1-magnesiotetrahydroisoquinolyloxazolines as chiral nucleophiles in stereoselective additions to aldehydes: Auxiliary optimization, asymmetric synthesis of (+)-corlumine, (+)-bicuculline, (+)-egenine, and (+)-corytensine, and preliminary 13C NMR studies of 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines

Article abstract of DOI:10.1021/jo961164u

Transmetalation of 1-lithiotetrahydroisoquinolyloxazolines with magnesium halides affords Grignard reagents that add to aldehydes with up to 80% selectivity for one of the four possible diastereomeric products. An oxazoline chiral auxiliary derived from camphor provides an optimal blend of diastereoselectivity and isomer separability. Synthetic applications of the optimal auxiliary, patterned after a literature approach in the racemic series, comprise an improved (formal) synthesis of bicuculline, egenine, and corytensine, as well as an efficient synthesis of corlumine. Preliminary NMR studies show that both 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines are dynamic mixtures in THF solution at low temperatures. The barrier to pyramidal inversion of the secondary Grignard reagent is in the 9.8-10.1 kcal/mol range, while an upper limit of about 8.2 kcal/mol can be assigned to the barrier to the organolithium inversion.

Full text of DOI:10.1021/jo961164u

J . Org. Chem. 1996, 61, 8103-8112
8103
1-Ma gn esiotetr a h yd r oisoqu in olyloxa zolin es a s Ch ir a l Nu cleop h iles
in Ster eoselective Ad d ition s to Ald eh yd es: Au xilia r y
Op tim iza tion , Asym m etr ic Syn th esis of (+)-Cor lu m in e,
(+)-Bicu cu llin e, (+)-Egen in e, a n d (+)-Cor yten sin e, a n d P r elim in a r y
13C NMR Stu d ies of 1-Lith io- a n d
1-Ma gn esiotetr a h yd r oisoqu in olyloxa zolin es†
Robert E. Gawley* and Pingsheng Zhang
Department of Chemistry, University of Miami, Coral Gables, Florida 33124-0431
Received J une 20, 1996X
Transmetalation of 1-lithiotetrahydroisoquinolyloxazolines with magnesium halides affords Grig-
nard reagents that add to aldehydes with up to 80% selectivity for one of the four possible
diastereomeric products. An oxazoline chiral auxiliary derived from camphor provides an optimal
blend of diastereoselectivity and isomer separability. Synthetic applications of the optimal auxiliary,
patterned after a literature approach in the racemic series, comprise an improved (formal) synthesis
of bicuculline, egenine, and corytensine, as well as an efficient synthesis of corlumine. Preliminary
NMR studies show that both 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines are dynamic
mixtures in THF solution at low temperatures. The barrier to pyramidal inversion of the secondary
Grignard reagent is in the 9.8-10.1 kcal/mol range, while an upper limit of about 8.2 kcal/mol can
be assigned to the barrier to the organolithium inversion.
In tr od u ction
carbon) is invariably low or nonexistent.11-14 On the face
of it, this is puzzling, since it implies that the diastere-
omeric transition states are (nearly) isoenergetic, assum-
ing that the addition occurs by a polar mechanism. For
lithiated tetrahydroisoquinolines (pivalamides and ox-
azoline activating groups), it appears that the lack of
stereoselectivity is due to the intervention of a single-
electron-transfer mechanism.15
In 1984, Seebach reported that transmetalation of
lithiated tetrahydroisoquinoline pivalamides from lithium
to magnesium affords a reagent that is 100% diastereo-
selective for the erythro (u) diastereomer,12,16,17 and the
method was used as the key step in highly stereoselective
syntheses of several (hydroxybenzyl)isoquinoline alka-
loids (e.g., the phthalide lactone â-hydrastine, the apor-
phine ushinsunine, and the protoberberine alkaloid
ophiocarpine) in racemic form.18,19 Efforts to extend this
method to the synthesis of the phthalide alkaloid corlu-
mine (nonracemic) were not as successful, since the 100%
stereoselectivity observed with unsubstituted tetrahy-
droisoquinolines and 6,7-(methylenedioxy)tetrahydroiso-
quinolines was lost when a 6,7-dimethoxytetrahydroiso-
quinoline was employed.20
Chiral organometallic compounds in which a metal is
bonded to a stereogenic carbon atom are gaining in
popularity as tools in asymmetric synthesis. For ex-
ample, the Meyers group has developed chiral forma-
midines as auxiliaries for the asymmetric alkylation of
lithiated tetrahydroisoquinolines and â-carbolines;1,2
Hoppe3-5 and Beak6,7 have shown that the sec-butyl-
lithium-sparteine complex is an excellent reagent for
enantioselective deprotonation of carbamates and pyr-
rolidines. These examples are representative of a grow-
ing class of chiral, nonracemic R-amino organolithiums
that are finding use in asymmetric synthesis.8-10
The utility of R-amino organolithiums is high with
electrophiles such as alkyl halides or symmetrical ke-
tones in which there is only one asymmetric center
produced in the product, at the former “carbanionic”
carbon. When an aldehyde is employed as the electro-
phile, an additional stereocenter is formed, but the
selectivity at the second stereocenter (the former carbonyl
† Dedicated to Professor V. Prelog, on the occasion of his 90th
birthday, with respect and admiration for his contributions to our
science and to the fellowship of chemists.
Several years ago, we reported an approach analogous
to that of Seebach (but using an oxazoline as a chiral
auxiliary) for the asymmetric synthesis of (hydroxyben-
zyl)isoquinolines.14 In preliminary work,13,21 we found
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) Highsmith, T. K.; Meyers, A. I. In Advances in Heterocyclic
Natural Product Synthesis; Pearson, W. H., Ed.; J AI: Greenwich, CT,
1991; Vol. 1, p 95.
(2) Meyers, A. I. Tetrahedron 1992, 48, 2589.
(3) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422.
(4) Hoppe, D.; Carstens, A.; Kra¨mer, T. Angew. Chem., Int. Ed. Engl.
1990, 29, 1424.
(5) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J .; Sommerfeld, P.; Haller, J .; Guarnieri, W.; Kolcze-
wski, S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479.
(6) Kerrick, S. T.; Beak, P. J . Am. Chem. Soc. 1991, 113, 9708.
(7) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231.
(8) Gawley, R. E.; Rein, K. In Comprehensive Organic Synthesis.
Selectivity, Strategy, and Efficiency in Modern Organic Chemistry;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, p 65.
(9) Gawley, R. E.; Rein, K. S. In Comprehensive Organic Synthesis;
Schreiber, S., Ed.; Pergamon: Oxford, 1991; Vol. 1, p 459.
(10) Gawley, R. E.; Zhang, Q. Tetrahedron 1994, 50, 6077.
(11) Beak, P.; Lee, W. K. J . Org. Chem. 1990, 55, 2578.
(12) Seebach, D.; Hansen, J .; Seiler, P.; Gromek, J . M. J . Organomet.
Chem. 1985, 285, 1.
(13) Rein, K. S.; Gawley, R. E. Tetrahedron Lett. 1990, 31, 3711.
(14) Rein, K. S.; Gawley, R. E. J . Org. Chem. 1991, 56, 1564.
(15) Rein, K. S.; Chen, Z.-H.; Perumal, P. T.; Echegoyen, L.; Gawley,
R. E. Tetrahedron Lett. 1991, 32, 1941.
(16) Syfrig, M. A.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1984,
23, 248.
(17) Seebach, D.; Syfrig, M. A. Angew. Chem., Int. Ed. Engl. 1984,
70, 1944.
(18) Seebach, D.; Huber, I. M. P. Chimia 1985, 39, 233.
(19) Seebach, D.; Huber, I. M. P.; Syfrig, M. A. Helv. Chim. Acta
1987, 70, 1375.
(20) Huber, I. M. P.; Seebach, D. Helv. Chim. Acta 1987, 70, 1944.
(21) Rein, K. S.; Gawley, R. E. J . Org. Chem. 1991, 56, 839.
S0022-3263(96)01164-4 CCC: $12.00 © 1996 American Chemical Society

8104 J . Org. Chem., Vol. 61, No. 23, 1996
Gawley and Zhang
Sch em e 1
that tetrahydroisoquinoline Grignard reagents add ste-
reoselectively (60% diastereoselectivity), giving a mixture
of the two erythro (u) diastereomers and none of the threo
(l) isomers. Initially, we used a readily available oxazo-
line auxiliary, derived from valine,22,23 to establish the
absolute configuration of the major addition product of
a 6,7-(methylenedioxy)isoquinoline by correlation of struc-
ture with (+)-bicucullinediol (Scheme 1).13 The asym-
metric addition, accompanied by a partial resolution later
in the synthesis, was used in syntheses of enantiopure
(-)-egenine, (-)-corytensine, and (-)-bicuculline.13,14 These
studies showed that, in contrast to reactions of the
lithiated compounds,23 the electrophile approaches the
anionic carbon from the face opposite the isopropyl.13,14
After an extensive search for a better auxiliary, we
reported that an oxazoline derived from camphor was
superior, affording diastereoselectivities in the 80% range
for one of the four possible diastereomers, with the added
advantage that separation of the diastereomeric addition
products was routine, obviating the need for the partial
resolution step.24
Sch em e 2
In this paper, we report the details of these optimiza-
tion studies, including our rationale for the design of
improved auxiliaries, the application of the optimal
auxiliary to the asymmetric synthesis of (+)-corlumine,
an improved (formal) synthesis of the alkaloids (+)-
bicuculline, (+)-egenine, and (+)-corytensine, and pre-
liminary 13C NMR studies of lithiated and magnesiated
isoquinolyloxazolines that allow estimation of the barrier
to pyramidal inversion in these species.
Resu lts a n d Discu ssion
Au xilia r y P r ep a r a tion . The synthesis of the iso-
quinolyloxazolines is detailed in Scheme 2. Condensation
of tetrahydroisoquinoline, 1, with ethoxyoxazolines 2a -f
afforded isoquinolyloxazolines 3a -f. Oxazolines 2a -e
and 3a -e, summarized in Scheme 2a, have been reported
previously.23 The diphenyloxazoline 2f was prepared by
addition of phenylmagnesium bromide to valine methyl
ester hydrochloride to give amino alcohol 4, which was
cyclized with phosgene and O-alkylated to give 2f, as
shown in Scheme 2b. Following the same protocol as
before, condensation of 1 and 2f afforded 3f, as shown in
Scheme 2c.
Thornton reported that reduction of camphor quinone
monooxime by a two-step sequence (sodium borohydride
followed by hydrogenation over platinum) provided amino
alcohol 6.25 We find that direct reduction by lithium
aluminum hydride works equally well (Scheme 2d).
Cyclization and O-alkylation afforded the ethoxyoxazo-
line 7, but attempted condensation with 1 failed. Instead
of condensation to an isoquinolyloxazoline, N-ethylation
of 1 occurred. Alternatively, the two-pot sequence
outlined in Scheme 2e afforded isoquinolyloxazoline 3g,
via urea 8, in good yield.
(22) Gawley, R. E.; Hart, G.; Goicoechea-Pappas, M.; Smith, A. L.
J . Org. Chem. 1986, 51, 3076.
Selectivity Op tim iza tion a n d Au xilia r y Testin g.
Metalation of the isoquinolyloxazolines was accomplished
with butyllithium at -78 °C, and transmetalation with
magnesium bromide etherate was complete after 20 min
(23) Rein, K.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart, G. C.;
Smith, G. A.; Gawley, R. E. J . Am. Chem. Soc. 1989, 111, 2211.
(24) Zhang, P.; Gawley, R. E. Tetrahedron Lett. 1992, 33, 2945.
(25) Bonner, M. P.; Thornton, E. R. J . Am. Chem. Soc. 1991, 113,
1299.

Stereoselective Additions to Aldehydes
J . Org. Chem., Vol. 61, No. 23, 1996 8105
Sch em e 3
Sch em e 4
this reaction. In the event, the selectivity at -78 °C was
about the same as we had observed with 3c (Table 1,
entry 10), but the product mixture could be purified to
diastereomer homogeneity with a single recrystallization.
Furthermore, a variable temperature study indicated
that addition at -65 °C is optimal (Table 1, entry 11)
and that the major diastereomer could be isolated by
recrystallization in 50% yield.
Ta ble 1. Selectivity of Ad d ition of Isoqu in olyloxa zolin e
Gr ign a r d Rea gen ts to Ben za ld eh yd e (See Sch em e 2 for
Str u ctu r e of Oxa zolin es 3 a n d Sch em e 3 F or
Str u ctu r e of 9)
entry
oxazoline
temp, °C
9 (R,S:S,R:R,R:S,S)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3c
3c
3c
3d
3e
3f
-78
-78
-78
-70
-60
-45
-78
-78
-78
-78
-65
50:50:0:0
62:38:0:0
71:29:0:0
55:45:0:0
42:58:0:0
58:42:0:0
71:29:0:0
70:30:0:0
80:20:0:0
33:67:0:0
20:80:0:0
In an effort to test the applicability of this auxiliary-
based approach to the problem encountered by the
Seebach group in the stereoselective addition of isoquino-
lines to aldehydes,20 we examined the stereoselectivity
of addition of 6,7-(methylenedioxy)- (10a ) and 6,7-
dimethoxytetrahydroisoquinoline (10b) derivatized with
the camphor-oxazoline auxiliary (3g) to benzaldehyde.24
The results are shown in Scheme 4 and are shown in
comparison to the unsubstituted case. Diastereoselec-
tivities were analyzed by removal of the auxiliary and
Pirkle analysis, as before.21 Initially, we used magne-
sium bromide for the transmetalation, and it worked well
for the unsubstituted isoquinoline (3g) and for the
methylenedioxy derivative (10a ), providing about 80%
diastereoselectivity in both cases. Unfortunately, trans-
metalation of the lithiated dimethoxy compound (10b)
and addition to benzaldehyde afforded a mixture of both
erythro and threo products, reminiscent of the results
obtained by the Seebach group.20
Clearly, there are subtle effects at work here, since the
methylenedioxy compound and the dimethoxy compound
are electronically similar, yet selectivity is completely lost
for the latter. In trying to rationalize this fact, we
recalled that the bromine atom and the pivaloyl oxygen
were found to be trans to each other in the crystal, as
indicated in Figure 1a.12 Assuming that the oxazoline
takes the place of the pivalamide as indicated in Figure
1b, a methylenedioxy substituent would not affect the
structure significantly (Figure 1c). However, molecular
mechanics calculations (Macromodel26) indicated that the
most stable conformation of the two methoxy groups has
the methyls oriented away from each other,24 and we
reasoned that, in this conformation, the methyl group of
the 7-methoxy substituent may encounter the bromine
trans to the oxazoline nitrogen (or pivalamide oxygen?,
cf. ref 20), as shown in Figure 1d. Such an interaction
could disrupt the geometry of the reagent in the ground
state and cause a change of mechanism or could desta-
bilize the transition state leading to the erythro products.
We hoped that changing the halide to a (smaller) chlorine
10
11
3g
3g
at 0 °C. After the solution was cooled to -78 °C, 1.5 equiv
of benzaldehyde was added. In all cases (3a -g) addition
afforded a mixture that contained only two of the four
possible diastereomeric addition products, as illustrated
in Scheme 3. Reduction of the addition product mixture
gives amino alcohols that can be acylated with naphthoyl
chloride and separated on a Pirkle column.21 The relative
configuration of the two new stereocenters was u, as
expected.13-15 The selectivity data are listed in Table 1.
For the monosubstituted oxazolines 3a -e, the maxi-
mum diastereoselectivity at -78 °C was about 70% (Table
1, entries 1-3, 7, and 8). For 3c, experiments at different
temperatures show a surprising effect: as the tempera-
ture is raised from -78 to -70 °C, the selectivity
decreases, reverses at -60 °C, and then reverses again
at -45 °C (entries 3-6). NMR studies, discussed below,
reveal a complex mixture of species in solution, and
rigorous interpretation of this phenomenon is not possible
with the data currently in hand. Acting on the hypoth-
esis that substitution at the 5-position of the oxazoline
would restrict conformational motion of the isopropyl
group, we tested 3f and found that the selectivity was
indeed higher (Table 1, entry 9).
From a preparative viewpoint, 80% diastereoselectivity
would be acceptable if the two diastereomers were easily
separable. Unfortunately, this is not the case for auxil-
iaries 3a -f. Thus, we looked for another type of oxazo-
line, one that had similar steric features and that would
give selectivities at least as high as those of 3f and that
may also afford addition products that are easily sepa-
rable. Regarding isomer separability and crystallinity,
camphor-derived auxiliaries are legendary. Thus, after
the appearance of Thornton’s report of an oxazolidinone
derived from camphor,25 we decided to try adapting it to
(26) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.

8106 J . Org. Chem., Vol. 61, No. 23, 1996
Gawley and Zhang
Sch em e 5
F igu r e 1.
may alleviate such a problem (the van der Waals radii
of bromine and chlorine are 195 and 181 pm, respec-
tively27). In the event, it did; transmetalation with
magnesium chloride restored the erythro selectivity to
82% diastereoselectivity, giving 11b in 58% isolated yield.
In the case of all three products (9, 11a ,b), recrystal-
lization or column chromatography provided the product
as a single diastereomer in the isolated yields indicated.
Note that these isolated yields compare favorably with
the yield of the more highly stereoselective model reaction
reported by the Seebach group.12,16,17
Sch em e 6
Syn th etic Ap p lica tion s. To demonstrate this meth-
odology in natural product synthesis, phthalide isoquino-
line alkaloids are an ideal target because of their
simplicity and because they may serve as starting
materials for synthesis of other (hydroxybenzyl)isoquino-
line alkaloid classes by known routes. Thus, we chose
phthalide alkaloids in our earlier effort.13,14 From a
synthetic standpoint, a major weakness of that effort was
the fact that the two erythro isomers could not be
separated. In order to obtain enantiopure products, we
had to incorporate a partial resolution after auxiliary
removal. With 10a and 10b, however, that is not
necessary, so we used this auxiliary for the asymmetric
synthesis of (the enantiomer of) a key intermediate in
the previously published synthesis of bicuculline, egenine,
and corytensine, as outlined in Scheme 5. Consistent
with the model studies outlined above, the (methylene-
dioxy)isoquinoline 10a , as its Grignard derivative, added
with 80% diastereoselectivity to piperonal, affording
(hydroxybenzyl)isoquinoline adduct 12 in 62% yield after
purification by flash chromatography. Auxiliary removal
afforded the key intermediate 13, the enantiomer of that
prepared previously.14
To demonstrate the use of a dimethoxyisoquinoline, we
chose as a target corlumine, a phthalide similar to these
three, because our results could be compared directly
with the Seebach effort.20 As shown in Scheme 6,
lithiation and transmetalation of 10b, followed by addi-
tion to piperonal with 80% diastereoselectivity, afforded
adduct 14 in 49% isolated yield. NMR and HPLC data
both indicated that this compound was isolated as a
single diastereomer. Reductive removal of the oxazoline
auxiliary was accomplished as before, and a two-step
sequence was employed to methylate the nitrogen. Thus,
cyclization of the amino alcohol 15 with phosgene af-
forded oxazolidinone 16 in 73% yield from 14. Reduction
gave the N-methyl compound 17. Directed metalation
and carboxylation were accompanied by lactonization
during acidic workup to give (+)-corlumine in 50% yield
(17% overall from 10b in five steps).
The low yield of the last step is due to large amounts
of recovered 17 (the yield based on unrecovered starting
material is 93%). We undertook a number of model
studies in the hopes of improving the efficiency of this
directed metalation, mostly by adding other directing
groups in the vicinity of the site of lithiation. None of
these efforts was successful, although an interesting
rearrangement was discovered in the process.28
NMR Stu d ies. In an effort to try to unravel the
structure of the metalated isoquinolyloxazoline reagents,
we decided to examine the 13C NMR spectrum of these
(27) Emsley, J . The Elements; Clarendon: Oxford, 1989.
(28) Zhang, P.; Gawley, R. E. J . Org. Chem. 1993, 58, 3223.

Stereoselective Additions to Aldehydes
J . Org. Chem., Vol. 61, No. 23, 1996 8107
Sch em e 7
we can estimate ∆ν and calculate a limiting value for the
inversion barrier. Thus, if one assumes that the shoulder
represents the other organolithium diastereomer, the
relative ratio is about 70:30 (the approximate ratio of
peak heights). This corresponds46,47 to a process with
inversion barriers (∆Gq) of about 8.0 and 8.2 kcal/mol (see
Supporting Information for details on the calculations).
Since a lower Tc would correspond to a lower activation
barrier, this can be taken as an approximate upper limit
for this process. These observations are consistent with
interpretations made earlier of a fast equilibrium be-
tween such organolithium stereoisomers.23,48 This tenta-
tive conclusion also clarifies the earlier quandary23,49
between thermodynamic or kinetic control in the stereo-
selective alkylation of these species. With such a low
barrier to inversion for equilibrating organolithium di-
astereomers, and since the ratio of alkylation products
is much higher than 70:30, the alkylation follows Curtin-
Hammett kinetics.50,51
Transmetalation of the lithiated species with magne-
sium bromide (3.7 molar equiv) afforded a species (0.14
M) whose partial 13C NMR spectrum is shown in Figure
3 (C-1 only). The spectrum reveals a species that is not
a simple monomeric Grignard reagent. Two regions can
be discerned: a low-field, temperature-independent re-
gion and a higher field region where a dynamic phenom-
enon is observed. Specifically, the peaks near 47 ppm
coalesce at -65 °C.
species. It is well-known that the NMR spectra of
organolithium species are complicated by pyramidal
inversion and aggregation phenomena29-39 and that
pyramidal inversion and Schlenk equilibria complicate
the NMR spectra of organomagnesium species.29,40-44
Nevertheless, we thought that such studies might provide
direct evidence for the existence of distinct organolithium
or organomagnesium diastereomers and that observation
of these species may shed some light on the process of
asymmetric induction in these reactions.
To that end, we prepared [1-13C]tetrahydroisoquinoline
by a Bischler-Napieralski cyclization of the 13C-enriched
formamide of phenethylamine, followed by reduction,
according to the procedure of Hesse, as shown in Scheme
7.45 Condensation with 2c afforded isoquinolyloxazoline
3c enriched with 13C at C-1.
Metalation with [6Li]butyllithium31 gave a C-Li doubly
labeled lithiated compound whose low-temperature 13C
NMR spectrum (C-1 only) is illustrated in Figure 2. The
equilibrating diastereomeric organolithiums (and/or equili-
brating aggregates) show fast exchange on the NMR time
scale, even at -100 °C, where 1J (6Li-13C) coupling is
apparent and a shoulder is beginning to appear. Further
lowering of the temperature was not possible due to
solvent freezing and/or solute crystallization. We cannot
say with certainty that the shoulder represents a C-1
epimer or some sort of diastereomeric aggregate. If it is
the latter, then the main peak at 61.5 ppm must be a
time average of the C-1 epimers and the barrier to
inversion must be extremely low. In the former instance,
The position of the Schlenk equilibrium (R2Mg +
MgBr2 a 2RMgBr) is affected by the concentrations of
magnesium halide and the solvent and the temperature.
Relevant to our work are the facts that, in THF at low
temperatures, the equilibrium is shifted to the left
(relative to its position in ether) and that the Schlenk
equilibrium is slow.52 Control experiments showed that,
as the magnesium bromide concentration was varied
between 0.2 and 0.5 M (equilibration at 0 °C), the
population of the upfield, temperature-dependent region
increased at the expense of the downfield region. We
interpret this as a shift of the Schlenk equilibrium to the
right (toward RMgBr). Thus, the upfield, temperature-
dependent region is assigned to the Grignard monomers
and the two peaks to the diastereomers epimeric at C-1.
Interestingly, integration of these two peaks in the -80
°C spectrum corresponds exactly to the isomer ratio found
in the carbonyl addition.
(29) Witanowski, M.; Roberts, J . D. J . Am. Chem. Soc. 1966, 88,
737.
(30) Fraenkel, G.; Beckenbaugh, W. E.; Yang, P. P. J . Am. Chem.
Soc. 1976, 98, 6878.
(31) Seebach, D.; Ha¨ssig, R.; Gabriel, J . Helv. Chim. Acta 1983, 66,
308.
(32) Fraenkel, G.; Henrichs, M.; Hewitt, M.; Su, B. M. J . Am. Chem.
Soc. 1984, 106, 255.
(33) Heinzer, J .; Oth, J . F. M.; Seebach, D. Helv. Chim. Acta 1985,
68, 1848.
(34) Gu¨nther, H.; Moskau, D.; Bast, P.; Schmalz, D. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1212.
(35) Bauer, W.; Klusener, P. A. A.; Harder, S.; Kanters, J . A.;
Duisenberg, A. J . M.; Brandsma, L.; Schleyer, P. v. R. Organometallics
1988, 7, 552.
(36) Fraenkel, G.; Winchester, W. R. J . Am. Chem. Soc. 1989, 111,
3794.
1
In 1965, Roberts showed that the H NMR spectra (in
ether) of dialkylmagnesium species change little below
+30 °C and that Grignard species do not change below
temperatures of -70 °C.42 Roberts also found that the
(Arrhenius) barrier to inversion of primary Grignard
reagents was 11 ( 2 kcal/mol (A ) exp 9.5 ( 1.5 s-1),41
and Fraenkel concluded that the mechanism involved a
dimeric species and that alkyl bridging is associated with
the transition state for inversion.53 Early attempts at
(37) Reich, H. J .; Medina, M. A.; Bowe, M. D. J . Am. Chem. Soc.
1992, 114, 11003.
(38) Bergander, K.; He, R.; Chandrakumar, N.; Eppers, O.; Gu¨nther,
H. Tetrahedron 1994, 50, 5861.
(39) Bauer, W.; Schleyer, P. v. R. In Advances in Carbanion
Chemistry; Snieckus, V., Ed.; J AI: Greenwich, CT, 1992; Vol. 1, p 89.
(40) Whitesides, G. M.; Kaplan, F.; Roberts, J . D. J . Am. Chem. Soc.
1963, 85, 2167.
(41) Whitesides, G. M.; Witanowski, M.; Roberts, J . D. J . Am. Chem.
Soc. 1965, 87, 2854.
(46) Shanan-Atidi, H.; Bar-Eli, K. H. J . Phys. Chem. 1970, 74, 961.
(47) Sandstro¨m, J . Dynamic NMR Spectroscopy; Academic Press:
London, 1982, p 81.
(48) Meyers, A. I.; Guiles, J .; Warmus, J . S.; Gonzalez, M. A.
Tetrahedron Lett. 1991, 32, 5505.
(49) Gawley, R. E. J . Am. Chem. Soc. 1987, 109, 1265.
(50) Curtin, D. Y. Rec. Chem. Progr. 1954, 15, 111.
(51) Seeman, J . I. Chem. Rev. 1983, 83, 83.
(42) Whitesides, G. M.; Roberts, J . D. J . Am. Chem. Soc. 1965, 87,
4878.
(43) Maercker, A.; Geuss, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 270.
(44) Liebfritz, D.; Wagner, B. O.; Roberts, J . D. Liebigs Ann. Chem.
1972, 763, 173.
(45) Gretler, R.; Askitoglu, E.; Ku¨hne, H.; Hesse, M. Helv. Chim.
Acta 1978, 61, 1730.
(52) Lindsell, W. E. In Comprehensive Organometallic Chemistry.
The Synthesis, Reactions and Structures of Organometallic Compounds;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford,
1982; Vol. 1, p 155.
(53) Fraenkel, G.; Cottrell, C. E.; Dix, D. T. J . Am. Chem. Soc. 1971,
93, 1704.

8108 J . Org. Chem., Vol. 61, No. 23, 1996
Gawley and Zhang
F igu r e 2. Variable temperature 13C NMR spectrum of C-1 of doubly labeled (6Li and 13C) 3c-Li. Only the signal for C-1 is
shown.
F igu r e 3. Variable temperature 13C NMR spectrum of C-1 of 3c-MgBr . Only the signals for C-1 are shown. See text for
explanation.
observation of inversion of secondary organomagnesium
reagents (4-6-membered saturated rings) showed that
the barrier to inversion was quite high,42,54,55 although
Maercker showed that a 3-cyclohexenyl Grignard reagent
undergoes somewhat more rapid inversion, with a lower
barrier in THF than in ether.43 The high barrier is
generally attributed to difficulty in bridging of the
(55) Pechhold, E.; Adams, D. G.; Fraenkel, G. J . Org. Chem. 1971,
36, 1368.
(54) Davies, A. G.; Roberts, B. P. J . Chem. Soc. (B) 1969, 317.

Stereoselective Additions to Aldehydes
J . Org. Chem., Vol. 61, No. 23, 1996 8109
1 h. The solution was then cooled to 0 °C, and to it was added,
portionwise, 6 g (36 mmol) of L-valine methyl ester hydrochlo-
ride. After the addition, the mixture was warmed to rt and
stirred overnight. The mixture was diluted with ether, and
the reaction was quenched with saturated NH4Cl solution. The
organic phase was separated, washed with brine, and dried
with Na2CO3. The drying agent was filtered, the solvent
removed, and the residue purified with flash chromatography
(ethyl acetate:hexane, 1:2) to afford 4.0 g (44% yield) of 4: mp
94-95 °C; 1H NMR 0.80-0.95 (6H, dd), 1.75 (1H, m), 2.20 (3H,
br), 3.80 (1H, s), 7.10-7.70 (10 H, m). The amino alcohol
obtained in this fashion was used in the next step without
further purification.
saturated secondary Grignard reagents, while the lower
barrier in the cyclohexenyl system is ascribed to as-
sistance by the double bond.52
The coalescence data from Figure 3 correspond to free
energies of activation (∆Gq) in the 9.8-10.1 kcal/mol
range at -65 °C, with ∆G° ) 0.3 kcal/mol for the two
C-1 epimers (see Supporting Information for details).46,47
This low barrier suggests that chelation, dipole stabiliza-
tion, and benzylic activation combine to lower the barrier
to inversion in these species, although further experi-
ments on simpler systems will be necessary to establish
this conclusively.
Su m m a r y. NMR studies indicate that both the orga-
nolithium and the organomagnesium species undergo
pyramidal inversion with barriers to inversion (∆Gq) of
less than 10 kcal/mol. The mechanism of the stereose-
lective addition of these Grignard reagents is complex,
in that it involves equilibrating organomagnesium dia-
stereomers that, as chiral nucleophiles, add stereoselec-
tively to the enantiotopic faces of aldehydes. We cannot
say much about the mechanism because we do not know
the configuration (at C-1) of the nucleophile. We there-
fore cannot say whether the reaction proceeds with
retention or inversion of configuration at the benzylic
carbon, and without that we cannot offer an explanation
for the observed erythro selectivity.
To a solution of 2.0 g (7.8 mmol) of 4 and 2 mL of
triethylamine in 12 mL of THF at rt was added 4.4 mL (8.5
mmol) of phosgene solution (1.93 M in toluene, Fluka).
A
white precipitate formed immediately. After the mixture was
stirred for 2 h, saturated Na2CO3 solution was added and the
organic phase separated. The aqueous phase was extracted
with CH2Cl2 twice. The organic phase was washed with brine,
dried with MgSO4, and evaporated. The residue was washed
with ether to afford 2.1 g of oxazolidinone as a white solid (95%
1
yield): mp 250-251 °C; H NMR 0.7 (3H, d, J ) 8.2 Hz), 0.9
(3H, d, J ) 8.2 Hz), 1.80-1.95 (1H, m), 4.2 (1H, d, J ) 5.1
Hz), 6.3 (1H, s), 7.2-7.6 (10H, m); 13C NMR 158.5, 143.9, 139.1,
128.5, 128.2, 128.1, 127.9, 126.3, 125.7, 89.4, 65.8, 29.6, 20.9,
15.6; IR 1740; MS (DCI/NH3) 282 (MH+), 183 (100). Anal.
Calcd for C18H19NO2: C, 76.87; H, 6.76. Found: C, 77.05; H,
6.82.
(S)-2-E t h oxy-4,5-d ih yd r o-5,5-d ip h en yl-4-isop r op ylox-
a zole (2f). To a solution of 3.6 g of oxazolidinone (9.25 mmol)
in 30 mL of CH2Cl2 at 0 °C was added slowly a solution of 2.1
g (11.1 mmol) of Meerwein’s reagent58 in 10 mL of CH2Cl2.
The mixture was warmed slowly to rt and stirred overnight.
The solution was poured into a cooled aqueous Na2CO3
solution. The organic phase was dried over anhydrous Na2-
CO3. The solvent was evaporated, and the residue was
purified by flash chromatography (ethyl acetate:hexane, 1:2)
to afford 2f (1.4 g, 50% yield) as a white solid: 1H NMR 0.58
(3H, d, J ) 6.7 Hz), 0.96 (3H, d, J ) 6.7 Hz), 1.37 (3H, d, J )
7.8 Hz), 1.77 (1H, m), 4.2-4.4 (2H, m), 4.55 (1H, d, J ) 4.4
Hz), 7.1-7.6 (10H, m); 13C NMR 160.4, 145.1, 140.4, 128.2,
127.8, 127.7, 127.1, 126.6, 93.4, 76.4, 66.4, 30.1, 21.7, 16.3, 14.3;
IR 1640; MS (DCI/NH3) 309 (M+), 182 (PhCOPh). Anal. Calcd
for C20H23NO2: C, 77.67; H, 7.44. Found: C, 77.68; H, 7.51.
(S)-2-(4,5-Dih ydr o-5,5-diph en yl-2-oxalyl)-1,2,3,4-tetr ah y-
d r oisoqu in olin e (3f). A solution of 1.13 g of oxazoline 2f
(3.66 mmol), 1.08 g (8.1 mmol) of 1,2,3,4-tetrahydroisoquino-
line, and a catalytic amount of p-toluenesulfonic acid in 20
mL of benzene was refluxed for 3 d. The solution was cooled
to rt, washed with a saturated Na2CO3 solution and brine, and
dried over MgSO4. The solvent was removed, and the residue
was purified by flash chromatography (CH2Cl2:ethanol, 10:1)
to afford 1.45 g (50% yield) of 3f as an oil: 1H NMR 0.58 (3H,
d, J ) 6.5 Hz), 0.95 (3H, d, J ) 6.5 Hz), 1.65-1.77 (1H, m),
4.55 (1H, d, J ) 2 Hz), 4.70 (2H, s), 7.0-7.6 (14H, m); 13C NMR
158.7, 145.5, 140.9, 134.2, 133.2, 128.6, 128.0, 127.7, 127.4,
126.7, 126.4, 126.0, 76.9, 47.2, 42.7, 30.4, 28.6, 21.6, 16.3; IR
Mechanistic ignorance notwithstanding, we have de-
veloped a general, auxiliary-based method for the ste-
reoselective addition of tetrahydroisoquinoline Grignard
reagents to aldehydes and have demonstrated its useful-
ness in efficient asymmetric synthesis of four phthalide
isoquinoline alkaloids.
Exp er im en ta l Section
Combustion analyses were performed by Atlantic Microlab.
NMR spectra were recorded (ppm) at an operating frequency
of 400 MHz for protons and 100 MHz for carbon. All reactions
were run under a balloon of nitrogen. THF was freshly
distilled from benzophenone sodium ketyl. Benzaldehyde and
piperonal were distilled and stored under nitrogen. Toluene
solutions of phosgene were purchased from Fluka. Magnesium
bromide solutions were prepared by the reaction of magnesium
with ethylene bromide in ether.56 The product of this reaction
is a two-phase mixture, the bottom of which is 2.56 M in
MgBr2. Magnesium chloride solutions in THF are prepared
in the same way or by reaction of HgCl2 with Mg (magnesium
does not react with ethylene chloride in ether).57 In this case,
the product is a homogeneous solution, and it can be standard-
ized by evaporation of an aliquot and weighing. The use of
inexpensive magnesium is satisfactory for these reactions, but
the use of high-purity magnesium (g99.98%) produces an
etherate solution with a longer shelf life. CSP-HPLC refers
to a Bakerbond DNBPG (covalent) Pirkle column, available
from J . T. Baker, Co. The stationary phase is (R)-N-(3,5-
dinitrobenzoyl)phenylglycine. Rotations were measured at rt.
1620; MS (DCI/NH4+) 397 (MH+). Anal. Calcd for C27H28
N2O: C, 81.82; H, 7.07. Found: C, 81.63; H, 7.07.
-
(1R,2S,3R,4S)-3-exo-Am in o-2-h yd r oxy-1,7,7-t r im et h -
ylbicyclo[2.2.1]h ep ta n e (6). To a suspension of LiAlH4 (7
g, 180 mmol) in 400 mL of ether was added a solution of
camphorquinone oxime 525 (10 g, 55 mmol) in 200 mL of ether
over a period of 1 h, and the suspension was then stirred at rt
for 2 d. The reaction was quenched slowly at 0 °C with 15
mL of water followed by 17 mL of 10% NaOH and 24 mL of
water.59 The solid was removed by filtration, and the filtrate
was concentrated. The residue was purified by sublimation.
The amino alcohol (6) was obtained in 75% yield (6.9 g): mp
190-194 °C (lit.25 mp 190-194 °C); 1H NMR 0.8 (3H, s), 0.95
IR spectral data are reported in cm-1
.
(S)-2-Am in o-3-m eth yl-1,1-d ip h en yl-1-bu ta n ol (4) a n d
(S)-3,3-Dip h en yl-4-isop r op yl-2-oxa zolid in on e. In a 1 L
round-bottom flask fitted with a reflux condenser and a
dropping funnel was placed 4.8 g (198 mmol) of magnesium.
The dropping funnel was charged with a solution of 28.2 g (180
mmol) of freshly distilled bromobenzene in 150 mL of THF,
and 10 mL of the solution was added to the flask. The flask
was heated gently to start the reaction. The rest of the
solution was added at such a speed that gentle reflux was
maintained. After the addition, the mixture was refluxed for
(58) Meerwein, H. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, p 581.
(59) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley and Sons: New York, 1967; Vol. 1, p 581.
(56) House, H. O.; Traficante, D. D.; Evans, R. A. J . Org. Chem.
1963, 28, 348.
(57) Ashby, E. C.; Arnott, R. C. J . Organomet. Chem. 1968, 14, 1.

8110 J . Org. Chem., Vol. 61, No. 23, 1996
Gawley and Zhang
(3H, s), 1.08 (3H, s), 1.10-2.00 (5H, m), 3.05 (1H, d, J ) 7.2
Hz), 3.45 (1H, d, J ) 7.2 Hz).
enedioxy analog of urea 8 was obtained in 71% yield: [R]D
+31.7 (c ) 2.5, CH2Cl2); 1H NMR 0.80 (3H, s), 0.95 (3H, s),
1.15 (3H, s), 1.00-1.20 (2H, m), 1.40-1.60 (1H, m), 1.65-1.80
(2H, m), 2.72 (2H, t, J ) 6.5 Hz), 5.30 (1H, s), 5.90 (2H, s),
6.55 (1H, s), 6.60 (1H, s); 13C NMR 157.5, 146.2, 146.1, 128.1,
126.3, 108.2, 106.3, 100.8, 58.8, 50.7, 49.0, 46.7, 45.3, 41.2, 33.5,
28.9, 26.1, 21.7, 11.3; IR 1630; MS 373 (MH+), 306 (100). Anal.
Calcd for C21H28N2O4: C, 67.74; H, 7.53. Found: C, 67.83; H,
7.65.
Cyclization to 10a was accomplished according to the
procedure given for 3g, 75% yield: [R]24D -24.8 (c ) 8.15, CH2-
Cl2); 1H NMR 0.8 (3H, s), 0.90 (3H, s), 1.00 (3H, s), 0.85-1.05
(2H, m), 1.40-1.50 (1H, m), 1.60-1.75 (1H, m), 1.90-2.00 (1H,
m), 2.60-2.80 (2H, m), 3.50-3.65 (2H, m), 3.95 (1H, d, J )
8.4 Hz), 4.28 (1H, d, J ) 8.4 Hz), 4.40-4.50 (2H, m), 5.90 (2H,
s), 6.50 (1H, s), 6.55 (1H, s); 13C NMR 161.5, 145.9, 127.1,
126.0, 108.3, 106.0, 100.5, 91.8, 74.0, 49.0, 48.0, 47.1, 46.2, 42.6,
31.9, 28.6, 25.6, 23.5, 19.0, 11.3; IR 1640; MS 355 (MH+, 100).
Anal. Calcd for C21H26N2O3: C, 71.19; H, 7.34. Found: C,
70.93; H, 7.38.
Ur ea 8 (P r ep a r ed fr om 1,2,3,4-Tetr a h yd r oisoqu in o-
lin e, P h osgen e, a n d 6). Gen er a l P r oced u r e. To a solution
of 4.0 equiv of phosgene (1.93 M in toluene, Fluka) and excess
triethylamine in THF (or CH2Cl2) at -78 °C was added slowly
a solution of 1.0 equiv of 1,2,3,4-tetrahydroisoquinoline in THF
(or CH2Cl2). The mixture was stirred at -78 °C for 1 h. The
mixture was slowly warmed to rt, and the unreacted phosgene
was removed by evaporation with an aspirator. More solvent
was added, and the mixture was cooled to -78 °C. To this
solution was added a solution of 0.95 equiv of 6 and excess
triethylamine in THF (or CH2Cl2). The solution was warmed
to rt and stirred overnight. Water was added to the mixture.
The aqueous phase was extracted twice with CH2Cl2. The
organic phases were washed with brine and dried with MgSO4.
The solvent was removed, and the residue was purified by flash
chromatography (ethyl acetate:hexane, 1:1 to 2:1), giving 8 as
a white solid, 71% yield: [R]D +31.7 (c ) 6.7, CH2Cl2); 1H NMR
0.80 (3H, s), 0.95 (3H, s), 1.15 (3H, s), 1.0-1.3 (2H, m), 1.40-
1.55 (1H, m), 1.6-1.9 (2H, m), 2.8-2.9 (2H, m), 3.5-3.7 (2H,
m), 3.7-3.9 (2H, m), 4.5 (2H, m), 5.35 (1H, s), 7.00-7.15 (4H,
m); 13C NMR 156.6, 139.0, 131.6, 129.2, 126.2, 123.9, 79.8, 58.6,
50.5, 48.9, 46.5, 43.3, 33.1, 26.9, 26.0, 23.6, 21.1, 20.6, 11.1;
IR 1640; MS (DCI/NH3) 329 (MH+), 311, 196, 134 (100). Anal.
Calcd for C20H28N2O2: C, 73.17; H, 8.54. Found: C, 73.04; H,
8.61.
6,7-Dim eth oxyisoqu in olyloxa zolin e 10b. Following the
general procedures given for compounds 8 and 3g, compound
10b was obtained in two steps. The 6,7-dimethoxy analog of
urea 8 was obtained in 66% yield: [R]D
+20.7 (c ) 0.4, CH2-
Cl2); 1H NMR 0.80 (3H, s), 0.95 (3H, s), 1.15 (3H, s), 1.00-
1.25 (2H, m), 1.40-1.60 (1H, m), 1.60-1.85 (2H, m), 2.60-
2.80 (2H, m), 3.40-3.70 (2H, m), 3.70-4.00 (8H, m), 4.40 (2H,
s), 5.40 (1H, s), 6.50-6.70 (2H, m); 13C NMR 157.6, 147.7,
126.9, 125.1, 111.3, 109.3, 80.1, 58.8, 50.9, 49.2, 58.8, 46.9, 45.2,
41.2, 33.4, 28.5, 26.2, 21.6, 21.2, 11.4; IR 1630; MS 389 (MH+).
Anal. Calcd for C22H32N2O4: C, 68.04; H, 8.25. Found: C,
67.86; H, 8.27.
Isoq u in olyloxa zolin e 3g (b y Cycliza t ion of 8 w it h
P OCl3). Gen er a l P r oced u r e. A 0.2 M solution of 8 and 8.0
equiv of POCl3 in toluene was refluxed overnight. The solution
was concentrated to near dryness, washed with saturated Na2-
CO3, and extracted with CH2Cl2. The organic phase was
washed with brine and dried with MgSO4. After the solvent
was removed, the residue was purified with flash chromatog-
raphy (ethanol:CH2Cl2, 1:20). Isoquinolyloxazoline 3g was
obtained as a colorless oil in 82% yield: [R]D -30.0 (c ) 2.55,
CH2Cl2); 1H NMR 0.81 (3H, s), 0.90 (3H, s), 1.05 (3H, s), 0.9-
1.20 (2H, m), 1.40-1.50 (1H, s), 1.60-1.70 (1H, m), 1.90-2.00
(1H, m), 2.85 (2H, t, J ) 5.3 Hz), 3.65 (2H, t, J ) 5.3 Hz), 3.95
(1H, d, J ) 9.5 Hz), 4.30 (1H, d, J ) 9.5 Hz), 4.55 (2H, s),
7.05-7.30 (4H, m); 13C NMR 161.3, 133.9, 133.0, 128.4, 125.9,
125.8, 91.5, 73.7, 48.9, 47.9, 46.8, 46.6, 42.4, 31.7, 28.5, 25.3,
23.2, 18.5, 11.1; IR 1635; MS 311(MH+). Anal. Calcd for
C20H26N2O: C, 77.42; H, 8.39. Found: C, 77.12; H, 8.43.
Gen er a l P r oced u r e for th e Selectivity Stu d ies. To a
0.1-0.2 M solution of isoquinolyloxazoline 3 in THF at -78
°C was added 1.2 equiv of a BuLi solution in hexane. After
the solution was stirred at this temperature for 20 min, 1.5
equiv of a 2.56 M solution of MgBr2‚OEt2 was added. The
reaction mixture was stirred at 0 °C for 20 min and then cooled
back to the temperature indicated in Table 1. To this solution
was added 1.5 equiv of benzaldehyde, and the mixture was
stirred at this temperature overnight. A saturated NH4Cl
solution was added, and the organic phase was separated. The
aqueous phase was extracted with CH2Cl2. The combined
organic phases were collected, washed with brine, and dried
with MgSO4. After the solvents were removed, the residue
was dissolved in THF. To this solution was added 4.0 equiv
of LiAlH4 at rt. The mixture was stirred for 10 min and then
refluxed overnight. The solution was cooled with ice-water,
and to it was added water dropwise. When no more gas was
formed, 10% NaOH solution was added. The mixture was
stirred for 10 min. The solid was filtered off, and the solution
was concentrated. The residue was purified by flash chroma-
tography (CH2Cl2:EtOH, 10:1) to afford a mixture of amino
alcohols. To a solution of the above mixture and excess
triethylamine in CH2Cl2 was added 1.5 equiv of 1-naphthoyl
chloride. The mixture was stirred at rt overnight. Saturated
Na2CO3 was added and the organic phase separated. The
organic phase was dried over MgSO4 and analyzed by CSP-
Cyclization to 10b was accomplished according to the
procedure given for 3g, 70% yield: [R]D -36.4 (c ) 3.55, CH2-
Cl2); 1H NMR 0.85 (3H, s), 0.95 (3H, s), 1.05 (3H, s), 0.90-
1.10 (1H, m), 1.40-1.50 (1H, m), 1.60-1.80 (1H, m), 1.90-
2.00 (1H, m), 2.80 (2H, m), 3.60 (2H, m), 3.85 (6H, d), 3.97
(1H, d, J ) 8.2 Hz), 4.30 (1H, d, J ) 8.2 Hz), 4.50 (2H, s), 6.58
(1H, s), 6.62 (1H, s); 13C NMR 160.1, 148.1, 147.9, 124.4, 121.5,
111.1, 108.9, 94.8, 64.4, 55.8, 55.7, 48.7, 47.7, 47.5, 45.3, 46.3,
30.8, 27.5, 24.1, 22.8, 18.5, 10.5; IR 1640; MS 371 (MH+). Anal.
Calcd for C22H30N2O3: C, 71.35; H, 8.11. Found: C, 71.55; H,
8.18.
Gen er a l P r oced u r e for P r ep a r a tive Ad d ition s to Al-
d eh yd es. To a 0.1 M solution of isoquinolyloxazoline 3g or
10 in THF at -78 °C was added 1.2 equiv of BuLi (1.6 M
solution in hexane). After the solution was stirred at that
temperature for 20 min, 1.5 equiv of magnesium halide
solution was added. The mixture was stirred at 0 °C for 20
min and then cooled to -65 °C. To this solution was added
1.5 equiv of aldehyde. The mixture was stirred at that
temperature for 2 d. A saturated NH4
and the organic phase was separated. The aqueous phase was
Cl2. The combined organic phases were
Cl solution was added,
extracted with CH2
washed with brine and dried with MgSO4. The solvent was
removed, and the residue was purified by either recrystalli-
zation from chloroform and hexane or flash chromatography
(ethyl acetate:hexane, 2:1 to 4:1).
1-Hyd r oxyben zylisoqu in olyloxa zolin e 9g was prepared
by the general procedure, 50% yield: mp 210-211 °C; [R]D
-80.7 (c ) 1.9, CH2Cl2); 1H NMR 0.85 (3H, s), 0.90 (3H, s),
1.00 (3H, s), 0.90-1.10 (2H, m), 1.40-1.60 (2H, m), 1.60-1.80
(1H, m), 1.90-2.00 (1H, m), 2.20-2.40 (1H, m), 2.80-3.00 (1H,
m), 3.10-3.30 (1H, m), 4.12 (1H, d, J ) 8.5 Hz), 4.48 (1H, d,
J ) 8.5 Hz), 5.15 (1H, s), 5.50 (1H, s), 6.80-7.50 (9H, m);
13C
NMR 165.0, 141.0, 135.6, 133.7, 127.8, 127.4, 126.9, 126.4,
92.8, 82.1, 72.9, 63.7, 49.5, 48.3, 46.4, 41.8, 31.9, 27.8, 25.5,
18.9, 11.2; IR 1635; MS 417 (MH+), 311, 107. Anal. Calcd for
C27H32N2O2P: C, 77.88; H, 7.69. Found C, 77.66; H, 7.74.
1-[2-(Hyd r oxyben zyl)-6,7-(m eth ylen ed ioxy)isoqu in oly-
l]oxa zolin e 11a was prepared by the general procedure, 58%
yield: mp 193-195 °C; [R]D -36.2 (c ) 2.85, CH2Cl2); 1H NMR
0.85 (3H, s), 0.88 (3H, s), 0.98 (3H, s), 0.95-1.10 (2H, m), 1.40-
1.80 (3H, m), 2.10-2.30 (1H, m), 2.89-2.90 (1H, m), 3.10-
3.25 (1H, m), 4.10 (1H, d, J ) 8.4 Hz), 4.42 (1H, d, J ) 8.4
Hz), 5.05 (1H, s), 5.40 (1H, s), 5.92 (1H, s), 5.98 (1H, s), 6.40
HPLC with
a
Pirkle column.21 The amino alcohols and
naphthamides obtained by this procedure from 3a -g were
identical to those reported previously.14,21
6,7-(Meth ylen ed ioxy)isoqu in olyloxa zolin e 10a . Fol-
lowing the general procedures given for compounds 8 and 3g,
compound 10a was obtained in two steps. The 6,7-methyl-

Stereoselective Additions to Aldehydes
J . Org. Chem., Vol. 61, No. 23, 1996 8111
(1H, s), 6.80-7.00 (3H, m), 7.10-7.20 (3H, m); 13C NMR 164.8,
146.4, 146.1, 141.0, 129.2, 127.4, 127.1, 126.9, 126.6, 107.8,
100.9, 92.7, 82.1, 72.9, 63.8, 49.6, 48.3, 46.4, 42.0, 32.3, 28.9,
25.7, 23.7, 19.1, 11.5; IR 1640; MS 461 (MH+, 100), 353. Anal.
Calcd for C28H32N2O4: C, 73.04; H, 6.96. Found: C, 72.85; H,
7.11.
1-[2-(Hyd r oxyben zyl)-6,7-dim eth oxyisoqu in olyl]oxa zo-
lin e (11b) was prepared by the general procedure, 53% yield:
[R]D -47.9 (c ) 2.75, CH2Cl2); 1H NMR 0.83 (3H, s), 0.87 (3H,
s), 0.98 (3H, s), 0.95-1.10 (2H, m), 1.40-1.70 (3H, s), 1.92 (1H,
d, J ) 0.50 Hz), 2.20-2.35 (1H, m), 2.70-2.90 (1H, m), 3.20-
3.30 (1H, m), 3.83 (3H, s), 3.86 (3H, s), 4.12 (1H, d, J ) 7.4
Hz), 4.42 (1H, d, J ) 7.4 Hz), 5.15 (1H, s), 5.40 (1H, s), 6.43
(1H, s), 6.80 (1H, s), 6.90-7.00 (2H, m), 7.10-7.25 (3H, m);
13C NMR 164.8, 147.8, 147.4, 141.1, 127.8, 127.4, 127.0, 126.8,
125.2, 110.6, 92.8, 81.6, 72.8, 63.3, 56.2, 49.2, 48.2, 46.4, 41.7,
31.8, 27.5, 25.8, 23.7, 18.9, 11.6; IR 1634; MS 477 (MH+). Anal.
Calcd for C29H36N2O4: C, 73.11; H, 7.56. Found: C, 73.22; H,
7.60.
were washed with brine and dried over MgSO4. The solvent
was removed, and the residue was purified with flash chro-
matography (CH2Cl2:ethanol, 20:1) to afford 200 mg of 16 (73%
1
yield from 14): [R]D +57.2 (c ) 2.0, CH2Cl2); H NMR 2.50-
2.62 (1H, m), 2.90-3.04 (1H, m), 3.07-3.20 (1H, m), 3.52 (3H,
s), 3.80 (3H, s), 4.4.12-4.22 (1H, m), 5.24 (1H, d, J ) 10.5 Hz),
5.77 (1H, d, J ) 10.5 Hz), 5.86 (2H, s), 5.90 (1H, s), 6.42-6.50
(2H, m), 6.64 (2H, s); 13C NMR 157.4, 148.0, 147.9, 147.8, 147.0,
129.2, 126.9, 122.5, 121.3, 111.6, 110.1, 107.7, 107.6, 101.2,
80.5, 59.3, 55.6, 39.5, 27.6; IR 1730; MS 369 (M+), 191 (100).
Anal. Calcd for C20H19NO6: C, 65.04; H, 5.15. Found: C,
64.75; H, 5.25.
N-Meth yla m in o Alcoh ol 17. To a suspension of LiAlH4
(103 mg, 2.71 mmol) in 10 mL of THF was added a solution of
compound 6 (200 mg, 0.54 mmol) in 5 mL of THF at 0 °C. The
solution was warmed to rt and refluxed overnight. The
solution was cooled to 0 °C and was diluted with an equal
volume of ether. The unreacted LiAlH4 was decomposed by
the dropwise addition of water and 10% NaOH.59 The solid
was filtered, and the filtrate was washed with brine and dried
with MgSO4. The solvent was removed, and the residue was
purified by flash chromatography (CH2Cl2:ethanol, 10:1) to
afford compound 17 (183 mg, 95%): [R]D -7.92 (c ) 3.7, CH2-
Cl2); 1H NMR 2.50-2.70 (2H, m), 2.60 (3H, s), 2.70-2.80 (1H,
m), 2.95-3.05 (1H, m), 3.47 (3H, s), 3.70 (1H, d, J ) 3.1 Hz),
3.83 (3H, s), 5.02 (1H, d, J ) 3.1 Hz), 5.80 (1H, s), 5.90 (2H,
s), 6.55 (1H, s), 6.60-6.80 (3H, m); 13C NMR 147.3, 146.3,
145.9, 135.5, 129.1, 123.9, 119.5, 111.8, 110.8, 107.7, 107.3,
100.7, 73.9, 70.1, 58.2, 55.6, 55.2, 50.5, 44.0, 28.1, 18.3; IR 3400
(OH); MS 358 (MH+), 206 (100). Anal. Calcd for C20H23NO5:
C, 67.23; H, 6.44. Found: C, 67.50; H, 6.48.
Ad d ition P r od u ct (12) was prepared by the general
1
procedure, 62% yield: [R]D -40.2 (c ) 9.5, CH2Cl2); H NMR
0.83 (3H, s), 0.86 (3H, s), 0.98 (3H, s), 0.95-1.10 (2H, m), 1.40-
1.60 (3H, m), 1.92 (1H, d, J ) 5.1 Hz), 2.10-2.30 (1H, m),
2.90-3.00 (1H, m), 3.10-3.30 (1H, m), 4.10 (1H, d, J ) 9.2
Hz), 4.45 (1H, d, J ) 9.2), 4.97 (1H, s), 5.35 (1H, s), 5.88 (2H,
s), 5.93 (1H, s), 5.97 (1H, s), 6.25 (1H, d, J ) 10.2 Hz), 6.41
(1H, s), 6.50-6.62 (2H, m), 6.82 (1H, s); 13C NMR 165.0, 147.0,
146.5, 146.2, 135.2, 129.2, 126.7, 120.2, 107.9, 107.7, 107.4,
101.0, 100.7, 93.0, 81.6, 72.8, 63.8, 49.3, 48.3, 46.5, 42.0, 31.9,
28.0, 25.6, 23.5, 18.9, 11.4; IR 1635; MS 505 (MH+), 353. Anal.
Calcd for C29H32N2O6: C, 69.05; H, 6.35. Found: C, 68.99; H,
6.41.
(+)-Cor lu m in e. To a solution of well-dried alcohol 17 (43
mg, 0.12 mmol) in 3 mL of THF was added 0.28 mL of a BuLi
solution (1.3 M in hexane) at -40 °C. The mixture was stirred
at this temperature for 2 h. The solution turned deep red.
The solution was then cooled to -78 °C, and through it a CO2
stream was bubbled in for 10 min. The mixture was warmed
to rt, and 5 mL of water was added. The aqueous phase was
extracted twice with ether. The combined organic phases were
washed with brine and dried with MgSO4. Evaporation of the
solvent afforded 20 mg (47%) of starting material. The
aqueous phase was made acidic by the addition of concd HCl
and was then stirred at 50 °C for 30 min. The solution was
then made basic by the addition of saturated Na2CO3 solution
and extracted three times with CH2Cl2. The combined organic
phases were washed with brine and dried with MgSO4. The
solvent was removed, and the residue was purified by flash
chromatography (CH2Cl2:ethanol, 95:5) to afford 23 mg of (+)-
corlumine (50%): [R]D +70 (c ) 0.75, CH2Cl2); 1H NMR 2.30-
2.40 (1H, m), 2.50-2.68 (2H, m), 2.60 (3H, s), 2.90-3.00 (1H,
m), 3.70 (3H, s), 3.90 (3H, s), 4.10 (1H, d, J ) 3.6 Hz), 5.64
(1H, d, J ) 3.6 Hz), 6.15 (2H, s), 6.21 (1H, d, J ) 8.0 Hz), 6.40
(1H, s), 6.60 (1H, s), 6.92 (1H, d, J ) 8.0 Hz).
Am in o Alcoh ol 13. To a suspension of LiAlH4 (117 mg,
3.1 mmol) in 10 mL of THF at 0 °C was added dropwise a
solution of 12 (310 mg, 0.62 mmol) in 10 mL of THF. The
reaction mixture was warmed to rt and then refluxed for 1 d.
After being cooled to 0 °C, the mixture was diluted with an
equal volume of ether. The unreacted LiAlH4 was decomposed
by the dropwise addition of water and 10% NaOH.59 The solid
was filtered, and the filtrate was washed with brine and dried
with MgSO4. The solvent was removed, and the residue was
purified by flash chromatography (CH2Cl2:ethanol, 10:1) to
afford amino alcohol 13 (130 mg, 64%), identical spectroscopi-
cally to that obtained previously:14 1H NMR 2.45-2.63 (2H,
m), 2.73-2.91 (2H, m), 4.13 (1H, d, J ) 4 Hz), 4.84 (1H, d, J
) 4 Hz), 5.92 (4H, s), 6.51 (1H, s), 6.68-6.80 (4H, m).
Ad d ition P r od u ct 14 was prepared by the general proce-
dure, 49% yield: [R]D -37.42 (c ) 1.4, CH2Cl2); 1H NMR 0.83
(3H, s), 0.86 (3H, s), 1.00 (3H, s), 0.90-1.10 (2H, m), 1.40-
1.80 (3H, m), 1.95 (1H, m), 1.25-1.40 (1H, m), 2.80-2.90 (1H,
m), 3.25-3.35 (1H, m), 3.85 (3H, s), 3.90 (3H, s), 4.12 (1H, d,
J ) 9.7 Hz), 4.45 (1H, d, J ) 9.7 Hz), 5.09 (1H, s), 5.40 (1H,
s), 5.90 (2H, s), 6.20-6.30 (1H, m), 6.45 (1H, s), 6.50-6.62 (2H,
m), 6.80-6.90 (1H, m); 13C NMR 164.5, 147.9, 147.6, 147.0,
146.6, 135.2, 127.8, 125.5, 120.1, 110.7, 110.5, 107.6, 107.3,
100.6, 92.9, 81.6, 72.9, 63.3, 56.0, 55.8, 49.3, 48.3, 46.4, 41.8,
31.9, 27.8, 25.5, 23.5, 18.9, 11.4; IR 1630; MS 521 (MH+), 369,
192 (100%). Anal. Calcd for C30H36N2O6: C, 69.23; H, 6.92.
Found: C, 68.98; H, 6.95.
Oxa zolid in on e 16. To a suspension of LiAlH4 (146 mg,
3.85 mmol) in 10 mL of THF was added dropwise a solution
of 14 (400 mg, 0.77 mmol) in 10 mL of THF at 0 °C. The
reaction mixture was warmed to rt and then refluxed for 1 d.
After being cooled 0 °C, the mixture was diluted with an equal
volume of ether. The unreacted LiAlH4 was decomposed by
the dropwise addition of water and 10% NaOH.59 The solid
was filtered, and the filtrate was washed with brine and dried
with MgSO4. The solvent was removed, and the residue was
purified by flash chromatography (CH2Cl2:ethanol, 10:1) to
afford amino alcohol 15. To a solution of 15 (200 mg, 0.58
mmol) and 0.5 mL of triethylamine in 10 mL of THF was added
0.36 mL of phosgene (0.69 mmol, 1.93 M solution in toluene).
The mixture was stirred at rt for 2 h. Saturated Na2CO3
solution was added, and the solution was stirred for 30 min.
The organic phase was separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic phases
N-(2-P h en yleth yl)for m a m id e-1-13C. On the basis of the
procedure in Fieser and Fieser,60 sodium formate is converted
to acetic formic anhydride, which is then used to acylate
phenethylamine. To 200 mg (2.9 mmol) of finely grounded
sodium 13C-formate in 1 mL of ether was added 226 mg (2.9
mmol) of acetyl chloride at rt. The mixture was then stirred
at rt overnight. To this solution were added 2 mL of THF and
701 mg (5.8 mmol) of phenethylamine at rt. The mixture was
again stirred overnight at rt. The solid was then filtered and
the filtrate concentrated. The residue was purified by flash
chromatography (CH2Cl2:ethanol, 100:8). The product was
obtained in 92% yield from sodium formate (400 mg). This
compound was used immediately to prepare [1-13C]tetrahy-
droisoquinoline by the procedure of Hesse.45 Then, condensa-
tion with 2c using the procedure described above afforded 3c
(1-13C), which showed a molecular ion at m/ z 245 and an
enriched 13C resonance at 47.1 ppm.
13C NMR Sp ectr a of (S)-[1-6Li,1-13C]-2-(4,5-Dih yd r o-4-
isopr opyl-2-oxazolyl)-1,2,3,4-tetr ah ydr oisoqu in olin e. Com-
pound 3c (1-13C) was distilled from calcium hydride under
(60) Fieser, M.; Fieser, L. Reagents for Organic Synthesis; Wiley-
Interscience: New York, 1969; Vol. 2, p 10.

8112 J . Org. Chem., Vol. 61, No. 23, 1996
Gawley and Zhang
reduced pressure (Kugelrohr oven) and dissolved in THF. The
solution was transferred into a 10 mm NMR tube and cooled
to -78 °C. To this solution was added BuLi [6Li31]. The whole
operation was done under the protection of argon. The NMR
tube was put into an NMR probe, and the temperature was
lowered to -100 °C. After 10 min for thermal equilibration,
the 13C NMR spectra were recorded. After the temperature
was changed incrementally, the system was equilibrated for
10 min and the magnet was reshimmed.
13C NMR Sp ectr a of [(S)-[1-13C]-2-(4,5-Dih yd r o-4-iso-
p r op yl-2-oxa zolyl)-1,2,3,4-tetr a h yd r oisoqu in olyl]m a gn e-
siu m Ha lid e. To the lithium compound solution used above
was added magnesium bromide etherate (or magnesium
chloride in THF). The mixture was shaken at 0 °C for 20 min.
The NMR tube was then put into the probe, and the NMR
spectra were recorded as described above.
Ack n ow led gm en t. We are grateful for the support
of this work by the National Institutes of Health (NIH)
(Grant GM-37985) and by a Maytag fellowship to P.Z.
NMR spectroscopy and MS instrumentation were pur-
chased with the help of grants from NIH (Grants RR-
03351 and RR-04680).
Su p p or tin g In for m a tion Ava ila ble: Details for the
DNMR calculations and 400 MHz 1H NMR spectra of com-
pounds 3g, 9, 10a ,b, 11a ,b, 12-14, 16-17, and corlumine (8
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, can be downloaded from the internet, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961164U