Asymmetric synthesis of 4-hydroxy-3-phenyltetrahydroisoquinoline derivatives using enantiopure sulfinimines (N-sulfinyl imines)

Article abstract of DOI:10.1021/jo991119x

Addition of lateral lithiated amides and phthalide anions to enantiopure sulfinimines (N-sulfinyl imines) represents a new approach for the asymmetric synthesis of 3-substituted isoquinolones and 3-substituted 4-hydroxy isoquinolones, respectively, important chiral building blocks for isoquinoline alkaloid synthesis. In one example 3-phenylisoquinolone (-)-15b was prepared in >95% ee by treatment of amide ion 10b with sulfinimine (S)- (+)-11 and subsequent deprotection of the N-sulfinyl auxiliary and cyclization. Oxaziridine-mediated hydroxylation of the anion of 16 afforded 4-hydroxy isoquinolone 19, which was transformed into 4-hydroxy-3- phenyltetrahydroisoquinoline (-)-22. In another approach 22 was prepared more directly by addition of phthalide ion 26 to (S)-(+)-11, creating the two stereogenic centers simultaneously. The selectivity proved to be highly counterion dependent.

Full text of DOI:10.1021/jo991119x

J . Org. Chem. 1999, 64, 8627-8634
8627
Asym m etr ic Syn th esis of
4-Hyd r oxy-3-p h en yltetr a h yd r oisoqu in olin e Der iva tives Usin g
En a n tiop u r e Su lfin im in es (N-Su lfin yl Im in es)
Franklin A. Davis* and Yemane W. Andemichael
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
Received J uly 13, 1999
Addition of lateral lithiated amides and phthalide anions to enantiopure sulfinimines (N-sulfinyl
imines) represents a new approach for the asymmetric synthesis of 3-substituted isoquinolones
and 3-substituted 4-hydroxy isoquinolones, respectively, important chiral building blocks for
isoquinoline alkaloid synthesis. In one example 3-phenylisoquinolone (-)-15b was prepared in >95%
ee by treatment of amide ion 10b with sulfinimine (S)-(+)-11 and subsequent deprotection of the
N-sulfinyl auxiliary and cyclization. Oxaziridine-mediated hydroxylation of the anion of 16 afforded
4-hydroxy isoquinolone 19, which was transformed into 4-hydroxy-3-phenyltetrahydroisoquinoline
(-)-22. In another approach 22 was prepared more directly by addition of phthalide ion 26 to (S)-
(+)-11, creating the two stereogenic centers simultaneously. The selectivity proved to be highly
counterion dependent.
Sch em e 1
Interest in 3-substituted 1,2,3,4-tetrahydroisoquino-
lines stems from their unique structure and diverse
biological properties. Relevant examples include koru-
pensamine A (1), ophiocarpine (2), and narciclasine (3),
members of the naphthylisoquinoline,1 protoberberine,2
and amaryllidaceae3 families, respectively (Scheme 1).
Korupensamine A (1) is a subunit of the michellamines,
which protect against HIV by inhibiting viral reverse
transcriptase and cellular fusion.1,4 Other naphthyliso-
quinolines show antimalarial, antifeedant, fungicidal,
molluscicidal, and larvicidal properties.1 The protober-
berine alkaloids such as ophiocarpine (2) are widely
distributed in nature and exhibit diverse biological
activities.2 Importantly, they also serve as the biosyn-
thetic and synthetic precursors of related structures,
including protopine, phthalidesioquinolines, and spiro-
benzylisoquinoline.2a The amaryllidaceae alkaloids nar-
ciclasine (3) and pancratistatin (4) are powerful antitu-
mor agents that inhibit eukaryotic protein synthesis at
the ribosomal level.3
the isoquinoline ring.6,7 In the asymmetric synthesis of
isoquinolines, the enantioselective synthesis of the â-aryl-
ethylamino precursors, as well as the compatibility of
functionalized derivatives with the harsh B-N and P-S
conditions,5 can be a problem.
3-Substituted 1(2H)-isoquinolones 6 are potentially
important chiral building blocks for the asymmetric
construction of isoquinolines because they can be reduc-
tively transformed into a variety of substituted 1,2,3,4-
tetrahydroisoquinolines 5 (Scheme 2). Clark and J ahan-
gir described the synthesis of 6 by condensation of lateral
lithiated amides 88 with racemic imines.9,10 This proce-
The cyclization of â-arylethylamino derivatives using
the Bishler-Napieralski (B-N) and Pictet-Spengler (P-
S) protocols has been the most widely employed route to
isoquinolines.1,5 Because nitrilium ion intermediates are
involved, side reactions occur, and there are difficulties
in controlling the regio- and stereoselective formation of
(1) For a review see: Bringmann, G.; Pokorny, F. The Naphthyl-
isoquinoline Alkaloids. The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1995; Vol. 46; p 127.
(2) For reviews see: (a) Hanaoka, M. Transformation Reactions of
Protoberberine Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1988; Vol. 33, p 141. (b) Bhakuni, D. S.; J ain, S.
Protoberberine Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1986; Vol. 28, p 95. (c) Santavy, F. Papaveraceae
Alkaloids. II. In The Alkaloids; Manske, R. H. F.; Rodrigo, R. G. A.,
Eds.; Academic Press: New York, 1986; Vol. 28, p 95.
(6) Hiemstra, H.; Speckamp, W. N. N-Acyliminium Ions as Inter-
mediates in Alkaloid Synthesis. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1988; Vol. 32, p 271.
(3) For reviews see: (a) Martin, S. The Amaryllidaceae Alkaloids.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987;
Vol. 30, p 252. (b) Polt, R. Amaryllidaceae Alkaloids with Antitumor
Activity. In Organic Synthesis: Theory and Applications; Hudlicky,
T., Ed.; J AI Press: Greenwich, 1996; Vol. 3, p 109.
(4) Hoye, T. R.; Chen, M.; Mi, L.; Priest, O. P. Tetrahedron Lett.
1994, 35, 8747.
(7) Larsen, R. D.; Reamer, R. E.; Corley, E. G.; Davis, P.; Grabowski,
E. J . J .; Reider, P. J .; Shinkai, I. J . Org. Chem. 1991, 56, 6034.
(8) For a review on lateral lithiation reactions see: Clark, R. D.;
J ahangir, A. Org. React. 1995, 47, 5.
(9) (a) Clark, R. D.; J ahangir, A. J . Org. Chem. 1987, 52, 5378. (b)
Clark, R. D.; J ahangir, A. J . Org. Chem. 1989, 54, 1174.
(10) For a chiral example see: Clark, R. D.; J ahangir, A.; Souchet,
M.; Kern, J . R. J . Chem. Soc., Chem. Commun. 1989, 930.
(5) Rozwadowski, M. D. Heterocycles 1994, 39, 903.
10.1021/jo991119x CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/21/1999

8628 J . Org. Chem., Vol. 64, No. 23, 1999
Davis and Andemichael
Sch em e 2
Sch em e 3
dure avoids many of the limitations of the B-N and P-S
protocols and should provide isoquinolines with substitu-
tion patterns not readily accessible by other means. What
has undoubtedly prevented the general application of this
methodology to the asymmetric synthesis of 6 is the
unreactivity of imines, the propensity of aliphatic ex-
amples to undergo R-deprotonation rather than addition,
and the lack of suitable chiral examples.
Recent studies in our laboratory and elsewhere have
demonstrated that the N-sulfinyl group in sulfinimines
(N-sulfinyl imines) 9 is superior to other imine auxiliaries
because it activates the CdN bond for addition to such
an extent that R-deprotonation is not an important
issue.11-19 It is highly stereodirecting and easily removed
under mild acidic conditions. We describe here the utility
of sulfinimines for the asymmetric synthesis of new
1(2H)-isoquinolone 6 building blocks and their elabora-
tion into 4-hydroxy-3-phenyltetrahydroisoquinoline de-
rivatives, which are potential precursors of the 13-
hydroxyprotoberberine alkaloids.20
Resu lts a n d Discu ssion
F r om La ter a l Lith ia ted Am id es. Initially the addi-
tion of the lateral lithiated amide generated from N,N-
diethyl-o-toluamide (10a ) to (S)-(+)-N-(benzylidene)-p-
toluenesulfinamide (11) was explored.21 Thus, treatment
of 10a with 2 equiv of LDA at -78 °C gave an intensely
colored burgundy solution of the lateral lithiated amide
to which was added 1 equiv of (+)-11 (Scheme 3). The
desired sulfinamide (+)-12a was obtained in only 24%
yield, and 3-phenyl-1(2H)-isoquinolone (13) was also
isolated in 26% yield. Sulfinamide 12a cannot be the
source 13 because reaction with base, under the reaction
conditions, produced none of the isoquinolone. However,
Poindexter reported that 13 is formed by reaction of the
amide ion of 10a with benzonitrile.22 Indeed, treatment
of sulfinimine 11 with 2.0 equiv of LDA at -78 °C
resulted in 1,2-elimination of p-toluenesulfenic acid anion
(p-tolylSO-) with formation of benzonitrile in 27% and
36% yield (HPLC) after 20 and 50 min, respectively.
(11) For a review on the chemistry of sulfinimines see: Davis, F.
A.; Zhou, P.; Chen, B-C. Chem. Soc. Rev. 1998, 27, 13.
(12) Amines: (a) Liu, G.; Cogan, D. A.; Ellman, J . A. J . Am. Chem.
Soc. 1997, 119, 9913. (b) Moreau, P.; Essiz, M.; Merour, J .-Y.; Bouzard,
D. Tetrahedron: Asymmetry 1997, 8, 591. (c) Hose, D. R. J .; Mahon,
M. F.; Molloy, K. C.; Raynham, T.; Wills, M. J . Chem. Soc., Perkin
Trans 1 1996, 691. (d) Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc.
1999, 121, 268.
(13) R-Amino acids: (a) Davis, F. A.; Srirajan, V.; Titus, D. J . Org.
Chem. 1999, 64, 6931. (b) Davis, F. A.; McCoull, W. J . Org. Chem.
1999, 64, 3396. (c) Davis, F. A.; Fanelli, D. L. J . Org. Chem. 1998, 63,
1981. (d) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J .
Org. Chem. 1996, 61, 440. (e) Bravo, P.; Crucianelli, M.; Vergani, B.;
Zanda, M. Tetrahedron Lett. 1998, 39, 7771. (f) Hua, D. H.; Lagneau,
N.; Wang, H.; Chen, J . Tetrahedron: Asymmetry 1995, 6, 349.
(14) â-Amino acids: (a) Davis, F. A.; Szewczyk, J . M. Tetrahedron
Lett. 1998, 39, 5951. (b) Davis, F. A.; Szewczyk, J . M.; Reddy, R. E. J .
Org. Chem. 1996, 61, 2222. (c) Fujisawa, T.; Kooriyama, Y.; Shimizu,
M. Tetrahedron Lett. 1996, 37, 3881. (d) Davis, F. A.; Reddy, R. E.;
Szewczyk, J . M.; J . Org. Chem. 1995, 60, 7037. (e) J iang, J .; Schuma-
cher, K. K.; J oullie, M. M.; Davis, F. A.; Reddy, R. E. Tetrahedron Lett.
1994, 35, 2121. (f) Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry
1994, 5, 955. (g) Garcia Ruano, J . L.; Fernandez, I.; de Prado Catalina,
M.; Hermoso, J . A.; Sanz-Aparicio, J .; Martinez-Ripoll, M. J . Org.
Chem. 1998, 63, 7157. (h) Hua, D. H.; Miao, S. W.; Chen, J . S.; Iguchi,
S. J . Org. Chem. 1991, 56, 4. (i) Wei, H.-X.; Hook, J . D.; Fitzgerald, K.
A.; Li, G. Tetrahedron: Asymmetry 1999, 10, 661. (j) Tang, T. P.;
Ellman, J . A. J . Org. Chem. 1999, 64, 12. (k) Adamczyk, M.; Reddy, R.
E. Tetrahedron: Asymmetry, 1998, 9, 3919.
(15) R-Amino phosphonates: (a) Lefebvre I. M.; Evans, S. A., J r. J .
Org. Chem. 1997, 62,7532. (b) Mikolajczyk, M.; Lyzwa, P.; Drabowicz,
J . Tetrahedron: Asymmetry 1997, 8, 3991. (c) See also ref 19.
(16) â-Amino phosophonates: Mikolajczyk, M.; Lyzwa, P.; Drabow-
icz, J .; Wieczorek, M. W.; Blaszczyk, J . J . Chem. Soc., Chem. Commun.
1996, 1503.
(17) Aziridines: (a) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy,
G. V.; Zhang, Y. J . Org. Chem. 1999, 64, 7559. Davis, F. A.; Liang,
C.-H.; Liu, H. J . Org. Chem. 1997, 62, 3796. (b) Davis, F. A.; Liu, H.;
Reddy, G. V. Tetrahedron Lett. 1996, 37, 5473. (c) Davis, F. A.; Reddy,
G. V. Tetrahedron Lett. 1996, 37, 4349. (d) Ruano, J . L. G.; Fernandez,
I.; Catalina, M. Cruz, A. A. Tetrahedron: Asymmetry 1996, 7 3407. (e)
Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995, 117, 3651.
(f) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, G. V. Tetrahedron:
Asymmetry 1995, 6, 1511. (g) Davis, F. A.; Zhou, P.; Reddy, R. E. J .
Org. Chem. 1994, 59, 3243. (h) Davis, F. A.; Zhou, P. Tetrahedron Lett.
1994, 35, 7525.
(18) Alkaloids: (a) Reference 3a. (b) Balasubramanian, T.; Hassner,
A. Tetrahedron: Asymmetry 1998, 9, 2201. (c) Balasubramanian, T.;
Hassner, A. Tetrahedron Lett. 1996, 37, 5755. (d) Viso, A.; de la
Pradilla, R. F.; Guerrero-Strachan, C.; Alonso, M.; Martinez-Ripoll, M.;
Andre, I. J . Org. Chem. 1997, 62, 2316.
(19) Aziridine 2-phosphonates/ azirinyl phosphonates: (a) Davis, F.
A.; McCoull, W. Org. Lett. 1999, 1, 1053. (b) Davis, F. A.; McCoull, W.
Tetrahedron Lett. 1999, 40, 249.
(20) Some aspects of this work were reported in preliminary form:
Davis, F. A.; Andemichael, Y. W. Tetrahedron Lett. 1998, 39, 3099.
(21) (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Portonovo, P.
S.; Reddy, G. V.; Zhang, H.; Fanelli, D.; Thimma Reddy, R.; Zhou, P.;
Carroll, P. J . J . Org. Chem. 1997, 62, 2555. (b) Davis, F. A.; Zhang;
Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J . Org. Chem.
1999, 64, 1403.
(22) Poindexter, G. S. J . Org. Chem. 1982, 47, 3787.

Synthesis of Substituted 4-Hydroxy Isoquinolines
J . Org. Chem., Vol. 64, No. 23, 1999 8629
Sch em e 4
When 1.2 equiv of LDA was used to generate the anion
of 10a , the yield of (+)-12a increased to 70%. It proved
difficult to determine the diastereomeric purity of sulfin-
amide (+)-12a by NMR. However, amine 14a was ob-
tained in >95% yield by treatment of 12a with TFA/
MeOH, and preparation of the Mosher amide from 14a
indicated that sulfinamide 12a was formed as a single
diastereoisomer (i.e., >95% de). Cyclization of 14a to the
isoquinolone (-)-15a was accomplished by treatment
with 3 equiv of tert-butyllithium. Attempts to directly
convert 12 to 15 under these conditions was unsuccessful,
most likely as a result of the stability of the N-sulfinyl-
amine anion.
Because suitable crystals for X-ray analysis of 12a
could not be obtained, it was necessary to determine the
absolute configuration of the new stereogenic center by
chemical means. In this context the enantioselective
synthesis of 4-hydroxy-6-methoxy-N-methyl-3-phenyl-
1,2,3,4-tetrahydroisoquinoline (21) was undertaken.
Dominguez and co-workers reported the asymmetric
synthesis of (3S,4R)-(+)-22 in a series of steps from an
enzyme-resolved cyanohydrin.23 Hydroxy isoquinolines
are potential precursors of the 13-hydroxyprotoberberines
such as ophiocarpine (2) and exhibit diverse biological
activities.24-26
Synthesis of the 6-methoxy analogue 15b was ac-
complished in 86% yield for the three steps as outlined
in Scheme 3. Interestingly, it was found that when about
50% of sulfinimine (+)-11 was added to the lateral
lithiated amide of 10b, the color of the anion discharged.27
If an additional equivalent of LDA was added, followed
by the rest of (+)-11, the yield of sulfinamide (+)-12b was
85-90%, obtained as a single isomer.27 Removal of the
auxiliary and cyclization gave 15b in 86% overall yield,
which was N-methylated with NaH/MeI (Scheme 4). To
introduce the C-4 hydroxy group into (-)-16 we planned
to carry out an oxaziridine-mediated hydroxylation of the
corresponding C-4 anion, which was generated with 3
equiv of LDA.28 Treatment with (()-2-(phenylsulfonyl)-
3-phenyloxaziridine 1720 or (camphorylsulfonyl)oxaziri-
dine (-)-18 afforded (+)-19 as a single hydroxy diaste-
reoisomer in 85% yield. The trans selectivity is consistent
with our earlier findings that the hydroxylation stereo-
chemistry is controlled by nonbonded steric interactions
in the transition state such that the oxygen of the
oxaziridine is delivered from the sterically least hindered
direction28a and also is in agreement with the small 3,4-
coupling constant of 2.1 Hz in (+)-19.29 The synthesis of
22 was completed by silylation with TBDPSCl/imidazole,
reduction with BH3‚DMS, and desilylation with tetrabu-
tylammonium fluoride (TBAF) to give (3R,4S)-(-)-22 in
78% yield for the three steps. The enantiomeric purity
of 22 was >95% ee as determined by a chiral shift 1H
NMR (500 MHz) experiment using Eu(hfc)3. The spectral
properties of this compound were identical in all respects
with those reported previously, except that it had the
opposite but equal sign of rotation. Therefore, the con-
figuration of the initially formed stereocenter in sulfin-
amide (+)-12b and by analogy to (+)-12a is S.
Mechanistic details of heteroatom-facilitated lateral
lithiation reactions are unknown.8 However, studies by
Beak et al.30 and others8 suggest that these species can
be represented as o-quinodimethane resonance struc-
tures, e.g., 23 (Scheme 5). This is based on the intense
colors of these anions, consistent with electronic delocal-
ization, and the fact that N-ethyl-2-isopropylbenzamide
does not form a tertiary benzylic species. In the latter
example steric hindrance may inhibit formation of the
planar anion. Steric and chelation control arguments
have been used to rationalize the asymmetric induction
for addition of organometallic reagents to sulfinimines
with regard to the participation of the chiral sulfinyl
group. Enolates,14,17 allyl14h and alkyl13d Grignard re-
agents, DIBAL-H,12c,14h and Et2AlCN13b,c are suggested
to react with sulfinimines via six-membered chairlike
transition states in which the metal ion is chelated to
the sulfinyl oxygen. However, steric arguments have been
evoked to explain the stereochemistry for additions of
benzyl Grignard,13a,c metal phosphites,15 R-metallo phos-
phonates,16 chloromethyl phosphonate anions,19 and 1,3-
dipoles18d to sulfinimines. On the basis of these consid-
erations and the assumption that the sulfinimine has the
E geometry,15a,21 a plausible rationalization for the pref-
(23) Tellitu, I.; Badia., D.; Dominguez, E.; Garcia, F. J . Tetrahe-
dron: Asymmetry 1994, 5, 1567.
(24) Haber, H.; Roske, I.; Rottmann, M.; Georgi, M.; Melzig, M. F.
Life Sci. 1997, 60, 79. Bases, H. A.; Garelick, J . S. J . Org. Chem. 1984,
49, 4552. Cohen, G.; Collins, M. Science 1970, 167, 1749.
(25) Grunewald, G. L.; Ye, Q.; Kieffer, L.; Monn, J . A. J . Med. Chem.
1988, 31, 169.
(26) Kihara, M.; Ikeuchi, M.; Yamauchi, A.; Nukatsuka, M.; Mat-
sumoto, H.; Toko, T. Chem. Pharm. Bull. 1997, 45, 939.
(27) Excess base may be necessary to shift the reaction equilibrium
to a more favorable position because isopropylamine formed on
deportonation quenches the anion. This effect is known as the “hidden
proton” effect. See Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27,
1624.
(28) For reviews on the oxygen transfer reactions of oxaziridines
see: (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (b) Davis,
F. A.; Chen, B.-C. In Stereoselective Synthesis; Helmchen, G., Hoffman,
R. W., Mulzer, J ., Schaumann, E., Eds.; 1995; Houben-Weyl: E21e,
4497. (c) Davis, F. A.; Thimma Reddy, R. Comprehensive Heterocyclic
Chemistry II; Padwa, A., Ed., Pergamon Press: Oxford, 1996; 1, 365.
(29) Cushman, M.; Choong, T.-C.; Valko, S. T.; Koleck, M. P. J . Org.
Chem. 1980, 45, 5067.
(30) Beak, P.; Tse, A.; Hawkins, J .; Chen, C.-W.; Mills, S. Tetrahe-
dron 1983, 39 1983.

8630 J . Org. Chem., Vol. 64, No. 23, 1999
Davis and Andemichael
Sch em e 5
ucts than the sequential method (Table 1, compare
entries 1 and 2, 7 and 8). Furthermore, the potassium
enolate gave a reaction mixture having fewer side
products. Solvent also played a role, with THF/Et2O (1:
1) giving better selectivity (Table 1, entries 2 and 3, 8
and 9). However, in pure ether the reaction mixture was
complex, consisting of multiple products, 27 and 28, that
were impossible to separate.
That the two diastereoisomers produced in the reaction
of (+)-11 with the anion of 26 are epimeric at the carbon
centers was determined by cyclizing the mixture with
NaH to give a single hydroxy isoquinolone 28. Further-
more, the pure diastereoisomers (SS,S,R)-(-)-27a and
(SS,R,S)-(-)-27b, isolated by flash chromatography, were
individually cyclized with 2.5 equiv of NaH to give the
same 3,4-trans-hydroxyisoquinolines (3S,4R)-(-)-28 and
(3R,4S)-(+)-28, respectively, with identical spectral prop-
erties but opposite optical rotations. The absolute con-
figuration of (3R,4S)-(+)-28 was established by silylation
with TBDPSCl and N-methylation to give (3R,4S)-(+)-
N-methyl-3-phenyl-3,4-dihydro-1(2H)-isoquinolone (20),
whose stereochemistry was determined in the preceding
section (vide supra).
An explanation for the observed stereochemistry is
given in Scheme 7. The preference for the (SS,S,R)-(-)-
27a is consistent with chelation control in which the
lithium ion is associated with the sulfinyl oxygen as in
TS-5 and the phthalide ion approaches the si face of 11.
Conversely, formation of (SS,R,S)-(-)-27b would involve
attack of phthalide anion at the less sterically hindered
re face of 11 as in TS-6. Thus chelation control by the Li
ion vs steric control with the poorer chelating Na and K
ions appears to be responsible for the reversibility of the
stereochemistry. Consistent with this hypothesis is the
observation that addition of N,N′-dimethylpropyleneurea
(DMPU), known to disrupt metal ion chelation, has no
effect on the stereoselectivity with NaHMDS, whereas
the selectivity was reversed with LiHMDS (Table 1,
compare entries 4 and 10).
erential formation of (S)-14 in the addition of amide anion
species 23 to (+)-11 is depicted in Scheme 5. In this
representation the lithium cation is chelated to the
sulfinyl oxygen and the o-quinodimethane 23 in a six-
member chairlike transition state TS-1-TS-4 (Scheme
5). Transition states TS-1 and TS-2 are expected to be
lower in energy than TS-3 and TS-4, in which the
interactions between the bulky amide anion and the
phenyl group and/or the phenyl and the p-tolyl groups
are unfavorable.
F r om P h th a lid e An ion s. Dodsworth et al. reported
that phthalide anions add to imines to give mixtures of
cis- and trans-4-hydroxy-3,4-dihydro-1(2H)-isoquino-
lines.31 In a related study Marsden and MacLean de-
scribed the synthesis of 13-hydroxytetrahydroprotober-
berines via the addition of phthalide anions to 1,4-
dihydroisoquinolines.32 Addition of phthalide anions to
enantiopure sulfinimines could therefore provide direct
access to enantiomerically enriched 4-hydroxy-3,4-dihy-
dro-1(2H)-isoquinolones such as 19 because the two chiral
centers are formed in a single operation. However, in
principle four stereoisomeric products could result.
Passing gaseous CH2O through a solution of the
o-lithiobenzamide of 24, prepared by treatment of the
amide with s-BuLi/TMEDA, afforded 25 in 72% yield
(Scheme 6). The alcohol was converted in 74% yield to
6-methoxyphthalide (26) by refluxing in toluene for 9 h
with p-toluenesulfonic acid. The phthalide anion of 26
was generated at -78 °C, and a solution of (S)-(+)-11 at
-78 °C was added via cannula (sequential addition).
Alternatively, the base was added to equivalent amounts
of 26 and (S)-11 at -78 °C (one portion). Flash chroma-
tography produced two diastereomeric products 27 as
indicated by the presence of two methoxy absorptions at
δ 3.79 and 3.84 ppm, respectively, in the 1H NMR
spectrum. Significantly, the product selectivity proved to
be counterion dependent, with lithium reagents (LDA,
LiHMDS) affording (SS,S,R)-27a (Table 1, entries 1-6)
and sodium and potassium reagents (NaHMDS, KH-
MDS) giving (SS,R,S)-27b (Table 1, entries 7-13). The
one-portion method gave better ratios and cleaner prod-
In summary, the addition of lateral lithiated amides
and phthalide anions to enantiopure sulfinimines repre-
sents a new methodology for asymmetric synthesis of
isoquinolones and hydroxy isoquinolones, important build-
ing blocks for isoquinoline alkaloid synthesis.
Exp er im en ta l Section
Gen er a l P r oced u r es. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analyti-
cal and preparative thin-layer chromatography was performed
on precoated silica gel plates (250 and 1000 microns) pur-
chased from Analtech Inc. TLC plates were visualized with
UV, in an iodine chamber or with phosphomolybdic acid unless
noted otherwise. THF was freshly distilled under nitrogen from
a purple solution of sodium and benzophenone. Elemental
analyses were performed in the Department of Chemistry,
University of Pennsylvania, Philadelphia, PA.
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification.
N,N-Diethyl-o-toluamide (10a ) and 4-methoxy-N,N-diethyl-o-
toluamide (10b) were prepared as previously described.33
Gen er a l P r oced u r e for th e Ad d ition of Lith iu m
o-Tolu a m id e An ion s to Su lfin im in es. (SS,S)-(+)-N-[1-
P h en yl-2-(2-N,N-dieth ylben zam ido)eth yl]-p-tolu en esu lfin -
a m id e (12a ). To a stirring solution of 1.14 g (6 mmol) of N,N-
diethyl-o-toluamide in THF (12 mL), in a 50 mL two neck
(31) Dodsworth, D. J .; Pia-Calcagno, M.; Ehrmann, E. U.; Quesada,
A. M.; Nunez, S. O.; Sammes, P. G. J . Chem. Soc., Perkin Trans 1
1983, 1453.
(32) Marsden, R.; MacLean, D. B. Can. J . Chem. 1984, 62, 1392.
(33) Mills, R. J .; Snieckus, V. J . Org. Chem. 1989, 54, 4386.

Synthesis of Substituted 4-Hydroxy Isoquinolines
J . Org. Chem., Vol. 64, No. 23, 1999 8631
Sch em e 6
Ta ble 1. Ad d ition of P h th a lid e 26 to Su lfin im in e (S)-(+)-11 a t -78 °C
entry
base
LiHMDS
solvent
conditions
(SS,S,R)-27a /(SS,R,S)-27a
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
THF
THF
THF/Et2O (1:1)
THF
THF
THF
THF
THF
THF/Et2O (1:1)
THF/Et2O (1:1)
Et2O
THF/Et2O (1:1)
THF/Et2O (2:1)
sequentiala
one portionb
one portion
one portion
sequential
one portion
sequential
one portion
one portion
one portion
one portion
one portion
one portion
7:1
10:1
8:1
1:2
76
80
85
40
75
LiHMDS
LiHMDS
LiHMDS/DMPUe
LDA
4:1
LDA
complex mixture
NaHMDS
NaHMDS
NaHMDS
NaHMDS/DMPUe
NaHMDS
KHMDS
complex mixturef
1:10
1:15
1:14
1:15
1:14
1:18
80
80
75
ca. 30f
70
85
KHMDS
a
b
d
Determined by NMR integration of the OMe groups in 27. Isolated yields. c Sulfinimine 11 added to the anion of 26. Base added
to 11 and 26. e Two equivalents added. f Complex reaction mixture; 28 also detected.
(LDA). After 10 min a -78 °C solution of (S)-(+)-1121 (0.73 g,
Sch em e 7
3 mmol) in THF (2 mL) was added via cannula. The reaction
mixture was quenched after 15 min by addition of saturated
NH4Cl (5 mL) at -78 °C, and the solution was extracted with
ethyl acetate (2 × 15 mL). The combined organic phases were
washed with brine (10 mL), dried (MgSO4), and concentrated.
The crude product was purified by silica gel flash chromatog-
raphy (4:6 EtOAc/hexane) to give 1.0 g (77%) of 12a : >98%
de; mp 100-101 °C; [R]20D 13.75 (c 1.6, MeOH); IR (KBr) 3151,
1610, 1438, 1093, 1067 cm-1; 1H NMR (CDCl3) δ 7.55-6.8 (m,
13H Ar), 4.6 (m, 1H), 3.7-3.4 (m, 2H), 3.4-3.0 (m, 2H), 2.9-
2.7 (m, 2H), 2.2 (s, 3H), 1.3 (t, 3H, J ) 7 Hz), 1.0 (t, 3H, J )
7 Hz); 13C NMR (CDCl3) δ 12.8, 14.0, 21.0, 39.4, 41.8, 43.2,
54.8, 125.3, 125.9, 126.3, 126.4, 126.5, 127.8, 128.4, 129.4,
130.4, 134.9, 136.3, 139.8, 141.0, 144.5, 171.4. Anal. Calcd for
C
26H29NO2S: C, 71.86; H, 6.96; N, 6.45. Found: C, 71.45; H,
6.98; N, 6.42.
Tr ea tm en t of N-(Ben zylid en e)-p-tolu en esu lfin a m id e
(11) w ith LDA. In a 25 mL two-neck round-bottomed flask
equipped with stirring bar and rubber septa under argon was
placed 0.072 g (0.296 mmol) of 11 in 3 mL of THF. To the
reaction mixture at -78 °C was added dropwise 0.40 mL (1.5
M, 2 equiv) of LDA. After 20 min an aliquot was withdrawn
and quenched with saturated NH4Cl (1 mL). The rest of the
reaction mixture was stirred for a total of 50 min and then
quenched with NH4Cl (1 mL). HPLC (benzophenone standard)
of the reaction mixture for the molar ratio of benzonitrile and
round-bottomed flask equipped with a stirring bar and rubber
septum under argon at -78 °C, was added 3.9 mL (1.5 M in
cyclohexane, 6.0 mmol, 1 equiv) of lithium diisopropylamide

8632 J . Org. Chem., Vol. 64, No. 23, 1999
Davis and Andemichael
unreacted 11 indicated a ratio of 27:73 for the 20 min reaction
and 36:64 for the 50 min reaction. The crude material was
purified by preparative TLC to provide 0.027 g (38%) of 11,
0.008 g (19%) of p-tolyl p-toluenethiosulfonate, and 0.015 g
(41%) of p-toluenedisulfide, the sulfenic acid decomposition
products.34
saturated NH4Cl (5 mL), dried (MgSO4), concentrated, and
purified by flash chromatography (3:7 EtOAc/hexane) to give
0.014 g (90%) of 15a : mp 130-131 °C [lit.9a mp 130-131 °C];
[R]20 -203.4 (c 1.03 CHCl3); IR (KBr), 3402, 1664, 909, 737
D
cm-1
;
1H NMR (CDCl3) δ 8.12, (d, J ) 7.5 Hz, 1H), 7.5-7.2
(m, 8H), 6.0 (bs, 1H), 4.86 (dd, J ) 11.5, 4.5 Hz, 1H, NH) 3.20
(dd, J ) 16, 11.5 Hz, 1H), 3.25 (dd, J ) 16, 4.5 Hz, 1H); 13C
NMR (CDCl3) δ 166.2, 140.9, 137.5, 132.4, 128.9, 128.3, 128.0,
127.3, 127.2, 126.4, 56.1, 50.7, 37.4.
(SS,S)-(+)-N-[1-P h en yl-2-(5-m eth oxy-2-N,N-dieth ylben z-
a m id o)-eth yl]-p-tolu en esu lfin a m id e (12b). To a solution
of 0.426 (1.92 mmol) of 10b in THF (8 mL) at -78 °C was
added 1.3 mL (1.5 M in cyclohexane, 1 equiv) of LDA. After
15 min a -78 °C solution of 0.467 g (1.92 mmol) of (S)-(+)-11
in THF (2 mL) was added dropwise via cannula until the color
of the anion was discharged. An additional amount of LDA
(0.5 mL, 0.4 equiv) was added, and to the resulting burgundy
colored solution was cannulated the solution of (+)-11. The
reaction mixture was quenched at -78 °C after 15 min with
saturated NH4Cl (10 mL), and the solution was extracted with
EtOAc (2 × 15 mL). The combined organic phases were washed
with brine (10 mL), dried (MgSO4), concentrated, and purified
by silica gel column flash chromatography (4:6 EtOAc/hexane)
(3S)-(-)-6-Meth oxy-3-p h en yl-3,4-d ih yd r o-1(2H)-isoqu i-
n olon e (15b). Purification by flash chromatography (3:7
EtOAc/hexane) gave 0.350 g (96%) of a solid: mp 127-128 °C;
[R]20D -131.6 (c 1.36, CHCl3); IR (KBr) 3466, 1669 cm-1; NMR
(CDCl3) δ 8.08 (d, 1H, J ) 8.5 Hz), 7.41-7 (m, 5H), 6.89 (dd,
J ) 6.5, 2 Hz 1H), 6.67 (d, J ) 2.5 Hz, 1H), 5.79 (bs, 1H), 4.84
(dd, J ) 15.5, 4.5 Hz, 1H), 3.85 (s, 3H, OMe), 3.18 (dd, J )
15.5, 11.5 Hz, 1H), 3.10 (dd, J ) 15.5, 4.5 Hz, 1H); 13C NMR
(CDCl3) δ 166.2, 162.6, 141.0, 139.5, 129.9, 128.7, 128.0, 126.2,
121.1, 112.4, 112.2, 55.7, 55.2, 37.4. Anal. Calcd for C16H15
-
NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.85; H, 6.00; N,
5.48.
to give 0.801 g (90%) of 12b: >98% de; mp 143-144 °C; [R]20
D
10.58 (c 1.2, CHCl3); IR (KBr) 1617, 1424, 1286, 1092, 1084
cm-1; 1H NMR (CDCl3) δ 7.20-6.80 (12H), 4.7 (br, 1H) 4.80-
3.40 (bm, 5H) 3.20-2.80 (bm, 4H), 2.23 (s, 3H) 1.62 (s, 1H)
1.29 (t, J ) 6.9 Hz, 3H) 1.02 (t, J ) 7 Hz, 3H); 13C NMR δ
171.5, 141.3, 140.0, 128.7, 127.8, 127.0, 126.8, 126.7, 126.5,
125.9, 115.8, 112.45, 112.38, 112.32, 112.29, 112.24, 55.0, 43.3,
42.0, 39.5, 21.1, 14.1, 12.9. Anal. Calcd for C27H32N2O3S: C,
69.80; H, 6.94; N, 6.03. Found: C, 69.62; H, 6.98; N, 5.83.
(3S)-(-)-6-Me t h oxy-N-m e t h yl-3-p h e n yl-3,4-d ih yd r o-
1(2H)-isoqu in olon e (16). To a stirring suspension of 0.416
g of NaH (60% w/w in mineral oil, 10.4 mmol, 10 equiv) and
0.264 g (1.04 mmol) of (-)-15b in THF (5 mL) at room
temperature was added 0.32 mL (5.12 mmol, 5 equiv) of
iodomethane. After 1 h the reaction mixture was filtered
through Celite, and the filtrate was washed with cold satu-
rated NH4Cl (5 mL), dried (MgSO4), concentrated, and purified
by flash chromatography (silica gel, hexane followed by 1:1
EtOAc/hexane) to give 0.262 g (94%) of 16: mp 124-125 °C;
Gen er a l P r oced u r e for th e Hyd r olysis of p-Tolu en e-
su lfin a m id es t o t h e Am in e. (S)-(+)-N,N-Diet h yl-2-(2-
a m in o-2-p h en yleth yl)ben za m id e (14a ). To a solution of
0.077 g (0.177 mmol) of 12a in dry MeOH (1.5 mL) at 0 °C
was added dropwise 0.9 mL (0.89 mmol, 5 equiv) of trifluoro-
acetic acid (TFA) in MeOH (0.2 mL). After 2 h, the solvent
was evaporated, and the residue was dissolved in EtOAc (20
mL), washed with 5% aqueous NaOH (10 mL), dried (MgSO4),
and concentrated. Purification by silica gel column chroma-
tography (1:4:0.1 MeOH/EtOAc/TEA) afforded 0.047 g (91%)
of the amine as a thick oil: [R]20D 10.65 (c 3.1, CHCl3); IR (neat)
[R]20 -136.5 (c 1.01, CHCl3); 1H NMR (CDCl3) δ 8.08 (d, J )
D
9 Hz, 1H), 7.26-7.20 (m, 3H), 7.10-7.08 (d, J ) 8 Hz, 2H),
6.82 (dd, J ) 8.5, 2.5 Hz, 1H), 6.5 (s, 1H), 4.74 (dd, J ) 6.5,
2.5 Hz, 1H), 3.77 (s, 3H), 3.65 (dd, J ) 16, 6.5 Hz, 1H), 3.08 (s,
3H), 2.97 (dd, J ) 16, 2.5 Hz, 1H); 13C NMR δ.164.8, 162.3,
140.0, 137.1, 129.8, 128.6, 127.5, 126.2, 122.1, 112.4, 112.3,
61.8, 55.1, 35.9, 34.1. Anal. Calcd for C16H15NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.49; H, 6.61; N, 5.03.
(3R,4S)-(+)-4-Hyd r oxy-6-m eth oxy-N-m eth yl-3-p h en yl-
3,4-d ih yd r o-1(2H)-isoqu in olon e (19). To a stirring solution
of 0.04 g (0.158 mmol) of (-)-16 in THF (3 mL) at -78 °C was
added dropwise 0.21 mL (1.5 M, 3 equiv) of LDA. After 20 min
0.054 g (0.237 mmol, 1.5 equiv) of (camphorylsulfonyl)oxaziri-
dine35 (-)-18 in THF (1 mL), cooled to -78 °C, was cannulated
until the deep purple color was discharged. After 20 min
saturated NH4Cl (5 mL) was added, and the reaction mixture
was extracted with ethyl acetate (2 × 10 mL), dried (MgSO4),
and concentrated. Purification by flash chromatography (silica
1
3294, 3367, 1625 cm-1; H NMR (CDCl3) δ 7.5-6.2 (m, 9H),
4.4-4.2 (m, 2H), 3.9-3.6 (m, 1H), 3.45-3.20 (m, 1H), 3.2-2.8
(m, 3H), 2.7 (dd, 1H, J ) 9 Hz), 1.83 (s, 2H, NH, 1.27 (t, 3H,
J ) 7 Hz), 1.0 (t, 3H, J ) 7 Hz). Spectral properties were
identical with literature values.9a
(S)-(-)-N,N-Diet h yl-4-m et h oxy-2-(2-a m in o-2-p h en yl-
eth yl)ben za m id e (14b). Purification by silica gel column
chromatography (1:4:0.1 MeOH/EtOAc/Et3N) afforded 0.473
g (99%) of the amine as a thick oil: [R]20D -4.10 (c 1.10, CHCl3);
1
IR (neat) 3372, 3304, 1626 cm-1; H NMR (CDCl3) δ 7.3-7.1
gel, 1:1 EtOAc/hexane) provided 0.032 g (85%) of a gum: [R]20
D
(m, 6H), 7.04 (d, J ) 8.5, 1H), 6.68 (d, J ) 8.5 Hz, 1H), 6.62
(bs, 1H), 4.16 (br, 1H), 3.64 9 (s, 3H), 3.5-2.76 (brm, 3H), 2.64
(dd, J ) 6.75, 4.75 Hz, 1H), 1.52 (br, 2H), 1.17 (t, J ) 7 Hz),
0.92 (t, J ) 7 Hz, 1H); 13C NMR (CDCl3) δ 170.6, 159.3, 145.8,
137.3, 129.7, 128.2, 127.0, 126.8, 126.2, 115.5, 111.8, 55.0, 44.0,
42.7, 38.7, 13.8, 12.7; HRMS calcd for C20H26N2O2 (M + H)
327.1994, found 327.207.
91.93 (c 0.86, CHCl3); IR (neat) 3315, 1635, 1475, 1281, 1033
cm-1; 1H NMR (CDCl3) δ 7.94 (d, J ) 8.66 Hz, 1H), 7.28-7.20
(m, 3H), 7.08-7.05 (m, 2H), 6.82 (dd, J ) 8.71, 2.51 Hz, 1H),
6.70 (d, J ) 2.45 Hz, 1H), 4.89 (d, J ) 2.1 Hz, 1H), 4.67 (d, J
) 2.1 Hz, 1H), 3.81 (s, 3H, OMe), 3.12 (s, 3H, NMe); 13C NMR
(CDCl3), δ 164.1, 162.4, 138.4, 136.8, 129.4, 128.7, 127.7, 126.4,
120.5, 114.5, 112.9, 72.0, 70.3, 55.2, 34.6; HRMS calcd for
C
17H17NO3 (M + H) 284.1208, found 284.1215
(3R,4S)-(+)-4-(ter t-Bu tyld ip h en ylsilyloxy)-6-m eth oxy-
P r ep a r a tion of th e Mosh er Am id es. The Mosher acid
chloride (1.2 equiv) was added to the crude amine in CH2Cl2
(5 mL) and 20% aqueous NaOH (2 mL). After 20 min of stirring
the organic phase was dried (MgSO4) and concentrated, and
the 19F NMR was determined and compared with racemic
material.
Gen er a l P r oced u r e for th e Ba se-In d u ced Cycliza tion s.
(3S)-(-)-3-P h en yl-3,4-d ih yd r o-1(2H)-isoqu in olon e (15a ).
To a solution of 0.020 g, (0.067 mmol) of (+)-14a dissolved in
of THF (1 mL) at -78 °C was added dropwise tert-butyllithium
(1.7 M in pentane, 0.12 mL, 0.20 mmol, 3 equiv). After 30 min
of stirring, the dark-brown mixture was quenched with a
saturated solution of NH4Cl (1 mL) and extracted with EtOAc
(2 × 5 mL). The combined organic portions were washed with
N-m eth yl-3-p h en yl-3,4-d ih yd r o-1(2H)-isoqu in olon e (20).
To a stirring solution of 0.025 g (0.088 mmol) of (+)-19 and
0.018 g (0.28 mmol, 3 equiv) of imidazole in CH2Cl2 (1.5 mL)
at room temperature was added 0.073 g (0.27 mmol, 3 equiv)
of tert-butylchlorodiphenylsilane (TBDPSCl). After 3 h, CH2-
Cl2 (2 × 10 mL) was added, and the crude mixture was washed
with saturated NH4Cl (10 mL). The organic portion was dried
(MgSO4), concentrated, and purified by flash chromatography
(silica gel, hexane and then 1:9 ethyl acetate/hexane) to give
0.043 g (95%): mp 187-188 °C; [R]20D 120.5 (c 0.6, CHCl3); IR
(KBr) 2960, 1646, 1254, 1047, 700 cm-1; H NMR (CDCl3) δ
8.15 (d, J ) 8.5 Hz, 1H), 7.83 (d, J ) 8 Hz, 1H), 7.60-7.36 (m,
1
(34) Davis, F. A.; Friedman, A. J .; Nadir, U. K. J . Am. Chem. Soc.
1978, 100, 2844.
(35) Weismiller, M. C.; Towson, J . C.; Davis, F. A. Org. Synth. 1990,
69, 158.

Synthesis of Substituted 4-Hydroxy Isoquinolines
J . Org. Chem., Vol. 64, No. 23, 1999 8633
8H), 7.20-7.0 (m, 3H), 6.90 (dd, 8.5, 2.5 Hz, 1H), 6.64 (d, J )
7.5 Hz, 1H), 6.62 (d, J ) 7.5 Hz, 1H), 6.5 (d, J ) 1.5 Hz, 1H),
4.58 (d, J ) 2.5 Hz, 1H), 4.54 (d, J ) 2 Hz, 1H), 3.62 (s, 3H),
3.1 (s, 3H), 1.06 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 164.0, 161.9,
137.6, 136.4, 135.9, 133.5, 132.9, 130.2, 129.9, 128.5, 128.1,
127.7, 127.5, 126.3, 122.0, 114.7, 113.1, 72.9, 69.9, 55.1, 34.4,
26.7, 19.2. Anal. Calcd for C33H35NO3Si: C, 75.97; H, 6.76; N,
for 9 h. The solvent was removed, and the residue was diluted
with CH2Cl2 (10 mL) and filtered through a short pad of silica
gel to give 0.267 g (74%) of a solid: mp 110-111 °C; IR (KBr)
1759, 1605 cm-1; 1H NMR (CDCl3) δ 7.83, (d, J ) 8.5 Hz, 1H),
7.05, (dd, J ) 8 Hz, 2.5 Hz, 1H), 6.92 (d, J ) 2.5 Hz, 1H), 5.26
(s, 2H), 3.91 (s, 3H); 13C NMR (CDCl3) δ, 170.80, 164.64,
149.32, 127.10, 116.46, 105.91, 69.05, 55.79. Anal. Calcd for
C9H8O3: C, 65.85; H 4.91; Found: C, 65.91; H, 4.97.
2.68. Found: C, 75.91; H, 6.98; N, 2.63. HRMS calcd for C33H35
-
NO3Si (M + H) 508.2593, found 508.2695.
Ad d ition of 6-Meth oxyp h th a lid e An ion to (S)-(+)-11 To
Give 27 [Sequ en tia l Ad d ition ]. To a stirring solution of
0.108 g (0.66 mmol) of 26 in THF (3 mL) in a 25 mL two-neck
round-bottomed flask under argon at -78 °C was added
dropwise 1.32 mL (1.32 mmol of a 1 M solution) of LiHMDS.
After 15 min 0.148 g (0.61 mmol) of (S)-11 in THF (1.5 mL) at
-78 °C was added to the orange solution via cannula. After
15 min, saturated NH4Cl (10 mL) was added, and the reaction
mixture was extracted with EtOAc (2 × 15 mL). The organic
portion was dried (MgSO4) and concentrated to give 0.250 g
of an oil containing two diastereomers, (SS,S,R)-27a and
(SS,R,S)-27b, in the ratio of 7:1 determined by integration of
the MeO absorptions at δ 3.79 and 3.84 ppm, respectively.
Silica gel flash chromatography (4:1 hexane/EtOAc) provided
the major diastereoisomer as a white powder, which was
further purified by dissolving in diethyl ether and trituration
with hexane to provide 0.190 g (76%) of (SSS,R)-(-)-27a ; mp
143-145 °C; [R]20D -62.4 (c 1.20, CHCl3); IR (neat) 3444, 1765,
(3R,4S)-(+)-4-(ter t-Bu tyld ip h en ylsilyloxy)-6-m eth oxy-
N-m et h yl-3-p h en yl-1,2,3,4-t et r a h yd r oisoq u in olin e (21).
To a stirring solution of 0.070 g (0.134 mmol) of (-)-20 in THF
(3 mL) at room temperature was added 0.67 mL (2 M, 10 equiv)
of BH3‚DMS. After 5 h of heating at reflux, the solvent was
evaporated, the residue was dissolved in diethyl ether (3 mL),
and 0.035 g (0.574 mmol) of ethanolamine was added. After
12 h at room temperature the precipitated solid was filtered
and washed with diethyl ether, and the combined organic
phases were filtered through Celite and concentrated. Purifi-
cation by flash chromatography (silica gel, 3:7 EtOAc/hexane)
gave 0.067 g (98%) of an oil: [R]20 33.53 (c 2.75, CHCl3); IR
D
(neat) 1615, 1506, 1266, 111, 1053, cm-1; H NMR (CDCl3) δ
1
7.66 (d, J ) 8 Hz, 2H), 7.52 (d, J ) 8 Hz, 2H), 7.45-7.15 (m,
9H), 6.70-7.0 (m, 3H), 6.71 (dd, J ) 8.5, 2.5 Hz, 1H), 6.46 (d,
J ) 2.5 Hz, 1H), 4.95 (d, J ) 4.5 Hz, 1H), 3.74 (d, J ) 14 Hz,
1H), 3.71 (d, J ) 4.5 Hz, 1H), 3.60 (d, J ) 14 Hz, 1H), 3.28 (s,
3H), 2.21 (s, 3H), 0.86 (s, 9H); 13C NMR δ 157.7, 139.6, 136.9,
136.8, 133.8, 133.2, 129.7, 129.3, 128.9, 128.1, 127.6, 127.3,
127.2, 126.8, 114.8, 113.1, 74.8, 73.3, 55.4, 54.7, 43.6, 26.7, 19.5.
Anal. Calcd for C33H37NO2Si: C, 78.06; H, 7.34; N, 2.76.
Found: C, 77.71; H, 7.33; N, 2.48.
1
1021 cm-1; H NMR (CDCl3) δ 7.6 (d, J ) 8 Hz, 2H), 7.52 (d,
J ) 8.5 Hz, 1H), 7.30 (d, J ) 8 Hz), 7.18 (m, br, 5H), 6.86 (dd,
J ) 2, 8.5 Hz, 1H), 6.65 (d, J ) 1.5 Hz), 5.58, (d, J ) 3 Hz),
5.11 (d, J ) 8 Hz), 5.03 (dd, J ) 7.5, 3 Hz, 1H), 3.8 (s, 3H),
2.40 (s, 3H). 13C NMR (CDCl3) δ 169.4, 164.2, 148.4, 141.7,
141.1, 135.2, 129.6, 128.2, 127.9, 127.0, 125.7, 118.7, 116.7,
106.6, 82.5, 59.5, 55.7, 21.3. Anal. Calcd for C23H21NO4S: C,
67.79; H, 5.19; N, 3.44. Found: C, 67.59; H, 5.36; N, 3.68.
Gen er a l P r oced u r e for th e Ad d ition of Ba se to P h th a l-
id e 26 a n d (S)-(+)-11 [On e P or tion ] To Give 27b. To a
stirring solution of 0.075 g (0.46 mmol) of 26 and 0.11 g (0.46
mmol) of (S)-(+)-11 in 2:1 THF/Et2O (10 mL) in a 100 mL two-
neck round-bottomed flask cooled to -78 °C was added 1.8 mL
(0.092 mmol) of KHMDS. After 20 min the reaction mixture
was quenched by addition of saturated NH4Cl (10 mL) followed
by EtOAc (20 mL). The organic phase was dried (MgSO4) and
concentrated to give an oil containing (SS,S,R)-27a and
(SS,R,S)-27b in the ratio of 1:18. The material was purified
by silica gel column chromatography (3:7 EtOAc/CH2Cl2) to
(3R,4S)-(-)-4-Hyd r oxy-6-m eth oxy-N-m eth yl-3-p h en yl-
1,2,3,4-tetr a h yd r oisoqu in olin e (22). To a stirred solution
of 0.060 g (0.118 mmol) of 21 in of THF (10 mL) at room
temperature was added 1.0 mL (1 M, THF, 8.5 equiv) of TBAF.
After 12 h, H2O (10 mL) was added, and the crude mixture
was extracted with CH2Cl2 (2 × 15 mL). The combined organic
phases were dried (MgSO4) and concentrated, and the residue
was purified by silica gel flash chromatography (1:1 EtOAc/
hexane) to provide 0.031 g (98%) of the product: mp 116-117
°C; [R]20 -59.75 (c 0.80 CHCl3) [lit.23 [R]20 59 (c 1.0 CHCl3)
D
D
for the (3S,4R)-enantiomer]; [lit.23 mp 87-88 °C]; H NMR δ
7.40-7.22 (m, 5H), 7.05 (d, J ) 2.6, 1H), 7.01 (d, J ) 8.5, 1H),
6.83 (dd J ) 8.5, 2.6, 1H), 4.79(d, J ) 6.5, 1H), 3.84 (s, 3H),
3.74 (d, J ) 15.2,1H), 3.55 (d, J ) 15.2, 1H), 3.43 (d, J ) 6.5,
1H), 2.21 (s, 3H); 13C NMR δ 158.6, 137.8, 137.4, 129.0, 128.6,
128.0, 126.8, 126.4, 114.5, 111.6, 72.9, 72.5, 56.0, 55.3, 43.3.
2-H yd r oxym e t h yl-4-m e t h oxy-N ,N -d iisop r op ylb e n z-
a m id e (25). To a stirred solution of 0.945 g (4.0 mmol) of
4-methoxy-N,N-diisopropylbenzamide (24)33 and 1.2 mL (2
equiv) of TMEDA in THF (20 mL) in a 100 mL two-neck round-
bottomed flask equipped with stirring bar and rubber septum
cooled to -78° C was added dropwise 6.2 mL (1.3 M solution,
2 equiv) of s-BuLi. After 30 min a THF solution of formalde-
hyde at -40 °C was added dropwise via syringe. The formal-
dehyde solution was prepared by cracking 0.6 g (20 mmol, 5
equiv) of paraformaldehyde with a heat gun, which was
bubbled into THF (15 mL) at -78 °C. After 2 h of stirring, the
reaction temperature was raised to room temperature over 8
h, saturated aqueous NH4Cl (15 mL) was added, and the
solution was extracted with EtOAc (2 × 20 mL). The organic
phase was dried (MgSO4) and concentrated, and the crude
material was purified by silica gel flash chromatography (7:3
hexane/EtOAc) to provide 0.77 g (72%) of the product as an
oil: IR (KBr) 3286, 1613.4, 1453 cm-1; 1H NMR δ 7.10 (d, J )
8 Hz, 2H), 6.95 (d, J ) 2.5 Hz, 1H), 6.81 (dd, J ) 8.5 Hz, 2.5
Hz, 1H), 4.61 (br, 1H), 4.35 (br, 1H), 2.89 (br, 1H), 3.83 (s,
3H), 3.52 (br, 1H), 1.53 (br, 6H), 1.18 (br, 3H); 13C NMR
(CDCl3) δ 171.29, 159.82, 140.29, 129.87, 125.05, 126.38,
114.54, 112.85, 63.80, 55.21, 51.20, 45.97, 20.92, 20.65, 20.49,
20.26. Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28.
Found: C, 67.59; H, 8.85; N, 5.12.
1
provide 0.16 g (86%) of (SSS,R)-(-)-27b: mp 127-130; [R]20
D
-72.0 (c 0.58, CHCl3); IR (KBr) 3444, 1764, 1038 cm-1 1H
;
NMR (CDCl3) δ 7.54 (d, J ) 8.5 Hz, 1H), 7.50 (d, J ) 8 Hz,
1H), 7.18 (d, J ) 8 Hz, 2H), 7.12-7.10 (m, 3H), 6.97 (d, J )
1.5 Hz, 1H), 6.95 (d, J ) 3 Hz, 1H), 6.86 (dd, J ) 9 Hz, 2 Hz,
1H), 6.63 (d, J ) 2 Hz, 1H), 5.00 (d, J ) 8.5 Hz, 1H), 4.97 (dd,
J ) 8.5 Hz, 3 Hz, 1H), 3.79 (s, 3 H), 2.55 (s, 3H); 13C NMR
(CDCl3) δ 169.49, 164.19, 148.43, 141.32, 140.53, 135.29, 129.4,
127.78, 127.51, 126.90, 126.05, 118.80, 116.6, 106.59, 82.96,
58.66, 55.74. Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19;
N, 3.44. Found: C, 67.80; H, 5.58; N, 3.09.
Na H-In d u ced Cycliza tion of 27 to (3S,4R)-(-)-4-Hy-
d r oxy-6-m et h oxy-3-p h en yl-3,4-d ih yd r o-1(2H )-isoq u in o-
lon e (28). To a stirring solution of 0.160 g (0.393 mmol) of
(SS,S,R)-(-)-27 in THF (4 mL) in a 25 mL two-neck round-
bottomed flask under argon at room temperature was added
0.023 g (0.983 mmol, 2.5 equiv) of NaH. After stirring for 3 h
the crude mixture was filtered through Celite, and the filtrate
was diluted with EtOAc (25 mL), washed with saturated
NH4Cl (10 mL), dried (MgSO4), and concentrated. Purification
by silica gel chromatography (1:1 EtOAc/hexane) gave 0.09 g
(85%) of (3S,4R)-28 as a gum: [R]20 -19.6 (c 1.12 CHCl3); IR
D
(KBr) 3264, 1666 cm-1
;
1H NMR (CDCl3) δ 7.60 (d, J ) 8.5
Hz, 1H), 7.31-7.27 (m, 5H), 6.92 (d, J ) 2.5 Hz, 1H), 6.64 (dd,
J ) 9 Hz, 2.5 Hz, 1H), 4.96 (d, J ) 5.5 Hz), 4.80 (d, J ) 5.5
Hz), 3.83 (s, 3H). 13C NMR δ 166.11, 162.20, 140.88, 138.40,
129.52, 128.92, 128.32, 127.07, 119.65, 114.28, 111.36, 71.94,
62.67, 55.42; HRMS calcd for C16H15NO3 (M + H) 270.1126,
found 270.1125. Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61;
N, 5.20. Found: C, 71.00; H, 5.55; N, 5.10.
6-Meth oxyp h th a lid e (26). A stirring solution of 0.594 g
(2.2 mmol) of 25 and 0.10 g (0.58 mmol) of p-TsOH in toluene
(10 mL) in a 25 mL round-bottomed flask was heated at reflux

8634 J . Org. Chem., Vol. 64, No. 23, 1999
Davis and Andemichael
(3R,4S)-(+)-4-Hydr oxy-6-m eth oxy-3-ph en yl-3,4-dih ydr o-
7.83 (dd J ) 8 Hz, 1.5 Hz, 1H), 7.53-7.35 (m, 6H), 7.10-7.07
(m, 3H), 6.90 (dd, J ) 16 Hz, 7 Hz, 1H), 6.46 (dd, J ) 8.5 Hz,
6.6.22 (d, J ) 9 Hz, 2H), 6.26 (d, J ) 2.5 Hz, 1H), 6.08 (d, J )
4 Hz, 1H), 4.72 (dd, J ) 4.5 Hz, 3 Hz), 4.70 (m, br, 1H), 3.59
(s, 3H), 1.00 (s, 9H); 13C NMR (CDCl3) δ 165.11, 162.54, 138.82,
138.37, 135.97, 133.40, 133.04, 130.16, 129.89, 129.79, 128.43,
128.06, 127.67, 127.54, 126.33, 121.15, 114.89, 113.26, 73.17,
62.21, 55.16, 26.73, 19.29.
1(2H)-isoqu in olon e (28): 76%, gum; [R]20 24.25 (c 1.60
D
CHCl3); IR (KBr) 3264, 1666 cm-1; H NMR (CD3OD) δ 7.90
1
(d, J ) 8.5 Hz, 1H), 7.31-7.27 (m, 5 H),7.02 (d, J ) 2.5 Hz
1H), 6.91 (dd, J ) 8.5 Hz, 2.5 Hz), 4.82 (d, J ) 8 Hz), 4.64 (d,
J ) 8 Hz), 3.83 (s, 3H); 13C NMR (CD3OD) δ 167.67, 165.0,
143.52, 140.46, 130.69, 129.64, 129.05, 128.33, 121.29, 115.06,
112.78, 72.48, 63.51, 56.01.
(3S,4R)-(-)-4-(ter t-Bu tyld ip h en ylsilyloxy)-6-m eth oxy-
3-p h en yl-1,2,3,4-tetr a h yd r oisoqu in olin e (29). To a stirring
solution of 0.120 g (0.446 mmol) of (-)-28 in CH2Cl2 (5.0 mL)
in a 25 mL two-neck round-bottomed flask at room tempera-
ture was added 0.184 g (0.670 mmol, 1.5 equiv) of TBDPSCl
followed by 0.091 g (2.01 mmol, 3 equiv) of imidazole. After
stirring for 1.5 h the reaction mixture was filtered through a
short column of silica gel (CH2Cl2 followed by 1:5 EtOAc/CH2-
(3S,4R)-(-)-4-(ter t-Bu tyld ip h en ylsiloxy)-6-m eth oxy-N-
m eth yl-3-p h en yl-1,2,3,4-tetr a h yd r oisoqu in olin e (20). To
a stirred solution of 0.078 g (0.153 mmol) of (-)-29 in THF
(3.0 mL) in a 25 mL two-neck round-bottomed flask under
argon at room temperature was placed 0.031 g (0.765 mmol,
5 equiv) of n-hexane-washed NaH (60% in mineral oil). A 0.109
g (5 mmol) portion of MeI was added. After 0.5 h the crude
mixture was filtered through Celite, and the solution was
concentrated and dissolved in CH2Cl2 (5 mL). The solution was
filtered through a short pad of silica gel and concentrated to
give 0.078 g (97%) of a solid: mp 187-188 °C; [R]20D -125.0 (c
0.20, CHCl3). This compound had spectral properties identical
to those of the enantiomer (3R,4S)-(+)-20 prepared above.
Cl2) to provide 0.197 g (97%) of a solid: mp 221-222 °C; [R]20
D
-62.4 (c 1.20, CHCl3); IR (KBr) 3380, 1667, 1608, 1056 cm-1
;
1H NMR (CDCl3) δ 8.11 (d, J ) 9 Hz, 1H), 7.81 (d J ) 8 Hz,
2H), 7.56 (d, J ) 8 Hz, 2H), 7.52-7.34 (m, 6H), 7.10-7.07 (m,
3H), 6.90 (dd, J ) 10 Hz, 2.5 Hz, 1H), 6.65 (d, J ) 9 Hz, 2H),
6.26 (d, J ) 2.5 Hz, 1H), 6.08 (d, J ) 4 Hz, 1H), 4.72 (dd, J )
4.5 Hz, 3 Hz), 4.70 (m, br, 1H), 3.59 (s, 3H), 1.00 (s, 9H); 13C
NMR (CDCl3) δ 165.21, 162.44, 138.76, 138.35, 135.92, 133.32,
133.00, 130.0, 129.84, 129.79, 128.35, 128.03, 127.62, 127.43,
126.28, 121.14, 114.84, 113.18, 73.09, 62.20, 55.10, 26.68,
11.24. Anal. Calcd for C32H33NO3Si: C, 75.70; H, 6.55; N, 2.76.
Found: C, 75.25; H, 6.60; N, 2.77.
Ack n ow led gm en t. We thank Dr. William McCoull
for helpful discussion. This work was supported by
grants from the National Institutes of Health (GM
51982) and the National Science Foundation.
Su p p or tin g In for m a tion Ava ila ble: IR and 1H and 13C
NMR spectra of (-)-14b and (+)-19. This material is available
free of charge via the Internet at http://pubs.acs.org.
(3R,4S)-(+)-4-(ter t-Bu tyld ip h en ylsilyloxy)-6-m eth oxy-
3-p h en yl-1,2,3,4-tetr a h yd r oisoqu in olin e (29): 78% yield;
mp 220-221 °C; [R]20 67.7 (c 1.18, CHCl3); IR (KBr) 3380,
D
1
1667, 1609 cm-1; H NMR (CDCl3) δ 8.15 (d, J ) 9 Hz, 1H),
J O991119X