5.70 (m, 1H), 5.98
(dd, J ) 5.1, 3.2 Hz, 1H), 6.51 (s, 1H), 6.65 (s, 1H) (* designates
partially overlapped signals); 13C NMR (CDCl3) δ 19.9, 20.4,
27.1, 28.4, 30.8, 36.4, 38.5, 45.0, 46.5, 46.7, 48.3, 48.6, 49.5,
50.1, 51.0, 52.2, 55.7, 56.1, 64.1, 75.3, 77.1, 109.6, 111.0, 119.9,
126.6, 128.9, 132.9, 134.7, 138.8, 147.3, 147.9, 167.7; MS (EI)
m/z (rel intensity) 510 (M+ - allyl, 22), 358 (10), 309 (31), 308
(100), 292 (33), 291 (3), 260 (8), 164 (1).
Rem ova l of Ch ir a l Au xilia r y by Red u ctive Desu lfin yl-
a tion . Syn th esis of (12bR)-(+)-11a -c a n d (12bS)-(-)-11a -
d . Gen er a l P r oced u r e. To a solution of isoindolisoquinolines
(12bR)-(+)-2 or (12bS)-(-)-2 (1 mmol) in dry THF (5 mL) were
added SmI2 (10 mmol), t-BuOH (10 mmol), and HMPA (70
mmol) sequentially at room temperature. The resulting mix-
ture was stirred at this temperature for 1.5 h (for the 12bR
series) or 2.5 h (for the 12bS series) and quenched by the
addition of cold HCl (15 mL of a 1 M solution). The organic
layer was separated, and the aqueous phase was extracted
with CHCl3 (3 × 10 mL). The combined organic extracts were
washed with saturated Na2S2O3 (3 × 10 mL) and with brine
(3 × 10 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by flash column chromatography afforded iso-
indoloisoquinolines (12bR)-(+)-11a -c or (12bS)-(-)-11a -d .
acetate) to afford (12bS)-2b as an oil (105 mg, 64%): [R]23
D
-94.2 (0.26, CHCl3); IR (CHCl3) 3421, 1675 cm-1 1H NMR
;
(CDCl3) δ 0.84 (t, J ) 7.1 Hz, 3H), 0.92 (s, 3H), 1.13-1.24 (m,
6H), 1.34-1.95 (m, 9H), 1.97-2.06 (m, 3H), 2.49-2.70 (m, 2H),
2.94-3.10 (m, 2H), 3.40-3.60 (m, 4H), 3.88 (s, 3H)*, 3.92 (s,
3H)*, 3.86-3.90 (m, 1H)*, 4.06-4.08 (m, 2H), 4.15 (dd, J )
12.7, 5.5 Hz, 1H), 5.05 (dd, J ) 5.5, 2.4 Hz, 1H), 5.90 (dd, J )
5.1, 3.2 Hz, 1H), 6.5 (s, 1H), 6.6 (s, 1H) (* designates partially
overlapped signals); 13C NMR (CDCl3) δ 13.8, 19.9, 20.4, 23.0,
27.1, 27.5, 28.5, 30.9, 36.8, 38.5, 45.0, 46.1, 46.5, 46.8, 48.3,
48.6, 49.6, 51.0, 53.0, 55.7, 56.1, 64.5, 75.3, 77.1, 109.4, 111.0,
126.5, 129.8, 134.6, 138.9, 147.4, 147.8, 167.9; MS (EI) m/z (rel
intensity) 568 (M+ + 1, 13), 511 (10), 510 (28), 349 (33), 366
(15), 309 (33), 308 (100), 292 (51), 291 (29), 164 (22), 109 (13),
107 (17), 93 (22), 91 (17), 57 (12).
(8a R ,9S ,12R ,12a S ,12b S )-(-)-8a -[(1S ,2R ,4R ,S R )-(2-
Hyd r oxy-7,7-d im eth ylbicyclo[2.2.1]h ep ta n -1-yl)m eth yl-
su lfin yl]-2,3-d im et h oxy-5,6,8a ,9,12,12a -h exa h yd r o-9,12-
m eth a n eisoin d olin [2,3-a ]isoqu in olin -8-on e [(12bS)-2c]. A
solution of the hydroxylactam 15 (118 mg, 0.22 mmol) in dry
CH2Cl2 (10 mL) was added at 0 °C to a mixture of NaBH4 (70
mg, 1.81 mmol) and TFA (0.4 mL, 5.37 mmol). The resulting
mixture was allowed to warm to room temperature and stirred
for 5 h. The reaction was quenched by the addition of NaOH
(10% aq, 10 mL). The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. The resulting crude reaction mixture was
purified by flash column chromatography (silicagel, ethyl
acetate) to afford (12bS)-2b as a white solid (73 mg, 64%):
(8a S,9S,12R,12a S,12bR)-(+)-2,3-Dim eth oxy-12b-m eth -
yl-5,6,8a ,9,12,12a -h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-
a ]isoqu in olin -8-on e [(12bR)-11a ]. According to General
Procedure, (12bR)-(+)-2a (100 mg, 0.2 mmol) was treated
sequentially with SmI2 (20 mL of a 0.1 M solution in THF, 2
mmol), t-BuOH (0.2 mL, 2.1 mmol), and HMPA (2.5 mL, 15
mmol). After workup, purification by flash column chroma-
tography (silicagel, ethyl acetate) afforded isoindoloisoquino-
line (12bR)-11a (59 mg, 83%), whose spectroscopic data are
[R]23 -126.6 (0.75, CHCl3); mp (AcOEt) 123-125 °C; IR
D
(CHCl3) 3425, 1678 cm-1
1.16-1.27 (m, 4H), 1.44-1.84 (m, 7H), 2.03 (d, J ) 8.7 Hz,
;
1H NMR (CDCl3) δ 0.89 (s, 3H),
identical to those previously reported for the racemate:18b [R]23
D
+ 202.8 (1.43, CHCl3); mp (Et2O) 183-184 °C [lit. racemate18b
J . Org. Chem, Vol. 69, No. 11, 2004 3883

Gonza´lez-Temprano et al.
1
(Et2O) 158-160 °C]; H NMR (CDCl3) δ 1.36 (d, J ) 8.2 Hz,
109.4, 111.1, 126.2, 132.5, 133.2, 134.1, 147.2, 147.5, 172.8;
1H), 1.37 (s, 3H), 1.55 (d, J ) 8.2 Hz, 1H), 2.29-2.42 (m, 1H),
2.80-2.98 (m, 2H), 3.00-3.08 (m, 2H), 3.10-3.20 (m, 2H), 3.73
(s, 3H), 3.82 (s, 3H), 4.01-4.10 (m, 1H), 6.10-6.16 (m, 2H),
6.41 (s, 1H), 6.59 (s, 1H) (* designates partially overlapped
signals). The enantiomeric excess determined by CSP HPLC
was >99%, by comparison with the racemic mixture. Chiralcel
OD, 20% hexane/2-propanol, 0.5 mL/min; tr[(12bR)-11a ] ) 18.4
min (>99%); tr(ent) ) 22.4 min (<1%).
MS (EI) m/z (rel intensity) 325 (M+, 5), 311 (11), 310 (52), 245
(19), 244 (100), 200 (4), 85 (2), 83 (2). Anal. Calcd for C20H23
-
NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.44; H, 6.95; N,
4.22. The enantiomeric excess determined by CSP HPLC was
>99%, by comparison with the racemic mixture. Chiralcel OD,
3% hexane/2-propanol, 1 mL/min; tr(ent) ) 38.1 min (<1%);
tr[(12bS)-11a ] ) 41.4 min (>99%).
(8a S,9S,12R,12a S,12bS)-(-)-12b -Bu t yl-2,3-d im et h oxy-
5,6,8a ,9,12,12a -h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-a ]-
isoqu in olin -8-on e [(12bS)-11b]. According to General Pro-
cedure, (12bS)-(-)-2b (72 mg, 0.13 mmol) was treated
sequentially with SmI2 (13 mL of a 0.1 M solution in THF, 1.3
mmol), t-BuOH (0.13 mL, 1.3 mmol), and HMPA (1.33 mL,
7.8 mmol). After workup, purification by flash column chro-
matography (silicagel, ethyl acetate) afforded isoindoloiso-
(8a S,9S,12R,12a S,12bR)-(+)-12b-Bu tyl-2,3-d im eth oxy-
5,6,8a ,9,12,12a -h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-a ]-
isoqu in olin -8-on e [(12bR)-11b]. According to General Pro-
cedure, (12bR)-(+)-2b (129 mg, 0.2 mmol) was treated
sequentially with SmI2 (20 mL of a 0.1 M solution in THF, 2
mmol), t-BuOH (0.2 mL, 2.1 mmol), and HMPA (2.5 mL, 15
mmol). After work up, purification by flash column chroma-
tography (silicagel, ethyl acetate) afforded isoindoloisoquino-
line (12bR)-11b (69 mg, 86%), whose spectroscopic data are
quinoline (12bS)-11b (41 mg, 60%): [R]23 -220.0 (0.10,
D
CHCl3); IR (CHCl3) 1673 cm-1; 1H NMR (CDCl3) δ 0.85 (t, J )
6.9 Hz, 3H), 1.11-1.23 (m, 4H), 1.30 (d, J ) 8.2 Hz, 1H), 1.39
(d, J ) 8.2 Hz, 1H), 1.73-1.94 (m, 2H), 2.45-2.52 (m, 1H),
2.53-2.67 (m, 1H), 2.80 (td, J ) 12.5, 4.5 Hz, 1H), 2.91-2.95
(m, 2H), 3.20 (broad s, 1H), 3.25-3.30 (m, 1H), 3.84 (s, 3H),
3.91 (s, 3H), 4.15 (dd, J ) 12.5, 5.3 Hz, 1H), 4.75-4.77 (m,
1H), 5.88-5.91 (m, 1H), 6.48 (s, 1H), 6.64 (s, 1H); 13C NMR
(CDCl3) δ 14.0, 22.8, 25.8, 28.6, 34.5, 43.9, 45.5, 47.0, 48.1,
50.2, 50.9, 55.7, 56.0, 64.7, 109.3, 111.1, 125.9, 132.7, 133.7,
134.0, 147.0, 147.3, 173.5; MS (EI) m/z (rel intensity) 311 (10),
310 (40), 246 (2), 245 (15), 244 (100), 200 (3). Anal. Calcd for
identical to those previously reported for the racemate:18b [R]23
D
+ 200.7 (0.06, CHCl3); 1H NMR (CDCl3) δ 0.89 (t, J ) 6.9 Hz,
3H), 1.43 (d, J ) 8.3 Hz, 1H), 1.18-1.53 (m, 4H), 1.62 (d, J )
8.3 Hz, 1H), 1.73-1.85 (m, 2H), 2.78 (dd, J ) 16.4, 6.3 Hz,
1H), 3.06 (ddd, J ) 13.4, 10.2, 9.5 Hz, 1H), 3.30-3.40 (m, 3H),
3.41 (broad s, 1H), 3.48-3.51 (m, 1H), 3.86 (s, 3H), 3.92 (s,
3H), 4.17 (dd, J ) 13.4, 7.4 Hz, 1H), 6.20 (dd, J ) 5.5, 2.5 Hz,
1H), 6.31 (dd, J ) 5.5, 2.1 Hz, 1H), 6.61 (s, 1H), 6.76 (s, 1H).
The enantiomeric excess determined by CSP HPLC was >99%,
by comparison with the racemic mixture. Chiralcel OD, 20%
hexane/2-propanol, 0.5 mL/min; tr[(12bR)-11b] ) 12.5 min
(>99%); tr(ent) ) 17.5 min (<1%).
C
23H29NO3: C, 75.17; H, 7.95; N, 3.81. Found: C, 74.86; H,
8.03; N, 3.56. The enantiomeric excess determined by CSP
HPLC was >99%, by comparison with the racemic mixture.
Chiralcel OD, 3% hexane/2-propanol, 1 mL/min; tr(ent) ) 44.2
min (<1%); tr[(12bS)-11b] ) 50.6 min (>99%).
(8a S ,9S ,12R ,12a S ,12b R )-(+)-2,3-Dim e t h oxy-5,6,8a ,9,
12,12a -h e x a h y d r o -9,12-m e t h a n e i s o i n d o li n [2,3-a ]-
isoqu in olin -8-on e [(12bR)-11c]. According to General
Procedure, a mixture of isoindoloisoquinolines (12bR)-(+)-2c
and 10c (124 mg, 0.22 mmol) (obtained from the intramolecu-
lar R-amidoalkylation reaction and used without further
purification) was treated sequentially with SmI2 (22 mL of a
0.1 M solution in THF, 2.2 mmol), t-BuOH (0.2 mL, 2.1 mmol),
and HMPA (2.8 mL, 16.4 mmol). After workup, purification
by flash column chromatography (silicagel, ethyl acetate)
afforded isoindoloisoquinoline (12bR)-11c (22 mg, 39% overall
(8a S ,9S ,12R ,12a S ,12b S )-(-)-2,3-Dim e t h oxy-5,6,8a ,9,
12,12a -h e x a h y d r o -9,12-m e t h a n e i s o i n d o li n [2,3-a ]-
isoqu in olin -8-on e [(12bS)-11c]. According to General
Procedure, (12bS)-(-)-2c (36.5 mg, 0.07 mmol) was treated
sequentially with SmI2 (7.1 mL of a 0.1 M solution in THF,
0.71 mmol), t-BuOH (0.07 mL, 0.71 mmol), and HMPA (0.48
mL, 2.84 mmol). After workup, purification by flash column
chromatography (silicagel, ethyl acetate) afforded isoindolo-
for two steps): [R]23 + 176.4 (0.1, CHCl3); mp oil; mp
isoquinoline (12bS)-11b (12.4 mg, 56%): [R]23 -182.4 (0.12,
D
D
(racemate, AcOEt) 155-156 °C; 1H NMR (CDCl3) δ 1.47 (d, J
) 8.3 Hz, 1H), 1.68 (d, J ) 8.3 Hz, 1H), 2.50-2.60 (m, 1H),
2.78-2.93 (m, 3H), 3.12 (dd, J ) 9.4, 4.1 Hz, 1H), 3.28 (broad
s, 2H), 3.83 (s, 3H), 3.90 (s, 3H), 4.03 (broad s, 1H), 4.16-4.29
(m, 1H), 6.23-6.26 (m, 1H), 6.3-6.32 (m, 1H), 6.54 (s, 1H),
6.65 (s, 1H); 13C NMR (CDCl3) δ 27.4, 36.9, 44.2, 45.4, 46.2,
50.9, 51.0, 55.6, 55.8, 59.1, 107.3, 111.3, 125.3, 130.0, 133.9,
136.5, 147.4, 147.6, 172.7; MS (EI) m/z (rel intensity) 312 (M+
+ 1, 1), 311 (M+, 4), 246 (15), 245 (100), 244 (44), 217 (6), 216
(7), 214 (3), 200 (4). Anal. Calcd for C19H21NO3: C, 73.29; H,
6.80; N, 4.50. Found: C, 72.98; H, 6.78; N, 4.10. The enantio-
meric excess determined by CSP HPLC was >99%, by com-
parison with the racemic mixture. Chiralcel OD, 15% hexane/
2-propanol, 0.4 mL/min; tr[(12bR)-11c] ) 30 min (>99%); tr(ent)
) 46.6 min (<1%).
CHCl3); IR (CHCl3) 1679 cm-1; H NMR (CDCl3) δ 1.34 (d, J
1
) 8.3 Hz, 1H), 1.43 (d, J ) 8.1 Hz, 1H), 2.47-2.66 (m, 2H),
2.77 (td, J ) 11.8, 4.2 Hz, 1H), 2.93 (m, 1H), 3.21-3.33 (m,
2H), 3.35-3.38 (m, 1H), 3.85 (s, 3H), 3.91 (s, 3H), 4.19-4.26
(m, 1H), 4.84 (d, J ) 8.5 Hz, 1H), 4.89-4.92 (m, 1H), 5.91-
5.94 (m, 1H), 6.53 (s, 1H), 6.65 (s, 1H); 13C NMR (CDCl3) δ
28.6, 37.4, 42.0, 45.7, 45.8, 50.2, 50.4, 55.8, 56.0, 57.3, 108.6,
111.4, 126.7, 127.5, 133.6, 134.0, 147.5, 173.5; MS (EI) m/z (rel
intensity) 311 (M+, 62), 310 (25), 246 (9), 245 (60), 244 (100),
230 (10), 217 (7), 216 (15), 215 (11), 214 (65), 202 (5), 200 (8),
192 (15), 191 (9), 176 (7), 91 (11), 77 (6), 66 (11), 65 (6). The
enantiomeric excess determined by CSP HPLC was >99%, by
comparison with the racemic mixture. Chiralcel OD, 10%
hexane/2-propanol, 0.8 mL/min; tr(ent) ) 23.4 min (<1%);
tr[(12bS)-11c] ) 26.5 min (>99%).
(8a S,9S,12R,12aS,12bS)-(-)-2,3-Dim eth oxy-12b-m eth yl-
5,6,8a ,9,12,12a -h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-a ]-
isoqu in olin -8-on e [(12bS)-11a ]. According to General Pro-
cedure,(12bS)-(-)-2a (71 mg,0.13 mmol)was treated sequentially
with SmI2 (13.5 mL of a 0.1 M solution in THF, 1.35 mmol),
t-BuOH (0.13 mL, 1.3 mmol), and HMPA (1.38 mL, 8.1 mmol).
After workup, purification by flash column chromatography
(silicagel, ethyl acetate) afforded isoindoloisoquinoline (12bS)-
(8a S,9S,12R,12a S,12b S)-(-)-12b -Allyl-2,3-d im et h oxy-
5,6,8a ,9,12,12a -h exa h yd r o-9,12-m eth a n eisoin d olin [2,3-a ]-
isoqu in olin -8-on e [(12bS)-11d ]. According to General Pro-
cedure, (12bS)-(-)-2d (36.5 mg, 0.06 mmol) was treated
sequentially with SmI2 (6.6 mL of a 0.1 M solution in THF,
0.66 mmol), t-BuOH (0.06 mL, 0.66 mmol), and HMPA (0.85
mL, 4.96 mmol). After workup, purification by flash column
chromatography (silicagel, ethyl acetate) afforded isoindolo-
11a (35 mg, 79%) as an oil: [R]23 -192.7 (0.60, CHCl3); IR
isoquinoline (12bS)-11d (14 mg, 60%) [R]23 -149.7 (0.3,
D
D
(CHCl3) 1668 cm-1
;
1H NMR (CDCl3) δ 1.29 (d, J ) 8.3 Hz,
CHCl3); IR (CHCl3) 1679 cm-1; H NMR (CDCl3) δ 1.31 (d, J
1
1H), 1.38 (d, J ) 8.5 Hz, 1H), 1.52 (s, 3H), 2.44-2.66 (m, 2H),
2.81-2.93 (m, 3H), 3.24 (broad s, 1H), 3.33-3.38 (m, 1H), 3.84
(s, 3H), 3.90 (s, 3H), 4.10-4.17 (m, 1H), 4.81-4.83 (m, 1H),
5.88-5.92 (m, 1H), 6.49 (s, 1H), 6.63 (s, 1H); 13C NMR (CDCl3)
δ 28.8, 32.3, 34.5, 45.7, 46.7, 49.6, 50.1, 50.6, 55.7, 56.0, 61.7,
) 8.7 Hz, 1H), 1.40 (d, J ) 8.7 Hz, 1H), 2.43-2.57 (m, 2H),
2.60-2.70 (m, 2H), 2.84-2.90 (m, 2H), 2.95-3.00 (m, 1H),
3.21-3.26 (m, 2H), 3.86 (s, 3H), 3.92 (s, 3H), 4.18 (dd, J )
13.0, 4.6 Hz, 1H), 4.79-4.81 (m, 1H), 5.11-5.16 (m, 2H), 5.64-
5.80 (m, 1H), 5.89-5.92 (m, 1H), 6.51 (s, 1H), 6.66 (s, 1H); 13
C
3884 J . Org. Chem., Vol. 69, No. 11, 2004

Enantiodivergent Synthesis of Pyrroloisoquinolines
NMR (CDCl3) δ 28.5, 34.4, 45.4, 46.7, 47.9, 48.0, 50.1, 50.6,
55.6, 56.0, 64.5, 109.2, 111.1, 119.5, 126.2, 131.6, 132.4, 133.6,
134.1, 147.0, 147.4, 173.6; MS (EI) m/z (rel intensity) 311 (5),
310 (22), 245 (17), 244 (100), 228 (4), 200 (12), 77 (4), 66 (8),
65 (5); HRMS calcd for C19H20NO3 (M+ - allyl) 310.1443, found
310.1433. The enantiomeric excess determined by CSP HPLC
was >99%, by comparison with the racemic mixture. Chiralcel
OD, 3% hexane/2-propanol, 1 mL/min; tr(ent) ) 26.1 min
(<1%); tr[(12bS)-11d ] ) 31.4 min (>99%).
6.13 (d, J ) 5.7 Hz, 1H), 6.59 (s, 1H), 6.69 (s, 1H), 7.22 (d, J
) 5.7 Hz, 1H). The enantiomeric excess determined by CSP
HPLC was >99%, by comparison with the racemic mixture.
Chiralcel OD, 20% hexane/2-propanol, 0.4 mL/min; tr[10bR)-
1b] ) 17.5 min (>99%); tr[(10bS)-1b] ) 19 min (<1%).
(10b S)-(-)-8,9-Dim et h oxy-10b-m et h yl-5,6d ih yd r op yr -
r olo[2,1-a ]isoqu in olin -3-on e [(10bS)-1a ]. A solution of iso-
indoloisoquinoline (12bS)-11a (35 mg, 0.11 mmol) in o-DCB
(5 mL) was refluxed for 9 days. The evolution of the reaction
was monitored by 1H NMR. The crude product was purified
by column chromatography (silica gel, 80% hexane/ethyl
acetate) (10 mg, 50%), whose spectroscopic data were identical
to those previously reported for the racemate:18b [R]23D -220.6
(0.29, CHCl3). The enantiomeric excess determined by CSP
HPLC was >99%, by comparison with the racemic mixture.
Chiralcel OD, 20% hexane/2-propanol, 0.4 mL/min; tr[10bS)-
1a ] ) 14.5 min (>99%); tr[(10bR)-1a ] ) 18.6 min (<1%).
(10bS)-(-)-10b-Bu tyl-8,9-dim eth oxy-5,6-dih ydr opyr r olo-
[2,1-a ]isoq u in olin -3-on e [(10bS)-1b ]. A solution of iso-
indoloisoquinoline (12bS)-11b (21 mg, 0.06 mmol) in o-DCB
(3 mL) was refluxed for 10 days. The evolution of the reaction
was monitored by 1H NMR. The crude product was purified
by column chromatography (silica gel, 80% hexane/ethyl
acetate) (12 mg, 70%), whose spectroscopic data were identical
to those previously reported for the racemate:18b [R]23D - 245.4
(0.20, CHCl3). The enantiomeric excess determined by CSP
HPLC was >99%, by comparison with the racemic mixture.
Chiralcel OD, 20% hexane/2-propanol, 0.4 mL/min; tr[10bR)-
1b] ) 17.5 min (<1%); tr[(10bS)-1b] ) 19 min (>99%).
Retr o Diels-Ald er Rea ction s. Syn th esis of En a n tio-
m er ica lly P u r e Isoqu in olin es (10bR)-1a ,b or (10bS)-1a ,b.
(10bR)-(+)-8,9-Dim eth oxy-10b-m eth yl-5,6dih ydr opyr r olo-
[2,1-a ]isoqu in olin -3-on e [(10bR)-1a ]. Isoindoloisoquinoline
(12bR)-11a (92 mg, 0.28 mmol) was heated at 560 °C under
vacuum (1 mmHg) for short periods of time (10 min). The
1
evolution of the reaction was monitored by H NMR, and the
procedure was repeated until complete consumption of starting
material was observed. The crude product was purified by flash
column chromatography (silicagel, 80% hexane/ethyl acetate)
(63 mg, 85%), whose spectroscopic data were identical to those
previously reported for the racemate:18b [R]23 +201.4 (0.35,
D
1
CHCl3); H NMR (CDCl3) δ 1.45 (s, 3H), 2.52 (dd, J ) 16.4, 2
Hz, 1H), 2.71-2.85 (m, 1H), 3.09 (td, J ) 13.1, 4.2 Hz, 1H),
3.68 (s, 3H), 3.74 (s, 3H), 4.26 (dd, J ) 13.1, 7.0 Hz, 1H), 5.94
(d, J ) 5.7 Hz, 1H), 6.47 (s, 1H), 6.62 (s, 1H), 7.29 (d, J ) 5.7
Hz, 1H). The enantiomeric excess determined by CSP HPLC
was >99%, by comparison with the racemic mixture. Chiralcel
OD, 20% hexane/2-propanol, 0.4 mL/min; tr[10bS)-1a ] ) 14.5
min (<1%); tr[(10bR)-1a ] ) 18.6 min (>99%).
(10bR)-(+)-10b-Bu tyl-8,9-dim eth oxy-5,6-dih ydr opyr r olo-
[2,1-a ]isoqu in olin -3-on e [(10bR)-1b]. Isoindoloisoquinoline
(12bR)-11b (129 mg, 0.35 mmol) was heated at 560 °C under
vacuum (1 mmHg) for short periods of time (10 min). The
Ack n ow led gm en t. Financial support from Gobierno
Vasco (PI-1999-165), MCYT (BQU2000-0223), and Uni-
versidad del Pa´ıs Vasco is gratefully acknowledged. We
also thank UPV/EHU and Gobierno Vasco for grants
(I.G.T. and I.O.).
1
evolution of the reaction was monitored by H NMR and the
procedure was repeated until complete consumption of starting
material was observed. The crude product was purified by
column chromatography (silicagel, 80% hexane/ethyl acetate)
(84 mg, 80%), whose spectroscopic data coincided with those
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterization data for compounds 3a ,b,
4-7, 13, 14, and 14′ and copies of 1H and 13C NMR spectra of
compounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
previously reported for the racemate:18b [R]23 + 240.5 (0.19,
D
CHCl3); 1H NMR (CDCl3) δ 0.84 (t, J ) 7.1 Hz, 3H), 1.08-
1.26 (m, 4H), 1.85-1.96 (m, 2H), 2.64 (dd, J ) 16.2, 4.1 Hz,
1H), 2.91 (td, J ) 16.2, 6.7 Hz, 1H), 3.15 (td, J ) 12.4, 4.1 Hz,
1H), 3.83 (s, 3H), 3.88 (s, 3H), 4.41 (dd, J ) 12.4, 6.7 Hz, 1H),
J O049672O
J . Org. Chem, Vol. 69, No. 11, 2004 3885