Enantioselective synthesis of rigid 2-aminotetralins. Utility of silicon as an oxygen and nitrogen surrogate in the tandem addition reaction

Article abstract of DOI:10.1021/jo0001131

Dimethylphenylsilyllithium undergoes a highly diastereoselective conjugate addition to chiral naphthyloxazoline 11. Electrophilic trapping of the resulting aza-enolate affords the tandem addition product (12) in high yields as a single diastereomer. The silicon, thus incorporated, may be protodesilylated and undergoes a Tamao oxidation to afford the corresponding alcohol. By chemical modification of the oxazoline, both the γ-lactone (28) and the δ-lactone (37) were prepared. Reduction of each lactone followed by oxidation of the ensuing diol gave the keto aldehyde. Double reductive animation of the 1,4-dicarbonyl (from the γ-lactone) allowed the synthesis of two novel hexahydrobenz[e]indoles, 20 and 35. Double reductive amination of the 1,5-dicarbonyl (from the δ-lactone) gave access to two novel octahydrobenzo[f]quinolines, 41 and 43. An unprecedented rearrangement of nitro alcohol 26 into lactone 28 is described and a reasonable mechanism for its formation postulated.

Full text of DOI:10.1021/jo0001131

J . Org. Chem. 2000, 65, 3503-3512
3503
En a n tioselective Syn th esis of Rigid 2-Am in otetr a lin s. Utility of
Silicon a s a n Oxygen a n d Nitr ogen Su r r oga te in th e Ta n d em
Ad d ition Rea ction
Andrew P. Degnan and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J anuary 27, 2000
Dimethylphenylsilyllithium undergoes a highly diastereoselective conjugate addition to chiral
naphthyloxazoline 11. Electrophilic trapping of the resulting aza-enolate affords the tandem addition
product (12) in high yields as a single diastereomer. The silicon, thus incorporated, may be
protodesilylated and undergoes a Tamao oxidation to afford the corresponding alcohol. By chemical
modification of the oxazoline, both the γ-lactone (28) and the δ-lactone (37) were prepared. Reduction
of each lactone followed by oxidation of the ensuing diol gave the keto aldehyde. Double reductive
amination of the 1,4-dicarbonyl (from the γ-lactone) allowed the synthesis of two novel hexa-
hydrobenz[e]indoles, 20 and 35. Double reductive amination of the 1,5-dicarbonyl (from the δ-lactone)
gave access to two novel octahydrobenzo[f]quinolines, 41 and 43. An unprecedented rearrangement
of nitro alcohol 26 into lactone 28 is described and a reasonable mechanism for its formation
postulated.
Reports of the potent anti-Parkinsonian activity of
apomorphine (1) have triggered research into the devel-
opment of drugs that mimic this agent.1 The postulated
mechanism of action of 1 involves a selective binding of
it to the D-1 and D-2 (dopamine) receptors.2 Structurally
simplified analogues of 1, 2-aminotetralins (2), have been
shown to maintain binding affinity to dopamine recep-
tors.3 Further, through the proper choice of substitution
pattern, 2-aminotetralins can show either potent sero-
tonin or dopamine agonist activity. The neurotransmit-
ters dopamine and serotonin have been implicated in
many central nervous system related disorders such as
anxiety, depression, schizophrenia, and Parkinson’s dis-
ease.
as octahydrobenzo[f]quinolines,5 and tested them for their
ability to bind to dopamine receptors. It was found that
most retained good dopamine agonist activity. Wikstro¨m6
later showed that certain analogues of 3 were devoid of
dopaminergic activity, yet showed serotonin agonism.
Both authors noted increased activity among the trans-
fused analogues of 3.
Later, Lin et al. prepared a series of pyrrolidine-fused
tetralins (4), formally referred to as hexahydrobenz[e]-
indoles, and tested them for their ability to bind selec-
tively to dopamine and serotonin receptors.7 The cis-fused
analogues were shown to be more active than the
corresponding trans-fused congeners. It was found that
analogues with 9-methoxy substitution showed mixed
serotonin (5-HT1A) and dopamine (D-2) agonism. In
contrast, it was found that analogues with 9-hydroxy
substitution showed binding only to 5-HT1A receptors.
The ability to change the binding selectivity to favor
one or the other through modification of the substituents
present on 3 or 4 poses not only potential medicinal value,
but also makes these more rigid ring-fused aminotetra-
lins useful in fundamental research into the mechanism
by which neurotransmitters function. Although dopamine
and serotonin possess no center of asymmetry, it is
apparent from in vivo assays that their respective recep-
tors possess a high degree of chirality, discriminating
between enantiomeric dopaminergic and serotoninergic
Cannon et al.4 synthesized a series of more structurally
rigid piperidine-fused tetralins (3), formally referred to
(5) For other syntheses of octahydrobenzo[f]quinolines, see: (a) Ripa,
L.; Hallberg, A. J . Org. Chem. 1998, 63, 84. (b) Tagmatarchis, N.;
Katerinopoulos, H. E. J . Heterocycl. Chem. 1996, 33, 983.
(6) (a) Wikstro¨m, H.; Andersson, B.; Elebring, T.; Svensson, K.;
Carlsson, A.; Largent, B. J . Med. Chem. 1987, 30, 2169. (b) Wikstro¨m,
H.; Andersson, B.; Elebring, T.; J acyno, J .; Allinger, N. L.; Svensson,
K.; Carlsson, A.; Sundell, S. J . Med. Chem. 1987, 30, 1567. (c)
Wikstro¨m, H.; Sanchez, D.; Lindberg, P.; Arvidsson, L.-E.; Hacksell,
U.; J ohansson, A.; Nilsson, J . L. G.; Hjorth, S.; Carlsson, A. J . Med.
Chem. 1982, 25, 925.
(7) (a) Lin, C.-H.; Haadsma-Svensson, S. R.; Lahti, R. A.; McCall,
R. B.; Piercey, M. F.; Schreur, P. D.; Von Voigtlander, P. F.; Smith, M.
W.; Chidester, C. G. J . Med. Chem. 1993, 36, 1053. (b) Cruse, S. F.;
Lear, J .; Klein, C. L.; Andersen, P. H.; Dick, R. M.; Crider, A. M. J .
Pharm. Sci. 1993, 82, 334.
(1) Cotzias, G. C.; Papavasiliou, P. S.; Fehling, C.; Kaufman, B.;
Mena, I. New Engl. J . Med. 1970, 282, 31.
(2) Vernier, V. G. Annu. Rep. Med. Chem. 1971, 1970, 42.
(3) McDermed, J . D.; McKenzie, G. M.; Phillips, A. P. J . Med. Chem.
1975, 18, 362.
(4) (a) Cannon, J . G.; Amoo, V. E. D.; Long, J . P.; Bhatnagar, R. K.;
Flynn, J . R. J . Med. Chem. 1986, 29, 2529. (b) Cannon, J . G.; Lee, T.;
Goldman, H. D.; Long, J . P.; Flynn, J . R.; Verimer, T.; Costall, B.;
Naylor, R. J . J . Med. Chem. 1980, 23, 1. (c) Cannon, J . G.; Suarez-
Gutierrez, C.; Lee, T.; Long, J . P.; Costall, B.; Fortune, D. H.; Naylor,
R. J . J . Med. Chem. 1979, 22, 341.
10.1021/jo0001131 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/11/2000

3504 J . Org. Chem., Vol. 65, No. 11, 2000
Degnan and Meyers
Sch em e 1
Sch em e 3
Sch em e 2
addition product 12 to give 13 followed by quaternization
of 13 with methyl triflate, reduction with sodium boro-
hydride, and hydrolysis of the resulting aminal gave
aldehyde 14 in 65% overall yield. The two-step process
was significantly improved by reversing the catalytic and
hydride reduction steps to afford the tetrahydronaph-
thylaldehyde in 95% overall yield from 12.
At this point, it was necessary to plan a sequence that
would incorporate the requisite C-N tether by condens-
ing 15 with nitromethane14 to furnish the nitroolefin, 16
(Scheme 4). The latent hydroxyl group, present as the
silyl substituent, would be liberated, by protodesilylation
and subsequent Tamao oxidation, to give the intermedi-
ate nitro alcohol, which would be oxidized to the nitro
ketone 17. It was initially anticipated that treatment of
17 with H2-Pd/C would introduce 5 mol of hydrogen to
produce the intermediate 18, which would be expected
to undergo intramolecular condensation to imine 19.
Under the hydrogenation conditions, it was thought that
this would be further reduced to liberate the target
compound 20. Thus, the latter, in enantiomerically pure
form, could hopefully be accessed in a single hydrogena-
tion step by reduction of nitroketone 17.
In actuality, the Henry reaction proceeded smoothly
affording a quantitative yield of nitro alkene 16 (Scheme
5). However, all attempts to desilylate this material to
21 were unsuccessful, giving rise to heavy decomposition.
This was not wholly unexpected as allyl silanes can
themselves be protodesilylated to give desilylated mate-
rial (as seen in Scheme 1). Furthermore, allyl silanes are
known to undergo conjugate addition reactions with R,â-
unsaturated nitro compounds.15 It was felt that these
obstacles could be bypassed by reduction of one or both
of the olefinic linkages present in 16.
agonists.8 As such there is a need to synthesize these
molecules in a highly enantioselective fashion.
In an earlier report,9 it was shown that dimethylphen-
ylsilyllithium undergoes conjugate addition10 to naph-
thyloxazoline 5 to afford 6 as a single diastereomer
(Scheme 1). In that work, the silane was a mere proton
surrogate, allowing the creation of chiral 1,1-disubsti-
tuted dihydronaphthalenes, 7. It was anticipated that
this same methodology would allow the incorporation of
a hydroxyl group via protodesilylation of the phenyl group
and subsequent Tamao oxidation11 of the incorporated
silicon (Scheme 2). As oxygen nucleophiles have been
found to be unsuitable to undergo the tandem addition
reaction, this would represent an expedient entry into
chiral 2-hydroxy tetralins, 9. It was felt that, once
installed, the hydroxyl could be elaborated to afford one
or more rigid 2-aminotetralins12 (10).
As described in our previous studies,9 dimethylphen-
ylsilyllithium underwent conjugate addition to oxazoline
11 to afford a single diastereomer13 of 12 after quenching
with methyl iodide (Scheme 3). The oxazoline moiety
could then be converted to the tetrahydronaphthylalde-
hyde 14 in either of two fashions. Hydrogenation of the
(8) Cannon, J . G. Prog. Drug Res. 1985, 29, 303.
(9) (a) Hulme, A. N.; Meyers, A. I. J . Org. Chem. 1994, 59, 952. (b)
Hulme, A. N.; Henry, S. S.; Meyers, A. I. J . Org. Chem. 1995, 60, 1265.
(10) For reviews on the use of chiral oxazolines in synthesis, see:
(a) Meyers, A. I. J . Heterocycl. Chem. 1998, 35, 991. (b) Gant, T. G.;
Meyers, A. I. Tetrahedron, 1994, 50, 2297. (c) Reuman, M.; Meyers, A.
I. Tetrahedron 1985, 41, 837.
(11) (a) J ones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599. (b)
Fleming, I.; Henning, R.; Plaut, H. J . Chem. Soc., Chem. Commun.
1984, 29. (c) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani,
R.; Yoshida, J .; Kumada, M. Tetrahedron 1983, 39, 990.
(12) For an earlier report of a naphthyloxazoline-based sythesis of
2-aminotetralins, see: Shimano, M.; Meyers, A. I. J . Org. Chem. 1995,
60, 7445.
Attention was then focused on the analogous saturated
silyl aldehyde, 14, wherein the styrene double bond had
(14) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
(15) Ochiai, M.; Arimoto, M.; Fujita, E. Tetrahedron Lett. 1980, 4557.
(13) Determined by 1H NMR.

Enantioselective Synthesis of Rigid 2-Aminotetralins
J . Org. Chem., Vol. 65, No. 11, 2000 3505
Sch em e 4
Sch em e 5
Sch em e 7
Ta ble 1. Attem p ts to Oxid ize Nitr o Alcoh ol 26 to
Nitr ok eton e 27
Sch em e 6
oxidation conditions
ratioa of 27:28
(COCl)2, DMSO (Swern oxid)
PCC, CH2Cl2
PDC, CH2Cl2
Dess-Martin periodinane, CH2Cl2
J ones reagent
1:3.0
1:1.8
1:1.8
1:2.8
1:3.5
1:19
TPAP, NMO, mole sieves, CH2Cl2
a
Determined by 1H NMR.
oxidize alcohol 26 to the corresponding nitro ketone
(Table 1) surprisingly gave mixtures of the desired
product (27) and a new lactone 28.
Generation of the lactone 28 from nitro alcohol 26 came
unexpectedly since a search of the literature revealed no
precedents for this transformation. In fact, there are
several reports of the expected oxidation of hydroxy nitro
compounds to nitro ketones.17 It is believed that the
lactone formation (to 28) occurs via the pathway shown
in Scheme 8. It seems reasonable that the electrophilic
center of the oxidant coordinates to the nitro group rather
than the neopentyl alcohol of 26, activating it toward
tautomerization to the aci-nitro form 30. The hydroxyl
group is then in a position to add intramolecularly to the
aci-nitro group, furnishing 31. This intermediate can, in
turn, eliminate the coordinated oxygen of the nitro group
to afford the N-hydroxyimidate 32. Hydrolysis of the
latter completes the formation to the observed lactone
28. This transformation may not be very general, and
occurs in this specific case because of two factors. First,
the sterically demanding nature of the neopentyl alcohol
in 26 inhibits the coordination of the electrophile to the
been reduced (Scheme 6). This material also underwent
the Henry reaction to give a quantitative yield of nitro
olefin 22. Subjection of 22 to HBF4 to introduce the
fluoride, 23, also gave rise to decomposition products.
Finally, the double bond adjacent to the nitro group was
quantitatively reduced by a method reported16 years ago
from these laboratories. Subjection of this fully saturated
nitro compound 24 to HBF4 gave clean conversion to the
silylfluoride 25, which underwent the Tamao oxidation
to give hydroxy nitro compound 26 (Scheme 7). Although
well precedented17 in the literature, all attempts to
(16) Meyers, A. I.; Sircar, J . C. J . Org. Chem. 1967, 32, 4134.
(17) Shvekhgeimer, M.-G. A. Russ. Chem. Rev. 1998, 67, 35.

3506 J . Org. Chem., Vol. 65, No. 11, 2000
Degnan and Meyers
Sch em e 8
Sch em e 9
Sch em e 10
hydroxyl lone pairs. Second, the close proximity of the
hydroxyl group to the R-carbon of the nitro group leads
to facile cyclization affording “aminal” 31.
Since the nitro ketone 27 was obtained in poor yield
and only led to the nitrone 33, which still required a
second reduction step19 to the corresponding pyrrolidine,
this route was abandoned. The unexpectedly efficient
conversion of the nitro ketone to lactone 28, suggested
that this intermediate may, in fact, be a suitable precur-
sor to the aminotetralin 20 (Scheme 10). In this regard,
reduction of the lactone 28 with LAH produced the
corresponding diol in 90% yield which was immediately
oxidized to keto aldehyde 34. The latter proved to be
highly unstable and was utilized directly without puri-
Although oxidation yields to nitroketone 27 could not
be improved beyond 36%, the process was continued by
reduction of 27 gave nitrone 33 as the sole product under
transfer hydrogen conditions. No trace of the tricyclic
pyrrolidine 20 was detected (Scheme 9). The nitrone
arises from the previously reported18 intramolecular
cyclization of the hydroxylamine before hydrogenation of
the nitro group could be completed.
(18) (a) Zschiesche, R.; Reissig, H.-U. Tetrahedron Lett. 1988, 29,
1685. (b) Zschiesche, R. Liebigs Ann. Chem. 1989, 551.
(19) Sar, C. P.; Kalai, T.; Baracz, N. M.; J erkovich, G.; Hideg, K.
Synth. Commun. 1995, 25, 2929.

Enantioselective Synthesis of Rigid 2-Aminotetralins
J . Org. Chem., Vol. 65, No. 11, 2000 3507
Sch em e 11
Sch em e 12
fication in a double reductive amination.20 This was
accomplished by treatment of keto aldehyde 34 with
benzhydrylamine and sodium cyanoborohydride and gave
a 71% yield of the desired ring system, 35, as a 9:1 ratio
of diastereomers13 that were readily separable by column
chromatography. The relative stereochemistry of the
major diastereomer (35) was unambiguously established
by NOE studies of the quaternary methyl with the
R-hydrogen, which confirmed the cis-fused ring system.
Removal of the benzhydryl group was readily accom-
plished under hydrogenolysis conditions to afford ami-
notetralin 20sthe primary target of this study.
tiomer of R-methylbenzylamine (Scheme 13). Further-
more, introduction of an additional stereocenter might
be expected to further bias the reduction leading to the
cis- and trans-fused product, respectively. When (S)-R-
methylbenzylamine was used, the double reductive ami-
nation proceeded with complete diastereoselectivity,13
affording only the cis-fused ring system (40) as deter-
mined by an NOE analysis. Treatment of this compound
with Pearlman’s catalyst (Pd(OH)2) in the presence of H2
gave rise to the single enantiomer of the cis-piperidine-
fused tetralin 41.
Since the γ-lactone, 28, was smoothly converted to the
pyrrolidine-fused tetralin 20, it was expected that elabo-
ration of aldehyde 14 to the analogous δ-lactone 37 would
provide the corresponding piperidine-fused tetralin, 41.
Horner-Wadsworth-Emmons olefination21 proceeded
smoothly on the saturated aldehyde 14, affording the
unsaturated ester exclusively as the E isomer13 in 95%
chemical yield (Scheme 11), which was cleanly reduced
(H2-Pd/C) to give a quantitative yield of the γ,γ-disub-
stituted butanoic ester 36. Treatment of the arylsilane
with HBF4 gave the silyl fluoride, which was taken on
directly, via the Tamao oxidation (utilizing excess per-
acetic acid and K2CO3 in acetic acid), to the hydroxy
estersthe precursor to lactone 37. Although most of the
hydroxy ester spontaneously cyclized to lactone 37, it was
found beneficial to include a separate acid-catalyzed
lactonization step to furnish the lactone 37, which was
produced in 91% yield over three steps (36 f 37).
The δ-lactone 37 was reduced with LAH to afford the
corresponding diol in 96% yield which, in turn, was
directly oxidized, under Swern conditions, furnishing 93%
of keto aldehyde 38 (Scheme 12). The latter proved to be
much more stable than its related keto-aldehyde 34, thus
allowing purification by column chromatography and
complete characterization. Double reductive amination
of 38 with benzhydrylamine and NaCNBH3 proceeded in
good chemical yield, but gave the piperidine 39 as a 3:2
ratio of cis and trans diastereomers.13 Attempts to
completely separate the epimers met with failure.
To assess whether the use of a chiral nonracemic amine
may direct the reductive amination to favor either of the
diastereomers of the cis- or trans-fused derivative, keto
aldehyde 38 was condensed, separately, with each enan-
Alternately, when (R)-R-methylbenzylamine was re-
ductively condensed with keto aldehyde 38, only the
trans-fused enantiomer 42 was observed.13 This was
supported by the absence of an NOE response between
the angular methyl and the adjacent methine. Subse-
quently, this assignment was confirmed by hydrogenoly-
sis of the benzylamine 42 to give aminotetralin 43, which
clearly differed from cis-fused aminotetralin 41, prepared
above.
Given this apparent directing affect associated with the
use of chiral R-methylbenzylamines in the double reduc-
tive amination, it was felt that the same directing effect
may be observed in the preparation of the pyrrolidine-
fused tetralins 44 and 45. It might also serve to improve
the earlier synthesis, which gave a 9:1 ratio of 36, epi-
35, respectively. If this was to hold true, it was expected
that use of (S)-R-methylbenzylamine would give rise to
the cis-fused aminotetralin (20) as a single enantiomer.
Alternately, it was hoped that use of (R)-R-methyl-
benzylamine would overcome the internal preference to
form the cis-fused ring system, affording the trans-fused
aminotetralin (47) preferentially.
Unfortunately, condensation of keto aldehyde 34 with
(S)-R-methylbenzylamine gave rise to a mixture of 44 and
45 as a 3:1 ratio of diastereomers (Scheme 14).13 As this
was well below the diastereoselectivity observed earlier
with benzyhydrylamine, attempts to improve the dia-
stereomeric ratio above 9:1 in favor of the cis-fused
aminotetralin were considered unlikely.
Even with the poor diastereoselectivity observed above,
it still seemed worthwhile to condense the keto aldehyde
34 with the (R)-enantiomer of R-methylbenzylamine in
the hopes of exceeding the 10-12% of the trans-fused
aminotetralin (48), obtained from the benzhydryl reduc-
tive amination. Condensation of the keto aldehyde 34
with (R)-R-methylbenzylamine gave rise to a 1:1 mixture
of 46 and 47.13 This finding was consistent with the
earlier result in the piperidine series (41, 43) that (R)-
R-methylbenzylamine appears to favor the formation of
(20) For other syntheses of pyrrolidines and piperidines using a
double reductive amination, see: (a) Barili, P. L.; Berti, G.; Catelani,
G.; D’Andrea, F.; De Rensis, F.; Puccioni, L. Tetrahedron 1997, 53,
3407. (b) Sole´, D.; Bosch, J .; Bonjoch, J . Tetrahdron 1996, 52, 4013.
(c) Baxter, E. W.; Reitz, A. B. J . Org. Chem. 1994, 59, 3175 and
references therein.
(21) For a review of phosphorous-based olefinations, see: Maryanoff,
B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.

3508 J . Org. Chem., Vol. 65, No. 11, 2000
Degnan and Meyers
Sch em e 13
Sch em e 14
the trans-fused ring system. Given the considerable bias
for 34 to form the cis-fused ring juncture (9:1), the
formation of a 1:1 mixture of epimers represents a
significant increase in selectivity, 11% to 50%. The
epimers 46 and 47 were separated via column chroma-
tography, and their structures were assigned on the basis
of the presence or absence of an NOE interaction between
the angular methyl and the adjacent methine. Reductive
removal of the chiral auxiliary of 47 gave the trans-fused
pyrrolidine (48) which, as expected, differed spectroscopi-
cally from the cis-fused pyrrolidine (20). Any attempts
to rationalize the stereo results of the reductive amina-
tion leading to 41, 43 and 44, 45 would be purely
speculative at this time.
stereocenters in fused tetralin systems (20, 28, 33, 37,
41, 43, 48).
In conclusion, dimethylphenylsilyllithium underwent
the tandem addition reaction to naphthyloxazoline 11
with complete diastereoselectivity to afford 12. The
silicon served as a surrogate first for oxygen and later
for nitrogen. As oxygen anions are not sufficiently nu-
cleophilic to undergo the tandem addition reaction to
naphthyl oxazolines this represents a convenient entry
into this important class of compounds. As a result of
this investigation a series of enantiomerically pure
oxygen and nitrogen heterocycles have been cleanly
accessed. Furthermore, all seven contain quaternary
Exp er im en ta l Section
Thin-layer chromatography (TLC) and flash chromatogra-
phy were performed with E. Merck silica gel (230-400 mesh).
NMR coupling constants (J ) are reported in hertz.All reagents
were purchased from Aldrich. All nonaqueous reactions were
conducted under an argon atmosphere in oven or flame-dried
apparatus. Microanalyses were performed by Atlantic Micro-
lab, Inc., Norcross, GA.
Ta n d em Ad d ition P r od u ct, 12. To a stirred suspension
of lithium wire (1.1 g, 159 mmol) in THF (20 mL) at room
temperature was added chlorodimethylphenylsilane (7.6 mL,
45 mmol). The flask was sonicated for 2 h to give a very

Enantioselective Synthesis of Rigid 2-Aminotetralins
J . Org. Chem., Vol. 65, No. 11, 2000 3509
reddish-brown suspension and was stirred an additional 1.5
h without sonication. The solution was added dropwise via a
very fine cannula over 30 min to a stirred solution of naph-
thyloxazoline 1112 (5.7 g, 23 mmol) in ether (80 mL, -72 °C)
and stirred for 87 h. MeI (2.8 mL, 45 mmol) was added via
syringe and the reaction allowed to warm to -20 °C before
quenching with MeOH and concentration in vacuo. The residue
was partitioned between water and ether (3×), washed with
brine, dried over Na2SO4, and concentrated. The crude oil was
filtered through a plug of silica gel using 10% EtOAc/Hex. The
material was recrystallized from ether to give 8.2 g (90%)
diastereomerically pure 12 as large cubes: [R]25D ) +309 (c )
Nitr o Olefin , 22. A pressure tube was charged with
aldehyde 14 (100 mg, 0.32 mmol), ammonium acetate (100 mg,
1.3 mmol), and nitromethane (2 mL) and purged with argon.
A Teflon cap was applied, and the reaction was heated at 120
°C for 24 h. The crude was filtered through cotton and
concentrated and the residue partitioned between brine and
ether. The water was twice more extracted with ether. The
ethereal was combined, dried over Na2SO4, and concentrated
to give 114 mg (100%) of 22 as an oil: [R]25 +155 (c ) 3.1,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.38 (s, 3H), 0.39 (s, 3H),
1.41 (dd, J ) 12.6, 1.8, 1H), 1.42 (s, 3H), 1.64 (dddd, J ) 12.3,
12.3, 11.4, 5.1, 1H), 1.96 (dddd, J ) 13.5, 5.1, 3.0, 3.0, 1H),
2.65-2.90 (m, 2H), 6.62 (d, J ) 13.5, 1H), 7.00-7.15 (m, 4H),
7.35-7.40 (m, 3H), 7.42 (d, J ) 13.2, 1H), 7.50-7.60 (m, 2H);
13C NMR (75 MHz, CDCl3) δ -2.27, -1.63, 22.3, 29.2, 31.7,
36.3, 42.3, 126.5, 126.8, 128.1, 128.4, 129.5, 129.7, 134.0, 137.1,
1
1.3, CHCl3); H NMR (300 MHz, CDCl3) δ 0.02 (s, 3H), 0.08
(s, 3H), 0.86 (s, 9H), 1.60 (s, 3H), 2.50 (dd, J ) 6.0, 0.9, 1H),
2.84 (dd, J ) 10.5, 8.4, 1H), 3.18 (dd, J ) 10.5, 8.7, 1H), 3.67
(dd, J ) 8.7, 8.4, 1H), 5.90 (dd, J ) 9.6, 6.3, 1H), 6.41 (d, J )
9.9, 1H), 6.80-7.50 (m, 9H); 13C NMR (75 MHz, CDCl3) δ -5.6,
-0.7, 26.2, 29.1, 33.6, 37.2, 44.2, 68.0, 75.7, 124.3, 126.3, 126.5,
126.9, 127.3, 127.9, 128.5, 129.6, 132.8, 133.0, 138.9, 140.1,
170.3; IR (thin film) 1654 cm-1. Anal. Calcd for C26H33NOSi:
C, 77.37; H, 8.24; N, 3.47. Found: C, 77.23; H, 8.29; N, 3.51.
Tetr a h yd r on a p h th yloxa zolin e, 13. A 250 mL flask was
charged with dihydronaphthyloxazoline 12 (1.0 g, 2.5 mmol),
palladium (100 mg, 10% on carbon), and absolute ethanol (90
mL). The flask was flushed with argon and then H2, before
finally affixing a balloon of H2. The suspension was stirred
overnight, filtered through silica gel (eluting with EtOAc), and
concentrated. Column chromatography (2-4% EtOAc/Hex)
138.3, 138.6, 140.0, 149.6; IR (thin film) 1348, 1523 cm-1
;
HRMS (FAB+) for C21H26NO2Si (M + 1)+ calcd 352.1733, found
352.1728.
Nitr oa lk a n e, 24. To a stirred solution of nitro olefin 22
(3.32 g, 9.5 mmol) in acetonitrile (40 mL, 0 °C) was added a
solution of NaBH4 (3.0 g, 79 mmol) in water (25 mL) made
basic with 10% NaOH in small portions via an addition funnel.
The pH was monitored with pH paper and was maintained
between 3 and 6 by addition of 1 N HCl as needed. Upon
completion of borohydride addition, the ice bath was removed
and the reaction stirred for 4 h at room temperature. Excess
hydride was destroyed by addition of solid NH4Cl and the
reaction concentrated. The residue was partitioned between
ether and water and the aqueous layer twice more extracted
with ether. The ethereal was washed with brine, dried over
Na2SO4, and concentrated to give 3.34 g of 24 (100%) as an
oil: [R]25D ) -82.0 (c ) 2.6, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.47 (s, 3H), 0.52 (s, 3H), 1.34 (dd, J ) 13.2, 2.7, 1H), 1.38
(s, 3H), 1.60 (dddd, J ) 13.5, 13.5, 11.1, 6.0, 1H), 2.02 (dddd,
J ) 13.5, 6.3, 3.0, 3.0, 1H), 2.34 (ddd, J ) 16.5, 11.4, 5.4, 1H),
2.47 (ddd, J ) 17.4, 11.1, 6.3, 1H), 2.72 (ddd, J ) 16.8, 10.5,
5.7, 1H), 2.84 (ddd, J ) 16.8, 5.7, 3.3, 1H), 3.85-4.05 (m, 2H),
7.00-7.65 (m, 9H); 13C NMR (75 MHz, CDCl3) δ -1.47, -0.76,
22.8, 31.5, 31.8, 36.9, 39.4, 39.5, 73.5, 125.8, 126.3, 126.3, 128.1,
129.4, 129.7, 134.0, 136.9, 138.8, 142.6; IR (thin film) 1379,
gave 0.82 g (82%) as an oil: [R]25 ) -142 (c ) 1.2, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 0.36 (s, 3H), 0.40 (s, 3H), 0.86
(s, 9H), 1.29 (dd, J ) 12.9, 2.7, 1H), 1.65 (s, 3H), 1.88 (m, 1H),
2.03 (m, 1H), 2.62 (m, 1H), 2.78 (m, 1H), 3.66 (m, 3H), 6.97-
7.60 (m, 9H); 13C NMR (75 MHz, CDCl3) δ -3.5, -0.7, 23.0,
26.3, 31.5, 32.0, 34.0, 35.4, 41.7, 68.4, 75.4, 126.0, 126.0, 127.6,
127.7, 128.9, 129.4, 134.1, 136.8, 139.8, 141.6, 171.2; IR (thin
film) 1654 cm-1
.
Un sa tu r a ted Ald eh yd e, 15. To a solution of oxazoline 12
(2.03 g, 5.03 mmol) in CH2Cl2 (2.5 mL) was added MeOTf (1.15
mL, 10.2 mmol) at 0 °C. The ice bath was removed and the
solution stirred overnight at room temperature. This solution
was transferred dropwise via cannula into a 250 mL round-
bottom flask containing NaBH4 (0.80 g, 21 mmol) in MeOH (5
mL) and THF (20 mL) at 0 °C. There was rapid evolution of
gas. Upon completion of addition, the ice bath was removed,
and stirring was continued 30 min. The solution was concen-
trated and the residue partitioned between ether and satu-
rated NaHCO3. The aqueous was washed twice more with
ether. The organics were combined, concentrated, and treated
with oxalic acid (1.25 g, 14 mmol), THF (30 mL), and water (6
mL). The flask was heated at reflux for 4 h and concentrated
and the residue partitioned between ether and water. The
aqueous was washed twice more with ether. The organics were
combined, dried over Na2SO4, and concentrated to give 1.49 g
1552 cm-1
.
Nitr o Alcoh ol, 26. To a stirred solution of nitrosilane 24
(0.50 g, 1.42 mmol) in CH2Cl2 (8 mL) at 0 °C was added HBF4
(2 mL, 54% in ether). The solution was allowed to gradually
warm to room temperature and was stirred overnight, and
then it was poured over an excess of solid NaHCO3. The
suspension was diluted with CH2Cl2, filtered, and concentrated
to give the crude silylfluoride. The residue was suspended in
CH3CO3H (2.5 mL, 32% in CH3CO2H) at 0 °C and treated with
Et3N (0.5 mL, 3.59 mmol). The solution was allowed to
gradually warm to room temperature and was stirred over-
night, and the resulting suspension was poured into 20% K2-
CO3 and extracted into ether (3×). The ethereal portion was
washed with 20% K2CO3 (2×), dried over Na2SO4, and con-
centrated. Column chromatography gave 0.33 g (75%) of 26
(97%) of 15 as a white solid: mp 49.9-51.5 °C; [R]25 ) +658
D
1
(c ) 4.1, CHCl3); H NMR (300 MHz, CDCl3) δ 0.07 (s, 3H),
0.10 (s, 3H), 1.25 (s, 3H), 2.02 (dd, J ) 6.3, 1.2, 1H), 5.73 (dd,
J ) 9.6, 6.3, 1H), 6.35 (d, J ) 9.9, 1H), 6.69 (dd, J ) 7.8, 0.9,
1H), 6.95-7.40 (m, 8H), 9.87 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ -2.87, -2.64, 23.3, 36.1, 53.6, 124.4, 125.8, 126.8,
127.8, 127.9, 128.0, 128.8, 129.5, 133.2, 133.7, 135.5, 137.8,
as an oil: [R]25 +26.4 (c ) 1.4, CHCl3); H NMR (300 MHz,
1
D
CDCl3) δ 1.36 (s, 3H), 1.80-2.10 (m, 2H), 2.22 (bs, 1H), 2.40
(ddd, J ) 14.1, 10.2, 6.0, 1H), 2.56 (ddd, J ) 14.1, 10.2, 5.4,
1H), 2.70-3.10 (m, 2H), 3.83 (dd, J ) 8.1, 3.0, 1H), 4.52 (m,
2H), 7.05-7.30 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 21.6,
22.7, 23.1, 31.6, 36.6, 69.2, 70.0, 121.8, 122.0, 122.2, 124.7,
203.4; IR (thin film) 1724 cm-1
.
Sa tu r a ted Ald eh yd e, 14. A flask was charged with alde-
hyde 15 (1.91 g, 6.23 mmol), Pd/C (300 mg, 0.28 mmol, 10%),
and EtOH (40 mL) and was purged with hydrogen. A hydrogen
balloon was attached, and the reaction was allowed to stir for
10 h. The reaction was filtered through a pad of silica gel,
eluting with EtOAc. Concentration gave 1.88 g of 14 (98%) as
130.6, 136.5; IR (thin film) 1383, 1549 cm-1
.
Nitr o Keton e, 27. To a solution of alcohol 26 (20 mg, 0.085
mmol) in CH2Cl2 (1.5 mL) was added PDC (55 mg, 0.15 mmol).
After 4 h, another portion of PDC was added (55 mg, 0.15
mmol) and stirring continued overnight. The reaction was
diluted with ether and filtered through silica gel. Column
chromatography gave 7 mg (36%) of 27 as an oil: [R]25D +75.5
an oil: [R]25 ) -195 (c ) 3.4, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 0.39 (s, 3H), 0.39 (s, 3H), 1.33 (dd, J ) 12.6, 2.4, 1H),
1.40 (s, 3H), 1.75 (m, 1H), 1.98 (m, 1H), 2.78 (m, 1H), 7.10 (m,
4H), 7.45 (m, 5H), 9.61 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
-2.7, -1.2, 23.0, 25.3, 31.3, 32.8, 52.4, 126.4, 126.7, 127.8,
128.5, 129.1, 129.7, 133.9, 136.7, 138.4, 138.5, 201.5; IR (thin
film) 1716 cm-1. Anal. Calcd for C20H24OSi: C, 77.87; H, 7.84.
Found: C, 77.74; H, 7.91.
1
(1.1, CHCl3); H NMR (300 MHz, CDCl3) δ 1.53 (s, 3H), 2.47
ddd, J ) 15.3, 10.2, 5.1, 1H), 2.63 (ddd, J ) 14.7, 5.7, 5.7, 1H),
2.80-2.95 (m, 2H), 3.00-3.20 (m, 2H), 3.96 (ddd, J ) 13.2,
10.2, 5.1, 1H), 4.17 (ddd, J ) 12.9, 10.2, 5.7, 1H), 7.20-7.40
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 28.5, 28.9, 35.7, 37.5,

3510 J . Org. Chem., Vol. 65, No. 11, 2000
Degnan and Meyers
50.0, 72.0, 126.3, 127.4, 127.8, 128.8, 135.8, 139.7, 212.8; IR
NMR (75 MHz, CDCl3) δ 24.5, 27.9, 31.0, 40.4, 44.9, 48.7, 67.3,
70.8, 125.2, 126.3, 126.9, 126.9, 127.5, 128.1, 128.2, 128.3,
128.7, 136.7, 142.2, 143.9, 145.8.
(thin film) 1383, 1552, 1712 cm-1
.
Nitr on e, 33. To a stirred solution of nitro ketone 27 (5 mg,
0.020 mmol) in THF/MeOH (1 mL, 1:1) were added NH4HCO2
(20 mg, 0.32 mmol) and Pd/C (2 mg, 10%). After being
overnight, the solution was diluted with ether (6 mL), filtered
through Celite, and concentrated. Column chromatography
(5% MeOH/CH2Cl2) gave 4 mg (93%) of 33 as a solid: mp 147-
Minor (trans): 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 3H),
1.45-1.65 (m, 2H), 1.76 (ddd, J ) 11.4, 11.4, 7.8, 1H), 1.96
(ddd, J ) 11.7, 8.4, 3.0, 1H), 2.46 (ddd, J ) 11.1, 11.1, 3.3,
1H), 2.57 (dd, J ) 12.3, 3.6, 1H), 2.71 (ddd, J ) 18.0, 9.0, 9.0,
1H), 2.87 (dd, J ) 18.0, 8.1, 1H), 3.19 (ddd, J ) 9.9, 8.1, 8.1,
1H), 4.76 (s, 1H), 6.95-7.50 (m, 14H); HRMS (FAB+) for
149 °C; [R]25 +99.8 (c ) 1.9, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.43 (s, 3H), 2.40-2.50 (m, 2H), 2.70-2.80 (m, 1H),
2.90-3.15 (m, 3H), 3.90-4.00 (m, 1H), 4.25-4.40 (m, 1H),
7.05-7.30 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 21.0, 26.4,
27.3, 34.1, 48.0, 61.4, 124.7, 127.0, 127.5, 128.7, 134.8, 143.1,
C
26H27N (M)+ calcd 353.2144, found 353.2138.
cis-P yr r olid in e-F u sed Tetr a lin , 20. A flask was charged
with benzhydryl-protected aminotetralin 35 (15 mg, 0.05
mmol), Pd(OH)2 (5 mg, 20% on carbon), TFA (0.2 mL, 2.6
mmol), and EtOH (5 mL). The atmosphere was flushed with
hydrogen, and a balloon was attached. After 4 h, the suspen-
sion was concentrated, made basic with a mixture of 10%
NaOH and EtOH, filtered, and concentrated. The residue was
partitioned between water and ether. The aqueous was further
washed twice with ether, dried over Na2SO4, and concentrated.
Column chromatography (neutral alumina, 1, 5% MeOH/CH2-
Cl2) gave 7.7 mg (97%) of 20 as an oil. [R]25D +86 (0.4, CHCl3);
1H NMR (300 MHz, C6D6) δ 1.16 (s, 3H), 1.60-1.90 (m, 4H),
2.40 (ddd, J ) 16.2, 6.9, 4.8, 1H), 2.70-3.20 (m, 4H), 4.59 (bs,
1H), 6.80-7.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 25.2,
26.5, 29.3, 41.2, 44.2, 45.2, 64.4, 126.2, 126.9, 127.5, 128.8,
135.4, 142.0; IR (thin film) 3322(br) cm-1; HRMS (FAB+) for
151.1; IR (thin film) 1622, 1198 cm-1. Anal. Calcd for C13H15
-
NO‚1/8H2O: C, 76.72; H, 7.55. Found: C, 76.82; H, 7.56.
γ-La cton e, 28. A flask was charged with nitro alcohol 26
(18 mg, 0.08 mmol), NMO (18 mg, 0.15 mmol), molecular sieves
(45 mg, 3 Å, powdered), and CH2Cl2 (0.75 mL). To this was
added TPAP (4 mg, 0.01 mmol) at 0 °C. The ice bath was
removed, and stirring was continued 30 min. The suspension
was diluted with ether and filtered through silica gel to give
14 mg (93%) of 28 as a white solid: mp 99.1-101 °C; [R]25
D
1
+164 (c ) 1.3, CHCl3); H NMR (300 MHz, CDCl3) δ 1.50 (s,
3H), 2.00-2.20 (m, 2H), 2.70 (ddd, J ) 16.5, 5.7, 5.7, 1H), 2.73
(d, J ) 17.1, 1H), 2.81 (d, J ) 17.1, 1H), 2.93 (ddd, J ) 16.5,
9.9, 5.7, 1H), 4.54 (dd, J ) 6.6, 3.3, 1H), 7.00-7.25 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 24.4, 24.8, 28.5, 42.5, 45.1, 85.1,
126.7, 127.2, 127.9, 128.9, 135.0, 139.7, 175.7; IR (thin film)
1780 cm-1. Anal. Calcd for C13H14O2: C, 77.20; H, 6.98.
Found: C, 76.93; H, 6.95.
C
13H18N (M + H)+ calcd 188.1439, found 188.1437.
Sa tu r a ted Ester , 36. To a solution of aldehyde 14 (500 mg,
1.62 mmol), LiCl (400 mg, 9.4 mmol), and triethylphospho-
noacetate (0.56 mL, 2.8 mmol) in ether (4 mL) and acetonitrile
(4 mL) was added DBU (0.42 mL, 2.8 mmol) and the reaction
allowed to stir 24 h at room temperature. After dilution with
ether, the solution was filtered through Celite and concen-
trated. Column chromatography (5-10% EtOAc/Hexanes) gave
Keto Ald eh yd e, 34. To a solution of lactone 28 (50 mg, 0.25
mmol) in THF (3 mL) at 0 °C was added LAH (30 mg, 0.79
mmol). After 15 min, the ice bath was removed, and stirring
was continued for 30 min. The suspension was diluted with
THF and was quenched by dropwise addition of saturated Na2-
SO4 in 20% KOH, until a filterable white solid formed. The
suspension was filtered and concentrated. Column chroma-
tography (50% EtOAc/Hex) gave 46 mg (90%) of the 1,4-diol
596 mg (97%) of the (E)-R,â-unsaturated ester as an oil: [R]25
D
1
-137 (c ) 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 0.34 (s,
3H), 0.37 (s, 3H), 1.28 (t, J ) 6.9, 3H), 1.32 (dd, J ) 12.3, 1.8,
1H), 1.39 (s, 3H), 1.63 (dddd, J ) 23.7, 11.1, 4.5, 2.1, 1H), 1.86
(dddd, J ) 13.5, 5.1, 3.0, 3.0, 1H), 2.60-2.85 (m, 2H), 4.17 (q,
J ) 6.9, 2H), 5.52 (d, J ) 15.6, 1H), 7.07 (m, 4H), 7.13 (d, J )
15.6, 1H), 7.33 (m, 3H), 7.52 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ -2.70, -1.16, 14.5, 22.1, 29.3, 31.9, 36.1, 43.7, 60.5,
119.0, 126.1, 126.2, 128.0, 128.9, 129.1, 129.4, 134.2, 137.3,
139.4, 141.8, 156.1, 167.0; IR (thin film) 1716 cm-1; HRMS
(FAB+) for C24H31O2Si (M + 1)+ calcd 379.2093, found 379.2091.
A pressure tube was charged with the unsaturated ester
from above (0.60 g, 1.6 mmol), Pd/C (90 mg, 0.09 mmol, 10%),
and EtOH (20 mL). The tube was purged with H2 and
pressurized to 80 psi for 22 h. The reaction was filtered
through a pad of silica gel, eluting with EtOAc. Concentration
gave 0.60 g (100%) 36 as an oil: [R]25D -77.2 (c ) 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 0.42 (s, 3H), 0.44 (s, 3H), 1.16 (t,
J ) 6.9, 3H), 1.30 (s, 3H), 1.31 (dd, J ) 12.3, 3.0, 1H), 1.75
(dddd, J ) 12.9, 12.9, 10.5, 5.4, 1H), 1.85-2.10 (m, 5H), 2.60-
2.90 (m, 2H), 3.97 (q, 2H), 6.95-7.60 (m, 10H); 13C NMR (75
MHz, CDCl3) δ -1.72, -0.48, 14.3, 22.6, 31.4, 31.6, 31.6, 36.8,
37.1, 39.7, 60.3, 125.6, 125.8, 126.5, 127.9, 128.9, 129.4, 134.1,
as a white solid: mp 78.8-79.8 °C; [R]25 +12.3 (c ) 1.1,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.32 (s, 3H), 1.84 (ddd,
J ) 15.0, 5.7, 2.4, 1H), 1.95-2.05 (m, 2H), 2.12 (ddd, J ) 15.3,
9.0, 3.3, 1H), 2.78 (ddd, J ) 17.4, 6.6, 6.6, 1H), 3.01 (ddd, J )
16.8, 6.9, 6.9, 1H), 3.63 (ddd, J ) 11.1, 6.0, 3.3, 1H), 3.70-
3.85 (m, 2H), 4.00-4.50 (bs, 2H), 7.00-7.25 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 26.8, 26.9, 27.1, 41.9, 42.0, 58.8, 73.6, 125.7,
126.2, 126.8, 129.0, 135.2, 144.0; IR (thin film) 3297 (br) cm-1
.
To a stirred solution of oxalyl chloride (0.38 mL, 0.75 mmol,
2 M in CH2Cl2) in CH2Cl2 (4.5 mL) at -78 °C was added DMSO
(0.1 mL, 1.4 mmol). The resulting solution was stirred for 15
min and treated with the diol described above (40 mg, 0.19
mmol) in CH2Cl2 (1 mL). The solution was stirred for 30 min
at -78 °C, allowed to warm to -50 °C in the dewar, and
recooled to -78 °C. It was treated with triethylamine (0.3 mL,
2.2 mmol) and stirred for 5 min before removing the ice bath
and allowing it to reach rt. The solution was poured into
saturated NaHCO3, extracted with CH2Cl2 (3×), dried over
Na2SO4, and concentrated to give 40 mg of 34 (100%) as an
oil which was used without purification.
137.1, 139.8, 144.1, 173.9; IR (thin film) 1732 cm-1
.
cis-N-Ben zh yd r ylp yr r olid in e-F u sed Tetr a lin , 35. A
flask was charged with keto aldehyde 34 (40 mg, 0.19 mmol),
benzhydrylamine hydrochloride (44 mg, 0.20 mmol), and
MeOH (2 mL). The solution was cooled to -78 °C and treated
with NaCNBH3 (20 mg, 0.32 mmol). After 1 h, an additional
portion of NaCNBH3 (20 mg, 0.32 mmol) was added, and the
solution was allowed to warm slowly to room temperature
overnight (Dewar flask). The suspension was treated with solid
NaHCO3 and K2CO3, stirred 15 min and diluted with ether,
filtered through silica, and concentrated. Column chromatog-
raphy (2% EtOAc/Hex) gave 49 mg (71%, 2 steps) of a 9:1
mixture of cis- and trans-35. Column chromatography (100%
toluene) gave complete separation of the two diastereomers.
Major (cis): [R]25D +3.57 (c ) 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.38 (s, 3H), 1.50-1.75 (m, 2H), 1.85-2.10 (m, 2H),
2.41 (ddd, J ) 16.2, 9.3, 3.9, 1H), 2.58 (ddd, J ) 9.3, 6.9, 6.9,
1H), 2.70-2.85 (m, 3H), 4.91 (s, 1H), 6.95-7.50 (m, 9H); 13C
δ-La cton e, 37. To a solution of alkylsilane 36 (1.0 g, 2.63
mmol) in CH2Cl2 (27 mL, 0 °C) was added HBF4 (3 mL, 54%
in ether). The solution was stirred 15 min at 0 °C, the ice bath
was removed, and stirring was continued overnight. The
solution was poured over solid NaHCO3 and filtered, and the
cake was washed with CH2Cl2 and concentrated. The crude
silyl fluoride was treated with K2CO3 (6.0 g, 43 mmol), cooled
to 0 °C, and treated with CH3CO3H (21 mL, 32% in CH3CO2H).
Effervescence was immediate. After 15 min, the ice bath was
removed and stirring continued at room temperature for 9 h.
The mixture was poured into water and extracted into ether
(3×). The ether layers were combined, back-extracted with 20%
K2CO3 (2×) and brine, dried over Na2SO4, and concentrated.
The crude mixture was redissolved in THF (12 mL), treated
with six Pasteur pipet drops of concentrated HCl, stored in
the freezer overnight, and concentrated. Column chromatog-
raphy neutral alumina 35, 50% EtOAc/Hex) gave 0.53 g (93%)

Enantioselective Synthesis of Rigid 2-Aminotetralins
J . Org. Chem., Vol. 65, No. 11, 2000 3511
as a white solid: mp 116-118 °C; [R]25D +164 (c ) 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.33 (s, 3H), 1.95-2.25 (m, 4H),
2.33 (ddd, J ) 13.2, 5.7, 4.2, 1H), 2.46 (ddd, J ) 17.1, 4.8, 3.3,
1H), 2.69 (ddd, J ) 16.8, 6.0, 2.4, 1H), 3.04 (ddd, J ) 17.7,
12.3, 6.0, 1H), 4.54 (dd, J ) 4.5, 1.8, 1H), 7.00-7.30 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 24.1, 24.4, 27.9, 30.5, 33.2, 35.8,
84.0, 126.0, 126.7, 127.1, 129.6, 136.0, 138.6, 171.7; IR (thin
film) 1714 cm-1. Anal. Calcd for C14H20O2‚1/3H2O: C, 75.67;
H, 7.56. Found: C, 75.36; H, 7.39.
twice more with ether, dried over Na2SO4, and concentrated
to give 9.9 mg (100%) of 41 as an oil: [R]25 +67 (c ) 0.5,
D
CHCl3); 1H NMR (300 MHz, C6D6) δ 0.68 (bs, 1H), 1.06 (s, 3H),
1.15-1.35 (m, 3H), 1.47 (dddd, J ) 13.5, 6.9, 4.5, 2.1, 1H), 1.94
(dddd, J ) 13.5, 12.0, 6.6, 2.4, 1H), 2.15-2.30 (m, 1H), 2.45-
2.60 (m, 3H), 2.70-2.80 (m, 1H), 3.00 (ddd, J ) 16.8, 12.0,
6.9, 1H), 7.00-7.30 (m, 4H); 13C NMR (75 MHz, C6D6) δ 23.9,
25.2, 26.3, 30.8, 32.3, 37.5, 37.8, 46.7, 60.4, 125.9, 126.4, 126.7,
130.0, 136.4, 143.4; IR (thin film) 3283(br) cm-1; HRMS (FAB+)
for C14H20N (M + H)+ calcd 202.1596, found 202.1596.
Keto Ald eh yd e, 38. To a solution of lactone 37 (50 mg, 0.23
mmol) in THF (3 mL) at 0 °C was added LAH (30 mg, 0.79
mmol). After 15 min, the ice bath was removed, and stirring
was continued for 30 min. The suspension was diluted with
THF and was quenched by dropwise addition of saturated Na2-
SO4 in 20% KOH, until a filterable white solid formed. The
suspension was filtered and concentrated. Column chroma-
tography (50% EtOAc/Hex) gave 49 mg (96%) of the 1,5-diol
as a white solid: mp 142-145 °C; [R]25D +17.0 (c ) 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.24 (s, 3H), 1.50-1.70 (m, 2H),
1.70-1.85 (m, 2H), 1.90-2.05 (m, 2H), 2.56 (bs, 2H), 2.75 (ddd,
J ) 17.1, 6.3, 6.3, 1H), 3.00 (ddd, J ) 17.4, 7.2, 7.2, 1H), 3.56
(m, 2H), 3.85 (dd, J ) 5.1, 5.1, 1H), 6.95-7.30 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 26.0, 26.4, 27.2, 27.5, 33.4, 41.2, 63.7,
73.3, 125.8, 126.0, 127.2, 129.1, 135.1, 143.2; IR (thin film)
tr a n s-N-r-Meth ylben zylp ip er id in e-F u sed Tetr a lin , 42.
A flask was charged with keto aldehyde 38 (25 mg, 0.12 mmol),
(R)-R-methylbenzylamine hydrochloride (25 mg, 0.15 mmol),
and MeOH (1 mL). The solution was cooled to -78 °C and
treated with NaCNBH3 (10 mg, 0.16 mmol). After 1 h, an
additional portion of NaCNBH3 (10 mg, 0.16 mmol) was added,
and the solution was allowed to warm to room temperature.
The reaction was treated with molecular sieves (50 mg, 3 Å,
powdered) and acetic acid (7 mL, 0.12 mmol) and allowed to
stir 4 h, and then treated with solid NaHCO3 and K2CO3 and
stirred 15 min. The suspension was diluted with ether, filtered
through silica, and concentrated. Column chromatography (2%
EtOAc/Hex) gave 27 mg (76%) of 42 as an oil: [R]25 +39.1 (c
D
1
) 1.5, CHCl3); H NMR (300 MHz, CDCl3) δ 1.32 (d, J ) 6.9,
3307 (br) cm-1
.
3H), 1.40 (s, 3H), 1.40-1.55 (m, 2H), 1.65-1.90 (m, 2H), 2.14
(ddd, J ) 12.3, 12.3, 3.0, 1H), 2.20-2.40 (m, 2H), 2.50-2.60
(m, 1H), 2.63 (dd, J ) 12.3, 3.3, 1H), 3.02 (d, J ) 4.8, 1H),
3.05 (d, J ) 4.8, 1H), 4.45 (q, J ) 6.9, 1H), 7.10-7.60 (m, 9H);
13C NMR (75 MHz, CDCl3) δ 9.1, 21.7, 22.7, 23.7, 29.2, 37.9,
38.7, 46.5, 53.7, 64.1, 125.3, 125.6, 125.9, 126.2, 127.8, 128.0,
134.4, 145.6, 147.0; HRMS (FAB+) for C22H28N (M + H)+ calcd
306.2222, found 306.2225.
To a stirred solution of oxalyl chloride (0.43 mL, 0.85 mmol,
2 M in CH2Cl2) in CH2Cl2 (5 mL) at -78 °C was added DMSO
(0.1 mL, 1.4 mmol). The resulting solution was stirred for 15
min and treated with the 1,5-diol from above (60 mg, 0.27
mmol) in CH2Cl2 (1 mL). The solution was stirred for 30 min
at -78 °C, allowed to warm to -50 °C in a Dewar flask, and
recooled to -78 °C. It was treated with triethylamine (0.4 mL,
2.9 mmol) and stirred for 5 min before removing the ice bath
and allowing it to reach rt. The solution was poured into
saturated NaHCO3, extracted with CH2Cl2 (3×), dried over
Na2SO4, and concentrated. Column chromatography (neutral
tr a n s-P iper idin e-Fu sed Tetr alin , 43. A flask was charged
with N-alkylaminotetralin 42 (15 mg, 0.05 mmol), Pd(OH)2 (5
mg, 20% on carbon), TFA (0.2 mL, 2.6 mmol), and EtOH (5
mL). The atmosphere was flushed with hydrogen, and a
balloon was attached. After 4 h, the suspension was concen-
trated, made basic with a mixture of 10% NaOH and EtOH,
filtered, and concentrated. The residue was partitioned be-
tween water and ether, and the aqueous phase was washed
twice more with ether, dried over Na2SO4, and concentrated
to give 9.9 mg (100%) of 43 as an oil: [R]25D +116 (1.0, CHCl3);
1H NMR (300 MHz, C6D6) δ 0.83 (bs, 1H), 1.22 (s, 3H), 1.20-
1.50 (m, 3H), 1.65-1.90 (m, 2H), 2.05-2.15 (m, 1H), 2.35-
2.50 (m, 2H), 2.60-2.85 (m, 2H), 2.89 (dd, J ) 11.7, 5.1, 1H),
6.90-7.30 (m, 4H); 13C NMR (75 MHz, C6D6) δ 22.6, 23.9, 26.6,
29.7, 30.7, 37.7, 48.4, 62.0, 125.4, 126.2, 126.5, 129.8, 135.2,
alumina 20, 40% EtOAc/Hex) gave 55 mg (93%) of 38 as an
1
oil: [R]25 +51.3 (1.6, CHCl3); H NMR (300 MHz, CDCl3) δ
D
1.43 (s, 3H), 1.95-2.10 (m, 2H), 2.16 (m, 1H), 2.41 (m, 1H),
2.57 (ddd, J ) 15.0, 5.7, 5.7, 1H), 2.74 (ddd, J ) 15.0, 8.4, 8.4,
1H), 3.04 (d, J ) 5.4, 1H), 3.06 (d, J ) 5.4, 1H), 7.10-7.30 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 27.8, 28.7, 31.6, 38.1, 40.2,
51.1, 126.5, 126.8, 127.4, 128.4, 136.0, 141.0, 201.3, 213.9; IR
(thin film) 1716 cm-1; HRMS (FAB+) for C13H17O2 (M + H)+
calcd 217.1229, found 217.1222.
cis-N-r-Meth ylben zylp ip er id in e-F u sed Tetr a lin , 40. A
flask was charged with keto aldehyde 38 (25 mg, 0.12 mmol),
(S)-R-methylbenzylamine hydrochloride (25 mg, 0.15 mmol),
and MeOH (1 mL). The solution was cooled to -78 °C and
treated with NaCNBH3 (10 mg, 0.16 mmol). After 1 h, an
additional portion of NaCNBH3 (10 mg, 0.16 mmol) was added,
and the solution was allowed to warm to room temperature.
The reaction was treated with molecular sieves (50 mg, 3 Å,
powdered) and acetic acid (7 mL, 0.12 mmol) and allowed to
stir 3 h. The suspension was treated with solid NaHCO3 and
K2CO3, stirred 15 min, and then diluted with ether, filtered
through silica, and concentrated. Column chromatography (2%
EtOAc/Hex) gave 25 mg (71%) of 40 as a white solid: mp 97.7-
147.4; IR (thin film) 3278(br) cm-1; HRMS (FAB+) for C14H20
N
(M + H)+ calcd 202.1596, found 202.1590.
tr a n s-N-r-Meth ylben zylpyr r olidin e-Fu sed Tetr alin , 47.
A flask was charged with keto aldehyde 34 (39 mg, 0.19 mmol),
(R)-R-methylbenzylamine hydrochloride (40 mg, 0.20 mmol),
and MeOH (2 mL). The solution was cooled to -78 °C and
treated with NaCNBH3 (10 mg, 0.16 mmol). After 1 h, an
additional portion of NaCNBH3 (10 mg, 0.16 mmol) was added,
and the solution was allowed to warm to room temperature
and stirred overnight when the resulting suspension was
treated with solid NaHCO3 and K2CO3 and stirred 15 min. The
suspension was diluted with ether, filtered through silica, and
concentrated. 1H NMR revealed a 1:1 mixture of epimers.
Column chromatography (5% EtOAc/Hex) gave 23 mg (41%)
of the cis isomer 20 as an oil and then 22 mg (39%) of the
trans isomer 48 as an oil. Trans: [R]25D +66.6 (c ) 1.7, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.20 (s, 3H), 1.34 (d, J ) 6.6,
3H), 1.85 (dddd, J ) 11.4, 7.8, 7.8, 7.8, 1H), 1.99 (ddd, J )
11.7, 8.4, 3.0, 1H), 2.55-3.10 (m, 5H), 3.88 (q, J ) 6.6, 1H),
7.00-7.50 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 16.0, 22.3,
25.2, 27.8, 34.6, 44.6, 46.4, 58.2, 66.7, 125.1, 125.6, 125.8, 126.6,
127.5, 128.2, 128.7, 135.5, 146.4, 147.2; HRMS (FAB+) for
99.5 °C; [R]25 -24.5 (c ) 1.4, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.31 (d, J ) 6.6, 3H), 1.30-1.40 (m, 1H), 1.55-1.75
(m, 2H), 1.67 (s, 3H), 1.80-2.15 (m, 3H), 2.20-2.45 (m, 2H),
2.85 (ddd, J ) 16.5, 10.8, 5.4, 1H), 2.97 (ddd, J ) 16.5, 4.8,
4.8, 1H), 3.14 (dd, J ) 10.8, 2.1, 1H), 3.79 (q, J ) 6.6, 1H),
7.05-7.50 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 16.1, 23.0,
27.0, 29.7, 30.5, 36.4, 38.2, 45.0, 60.0, 60.3, 125.4, 126.1, 126.6,
127.0, 127.2, 128.4, 128.9, 135.3, 147.4, 148.0; HRMS (FAB+)
for C22H27N (M)+ calcd 305.2144, found 305.2135.
cis-P ip er id in e-F u sed Tetr a lin , 41. A flask was charged
with N-alkylaminotetralin 40 (15 mg, 0.05 mmol), Pd(OH)2 (5
mg, 20% on carbon), TFA (0.2 mL, 2.6 mmol), and EtOH (5
mL). The atmosphere was flushed with hydrogen, and a
balloon was attached. After 4 h, the suspension was concen-
trated, made basic with a mixture of 10% NaOH and EtOH,
filtered, and concentrated. The residue was partitioned be-
tween water and ether, and the aqueous phase was washed
C
21H26N (M + H)+ calcd 292.2065, found 292.2052.
Cis: [R]25 +78.9 (c ) 1.5, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.24 (s, 3H), 1.45 (d, J ) 6.6, 3H), 1.69 (dddd, J )
13.2, 9.0, 9.0, 3.9, 1H), 1.80-2.05 (m, 3H), 2.56 (ddd, J ) 15.6,
9.6, 3.9, 1H), 2.60-2.70 (m, 2H), 2.75-2.90 (m, 2H), 3.89 (q, J
) 6.6, 1H), 7.00-7.40 (m, 9H); 13C NMR (75 MHz, CDCl3) δ

3512 J . Org. Chem., Vol. 65, No. 11, 2000
Degnan and Meyers
22.8, 26.9, 27.8, 30.9, 40.0, 44.9, 47.9, 60.9, 66.9, 125.2, 126.4,
126.9, 127.6, 128.0, 128.1, 128.1, 128.2, 128.2, 136.9, 143.8,
146.1; HRMS (FAB+) for C21H26N (M + H)+ calcd 292.2065,
found 292.2055.
125.8, 126.1, 129.0, 135.5, 146.2; IR (thin film) 3266(br) cm-1
HRMS (FAB+) for C13H18N (M + H)+ calcd 188.1439, found
188.1437.
;
tr a n s-P yr r olidin e-Fu sed Tetr alin , 48. A flask was charged
with N-alkylaminotetralin 47 (15 mg, 0.05 mmol), Pd(OH)2 (5
mg, 20% on carbon), TFA (0.2 mL, 2.6 mmol), and EtOH (5
mL). The atmosphere was flushed with hydrogen, and a
balloon was attached. After 4 h, the suspension was concen-
trated, made basic with a mixture of 10% NaOH and EtOH,
filtered, and concentrated. The residue was partitioned be-
tween water and ether, and the aqueous was washed twice
more with ether, dried over Na2SO4, and concentrated to give
Ack n ow led gm en t. The authors are grateful to the
National Science Foundation and the National Institute
of Health for financial support of this work. A Graduate
Fellowship (A.P.D.) from Boehringer-Ingelheim is grate-
fully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Spectral data (1H
and 13C) of all key intermediates and final products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
9.6 mg (100%) of 48 as an oil: [R]25 +67 (c ) 0.5, CHCl3); 1H
D
NMR (300 MHz, C6D6) δ 0.93 (s, 3H), 0.97 (bs, 1H), 1.55-1.85
(m, 4H), 2.60-3.05 (m, 4H), 6.95-7.15 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 22.4, 22.6, 28.1, 30.5, 36.8, 44.5, 63.7, 125.8,
J O0001131