Synthetic applications of lithiated N-Boc allylic amines as asymmetric homoenolate equivalents

Article abstract of DOI:10.1021/jo0260084

Lithiation of N-(Boc)-N-(p-methoxyphenyl) allylic amines in the presence of (-)-sparteine provides asymmetric homoenolate equivalents which react with electrophiles to provide highly enantioenriched enecarbamates. Acidic hydrolysis of the enecarbamates can provide the corresponding β-substituted aldehydes. A synthetic sequence that involves a stereocontrolled intramolecular nitrone-olefin dipolar cycloaddition has been developed for the preparation of enantioenriched 2-formyl-4-phenyl-1-aminocyclopentanes from one β-allyl-substituted aldehyde. Further manipulations allow access to an enantioenriched β-lactam. In another synthetic sequence, transmetalation of the lithiated intermediates and reactions with aldehyde electrophiles can be controlled to afford highly enantioenriched anti homoaldol products. Use of an anti aldehyde homoaldol product as the chiral electrophile in an iterative reaction provides a double homoaldol product containing four stereogenic centers with high diastereoselectivity and enantioselectivity. Reaction pathways are proposed to account for the observed products.

Full text of DOI:10.1021/jo0260084

Syn th etic Ap p lica tion s of Lith ia ted N-Boc Allylic Am in es a s
Asym m etr ic Hom oen ola te Equ iva len ts
Marna C. Whisler and Peter Beak*
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue,
Urbana, Illinois 61801
beak@scs.uiuc.edu
Received J une 3, 2002
Lithiation of N-(Boc)-N-(p-methoxyphenyl) allylic amines in the presence of (-)-sparteine provides
asymmetric homoenolate equivalents which react with electrophiles to provide highly enantioen-
riched enecarbamates. Acidic hydrolysis of the enecarbamates can provide the corresponding
â-substituted aldehydes. A synthetic sequence that involves a stereocontrolled intramolecular
nitrone-olefin dipolar cycloaddition has been developed for the preparation of enantioenriched
2-formyl-4-phenyl-1-aminocyclopentanes from one â-allyl-substituted aldehyde. Further manipula-
tions allow access to an enantioenriched â-lactam. In another synthetic sequence, transmetalation
of the lithiated intermediates and reactions with aldehyde electrophiles can be controlled to afford
highly enantioenriched anti homoaldol products. Use of an anti aldehyde homoaldol product as
the chiral electrophile in an iterative reaction provides a double homoaldol product containing four
stereogenic centers with high diastereoselectivity and enantioselectivity. Reaction pathways are
proposed to account for the observed products.
In tr od u ction
seminal. Asymmetric homoenolate equivalents were re-
ported from lithiation of (E)- and (Z)-2-butenyl carbam-
ates and (E)-3-trimethylsilyl-2-propenyl carbamates.2
Oxygen-based systems have been very well developed in
the Hoppe laboratories for a variety of asymmetric
syntheses, including deoxy sugar analogues and bicyclic
tetrahydrofuran carboxaldehydes.3
The chemistry of homologues of aldehyde enolates,
depicted by the synthetic equivalent 1, is emerging as a
useful synthetic strategy. One general approach is the
metalation of a heteroatom-substituted allyl derivative
2 to provide 3, which is the actual species represented
by 1. Reaction of 3 with an electrophile at the γ position
affords 4, which can be hydrolyzed to provide a â-sub-
stituted aldehyde 5.1
We have developed the chemistry of (-)-sparteine-
complexed lithiated intermediates of N-(Boc)-N-(p-meth-
oxyphenyl) allylic amines as asymmetric homoenolate
synthetic equivalents.4 Lithiated N-Boc cinnamylamine
substrates have been investigated and found to give
products with high regio-, diastereo-, and enantioselec-
tivities upon reaction with alkyl halide,4 Michael accep-
tor,5 and nitroalkene6 electrophiles. Transmetalation and
reaction with aldehyde electrophiles allow access to
(2) (a) Zschage, O.; Schwark, J .-R.; Kra¨mer, T.; Hoppe, D. Tetrahe-
dron 1992, 48, 8377-8388. (b) Zschage, O.; Schwark, J .-R.; Hoppe, D.
Angew. Chem., Int. Ed. Engl. 1990, 29, 296-298. (c) Hoppe, D.;
Zschage, O. Angew. Chem., Int. Ed. Engl. 1989, 28, 69-71. (d) Hoppe,
D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg, F.; van Hu¨lsen, E. Chem.
Ber. 1985, 118, 2822-2851. (e) Hoppe, D.; Lichtenberg, F. Angew.
Chem., Int. Ed. Engl. 1982, 21, 372.
(3) (a) Peschke, B.; Lu¨ssmann, J .; Dyrbusch, M.; Hoppe, D. Chem.
Ber. 1992, 125, 1421-1430. (b) Paulsen, H.; Graeve, C.; Fro¨lich, R.;
Hoppe, D. Synthesis 1996, 145-148.
(4) (a) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J .; Beak, P.
J . Am. Chem. Soc. 1999, 121, 9522-9530. (b) Park, Y. S.; Weisen-
burger, G. A.; Beak, P. J . Am. Chem. Soc. 1997, 119, 10537-10538.
(c) Weisenburger, G. A.; Beak, P. J . Am. Chem. Soc. 1996, 118, 12218-
12219. (d) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Th-
ayumanavan, S. Acc. Chem. Res. 1996, 29, 9, 552-560.
(5) Curtis, M. D.; Beak, P. J . Org. Chem. 1999, 64, 2996-2997.
(6) J ohnson, T. J .; Curtis, M. D.; Beak, P. J . Am. Chem. Soc. 2001,
123, 1004-1005.
The value of this methodology has been significantly
enhanced by recent developments of convenient asym-
metric homoenolate synthetic equivalents. The work of
Hoppe and co-workers, which revealed that (-)-sparteine-
controlled lithiations adjacent to the oxygen of allyl
carbamates provided such synthetic equivalents, was
(1) (a) For a review, see: Ahlbrecht, H.; Beyer, U. Synthesis 1999,
3, 365-390. (b) O¨ zlu¨gedik, M.; Kristensen, J .; Wibbeling, B.; Fro¨hlich,
R.; Hoppe, D. Eur. J . Org. Chem. 2002, 414-427.
10.1021/jo0260084 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
J . Org. Chem. 2003, 68, 1207-1215
1207

Whisler and Beak
highly enantioenriched homoaldol products.7 The mech-
anisms of these reactions have been investigated4a,7 and
products resulting from lithiation/substitution of the
N-Boc cinnamylamine substrates have been converted
into highly enantiomerically enriched substituted pip-
eridines, pyrrolines,6 fused bicarbocyclic compounds,8 and
fused bicyclic lactams.9
TABLE 1. Resu lts of Lith ia tion /Su bstitu tion of
N-(Boc)-N-(p-m eth oxyp h en yl)cr otyla m in e (11)
We have previously established that (-)-sparteine-
mediated R-lithiation of N-(Boc)-N-(p-methoxyphenyl)-
cinnamylamine (6) in toluene at -78 °C provides a
configurationally stable η3-lithiated intermediate 8 of
known absolute configuration.10 The pro-R proton of 6 is
selectively removed by the chiral base complex to provide
the lithiated intermediate, which undergoes reaction with
a variety of electrophiles to afford highly enantioenriched
γ-substituted Z-enecarbamates 9.4a,c Reaction of 8 with
allyl bromide, benzyl bromide, methyl iodide, and cin-
namyl bromide occurs with inversion of configuration at
the metalated center. The enecarbamates 9 can be easily
hydrolyzed to provide â-substituted aldehydes 10 in high
yields without loss of enantioenrichment. In this se-
quence, the lithiated intermediate 8 is the asymmetric
homoenolate synthetic equivalent.
methoxyphenyl)cyclohexyl allylamine (12) in lithiation/
substitution sequences. The lithiation of the N-Boc cro-
tylamine 11 with n-BuLi‚(-)-sparteine followed by reac-
tion with allyl bromide provides Z and E geometrical
isomers of the γ-substituted product, 13 and 14, respec-
tively, with the enantiomeric ratios of 94:6 and 92:8,
respectively. The Z and E geometrical isomers are easily
separable by column chromatography. The absolute con-
figuration of 13 is assigned based on analogy to 9 for E
) benzyl4c and is provisional. The configurations of 13
and 14 are assigned as opposite based on isomerization
of 13 to 19 and comparison of optical rotation with 14
(vide infra). The lithiated complex of the N-Boc croty-
lamine undergoes stereoselective reaction with benzyl
bromide to provide Z and E γ-substituted products 16
and 17 as well as the R-substituted product 18. The
enecarbamates 16 and 17 are obtained with enantiomeric
ratios of 94:6 and 98:2, respectively. The E geometrical
isomer 17 is easily purified by column chromatography;
however, the Z γ-substituted product 16 was not sepa-
rable from the R-substituted product 18. The enantiomers
of 18 were not completely separable by chiral HPLC, but
the enantiomeric ratio was determined to be >80:20. The
results of the reactions with the N-Boc crotylamine 11
are shown in Table 1.
In the present report, we provide new information
about the scope of the conversion of 2 to 4 for the N-Boc
allylic amine derivatives, a sequence for the enantiose-
lective conversion of the allyl-substituted compound to
enantioenriched 2-formyl-4-phenyl-1-aminocyclopentane
derivatives, including â-lactam substitution, and an
iterative homoaldol reaction that is highly diastereo- and
enantioselective.
The enantiomeric ratio of the Z γ-substituted product
13 was determined by chiral HPLC. The Z enecarbamate
13 was isomerized to the E enecarbamate 19 with TFA/
TFAA in CH2Cl2. The optical activity of the E enecar-
bamate 19, which has a known enantiomeric ratio of 94:
6, was measured. Comparison of this value with the
optical rotation of the E enecarbamate 14 allows an er
of 92:8 to be assigned to 14.11 This procedure was also
Resu lts a n d Discu ssion
(-)-Sp a r tein e-Med ia ted Lith ia tion s a n d Su bstitu -
tion s. We now report our investigation of the N-(Boc)-
N-(p-methoxyphenyl)crotylamine (11) and N-(Boc)-N-(p-
(7) Whisler, M. C.; Vaillancourt, L.; Beak, P. Org. Lett. 2000, 2,
2655-2658. This publication contains errors in the abstract graphic
and in footnote 1 of Table 2. Transmetalation with a titanium reagent
provides products with Z:E ratios of 98:2, not E:Z ratios of 98:2, as
reported.
(8) Lim, S. H.; Curtis, M. D.; Beak, P. Org. Lett. 2001, 3, 711-714.
(9) Lim, S. H.; Ma, S.; Beak, P. J . Org. Chem. 2001, 66, 9056-9062.
(10) Pippel, D. J .; Weisenburger, G. A.; Wilson, S. R.; Beak, P.
Angew. Chem., Int. Ed. 1998, 37, 2522-2524.
(11) In most cases, enantiomeric ratios are determined by chiral
HPLC comparison with racemic standards. In these cases, reaction
with the achiral diamine TMEDA to prepare racemic material provides
only Z γ-substituted product and R-substituted product.
1208 J . Org. Chem., Vol. 68, No. 4, 2003

Lithiated N-Boc Allylic Amines as Homoenolate Equivalents
TABLE 2. Lith ia tion /Su bstitu tion of
N-(Boc)-N-(p-m eth oxyp h en yl)cycloh exyl Allyla m in e (12)
TABLE 3. Hyd r olysis a n d Cycloa d d ition of
En eca r ba m a te 29
aldehyde functionality in the hydrolysis products of the
enantioenriched allyl-substituted enecarbamates sug-
gests that cyclopentane ring-forming reactions should be
investigated. We have found that intramolecular ni-
trone-olefin dipolar cycloadditions,12 which can be initi-
ated by reaction of the aldehyde and an N-substituted
hydroxylamine hydrochloride, proceed efficiently. As
shown in Table 3, reaction of aldehyde 30, obtained by
hydrolysis of 29, with N-benzylhydroxylamine hydrochlo-
ride, N-methylhydroxylamine hydrochloride, or N-iso-
propylhydroxylamine hydrochloride provides the ex-
pected cyclopentyl products 32-34 in good yields with
moderate diastereoselectivities, presumably via the ni-
trone 31. The reaction of 30 with N-benzylhydroxylamine
hydrochloride proceeds at room temperature; the reac-
tions of 30 with N-methylhydroxylamine hydrochloride
and N-isopropylhydroxylamine hydrochloride require
heating to reflux for product formation. The diastereo-
mers are readily separable by column chromatography.
The absolute configuration of the major diastereomer of
32, from the reaction of aldehyde 30 with N-benzylhy-
droxylamine hydrochloride, was determined by X-ray
crystallographic analysis.13 The stereochemistry of 33 and
34 is assigned by analogy to 32. The reaction can be
carried out without isolation from N-Boc-anisidene, the
byproduct of the hydrolysis, to provide the products in
similar yields and stereoselectivities to those in Table 3.
used to determine the enantiomeric ratios of 16, 17, 23,
and 24 (vide infra).
The (-)-sparteine-mediated lithiation and substitution
of N-Boc cyclohexyl allylamine 12 provides the expected
products with methyl iodide, allyl bromide, and benzyl
bromide as electrophiles, as shown in Table 2. The
products of methylation, 20 and 21, are obtained with
enantiomeric ratios of 92:8 and 96:4, respectively. How-
ever, the products obtained from the reactions with allyl
bromide, 23 and 24, and benzyl bromide, 26 and 28, have
low enantiomeric ratios. The enantiomeric ratios of 23
and 24 are 57:43 and 67:33, respectively, and the ers of
26 and 28 are 55:45 and 72:27, respectively. The R-sub-
stituted products 25 and 28 were isolated in significant
yields. In these reactions, the E geometrical isomer was
separable by column chromatography; however, the Z
γ-substituted products 20, 23, and 26 were not separable
from the R-substituted products 22, 25, and 28.
Three new stereocenters can be formed in the cycload-
diton by using a more highly substituted allyl group on
the enecarbamate starting material. Use of cinnamyl
bromide in the lithiation/substitution reaction provided
the γ-substituted enecarbamate 35. Reaction of aldehyde
36 with N-benzylhydroxylamine hydrochloride under the
same reaction conditions as described above led to the
bicyclic product 37 in 64% yield with an 86:14 ratio of
easily separable diastereomers. The absolute configura-
(12) LeBel, N. A.; Post, M. E.; Whang, J . J . J . Am. Chem. Soc. 1964,
86, 3759-3767.
(13) The crystallographic data for 32 and 54 have been depositied
with the Cambridge Crystallographic Data Centre as supplementary
publication nos. 186903 and 186902, respectively. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, U.K. (fax (+44) 1223-336033; e-mail deposit@
ccdc.cam.ac.uk).
Syn th esis of 2-For m yl-5-p h en yl-1-a m in ocyclop en -
ta n es. The 1,5 relationship of the allyl group and the
J . Org. Chem, Vol. 68, No. 4, 2003 1209

Whisler and Beak
tion of 37 has been assigned by analogy to 32 and by a
reasonable transition state model (vide infra).
acid 41, a structurally modified analogue of cispentacin.16
Coupling of the crude amino acid 41 according to Ohno’s
procedure17 with 2,2′-dipyridyl disulfide (Aldrithiol),
PPh3, and NEt3 provides â-lactam 42 in 65% over the two
steps. Benzyl deprotection is achieved with a dissolving
metal reduction using sodium metal and liquid ammonia
at -78 °C. The deprotected highly enantiomerically
enriched â-lactam 43 was isolated in 67% yield.
A 1,2-trans-substituted chiral cyclopentane can be
accessed by a two-step sequence from the chiral cis-
substituted N-protected amino alcohol 39. Swern oxida-
tion of 39 provides the cis cyclopentyl aldehyde 44 in 86%
yield, including approximately 10% of the epimerized
product. Treatment of 44 with NaHCO3 in refluxing
EtOH provides the 1,2,4-trans-substituted aldehyde 45
in 90% yield.
The nature and position of the functional groups in 32-
34 offer an opportunity for the synthesis of highly
enantioenriched â-lactams.14 The reaction sequence we
have developed is shown for the conversion of 32 to 43.
Syn th esis of Ma sk ed Hom oa ld ol P r od u cts. Reac-
tions in which two stereogenic centers are created with
high diastereo- and enantioselectivity are of exceptional
value in asymmetric synthesis. Homoaldol reactions are
of particular interest because of the novel addition of an
aldehyde â to a carbonyl functionality.18 A number of
methods have been reported for the asymmetric synthesis
of homoaldol reaction products. Hoppe and co-workers
have thoroughly studied the (-)-sparteine-mediated lithi-
ation/transmetalation/substitution sequences of N,N-
diisopropylcarbamates for the synthesis of homoaldol
precursors.2 An (S)-2-prolinol ether chiral auxiliary ap-
proach has been developed by Ahlbrecht and co-workers
for lithiation and aldehyde electrophile substitution of
R-substituted allylamines.19 Hoffmann and co-workers
(16) Cispentacin has recently been isolated from Bacillus cereus and
Streptomyces setonii and shown to have potent activity as an antifungal
antibiotic in mice. See: (a) Konishi, M.; Nishio, M.; Saitoh, T.; Miyaki,
T.; Oki, T.; Kawaguchi, H. J . Antibiot. 1989, 42, 1749-1755. (b) Oki,
T.; Hirano, M.; Tomatsu, K.; Numata, K.; Kamei, H. J . Antibiot. 1989,
42, 1756-1762. (c) Iwamoto, T.; Tsujii, E.; Ezaki, M.; Fujie, A.;
Hashimoto, S.; Okuhara, M.; Kohsaka, M.; Imanaka, H. J . Antibiot.
1990, 43, 1-7. (d) Kawabata, K.; Inamoto, Y.; Sakane, K. J . Antibiot.
1990, 43, 513-518. Cispentacin is a compound of synthetic interest:
(e) Fu¨lo¨p, F.; Palko´, M.; Ka´ma´n, J .; La´za´r, L.; Sillanpa¨a¨, R. Tetrahe-
dron: Asymmetry 2000, 11, 4179-4187. (f) Aggarwal, V. K.; Roseblade,
S. J .; Barrell, J . K.; Alexander, R. Org. Lett. 2002, 7, 1227-1229.
In the first step toward the â-lactam synthesis, the
N-O bond of isoxazoline 32 is cleaved by treatment with
Zn/HOAc to provide amino alcohol 38 in 85% yield, which
on Boc protection of the secondary amine provides 39 in
77% yield.15 Oxidation of the protected amino alcohol 39
with RuCl3/NaIO4 affords the N-protected amino acid 40
in 88% yield. Deprotection with TFA provides the amino
(14) Chiral â-lactams are of considerable interest, as many phar-
macologically active compounds contain this framework. See: Antibiot-
ics Containing the â-Lactam Structure; Morin, R. B., Goldman, M.,
Eds.; Academic Press: New York, 1983; Vols. 1-3. Recent efforts for
efficient asymmetric syntheses of azetidin-2-ones have concentrated
on stereoselective ketene-imine cycloadditions and ester enolate-
imine condensations. See: (a) Palomo, C.; Aizpurua, J . M.; Ganboa,
I.; Oiarbide, M. Eur. J . Org. Chem. 1999, 3223-3225. (b) Benaglia,
M.; Cinquini, M.; Cozzi, F. Eur. J . Org. Chem. 2000, 563-572.
(15) A number of attempts made to simultaneously cleave the N-O
bond of 32 and Boc-protect the resulting secondary amine 38 by Pd-
catalyzed hydrogenation in the presence of Boc2O were unsuccessful.
(17) Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J . Am. Chem.
Soc. 1981, 103, 2406-2408.
(18) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932-948.
(19) Ahlbrect, H.; Kramer, A. Chem. Ber. 1996, 129, 1161-1168.
1210 J . Org. Chem., Vol. 68, No. 4, 2003

Lithiated N-Boc Allylic Amines as Homoenolate Equivalents
developed a series of useful allylic boron reagents for the
preparation of homoallylic alcohols.20
of two diastereomers. Oxidation23 of 53 with m-CPBA and
BF3‚OEt2 in CH2Cl2 gave a single diastereomer of 54 in
76% yield. A crystal suitable for X-ray crystallography
was obtained by recrystallization.
We have recently communicated the fact that lithiation
of 6 or 12 upon subsequent transmetalation with Et2AlCl
or TiCl(Oi-Pr)3 provides intermediates which undergo
stereoselective reaction with aldehydes to give masked
homoaldol products 46 and 47.7 This approach allows
either enantiomer of a desired masked anti homoaldol
product to be prepared with high stereointegrity.21
Rea ction P a th w a ys. Previous work has established
that the lithiated intermediate 8 is an η3 species in the
solid state and in solution with the absolute configuration
shown.4a The absolute configurations of products from the
alkylations of 8 require an invertive carbon-carbon bond
formation. Our postulate is that the (-)-sparteine re-
stricts access to the lithium ion and the sp2 character of
the allyl anion allows access to the electrophile by the si
face of the nucleophile to allow the reactions to proceed
with the inversion of configuration as shown for 55.
Absolute configurations were assigned by derivatiza-
tion and X-ray crystallography and also by calculation
of optical rotations.22 Demasking of homoaldol products
48 and 49 by O-protection and subsequent hydrolysis
provided the 3,4-disubstituted-4-alkoxy-aldehydes 50
and 51.
We now report that these homoaldol products can be
utilized as chiral electrophiles in the homoaldol reaction.
Lithiation and Et2AlCl transmetalation of 6 followed by
addition of O-protected homoaldol product 50 provides
the iterative product 52 in 73% yield. The diastereose-
lectivity of the reaction is high; only two trans configured
diastereomers in a ratio of 93:7 are detected.
Previous investigations of the kinetics and mechanism
of the enantioselective deprotonation of 12 provide evi-
dence that the lithiated intermediate of 12 is an enan-
tioenriched, configurationally stable, R-lithiated η1 spe-
cies complexed to (-)-sparteine.24 We presume this is also
the case for the crotyl system 11. The intermediates may
be postulated to exist as two rotamers, 56 and r ot-56 (R
) Cy) and 57 and r ot-57 (R ) Me).25 The η1 character of
the species should allow rotation for these intermediates
more easily than for the η3 intermediate 8. The rate of
rotation and the rate of reaction with electrophile were
evaluated by an adapted Hoffmann’s test for configura-
tional stability.26 The lithiated intermediate of 12 was
reacted with 0.1 equiv of MeI. The resulting γ-substituted
products were isolated in a 2:1 Z:E ratio, which is the
same result as with excess MeI electrophile. This experi-
The absolute configuration of 52 was determined by
derivatization and X-ray crystallographic analysis. Meth-
anolysis of 52 provided lactol 53 in 79% yield as a mixture
(20) (a) Hoffmann, R. W.; Dresely, S.; Lanz, J . Chem. Ber. 1988,
121, 1501-1507. (b) Hoffmann, R. W.; Dresely, S. Chem. Ber. 1989,
122, 903-909.
(21) It is of interest to note that the lithiation/transmetalation/
substitution reactions with cyclohexyl allylamine 12 do not suffer the
stereoselectivity problems observed for reaction of lithiated intermedi-
ates 56 and r ot-56 with alkyl bromides.
(23) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
18, 419-420.
(24) Pippel, D. J .; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J .
Am. Chem. Soc. 2001, 123, 4919-4927.
(25) These rotamers are indistinguishable at -78 °C by 6Li and 13C
NMR. See ref 22.
(22) Kondru, R. K.; Wipf, P.; Beratan, D. N. Science 1998, 282,
2247-2250. The [R]D calculations were performed by Gustavo Mouro,
David Beratan, and Peter Wipf at the University of Pittsburgh.
(26) (a) Hoffmann, R. W.; Ru¨hl, T.; Harbach, J . Liebigs Ann. Chem.
1992, 725-730. (b) Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125,
975-982. See also ref 4d.
J . Org. Chem, Vol. 68, No. 4, 2003 1211

Whisler and Beak
ment is consistent with the rotamers undergoing equili-
bration at a rate faster than reaction with electrophile,
exhibiting classic Curtin-Hammett reactivity.27
The presence of two rotamers is consistent with olefin
geometry and absolute configurations of the products
obtained from the lithiation/substitution reactions. The
transition states leading to the γ-substituted E and Z
isomeric products may be considered to arise from
reactions of the electrophile with each of the rotameric
lithiated intermediates 56 and r ot-56 (R ) Cy) and 57
and r ot-57 (R ) Me). Since each rotamer places the
lithium‚(-)-sparteine complex on a different face of the
substrate, the geometries and the configurations of the
products are correlated and formed by invertive reactions
in transition structures which are shown to resemble
each allyllithium species. Products 13, 14, 16, 17, 20, and
21 also are considered to arise by similar transition
structures.
transmetalated homoaldol reactions. Transmetalation of
8 with Et2AlCl is considered to proceed with inversion of
configuration to give 58, which is in equilibrium with
conformation r ot-58. Favorable coordination between the
Boc group and the aluminum atom in the transition state
for the carbon-carbon bond formation is shown for the
six-membered transition state28 59, which leads to 52.
Precoordination of the aldehyde electrophile to the metal
atom leads to addition to the electrophile with retention
of configuration.29
It has been established that transmetalation with TiCl-
(Oi-Pr)3 provides Z-enecarbamate products, e.g. 47, with
the opposite absolute configuration30 to that described for
the Et2AlCl transmetation/substitution. We suggest that
transmetalation with TiCl(Oi-Pr)3 also proceeds with
inversion of configuration to provide a newly metalated
intermediate 60. The reaction of this intermediate with
aldehyde electrophile is suggested to occur through
transition state 61 to provide Z-configured enecarbam-
ates 47 with absolute and geometrical configurations
opposite to the products resulting from the reaction with
Et2AlCl. The difference between transition states 59 and
61 may be attributed to the ligands around the metal
atoms. The two diethyl groups around aluminum do not
sterically interfere with the larger -N(Boc)Ar group in
59. Thus, the -N(Boc)Ar group adopts an energetically
favorable pseudoequatorial position during reaction with
the electrophile. However, upon reaction with electrophile
in the titanium complex, the -N(Boc)Ar moiety may
adopt a pseudoaxial position in 61 because of interference
The low enantioenrichment observed for products 23,
24, 26, and 28 resulting from reaction of 56 and r ot-56
with allyl bromide and benzyl bromide may be ascribed
to the bulk of the cyclohexyl substituent of the allylic
amine. The increased amount of R-substitution from 56
relative to 57 is consistent with a higher energy of
activation for reaction at the γ position of 57. An increase
in the energy of activation for the stereoselective γ
substitution may allow other facially less discriminating
pathways to be competitive and lower the enantiomeric
ratio of the products. Because the smaller methyl sub-
stituent does not cause as much steric congestion as the
cyclohexyl group, products 13, 14, 16, and 17 are obtained
with high enantiomeric ratios. A single electron-transfer
mechanism (SET) was discounted because of the high
enantiomeric ratios observed in products obtained by
lithiation and substitution of 6 and 11. All reactions were
run under the same conditions at -78 °C.
(28) These allylmetal reactions are presumed to proceed through
six-membered transition states. See: Yamamoto, Y.; Asao, N. Chem.
Rev. 1993, 2207-2293.
(29) Upon coordination with aldehyde, the coordination sphere
around aluminum is proposed to be tetrahedral. See: Crabtree, R. H.
The Organometallic Chemistry of the Transition Metals; J ohn Wiley
& Sons: New York, 1994; Chapters 1 and 2.
(30) The absolute configurations of the products obtained by trans-
metalation with TiCl(Oi-Pr)3 were determined by O-protection and
hydrolysis to the corresponding O-protected aldehyde (vide supra).
Comparison of optical rotations was made with aldehydes 50 and 51,
whose absolute configuration was determined by X-ray crystal analysis
of derivatives.
Knowledge of the absolute configurations of products
allows assignment of a stereochemical course for the
(27) A possibility exists that the rotamers do not, in fact, intercon-
vert on the time scale of the reaction and that the energies of activation
for reaction with electrophile are coincidentally the same.
1212 J . Org. Chem., Vol. 68, No. 4, 2003

Lithiated N-Boc Allylic Amines as Homoenolate Equivalents
with the three sterically demanding isopropoxy groups
around the titanium atom.31
as new approaches to desirable target compounds are
described. In this report, we demonstrate the use of
lithiated N-Boc allylic amines for syntheses of highly
enantioenriched γ-substituted enecarbamates, 2-formyl-
4-phenyl-1-aminocyclopentanes, â-lactams, and iterative
homoaldol products. This work demonstrates a value of
the homoaldol approach for the efficient preparation of
complex molecules with up to four stereogenic centers.
Reasonable reaction pathways can be proposed to account
for the observed products. Reactions of the lithiated
intermediated with transmetalating reagents and with
alkyl halide electrophiles occur with inversion of config-
uration, while reactions of the transmetalated titanium
and aluminum species with aldehyde electrophiles are
postulated to occur with retention of configuration.
The formation of the cyclopentyl rings by the 1,3-
dipolar cycloaddition reactions is consistent with reaction
via transition structure 62.32 The absolute configuration
of the stereocenter in 32 is known; thus, transition state
62 accounts for the absolute configuration of the products
32-34. The phenyl ring occupies a pseudoequatorial
position in order to alleviate any unfavorable interac-
tions.
Exp er im en ta l Section
All glassware used in lithiation reactions was either flame-
dried or oven-dried, and cooled under a nitrogen atmosphere.
Solvents and reagents were used as received, unless noted.
Toluene and dichloromethane were freshly distilled from CaH2
under N2 prior to use. Tetrahydrofuran (THF) was distilled
from Na/benzophenone under N2. n-BuLi in hexanes was used
at a concentration determined by titration with N-pivaloyl-o-
toluidine.33 (-)-Sparteine was distilled under N2 from CaH2
prior to first use.
Mass spectrometric data were acquired at the University
of Illinois Mass Spectrometry Laboratory by electron ionization
(EI) or fast atom bombardment (FAB) technique. Elemental
analyses were carried out by the University of Illinois Mi-
croanalytical Service Laboratory. Sample purity was deter-
mined to be >95% by 13C NMR spectra. Diastereomeric purity
1
was determined by H NMR integration. “Standard workup”
refers to dilution with ether, addition of H2O, separation of
phases, extraction of the aqueous layer with ether, combination
of the organic phases, drying with MgSO4, and concentration
by rotary evaporation.
The absolute configuration for the major diastereomer
of 37 can be postulated based on the transition state for
the cycloaddition. The reaction is known to be kinetically
controlled,12 allowing for retention of olefin configuration
in the transition state 63 and in the resulting isoxazoline
37.
Rep r esen ta tive Nitr on e-Olefin Dip ola r Cycloa d d i-
tion : Syn th esis of (5S)-1-Ben zyl-5-p h en yl-h exa h yd r o-
cyclop en ta [c]isoxa zole (32). To a stirring solution of 30 (60
mg, 0.345 mmol) in toluene (3 mL, 0.12 M) was added
benzylhydroxylamine hydrochloride (121 mg, 0.759 mmol),
triethylamine (0.11 mL, 0.759 mmol), and molecular sieves.
The mixture was allowed to stir overnight at room temperature
and was monitored by TLC. When no starting material
remained, the mixture was poured into water. Standard
workup provided crude 32 as a light yellow oil. Column
chromatography (90:10 petroleum ether:EtOAc) provided the
product as a white solid (78 mg, 81%): mp 55-57 °C. A crystal
suitable for X-ray crystallographic analysis was grown by
recyrstallization from EtOH. The more retained minor dias-
tereomer was characterized spectroscopically: 1H NMR (acetone-
d6, 400 MHz) δ 1.71 (m, 1H, CH2CHCH2O), 1.82 (m, 1H,
CH2CHCH2O), 1.98 (m, 2H, CH2CHN), 3.24 (qt, 1H, J ) 8.1
Hz, PhCH), 3.45 (sept, 1H, J ) 6.1 Hz, CHCH2O), 3.49 (m,
1H, CHN), 3.57 (dd, 1H, J ) 8.4, 6.3 Hz, CH2O), 3.99 (AB,
2H, J ) 13.4 Hz; νa ) 4.03 ppm; νb ) 3.95 ppm, PhCH2), 4.25
(t, 1H, J ) 8.6 Hz, CH2O), 7.19-7.44 (m, 10H, ArH). 13C NMR
(acetone-d6, 100 MHz) δ 38.9, 42.8, 47.5, 61.1, 71.6, 72.4, 72.8,
126.2, 127.0, 127.3, 128.1, 128.4, 129.1, 138.8, 144.1. HRMS-
FAB (M + 1) calcd for C19H22NO 279.1623, found 279.1623.
The less retained major diastereomer was obtained as a white
solid and was characterized spectroscopically: 1H NMR (acetone-
d6, 400 MHz) δ 1.53 (m, 1H), 1.66 (q, J ) 11.5 Hz, 1H), 2.14
(m, 1H), 2.34 (m, 1H), 3.01 (sept, J ) 6.1 Hz, 1H), 3.20 (m,
1H), 3.59 (dd, J ) 8.5, 2.7 Hz, 1H), 3.69 (q, J ) 8.1 Hz, 1H),
3.90 (AB, J ) 13.4 Hz; νa ) 3.96 ppm; νb ) 3.84 ppm, 2H),
Su m m a r y
The synthetic utility of asymmetric homoenolate equiva-
lents has been demonstrated by syntheses from several
laboratories; development of the methodology continues
(31) Although unusual, a pentacoordinate titanium atom is not
unprecedented. The geometry around the titanium atom is postulated
as trigonal bipyramidal. For an X-ray crystal structure of a pentaco-
ordinate titanium complex, see: Kirschbaum, K.; Conrad, O.; Giolando,
D. M. Acta Crystallogr., Sect. C 2000, C56, e541. For proposals of other
reaction pathways through a pentacoordinate titanium complex, see:
Adam, W.; Corma, A.; Reddy, T. I.; Renz, M. J . Org. Chem. 1997, 62,
3631-3637 and ref 2a.
(32) Confalone, P. N.; Huie, E. M. In Organic Reactions; Kende, A.
S., Ed.; J ohn Wiley & Sons: New York, 1988; Vol. 36, Chapter 1.
(33) Suffert, J . J . Org. Chem. 1989, 54, 509-510.
J . Org. Chem, Vol. 68, No. 4, 2003 1213

Whisler and Beak
4.11 (m, 1H), 7.14-7.40 (m, 10H). 13C NMR (acetone-d6, 125
MHz) δ 40.2, 40.8, 46.3, 47.6, 59.6, 59.9, 71.5, 126.3, 127.1,
peaks) δ 1.45 (br s, 9H), 2.14 (br s, 1H), 2.20 (m, 1H), 2.35 (t,
J ) 8.5 Hz, 2H), 2.97 (m, 1H), 3.48 (m, 1H), 4.44 (m, 1H), 4.74
(br m, 2H), 7.19-7.63 (m, 10H). 13C NMR (CDCl3, 100 MHz)
δ 28.6, 35.9, 37.8, 42.9, 46.3, 49.2, 59.8, 80.9, 126.8, 126.9,
127.4, 127.4, 128.6, 128.7, 139.8, 143.5, 156.4, 180.0. HRMS-
FAB (M + 1) calcd for C24H30NO4 396.2175, found 396.2176.
127.1, 128.3, 128.6, 129.2, 138.7, 143.9. Anal. Calcd for C19H21
-
NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.27; H, 7.48; N,
5.15.
Rep r esen ta tive Lith ia tion a n d Su bstitu tion : Syn th e-
sis of (3S)-N-(ter t-Bu t oxyca r b on yl)-3,6-d ip h en yl-N-(4-
m eth oxyp h en yl)-(1Z,5E)-h exa d ien -1-a m in e (35). To a stir-
ring solution of 6 (205 mg, 0.60 mmol) in toluene (12 mL, 0.05
mmol) was added (-)-sparteine (0.19 mL, 0.84 mmol). The
mixture was cooled to -78 °C and n-BuLi (0.962 mL, 0.52
mmol) was added dropwise. After being stirred for 1 h at -78
°C, cinnamyl bromide (0.18 mL, 1.21 mmol) was added to the
mixture and the stirring was continued for 2 h. The mixture
was then quenched with MeOH (1 mL) and warmed to room
temperature. Standard workup and subsequent column chro-
matography and preparative HPLC (95:5 petroleum ether:
(3S)-6-Aza -6-b en zyl-3-p h en yl-b icyclo[3.2.0]h ep t a n -7-
on e (42). To a stirring solution of 40 (27 mg, 0.067 mmol) in
CH2Cl2 (1 mL, 0.07M) was added approximately 0.25 mL of
30% TFA in CH2Cl2. The mixture was allowed to stir at room
temperature for 12 h and was monitored by TLC. Concentrated
TFA (0.25 mL) was then added and the reaction stirred until
complete consumption of starting material was observed. Upon
consumption of starting material, the TFA/CH2Cl2 mixture was
removed in vacuo. Residual TFA was removed by azeotroping
with CHCl3 and toluene in vacuo. The crude, deprotected
amino acid 41 was dissolved in CH3CN (1.5 mL, 0.045 M) and
NEt3 (14 µL, 0.10 mmol) was added. A small amount of white
precipitate immediately formed and the reaction was stirred
for 10 min. PPh3 (21 mg, 0.08 mmol) and 2,2′-dipyridyl
disulfide (Aldrithiol, 18 mg, 0.08 mmol) were then added. The
reaction was heated to 60 °C for 8 h. The yellow homogeneous
reaction mixture was then diluted with H2O and washed with
EtOAc. The organic layers were combined, washed with brine,
dried over MgSO4, and concentrated to provide crude 42 as a
yellow oil. Column chromatography (50:50 petroleum ether:
EtOAc) provided pure 42 (12 mg, 65%) as a colorless oil. 1H
NMR (CDCl3, 500 MHz) δ 2.01 (m, 2H), 2.08 (ddd, J ) 16.7,
8.8, 7.7 Hz, 1H), 2.52 (ddd, J ) 14.2, 5.1, 3.2 Hz, 1H), 3.58 (qt,
1
EtOAc) provided pure 35 as a colorless oil (276 mg, 93%). H
NMR (acetone-d6, 400 MHz) δ 1.37 (s, 9H), 2.34 (m, 2H), 3.13
(m, 1H), 3.78 (s, 3H), 5.09 (t, J ) 9.5 Hz, 1H), 5.93 (m, 1H,),
6.25 (d, J ) 9.8 Hz, 1H), 6.65 (d, J ) 9.1 Hz, 1H), 6.85-7.29
(m, 14H). 13C NMR (acetone-d6, 100 MHz) δ 27.7, 40.4, 42.3,
55.1, 80.5, 114.0, 121.0, 126.1, 126.2, 127.1, 127.5, 127.6, 128.3,
128.4, 128.7, 131.4, 135.2, 138.0, 144.2, 153.3, 158.2.
(1S,2S,4S)-1-Am in o-N-ben zyl-2-h yd r oxym eth yl-4-p h e-
n ylcyclop en ta n e (38). To a stirring solution of 32 (153 mg,
0.548 mmol) in 10 M AcOH (10 mL, 0.06 M) was added Zn
dust (717 mg, 10.97 mmol). The mixture was heated to 55 °C.
After being stirred for 3 h, the mixture was cooled to room
temperature, diluted with water, basified with 6 M KOH, and
extracted with CH2Cl2. The organic layers were combined,
dried (MgSO4), and concentrated to provide 38 as a pure
colorless oil (130 mg, 85%) requiring no further purification.
1H NMR (acetone-d6, 400 MHz) δ 1.65 (m, 2H), 2.09 (m, 1H),
2.36 (m, 2H), 2.98 (m, 1H), 3.30 (br s, 1H), 3.39 (m, 1H), 3.71
(d, J ) 5.8 Hz, 2H), 3.82 (AB, J ) 13.2 Hz; νa ) 3.87 ppm; νb
) 3.76 ppm, 2H), 7.13-7.39 (m, 10H). 13C NMR (acetone-d6,
125 MHz) δ 36.6, 41.8, 43.2, 43.2, 52.8, 60.5, 63.2, 126.0, 126.9,
127.2, 128.3, 128.4, 128.5, 141.2, 145.6. HRMS-FAB (M + 1)
calcd for C19H24NO 282.1858, found 282.1857.
(1S,2S,4S)-1-Am in o-N-ben zyl-N-(ter t-bu toxyca r bon yl)-
2-h yd r oxym eth yl-4-p h en ylcyclop en ta n e (39). To a stirring
solution of 38 (55 mg, 0.195 mmol) in MeOH (3 mL, 0.07 M)
was added NaHCO3 (115 mg, 1.37 mmol). (Boc)2O (0.13 mL,
0.585 mmol) was then added and the mixture was stirred at
room temperature overnight. The mixture was poured into
water and extracted with CH2Cl2. The combined organic layers
were dried (MgSO4) and concentrated to provide the crude
product as a yellow oil. Purification by column chromatography
(80:20 petroleum ether:EtOAc) provided 39 (57 mg, 77%) as a
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.45 (s, 9H), 1.78
(q, J ) 11.8 Hz, 1H), 2.16 (br m, 3H), 2.55 (m, 1H), 2.92 (br s,
1H), 3.02 (m, 1H), 3.66 (m, 2H), 4.37 (m, 2H), 4.63 (br m, 1H),
7.18-7.33 (m, 10H). 13C NMR (CDCl3, 100 MHz) δ 28.6, 28.6,
35.9, 37.4, 42.8, 59.5, 60.7, 63.1, 80.7, 126.4, 126.6, 127.0, 127.3,
128.6, 128.7, 139.7, 144.4, 157.2. HRMS-FAB (M + 1) calcd
for C24H31NO3 382.2382, found 382.2383.
(1R,2S,4S)-2-Am in o-N-ben zyl-N-(ter t-bu toxyca r bon yl)-
4-p h en yl-1-cyclop en ta n eca r boxylic Acid (40). To protected
amino alcohol 39 (57 mg, 0.150 mmol) was added 1.5 mL of
solvent (1:1:1.5 CH3CN:CCl4:H2O) and NaIO4 (128 mg, 0.598
mmol). RuCl3 (0.7 mg, 0.022 mmol) was then added and the
colorless solution became yellowish brown in color. The
mixture was allowed to stir overnight. H2O was then added
and the solution was poured into a separatory funnel and
washed with CH2Cl2. The organic layers were combined, dried
(MgSO4), and concentrated. The light brown oil was dissolved
in ether and filtered through a pad of Celite. Concentration of
the filtered solution provided the product 40 (52 mg, 88%),
which was carried directly to the subsequent deprotection
reaction without further purification. 1H NMR (acetone-d6, 400
MHz) (Note: restricted rotation causes severe broadening of
J ) 7.1 Hz, 1H), 3.62 (m, 1H), 3.88 (AB, J ) 15.0 Hz; νa
)
4.28 ppm; νb ) 3.47 ppm, 2H), 7.12-7.36 (m, 10H). 13C NMR
(CDCl3, 100 MHz) δ 29.3, 35.6, 44.4, 46.2, 55.6, 58.1, 126.3,
126.7, 127.8, 128.6, 128.6, 129.0, 135.8, 143.5, 169.9. IR
(CHCl3) 1742 cm-1. HRMS-FAB (M + 1) calcd for C19H20NO
278.1545, found 278.1546.
6-Aza -(3S)-p h en yl-bicyclo[3.2.0]h ep ta n -7-on e (43). To
approximately 5 mL of NH3 at -78 °C was added the protected
â-lactam 42 dissolved in THF (0.5 mL, 0.12 M) dropwise with
a syringe. Small bits of sodium were added until the dark blue
color persisted. The reaction was allowed to stir for 5 min,
whereupon NH4Cl(s) was added to quench the sodium. When
the mixture was colorless, the reaction was allowed to warm
to room temperature and the NH3 evaporated. The residue was
then dissolved in sat. NH4Cl. The aqueous mixture was washed
with CH2Cl2. The combined organic layers were washed with
H2O and brine, dried over MgSO4, and concentrated to provide
crude 43 as a colorless oil. The product was further purified
by column chromatography (90:10 CHCl3:MeOH) to provide
pure 43 (8 mg, 67%) as a colorless oil. 1H NMR (CDCl3, 400
MHz) δ 2.09 (ddd, J ) 13.9, 6.6, 2.7 Hz, 1H), 2.16 (m, 1H),
2.26 (m, 1H), 2.44 (ddd, J ) 13.9, 6.4, 4.2 Hz, 1H), 3.60 (qt, J
) 7.6 Hz, 1H), 3.68 (m, 1H), 4.20 (m, 1H), 5.66 (br s, 1H), 7.18-
7.34 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 30.8, 38.7, 47.8,
55.0, 57.2, 126.4, 126.9, 128.6, 143.7, 171.2. HRMS-FAB (M +
1) calcd for C12H14NO 188.1075, found 188.1075.
(1R,2S,4S)-2-Am in o-N-ben zyl-N-(ter t-bu toxyca r bon yl)-
4-p h en yl-1-cyclop en ta n eca r boxylic Acid (44). CH2Cl2 (0.5
mL) and oxalyl chloride (21 µL, 0.25 mmol) were added to a
flame-dried flask and cooled to -78 °C. DMSO (32 µL, 0.45
mmol) was dissolved in CH2Cl2 (0.25 mL) and added to the
reaction mixture. After the mixture was stirred for 30 min,
the alcohol 39 (34 mg, 0.09 mmol), dissolved in CH2Cl2 (1 mL),
was added dropwise. After this mixture was stirred at -78 °C
for 1.5 h, diethylisopropylamine (0.14 mL, 0.82 mmol) was
added and the reaction was warmed to room temperature. The
mixture was poured into 1 M HCl (25 mL) and the layers were
separated. The organic layer was washed with 1 M HCl, H2O,
and brine, dried over MgSO4, and concentrated to provide
crude 44 as a light yellow oil. Column chromatography (80:20
petroleum ether:EtOAc) provided the pure 44 as a colorless
oil in 86% yield (29 mg). Approximately 10% of the epimerized
product was observed by 1H NMR. 1H NMR (CDCl3, 400 MHz)
1214 J . Org. Chem., Vol. 68, No. 4, 2003

Lithiated N-Boc Allylic Amines as Homoenolate Equivalents
(Note: restricted rotation causes severe broadening of peaks)
δ 1.47 (s, 9H), 2.02 (m, 1H), 2.13 (q, J ) 11.5 Hz, 1H), 2.20
(m, 1H), 2.40 (m, 1H), 2.92 (sept, J ) 6.3 Hz, 1H), 3.20 (br s,
1H), 4.35-4.48 (br m, 3H), 7.18-7.36 (m, 10H), 9.73 (s, 1H).
13C NMR (CDCl3, 125 MHz) δ 28.6, 33.3, 38.1, 42.8, 51.8, 55.1,
60.4, 80.7, 126.7, 127.1, 127.3, 127.4, 128.7, 128.8, 139.1, 143.3,
155.8, 203.2. HRMS-FAB (M + 1) calcd for C24H30NO3 380.2226,
found 380.2226.
(1S,2S,4S)-2-Am in o-N-ben zyl-N-(ter t-bu toxyca r bon yl)-
4-p h en yl-1-cyclop en ta n eca r boxylic Acid (45). To a stir-
ring solution of 44 (9 mg, 0.02 mmol) in EtOH (1 mL, 0.02M)
was added NaHCO3. The mixture was heated to 110 °C for 3
h. The mixture was then cooled to room temperature and
filtered over Celite to afford the epimerized product 45 (8 mg,
90%), which required no further purification. 1H NMR (CDCl3,
400 MHz) (Note: restricted rotation causes severe broadening
of peaks) δ 1.48 (br s, 9H), 2.09 (m, 2H), 2.14 (qt, J ) 11.7 Hz,
1H), 2.33 (m, 1H), 2.90 (m, 1H), 3.20 (m, 1H), 4.35-4.58 (br
m, 3H), 7.18-7.36 (m, 10H), 9.65 (s, 1H). 13C NMR (CDCl3,
125 MHz) δ 28.6, 29.9, 32.3, 42.8, 50.4, 58.6, 61.7, 80.9, 126.7,
126.7, 127.1, 127.5, 128.7, 128.7, 128.8, 139.1, 143.3, 202.5.
HRMS-FAB (M + 1) calcd for C24H30NO3 380.2226, found
380.2223.
δ 1.40 (s, 9H), 1.91 (m, 2H), 2.21 (m, 1H), 3.19 (d, J ) 4.9 Hz,
1H), 3.22 (m, 1H), 3.35 (dd, J ) 9.8, 4.2 Hz, 1H), 3.62 (m, 1H),
3.80 (s, 3H), 4.32 (AB, J ) 11.7 Hz, νa ) 4.39 ppm; νb ) 4.25
ppm, 2H), 4.52 (d, J ) 7.1 Hz, 1H), 4.79 (dd, J ) 14.2, 9.8 Hz,
1H), 6.89-7.36 (m, 25H). 13C NMR (acetone-d6, 100 MHz) δ
27.7, 37.4, 49.4, 51.3, 55.0, 70.7, 72.9, 80.4, 86.1, 108.9, 114.4,
125.9, 126.3, 127.3, 127.4, 127.5, 127.6, 128.0, 128.0, 128.1,
128.3, 128.5, 129.2, 129.9, 131.9, 132.2, 139.2, 141.0, 142.7,
144.7, 152.5, 158.8. HRMS-FAB (M + 1) calcd for C44H47NO5
670.3532, found 670.3530.
(4R,5S)-5-(2S,3S-Dip h en yl-3-ben zoxy-p r op yl)-4-p h en -
yl-bu tyr ola cton e (54). To a stirred solution of 52 (72 mg,
0.11 mmol) in MeOH (1.5 mL, 0.07 M) at room temperature
was added methanesulfonic acid (3.5 µL, 0.05 mmol). The
reaction was allowed to stir overnight and was then poured
into a mixture of KOH and brine. Standard workup provided
lactol 53. The crude product was purified by column chroma-
tography (90:10 petroleum ether:EtOAc) to afford colorless oil
53 as an equal mixture of two diastereomers in 79% yield (41
mg). The diastereomers were not separated and were carried
directly to the subsequent m-CPBA/BF3‚OEt2 oxidation reac-
tion. To a stirring solution of 53 (41 mg, 0.09 mmol) in CH2-
Cl2 (2 mL, 0.04 M) was added m-CPBA (44 mg, 0.26 mmol)
and BF3‚OEt2 (3.2 µL, 0.03 mmol). The cloudy reaction mixture
was allowed to stir overnight and was then poured into
NaHSO3 (aq). The organic layer was removed and the aqueous
layer washed with CH2Cl2. The combined organic layers were
washed with NaHCO3 (aq), dried over MgSO4, filtered, and
concentrated to afford the crude light yellow oil. The crude
product was purified by column chromatography (90:10 pe-
troleum ether:EtOAc) to afford white solid 54 in 76% yield (30
Rep r esen ta tive Lith ia tion /Tr a n sm eta la tion /Su bstitu -
tion : Syn th esis of (3R,4S,6S,7S)-7-Ben zoxy-N-(ter t-bu -
toxycar bon yl)-4-h ydr oxy-N-(4-m eth oxyph en yl)-3,6,7-tr iph -
en yl-(E)-1-h ep ten -1-a m in e (52). To a stirred solution of 6
(52 mg, 0.152 mmol) in toluene (2.5 mL, 0.06 M) under N2 was
added (-)-sparteine (49 µL, 0.212 mmol). The solution was
cooled to -78 °C. n-BuLi (0.12 mL, 0.182 mmol) was added
dropwise, ensuring that the temperature of the mixture did
not exceed -76 °C. The bright yellow solution was allowed to
stir for 30 min, whereupon Et2AlCl (0.17 mL, 0.303 mmol, 1.8
M solution in toluene) was added dropwise with careful
temperature control. The solution became colorless within 2
min and was allowed to stir for 1 h. A solution of aldehyde 50
(100 mg, 0.303 mmol) in 0.5 mL of toluene was then added,
ensuring that the temperature of the mixture did not exceed
-76 °C. The reaction was allowed to stir at -78 °C for 3 h,
and was then quenched with MeOH (1 mL) and allowed to
warm to room temperature. The solution was diluted with
ether and poured onto 50 mL of 2 M HCl. The organic layer
was removed, and the aqueous layer was washed with ether.
The combined organic layers were dried (MgSO4) and concen-
trated to provide the crude product as a yellow oil. The crude
product was purified by column chromatography (80:20 pe-
troleum ether:EtOAc) to afford 52 as a colorless oil (73 mg,
75%). The E geometrical isomer was obtained with a dr of 92:
8. The diastereomers were separated by preparative HPLC
with a solvent system of 90:10 hexanes:EtOAc. A crystal
suitable for X-ray crystallographic analysis was grown by
1
mg): mp 155-157 °C. H NMR (CDCl3, 500 MHz) δ 2.33 (m,
1H), 2.53 (m, 1H), 2.77 (ABX, νa ) 2.89 ppm; νb ) 2.63 ppm;
J AB ) 17.7 Hz; J AX ) 8.7 Hz; J BX ) 10.4 Hz, 2H), 2.94 (X of
ABX, 1H), 3.24 (q, J ) 8.6 Hz, 1H), 4.28 (AB, J ) 11.8 Hz, νa
) 4.41 ppm; νb ) 4.14 ppm, 2H), 4.30 (d, J ) 7.9 Hz, 1H), 4.54
(q, J ) 8.1 Hz, 1H), 6.63-7.34 (m, 20H). 13C NMR (CDCl3,
125 MHz) δ 29.9, 37.6, 38.6, 48.6, 49.1, 60.6, 70.8, 85.7, 126.7,
127.5, 127.7, 127.8, 127.8, 128.0, 128.2, 128.2, 128.5, 128.6,
129.3, 138.5, 139.5, 140.3, 141.1, 175.8. HRMS-FAB (M + 1)
calcd for C32H31NO3 463.2273, found 463.2273.
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (GM-
18874). We are grateful for this support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds 13-17, 24, 26-28,
32-35, 37-40, 42-45, 52, and 54. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
recrystallization from EtOH. H NMR (acetone-d6, 400 MHz)
J O0260084
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