Highly enantioselective syntheses of anti homoaldol products by (-)-sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines

Article abstract of DOI:10.1021/ol006186o

(equation presented) (-)-Sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines provides anfi-configured homoaldol precursors in yields of 38-85% and enantiomeric ratios of 83:17-99:1. Subsequent O-protection and hydrolysis all

Full text of DOI:10.1021/ol006186o

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2655-2658
Highly Enantioselective Syntheses of
anti Homoaldol Products by
(−)-Sparteine-Mediated Lithiation/
Transmetalation/Substitution of N-Boc
Allylic Amines
Marna C. Whisler, Louis Vaillancourt, and Peter Beak*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
beak@scs.uiuc.edu
Received June 9, 2000
ABSTRACT
(−)-Sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines provides anti-configured homoaldol precursors in yields
of 38−85% and enantiomeric ratios of 83:17−99:1. Subsequent O-protection and hydrolysis allows access to O-protected homoaldol adducts
in good yields. The absolute configurations of the homoaldol products have been assigned by calculation of optical rotations and by X-ray
crystallography of derivatives. A stereochemical course of reaction for the lithiation/transmetalation/substitution sequence is proposed.
Homologated aldol products are an important class of organic
compounds that are generally prepared by the reaction of a
homoenolate synthetic equivalent with aldehydes or ketones.1
In our laboratories, N-Boc-N-(p-methoxyphenyl)cinnamyl-
amine2 1 and N-Boc-N-(p-methoxyphenyl)-3-cyclohexyl-
allylamine3 2 have been shown to undergo metalation with
n-BuLi/(-)-sparteine to provide chiral homoenolate equiva-
lents. We now report that these lithiated allylamine deriva-
tives can be transmetalated, reacted with aldehydes, and
hydrolyzed to afford anti homoaldol adducts in good yields
and enantiomeric ratios. This methodology allows entry into
a class of synthetically useful compounds. Hoppe et al. have
reported homoenolate synthetic equivalents from the lithia-
tion/transmetalation/substitution of (E)- and (Z)-2-butenyl
carbamates4 and (E)-3-trimethylsilyl-2-propenyl carbamates.5
Treatment of allylic amines 1 or 2 with n-BuLi/(-)-
sparteine results in lithiated complexes with assigned con-
figurations.6 Reaction of these lithiated intermediates with
(1) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. For a review
of chiral homoenolate equivalents, see: Ahlbrecht, H.; Beyer, U. Synthesis
1999, 365.
(2) (a) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118,
12218. (b) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J.
Am. Chem. Soc. 1999, 121, 9522.
(4) Hoppe, D.; Lichtenberg, F. Angew. Chem., Int. Ed. Engl. 1984, 23,
239. For reviews, see: (a) Hoppe, D.; Kra¨mer, T.; Schwark, J.-R.; Zschage,
O. Pure Appl. Chem. 1990, 62, 1999. (b) Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282.
(5) (a) van Hu¨lsen, E.; Hoppe, D. Tetrahedron Lett. 1985, 26, 411. (b)
Zschage, O.; Schwark, J.-R.; Hoppe, D. Tetrahedron 1992, 48, 5657. (c)
Marsch, M.; Harms, K.; Zschage, O.; Hoppe, D.; Boche, G. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 321.
(3) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am.
Chem. Soc., submitted for publication.
10.1021/ol006186o CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/28/2000

aldehydes provides a mixture of products with low diaste-
reoselectivity. However, if the lithiated intermediate is
transmetalated before addition of aldehyde electrophile, high
yields of diastereomerically pure products can be obtained.
Absolute configuration and E/Z selectivity in the masked
homoaldol products are controlled by the transmetalating
reagent. Thus, transmetalation with Et2AlCl, Ti(Oi-Pr)4, or
TiCl(Oi-Pr)3 allows access to the desired olefin geometry
and absolute configuration.
Scheme 1
The results of our standard protocol for these masked
homoaldol reactions are shown in Table 1. The allylic amine
The absolute configurations of the homoaldol precursors
3 and 7 were assigned by two methods. The enamides 3 and
7 were converted to the lactones 14 and 17 respectively, and
values for the signs and magnitudes of the optical rotations
for 14 and 17 were calculated.7 The [R]D value calculated
for 14 is +119.8 (er > 99:1), while the experimental [R]D is
+102.4 (er ) 98:2). For 17, the calculated [R]D value is
+48.1 (er > 99:1), while the experimental [R]D is +23.4
(er ) 94:6). The absolute configurations shown in Schemes
2 and 3 are in accord with experimental values.
Table 1. Results from Lithiation/Et2AlCl Transmetalation/
Substitution Sequences
Scheme 2
entry
R
R′
product
yield (%)a
erb
E:Z
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Cy
Cy
Cy
Cy
Ph
3
4
5
6
7
8
9
10
85
66
61
66
82
72
81
84
97:3
92:8
95:5
98:2
94:6
93:7
94:6
95:5
90:10
95:5
98:2
95:5
90:10
97:3
98:2
98:2
Me
i-Pr
Cy
Ph
Me
i-Pr
Cy
a The reported yield is a mixture of E and Z isomers of opposite absolute
configuration. If the isomers are not separated, the er of the product would
be reduced when carried through the hydrolysis sequence. Separation of
the E and Z isomers of 3 was achieved by preparative HPLC. b In all cases,
the ratio anti:syn > 99:1.
The absolute configuration of 3 was also established by
preparation of 15, a compound suitable for X-ray diffraction.
Methanolysis of 3 and subsequent oxidation8 of 13 provides
lactone 14. Enolization of 14 with KHMDS and p-bro-
mobenzyl bromide provides crystalline (3S,4R,5S)-diphen-
ylbutyrolactone (15), whose absolute configuration was
assigned by X-ray crystallography using anomolous disper-
sion (Scheme 2).9
1 or 2 is treated with n-BuLi/(-)-sparteine at -78 °C and
subsequently transmetalated with Et2AlCl. The reaction is
stirred for 45 min before addition of the aldehyde. After
workup, homoaldol precursors 3-10 are obtained in good
yields. As shown in Table 1, high E/Z selectivities and good
anti:syn and enantiomeric ratios are obtained upon additions
to benzaldehyde (entries 1 and 5) and three alkyl aldehydes
(entries 2-4, 6-8).
In all cases, the relative configuration of the two newly
formed stereogenic centers is anti and the E geometrical
isomer is the primary product. Deblocking of the enamide
to the aldehyde functionality is performed in two steps, as
is demonstrated by two examples in Scheme 1. The alcohol
functionality is protected with NaH/benzyl bromide to
provide the O-benzyl enecarbamate. Acid hydrolysis of the
crude enecarbamate affords the aldehydes 11 or 12 as
O-protected homoaldol products.
Derivatization and X-ray crystallography were carried out
to establish the absolute configuration of cyclohexyl allylic
amine 7. Lactone 17 was prepared by a sequence similar to
that used for the cinnamylamine derivative. Compound 17
underwent ring opening with (S)-(-)-1-(1-naphthyl)-ethyl-
amine in the presence of Me3Al10 to give crystalline
(7) Kondru, R. K.; Wipf, P.; Beratan, D. N. Science 1998, 282, 2247.
The [R]D calculations were performed by Gustavo Mouro, David Beratan,
and Peter Wipf at the University of Pittsburgh.
(8) Grieco, P. A.; Oguri, T., Yokoyama, Y. Tetrahedron Lett. 1978, 18,
419.
(9) The crystallographic data for 15 and 18 have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
nos. 145026 and 145027, 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; email: deposit@ccdc.cam.ac.uk).
(6) The configuration of the lithiated intermediate of 2 is assigned by
analogy to that of 1, which has been established by X-ray crystallography.
See: Pippel, D. J.; Weisenburger, G. A.; Wilson, S. R.; Beak, P. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2522.
2656
Org. Lett., Vol. 2, No. 17, 2000

Scheme 3
Table 2. Results from Lithiation/Titanium Transmetalation/
Substitution Sequences
(3R,4S,1′S)-18, a product with known configuration at one
stereogenic center (Scheme 3).
The absolute configurations of both 3 and 7 reveal overall
inversion of configuration from the organolithium intermedi-
ate. Scheme 4 illustrates the proposed stereochemical course
transmetalation
entry
reagent
product yield (%) anti:syna
erb
1
2
3
4
TiCl(Oi-Pr)3
Ti(Oi-Pr)4
TiCl(Oi-Pr)3
Ti(Oi-Pr)4
22
23
24
en t-24
64
63
38
69
>99:1
46:54
>99:1
>99:1
>99:1
95:5c
94:6
Scheme 4
84:16
a In all cases, the ratio E:Z is 98:2. b The er reported is of the major
diastereomer. c The er reported is of the syn diastereomer, the absolute
configuration of which has not been assigned. The er of the major
enantiomer of the anti diastereomer (3S,4R) is 83:17.
provides the Z-enecarbamates 22-24, as shown in Table 2.
Use of TiCl(Oi-Pr)3 for transmetalation allows access to the
Z-homoaldol precursors with absolute configurations opposite
to those reported in Table 1. Transmetalation of the lithiated
intermediate of 1 with TiCl(Oi-Pr)3 is presumed to proceed
with inversion of configuration. Subsequent reaction with
PhCHO provides 22 (Table 2, entry 1). The lithiated
intermediate of 1 may not undergo transmetalation with Ti-
(Oi-Pr)4 and therefore exhibits little facial selectivity in
reaction with benzaldehyde (anti:syn ) 46:54, Table 2, entry
2).13 In fact, reaction of the lithiated intermediate of 1 with
isobutyraldehyde provides the homoaldol precursor 5 with
an anti:syn ratio of 44:56.
of the reaction of cinnamylamine derivative 1, n-BuLi/(-)-
sparteine, Et2AlCl, and benzaldehyde. Reaction of 1 with
n-BuLi/(-)-sparteine affords the η3 complex 19 with known
configuration as shown.6 Transmetalation with Et2AlCl
proceeds with inversion of configuration to give 20. The
reaction of 20 with benzaldehyde is proposed to occur
through six-membered transition state 2111 with retention of
configuration to provide (3R,4S)-3.12 The proposed stereo-
chemical course of reaction for the cyclohexyl allylic amine
is analogous, although the Li‚(-)-sparteine complex is
known to be coordinated in an η1 fashion to the cyclohexyl
allylic amine.3
Transmetalation of the lithiated intermediate of 2 with
TiCl(Oi-Pr)3 and reaction with PhCHO (Table 2, entry 3)
provides 24, while transmetalation with Ti(Oi-Pr)4 provides
ent-24 (Table 2, entry 4).14 For the reaction sequence with
2, transmetalation with TiCl(Oi-Pr)3 is presumed to proceed
Treatment of the lithiated intermediate of 1 or 2 with a
titanium reagent and subsequent reaction with electrophile
(13) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2158.
(10) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
4171.
(11) These allylmetal reactions are presumed to proceed through six-
membered transition states. See: Yamamoto, Y.; Asao, N. Chem. ReV. 1993,
2207.
(14) The absolute configurations of the products obtained by transmeta-
lation with a titanium reagent were determined by O-protection and
hydrolysis to the corresponding O-protected aldehyde (vide supra). Com-
parison of optical rotations was made with aldehydes 11 and 12, whose
absolute configuration was determined by X-ray crystal analysis of
derivatives 15 and 18.
(12) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097.
Org. Lett., Vol. 2, No. 17, 2000
2657

with inversion of configuration, while reaction with Ti(Oi-
Pr)4 is suggested to occur with retention of configuration.
We propose that the lithiated intermediate of cyclohexyl
derivative 2 precoordinates with the oxygen of the
Ti(Oi-Pr)4 reagent, allowing transmetalation to proceed with
retention of configuration.
For the titanium sequences, product selectivities are
attributed to reaction via the six-membered transition states
depicted in Figure 1. The R′ substituent of the aldehyde is
homoaldol precursors. In the cases reported by Hoppe et al.,
stereoselectivity is achieved by kinetic resolution16 or
preferential crystallization5 of one diastereomeric complex.
The N-Boc allylamine substrates 1 and 2 behave differently
from similar cases investigated by Hoppe et al., where
transmetalation with Ti(Oi-Pr)4 proceeds with inversion of
configuration and transmetalation with TiCl(Oi-Pr)3 is non-
stereoselective.17
The present work allows access to either enantiomer of
homoaldol product from the achiral substrate 1 or 2 and the
chiral diamine (-)-sparteine. The methodology of Hoppe et
al. allows access to the opposite enantiomer by transmeta-
lation and substitution of (oxybutenyl) stannanes, which in
their preparation require the use of the alkyl tin halide
reagents.18
In summary, a protocol has been developed for the
transformation of N-Boc-N-aryl achiral allylic amines into
homoaldol products with stereocontrolled formation of two
contiguous stereogenic centers. Proper choice of transmeta-
lating reagent in the (-)-sparteine-mediated lithiation/trans-
metalation/substitution/protection/hydrolysis sequence allows
access to both enantiomers of the anti-configured O-protected
homoaldol products, in good yields with high diastereo-
selectivities and enantioselectivities.
Figure 1. Proposed transition states for reaction of allylic amine,
aldehyde, and Ti(Oi-Pr)4 or TiCl(Oi-Pr)3.
preferentially located in a pseudoequatorial position, giving
rise to anti products. The geometrical selectivity observed
upon transmetalation with a titanium reagent is opposite to
that obtained upon transmetalation with Et2AlCl. The reaction
between an aldehyde and the metalated N-Boc allylic amine
can be dissected into two steps: aldehydic oxygen com-
plexation with the metal atom followed by carbon-carbon
bond formation between the allylic double bond and the
aldehyde. Depending on the transmetalating agent used,
either step in the reaction sequence may be rate-limiting or
stereodetermining.15
Acknowledgment. This work was supported by a grant
from the National Institute of Health (GM-18874). We are
grateful for this support. We thank Dr. Peter Wipf, Mr.
Gustavo Mouro, and Dr. David Beratan at the University of
Pittsburgh for the [R]D calculations.
Supporting Information Available: Experimental pro-
cedures for the preparation of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The present methodology entails (-)-sparteine-mediated
asymmetric deprotonation, followed by stereoselective trans-
metalation and substitution to afford highly stereoenriched
OL006186O
(16) Zschage, O.; Schwark, J.-R.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1990, 29, 296.
(17) See: ref 13 and Kra¨mer, T.; Hoppe, D. Tetrahedron 1987, 28, 5149.
(18) (a) Kra¨mer, T.; Schwark, J.-R.; Hoppe, D. Tetrahedron Lett. 1989,
30, 7037. (b) Zschage, O.; Schwark, J.-R.; Kra¨mer, T.; Hoppe, D.
Tetrahedron 1992, 48, 8377. (c) Paulsen, H.; Graeve, C.; Hoppe, D.
Synthesis 1996, 141.
(15) A possible origin of the E and Z selectivites may be as described
by Hoffmann et al. See: Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986,
119, 1039 for a discussion on the E/Z selectivities observed upon addition
of allylboronates to aldehydes.
2658
Org. Lett., Vol. 2, No. 17, 2000