Asymmetric synthesis of β-amino-γ-substituted-γ- butyrolactones: Double diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters

Article abstract of DOI:10.1039/b712937h

Chiral α,β-unsaturated esters, containing a single, γ-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(α-methylbenzyl)amide to the homochiral α,β-unsaturated esters display matching and mismatching effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding β-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant β-amino adducts gives access to the corresponding β-amino-γ-substituted-γ- butyrolactones in good yield and high de. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b712937h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of b-amino-c-substituted-c-butyrolactones: double
diastereoselective conjugate addition of homochiral lithium amides to
homochiral a,b-unsaturated esters†‡
Tha¨ıs Cailleau,a Jason W. B. Cooke,a Stephen G. Davies,*a Kenneth B. Ling,a Alan Naylor,b
Rebecca L. Nicholson,a Paul D. Price,a Paul M. Roberts,a Angela J. Russell,a Andrew D. Smitha and
James E. Thomsona
Received 22nd August 2007, Accepted 20th September 2007
First published as an Advance Article on the web 24th October 2007
DOI: 10.1039/b712937h
Chiral a,b-unsaturated esters, containing a single, c-stereogenic centre, show modest levels of substrate
control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate
additions of homochiral lithium N-benzyl-N-(a-methylbenzyl)amide to the homochiral a,b-unsaturated
esters display “matching” and “mismatching” effects. In each case, however, these additions proceed
under the dominant stereocontrol of the lithium amide to give the corresponding b-amino esters in high
de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an
oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant b-amino adducts gives
access to the corresponding b-amino-c-substituted-c-butyrolactones in good yield and high de.
Introduction
The conjugate addition of homochiral secondary lithium amides
derived from a-methylbenzylamine to a,b-unsaturated esters and
amides has been widely used for the asymmetric synthesis of
b-amino acid derivatives.1 This methodology has found use in
a plethora of applications ranging from total synthesis2 to kinetic
resolution,3 and has recently been reviewed.1 As part of our
ongoing investigations directed toward the de novo asymmetric
synthesis of monosaccharides and amino sugars, we have pre-
viously demonstrated the extension of this methodology to the
conjugate addition to achiral c-benzyloxy- and c-silyloxy-a,b-
unsaturated esters and amides for the asymmetric synthesis of
b-amino-c-butyrolactones.4 In order to extend further the utility
of this conjugate addition methodology, its application to the
preparation of a range of b-amino-c-substituted-c-butyrolactones
was investigated. It was envisaged that an investigation of the
double diastereoselectivity5 observed upon conjugate addition of
homochiral lithium amides to chiral a,b-unsaturated esters 1 con-
taining a c-stereogenic centre, and subsequent cyclisation, would
generate a range of b-amino-c-substituted- and a,c-disubstituted-
b-amino-c-butyrolactones 4 and 5 with high stereocontrol (Fig. 1).
The conjugate addition of lithium amides to a,b-unsaturated
esters containing a c-alkoxy stereogenic centre has been previ-
ously reported in the literature. For example, Yamamoto et al.
have demonstrated that conjugate addition of lithium N-benzyl-
Fig.
1
Proposed route to homochiral b-amino-c-substituted-c-
butyrolactones 4 and a,c-disubstituted-b-amino-c-butyrolactones 5.
N-trimethylsilylamide 6 to the mandelate-derived a,b-unsaturated
ester 7 proceeds with exclusive anti selectivity to furnish b-amino
ester anti-8, whilst conjugate addition of lithium amide 6 to
the lactate-derived a,b-unsaturated ester 9 occurs with high syn
selectivity. Conjugate addition of lithium dibenzylamide 12 to
lactate-derived a,b-unsaturated ester 9, meanwhile, is moderately
anti selective (Fig. 2).6
Furthermore, Sewald et al. have shown that conjugate addition
of homochiral lithium N-(a-methylbenzyl)-N-trimethylsilylamide
16 to the homochiral a,b-unsaturated ester (S,E)-17 (derived from
glyceraldehyde 15) in Et2O proceeds under the stereocontrol of the
chiral acceptor, with high syn selectivity noted independent of
the absolute configuration of the nucleophile. In THF, however,
the additions proceed with no stereocontrol (Fig. 3).7
aDepartment of Organic Chemistry, Chemistry Research Laboratory, Uni-
versity of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail:
steve.davies@chem.ox.ac.uk
bDepartment of Medicinal Chemistry, Neurology and Gastrointestinal
Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, New
Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
We detail herein our full studies concerning the stereoselectivity
observed upon conjugate addition of homochiral lithium amides
to a range of homochiral a,b-unsaturated acceptors containing
a c-stereogenic centre. In each case, an evaluation of substrate
control through the conjugate addition of an achiral lithium amide
† Electronic supplementary information (ESI) available: Further experi-
mental details. See DOI: 10.1039/b712937h
‡ CCDC reference number 634215. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b712937h
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Scheme 1 Reagents and conditions: (i) TBDMSCl, imidazole, DMF, rt;
(ii) DIBAL-H, −78 ◦C, PhMe; (iii) tert-butyl diethylphosphonoacetate,
NaH, THF, −78 ◦C to rt. Isolated as a single alkene stereoisomer
a
(>98% de).
Previous investigations from this laboratory concerning the
kinetic resolution of 3- and 5-alkyl-cyclopentene-1-carboxylates
have demonstrated that the stereoselectivity in these systems is best
evaluated through an initial investigation of the level of substrate
control upon conjugate addition of an achiral lithium amide to
the chiral acceptor. The level of enantiorecognition between the
substrate and the chiral lithium amide is subsequently evaluated
through their mutual kinetic resolution (addition of racemic accep-
tor to an excess of racemic lithium amide).3 The application of this
experimental protocol to acyclic a,b-unsaturated ester (RS,E)-26
was thus examined, with conjugate addition of lithium dibenzy-
lamide 12 to (RS,E)-26 giving an inseparable 88 : 12 mixture of
anti-28 : syn-29 in 96% isolated yield. Having demonstrated that
the c-stereocentre within 26 exerts moderate levels of stereocontrol
upon addition of lithium dibenzylamide 12, the extent of enan-
tiorecognition upon reaction of (RS,E)-26 with lithium (RS)-N-
benzyl-N-(a-methylbenzyl)amide (RS)-30 was probed. Conjugate
addition of lithium amide (RS)-30 to (RS,E)-26 gave a 92 : 8
mixture (84% de) of anti-31 : syn-32 only, which was isolated in
91% yield, consistent with E = 1211 (Scheme 2). Lithium N-benzyl-
N-(a-methylbenzyl)amide 30 is known to add to acyclic a,b-
unsaturated esters with extremely high, and predictable, levels of
stereocontrol (typically >95% de),1,12,13 and the anti configuration
within the major diastereoisomer 31 was therefore assigned on
the basis of high levels of enantiorecognition between the chiral
a,b-unsaturated ester and chiral lithium amide. The syn configu-
ration of the minor diastereoisomer 32 was assumed on the basis
that the high stereocontrol of the lithium amide overrides the
moderate substrate control of the ester. The configuration at C(3)
within both anti-31 and syn-32 relative to the N-a-methylbenzyl
stereocentre was thus assigned by analogy to the model developed
Fig. 2 Conjugate additions of lithium N-benzyl-N-trimethylsilylamide
6 and lithium dibenzylamide 12 to mandelate- and lactate-derived
homochiral a,b-unsaturated esters 7 and 9.
Fig. 3 Conjugate addition of homochiral lithium N-(a-methylbenzyl)-
N-trimethylsilylamide 16 to glyceraldehyde-derived homochiral
a,b-unsaturated ester (S,E)-17.
to the chiral acceptor is used to predict the configuration of the
“matched” reaction pairing.
Results and discussion
Double diastereoselective conjugate addition of homochiral lithium
amides to homochiral c-silyloxy-a,b-unsaturated esters
Initial studies were directed toward the preparation of c-tert-
butyldimethylsilyloxy-a,b-unsaturated esters derived from methyl
mandelate and methyl lactate, containing a single stereogenic
centre at the c-position. Following established experimental
procedures8 methyl (RS)-mandelate (RS)-22 was silylated and
subsequently reduced with DIBAL-H to give aldehyde (RS)-24
in 96% yield over two steps. Treatment of aldehyde (RS)-24 with
the sodium anion of tert-butyl diethylphosphonoacetate gave a
92 : 8 (E) : (Z) mixture of olefins, from which (RS,E)-26
was isolated in 75% yield as a single geometric isomer after
chromatography. The corresponding homochiral a,b-unsaturated
ester (R,E)-26 (>98% de, 98% ee)9 was prepared in an analogous
fashion from methyl (S)-mandelate (S)-22, and similar elaboration
of methyl (S)-lactate (S)-23 gave (S,E)-2710 (Scheme 1).
Scheme 2 Reagents and conditions: (i) lithium dibenzylamide 12, THF,
−78 ◦C, 2 h; (ii) lithium (RS)-N-benzyl-N-(a-methylbenzyl)amide (RS)-30,
THF, −78 to −50 ◦C, 12 h.
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to explain the high stereoselectivity observed during addition of
lithium N-benzyl-N-(a-methylbenzyl)amide 30 to a,b-unsaturated
acceptors.12 The preferential anti stereoselectivity upon conjugate
addition to tert-butyl ester (RS,E)-26 is analogous to that de-
scribed by Yamamoto et al. for the conjugate addition of lithium
N-benzyl-N-trimethylsilylamide 6 to the corresponding iso-propyl
ester 7 (vide supra, Fig. 2), and was subsequently confirmed
unambiguously by a separate synthesis in the enantiomerically
pure series.
addition of lithium amide (R)-30 gave an inseparable 5 : 95 mixture
of anti-37 : syn-38 in 95% isolated yield (Scheme 4).
As chiral a,b-unsaturated ester 26 shows reasonable substrate
control upon conjugate addition of achiral lithium dibenzyl-
amide 12, double diastereoselectivity upon conjugate addition of
homochiral lithium amides (S)-30 and (R)-30 was anticipated;
conjugate addition of lithium amide (S)-30 to homochiral a,b-
unsaturated ester (R,E)-26 was expected to represent the doubly
diastereoselective “matched” case, with addition of lithium amide
(R)-30 to (R,E)-26 the “mismatched” case, although the high
stereocontrol of the lithium amide was predicted to override the
modest control of the a,b-unsaturated ester. Indeed, conjugate
addition of lithium amide (S)-30 to (R,E)-26 gave anti-31 as a
single diastereoisomer (>98% de) in 95% yield, whilst conjugate
addition of lithium amide (R)-30 to (R,E)-26 gave a chromato-
graphically inseparable 11 : 89 mixture of anti-33 : syn-32 in 94%
yield (Scheme 3). The anti diastereoisomer 31 from the “matched”
addition, and the major syn diastereoisomer 32 from the
“mismatched” addition were spectroscopically identical to the
b-amino ester products 31 and 32 observed from conjugate addi-
tion of racemic lithium amide (RS)-30 to racemic a,b-unsaturated
ester (RS,E)-26 thus confirming the assigned configurations.
Scheme 4 Reagents and conditions: (i) lithium dibenzylamide 12, THF,
−78 ◦C, 2 h; (ii) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide (S)-30,
THF, −78 ◦C, 2 h; (iii) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide
(R)-30, THF, −78 ◦C, 2 h.
The levels of 1,2-asymmetric induction exerted upon conjugate
additions of a range of nucleophiles to acyclic a,b-unsaturated
carbonyl systems with an adjacent stereocentre have been reported
widely.14 The sense of stereoselectivity in these transformations
is generally rationalised by invoking a modified Felkin–Anh
model.15,16 It is generally assumed that the preferred transi-
tion states for such reactions proceed with an allylic r-bond
antiperiplanar to the trajectory of the approaching reagent,
although the conformational preference of the allylic stereocentre
may be biased by steric effects (approach anti to the largest
allylic substituent), stereoelectronic effects (approach anti to the
best electron acceptor), and minimisation of 1,3-allylic strain
(preferred orientation of an allylic C–H in the same plane
or the same sector as the a-vinylic hydrogen). In the case of
conjugate addition of lithium dibenzylamide 12 to mandelate-
and lactate-derived a,b-unsaturated esters (R,E)-26 and (S,E)-27,
the following transition states may be invoked. Assuming that
any possible chelation-controlled delivery of the lithium amide
by the c-oxygen substituent can be discounted due to the low
propensity of silyl ethers to coordinate lithium,17 and placing the
c-tert-butyldimethylsilyloxy group perpendicular to the plane of
the a,b-unsaturated carbonyl system on stereoelectronic grounds,
then conjugate addition of lithium dibenzylamide 12 to (R,E)-26
or (S,E)-27 in conformation A leads to the observed anti products.
Conformation B (leading to the corresponding syn products) is
presumably disfavoured due to increased 1,3-allylic strain. The in-
creased substrate control observed upon conjugate addition to the
mandelate-derived a,b-unsaturated ester (R,E)-26 (with a c-phenyl
substituent) as compared to the lactate-derived a,b-unsaturated
ester (S,E)-27 (with a c-methyl substituent) is potentially due to
the increased steric demand in the former case, making reaction
through conformation B much less favourable (Fig. 4).18 This
substrate control, combined with the known facial preference
observed upon conjugate addition of the antipodes of lithium
N-benzyl-N-(a-methylbenzyl)amide 301,12,13 is also successful in
rationalising the “matched” and “mismatched” reaction pairings.
Scheme
3
Reagents and conditions: (i) lithium (S)-N-benzyl-
N-(a-methylbenzyl)amide (S)-30, THF, −78 to −50 ◦C, 12 h; (ii) lithium
(R)-N-benzyl-N-(a-methylbenzyl)amide (R)-30, THF, −78 to −50 ◦C,
12 h.
The extension of this protocol to conjugate addition to the
lactate-derived a,b-unsaturated ester (S,E)-27 was investigated. In
accordance with the observations of Yamamoto et al. concerning
conjugate addition of lithium dibenzylamide 12 to lactate-derived
a,b-unsaturated ester 9 (vide supra, Fig. 2)6 the conjugate addition
of lithium dibenzylamide 12 to (S,E)-27 gave a chromatographi-
cally separable 80 : 20 mixture of anti-34 : syn-35 in 81% combined
yield, consistent with the chiral a,b-unsaturated ester 27 also giving
preferentially anti substrate control, but to a lower extent than
chiral a,b-unsaturated ester 26. In support of this hypothesis, the
“matched” addition of lithium amide (S)-30 gave anti-36 as a single
diastereoisomer (>98% de) in 96% yield, whilst “mismatched”
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Fig. 4 Proposed transition states for the conjugate addition of lithium
dibenzylamide 12 to mandelate- and lactate-derived a,b-unsaturated esters
(R,E)-26 and (S,E)-27.
Having shown that conjugate addition of lithium amide
(S)-30 to both homochiral a,b-unsaturated esters (R,E)-26 and
(S,E)-27 represents the “matched” combination, methylation
of the b-amino enolates arising from these “matched” pairs
was investigated. Conjugate addition of lithium amide (S)-30
to the mandelate-derived a,b-unsaturated ester (R,E)-26 and
subsequent addition of methyl iodide gave a 73 : 27 mixture of
2,3-anti-3,4-anti-39 : 2,3-syn-3,4-anti-40,19 from which the major
diastereoisomer 39 was isolated in >98% de (Scheme 5). The
relative 2,3-anti-3,4-anti-configuration within 39 was unambigu-
ously established by single crystal X-ray analysis,20‡ with the
absolute (2S,3R,4S,aS)-configuration determined from the known
(S)-configuration of the a-methylbenzyl stereocentre (Fig. 5).
Conjugate addition of lithium amide (S)-30 to the lactate-derived
a,b-unsaturated ester (S,E)-27 and subsequent addition of methyl
iodide gave a 93 : 7 mixture of 2,3-anti-3,4-anti-41 : 2,3-syn-3,4-
anti-42 from which the major diastereoisomer 41 was isolated
in 78% yield and >98% de. Furthermore, conjugate addition of
lithium amide (R)-30 to (S,E)-27 and in situ methylation gave a
95 : 5 mixture of 2,3-anti-3,4-syn-43 : 2,3-anti-3,4-anti-44, with the
major diastereoisomer 43 purified to homogeneity. The configu-
ration at C(2) within both 43 and 44 was assigned on the basis
of preferential alkylation anti to the C(3)-amino functionality19
as shown for “matched” reagent pairings (Scheme 5). It is
apparent from this study that the configurations of both the
N-a-methylbenzyl and c-stereocentres seem to have a pronounced
bearing upon the selectivity of enolate alkylation, as alkylations of
Fig. 5 Chem 3D representation of the X-ray crystal structure of 39
(some H atoms removed for clarity). There are two molecules of 39 in
the asymmetric unit; only one of these is shown, the other suffers from
disorder of the TBDMS group.
simple c-silyloxy-b-amino enolates lacking a c-stereogenic centre
proceed with a modest syn preference.4
With a range of polyfunctionalised b-amino esters pre-
pared stereoselectively following these double diastereoselective
conjugate addition reactions, their conversion to the corre-
sponding b-amino-c-substituted- and a,c-disubstituted-b-amino-
c-butyrolactones was carried out. b-Amino esters anti-31 (>98%
de) and anti-36 (>98% de), derived from the “matched” pairings
[(S)-30/(R,E)-26 and (S)-30/(S,E)-27], and syn-38 (90% de),
derived from the “mismatched” pairing in the lactate series [(R)-
30/(S,E)-27], were therefore treated with tetrabutylammonium
fluoride (TBAF) and then trifluoroacetic acid (TFA) to promote
intramolecular cyclisation, to give the corresponding lactones 45,
46 and 47 in 66, 86 and 65% yield respectively, and in >98%
de in each case after purification. N-Deprotection of 46 by
hydrogenolysis with Pd/C in ethanol followed by treatment with
benzoyl chloride gave a chromatographically separable mixture of
b-amino-c-methyl-c-butyrolactone 48 and b-amino ethyl ester 49,
which were isolated in 64 and 10% yield, respectively. However,
treatment of ethyl ester 49 with TFA promoted cyclisation to
lactone 48 (Scheme 6).
In a similar fashion, deprotection of the polyfunctionalised
a-methyl-b-amino esters 39–41 and 43 to the corresponding lac-
tones was investigated. In the mandelate-derived series, treatment
of both 2,3-anti-3,4-anti-39 (>98% de) and 2,3-syn-3,4-anti-40
(60% de) with TBAF gave a single diastereoisomeric lactone 50
in 85 and 68% yield, respectively. The production of only a single
diastereoisomeric lactone from the C(2)-epimeric b-amino esters
39 and 40 is consistent with epimerisation taking place under the
reaction conditions to give the thermodynamic lactone 50.4,21 In
the lactate-derived series, treatment of a-methyl-b-amino esters
41 and 43 under identical conditions gave lactones 51 and 52,
respectively, as single diastereoisomers. The configurations of 51
and 52 were assigned by analogy to 50, assuming that, in each
case, epimerisation of the a-stereocentre of the lactone to give the
Scheme
5
Reagents and conditions: (i) lithium (S)-N-benzyl-
N-(a-methylbenzyl)amide (S)-30, THF, −78 ◦C then MeI, −78 ◦C to
rt, 12 h; (ii) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (R)-30, THF,
−78 ◦C then MeI, −78 ◦C to rt, 12 h.
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55, which shows only low stereoselectivity upon conjugate addition
to achiral a,b-unsaturated esters,1,13 was next evaluated, with
addition of lithium amide (S)-55 to (S,E)-17 giving a separable
17 : 83 mixture of anti-18 : syn-19 in 92% combined yield {syn-19
[a]D21 −35.8 (c 1.1 in CHCl3); lit.7 [a]D21 −32.0 (c 1.1 in CHCl3)},
while addition of lithium amide (R)-55 to (S,E)-17 gave a partially
separable 12 : 88 mixture of anti-20 : syn-21 in 83% combined
yield {syn-21 [a]D21 +22.7 (c 1.0 in CHCl3); lit.7 [a]2D1 +24.0 (c 1.0
in CHCl3)} (Scheme 8). The preferential syn selectivity observed
upon conjugate addition of lithium dibenzylamide 12 and the
antipodes of lithium N-(a-methylbenzyl)amide 55 to (S,E)-17 is
consistent with the preferential syn addition noted by Sewald
et al. upon conjugate addition of lithium N-(a-methylbenzyl)-
N-trimethylsilylamide 16 (vide supra, Fig. 3).7
Scheme 6 Reagents and conditions: (i) TBAF, THF, 50 ◦C, then TFA, rt;
(ii) Pd/C, H2 (6 bar), EtOH, 60 ◦C, then PhCOCl, pyridine, DCM, rt;
(iii) TFA, PhMe, rt.
thermodynamically more stable product occurs under the reaction
conditions (Scheme 7).
Scheme 8 Reagents and conditions: (i) lithium dibenzylamide 12, THF,
−78 ◦C, 2 h; (ii) lithium (S)-N-(a-methylbenzyl)amide (S)-55, THF,
−78 ◦C, 2 h; (iii) lithium (R)-N-(a-methylbenzyl)amide (R)-55, THF,
−78 ◦C, 2 h.
Scheme 7 Reagents and conditions: (i) TBAF, THF, 50 ◦C, then TFA, rt.
Consistent with this syn substrate control, the conjugate ad-
dition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide (S)-30
to (S,E)-17 was predicted to be the “matched” reaction pairing.
Thus, conjugate addition of lithium amide (S)-30 to (S,E)-17
gave a 5 : 95 mixture of anti-56 : syn-57, giving syn-57 as a
single diastereoisomer (>98% de) in 52% yield after purification,
while in the “mismatched” series conjugate addition of lithium
amide (R)-30 to (S,E)-17 gave an inseparable 62 : 38 mixture of
anti-58 : syn-59 in 57% isolated yield. While the additions of the
antipodes of lithium amide 30 to (S,E)-17 in THF proceed pre-
dominantly under the stereocontrol of the lithium amide, the effect
of changing the solvent to Et2O, previously noted by Sewald et al.
to have a dramatic effect upon the stereoselectivity of conjugate
addition of lithium N-trimethylsilyl-N-(a-methylbenzyl)amide 16,
was investigated. Preliminary investigations showed that lithium
N-benzyl-N-(a-methylbenzyl)amide 30 in Et2O at −78 ◦C showed
decreased reactivity relative to that in THF, although in Et2O at
−20 ◦C conjugate addition of lithium amide (R)-30 to (S,E)-17
gave a 72 : 28 mixture of anti-58 : syn-59, representing an increase
in stereoselectivity as compared to addition in THF at −78 ◦C
(anti-58 : syn-59, 62 : 38). However, conjugate addition of lithium
Double diastereoselective conjugate addition of homochiral lithium
amides to a homochiral a,b-unsaturated ester and oxazolidinone
derived from glyceraldehyde
Having demonstrated that conjugate addition of homochiral
lithium amide 30 to the chiral c-silyloxy-a,b-unsaturated esters
26 and 27 proceed predominantly under the stereocontrol of the
lithium amide, the stereoselectivity upon conjugate addition to
the chiral a,b-unsaturated ester 17, derived from glyceraldehyde,
was investigated. Homochiral ester (S,E)-17 was readily pre-
pared from D-mannitol through conversion to (R)-isopropylidene
glyceraldehyde according to literature procedures,22 followed by
Horner–Wadsworth–Emmons reaction with the sodium anion
of tert-butyl diethylphosphonoacetate. To evaluate the levels
of substrate control offered by (S,E)-17 upon lithium amide
conjugate addition in THF, the stereoselectivity upon reaction
with lithium dibenzylamide 12 was probed, giving a separable
29 : 71 mixture of anti-53 : syn-54 in 57% combined yield. Conjugate
addition of the enantiomers of lithium N-(a-methylbenzyl)amide
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amide (S)-30 in Et2O at −20 ◦C gave a 27 : 73 mixture of anti-56 :
syn-57, a decrease in stereoselectivity compared to the analogous
addition in THF at −78 ◦C (anti-56 : syn-57, 5 : 95) (Scheme 9).
of the “matched” and “mismatched” reaction pairings. In
the “mismatched” case, conjugate addition of lithium amide
(S)-30 gave a 12 : 88 mixture of anti-67 : syn-68, giving syn-68 in
>98% de and in 68% yield after purification, while “matched”
conjugate addition of lithium amide (R)-30 gave anti-66 as a
single diastereoisomer, isolated in 60% isolated yield and >98%
de (Scheme 11).
Scheme
9
Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide (S)-30, THF, −78 ◦C,
2 h; (ii) lithium (S)-
N-benzyl-N-(a-methylbenzyl)amide (S)-30, Et2O, −20 ◦C, 6 h; (iii)
lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (R)-30, THF, −78 ◦C, 2 h;
(iv) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (R)-30, Et2O, −20 ◦C,
6 h.
The effect of changing the ester functionality within the
acceptor to an oxazolidinone was next investigated. The desired
a,b-unsaturated oxazolidinone (S,E)-63 was prepared from
oxazolidinone 6023 by a simple three-step procedure. Acylation of
the lithium anion of 60 with bromoacetylbromide24 gave 61 in 88%
yield, with subsequent reaction with triethylphosphite generating
the phosphonate 62 in 50% yield. Reaction of phosphonate
62 with (R)-isopropylidene glyceraldehyde22 under Masamune–
Roush conditions25 gave a 95.5 : 4.5 (E) : (Z) mixture of the
corresponding a,b-unsaturated oxazolidinones, with purification
giving (S,E)-63 in 72% yield and >98% de (Scheme 10).
Scheme 11 Reagents and conditions: (i) lithium dibenzylamide 12, THF,
−78 ◦C, 2 h; (ii) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (R)-30,
THF, −78 ◦C, 2 h; (iii) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide
(S)-30, THF, −78 ◦C, 2 h.
The assigned relative configurations within b-amino oxazo-
lidinones 64–68 were next established by chemical correlation.
The major diastereoisomer anti-64, from the conjugate addition
of lithium dibenzylamide 12, and anti-66, resulting from the
“matched” addition of lithium amide (R)-30, were treated with
Pearlman’s catalyst in MeOH under hydrogen (5 atm), promoting
hydrogenolysis and methanolysis, giving the known anti-b-amino
ester 69.26 Under identical conditions the major diastereoisomer
syn-68 resulting from the “mismatched” addition of lithium amide
(S)-30 gave the known syn-b-amino ester 7026 (Scheme 12).
Scheme 10 Reagents and conditions: (i) BuLi, THF, −78 ◦C then
BrCH2COBr; (ii) P(OEt)3, PhMe, reflux; (iii) (R)-isopropylidene glycer-
aldehyde, iPr2NEt, LiCl, MeCN, rt.
Upon conjugate addition of lithium dibenzylamide 12 to
(S,E)-63, a complex mixture of reaction products, containing a
72 : 28 mixture of b-amino oxazolidinones anti-64 : syn-65, was
formed. Extensive purification allowed the isolation of the major
diastereoisomer anti-64 in 28% yield and >98% de, consistent with
a,b-unsaturated oxazolidinone (S,E)-63 showing approximately
the same magnitude but the opposite sense of stereoinduction
as the corresponding tert-butyl ester (S,E)-17 upon addition
of lithium dibenzylamide 12. Furthermore, conjugate addition
of the antipodes of lithium N-benzyl-N-(a-methylbenzyl)amide
(S)-30 and (R)-30 to (S,E)-63 resulted in a reversal in the sense
Scheme 12 Reagents and conditions: (i) Pd(OH)2/C, H2 (5 atm),
MeOH, rt.
The conversion of b-amino esters syn-57 and anti-58, and
oxazolidinones syn-68 and anti-66 to the corresponding b-amino-
c-substituted-c-butyrolactones was next attempted. b-Amino ester
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syn-57 (>98% de) and oxazolidinone syn-68 (>98% de), derived
from conjugate addition of lithium amide (S)-30, were therefore
treated with 60% aqueous TFA, giving lactone 71 in both cases,
with subsequent oxidative debenzylation of 71 with CAN giving
the known lactone 72 {[a]D21 −67.8 (c 0.35 in CHCl3); lit.7 [a]D21 −78.6
(c 1.85 in CHCl3)} (Scheme 13). Similarly, under identical condi-
tions, b-amino ester anti-58 (>98% de) and oxazolidinone anti-66
(>98% de), derived from conjugate addition of lithium amide
(R)-30, gave lactone 73.27 Subsequent oxidative debenzylation of
73 gave lactone 74 in good yield (Scheme 14).
amide to the homochiral a,b-unsaturated esters proceeds in
high de under the dominant stereocontrol of the lithium
amide. The resultant b-amino esters can be deprotected and cy-
clised to give the corresponding b-amino-c-substituted-c-butyro-
lactones. The application of this methodology to the synthesis
of a range of natural products is currently underway in this
laboratory.
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
R
workers.28 Water was purified by an Elixꢀ UV-10 system. All other
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq. KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
Scheme 13 Reagents and conditions: (i) TFA (60% aq.), rt; (ii) CAN,
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford,
UK. Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin–Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g per 100 mL. IR spectra were recorded on a
Bruker Tensor 27 FT-IR spectrometer as either a thin film on NaCl
plates (film), as a KBr disc (KBr), or as chloroform solutions in
0.1 mm cells (CHCl3), as stated. Selected characteristic peaks are
reported in cm−1. NMR spectra were recorded on Bruker Avance
spectrometers in the deuterated solvent stated. The field was locked
by external referencing to the relevant deuteron resonance. Low-
resolution mass spectra were recorded on either a VG MassLab
20–250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF and were
internally calibrated with polyanaline in positive and negative
modes, or a Micromass GCT instrument fitted with a Scientific
Glass Instruments BPX5 column (15 m × 0.25 mm) using amyl
acetate as a lock mass.
MeCN/H2O (5:1), rt.
Scheme 14 Reagents and conditions: (i) TFA (60% aq.), rt; (ii) CAN,
MeCN/H2O (5:1), rt.
Conclusion
General procedure 1a for lithium amide conjugate addition
In conclusion, chiral a,b-unsaturated esters containing a sin-
gle, c-stereogenic centre, derived from methyl lactate, methyl
mandelate and isopropylidene glyceraldehyde, show reasonable
levels of substrate control upon conjugate addition of lithium
dibenzylamide. In each case, the anti or syn stereoselectivity
observed upon conjugate addition of lithium dibenzylamide
to the chiral acceptors (substrate control), combined with the
known facial selectivity of lithium N-benzyl-N-(a-methylbenzyl)-
amide, allows a prediction of the doubly diastereoselective
“matched” reaction pairing. Double diastereoselective conjugate
addition of homochiral lithium N-benzyl-N-(a-methylbenzyl)-
BuLi (as a solution in hexanes) was added dropwise via syringe to
a stirred solution of the requisite amine in THF at −78 ◦C. After
stirring for 30 min, a solution of the requisite a,b-unsaturated
◦
carbonyl compound in THF at −78 C was added dropwise via
cannula. After stirring for a further 2 h at −78 ◦C the reaction
mixture was quenched with sat. aq. NH4Cl and allowed to warm
to rt over 15 min. The reaction mixture was concentrated in vacuo
and the residue was partitioned between DCM and 10% aq. citric
acid. The organic layer was separated and the aqueous layer was
extracted twice with DCM. The combined organic extracts were
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washed sequentially with sat. aq. NaHCO3 and brine, dried and
concentrated in vacuo.
Data for anti-28: dH (400 MHz, CDCl3) −0.33 (3H, s, SiMeA),
0.04 (3H, s, SiMeB), 0.85 (9H, s, SiCMe3), 1.44 (9H, s, OCMe3),
2.58 (1H, dd, J 15.4, 5.2 Hz, C(2)HA), 2.70 (1H, dd, J 15.4,
7.4 Hz, C(2)HB), 3.43–3.49 (1H, m, C(3)H), 3.70 (4H, app s,
N(CH2Ph)2), 4.84 (1H, d, J 6.0 Hz, C(4)H), 7.10–7.27 (15H,
m, Ph); dC (100 MHz, CDCl3) −4.8 (SiMeA), −4.2 (SiMeB),
18.1 (SiCMe3), 26.0 (SiCMe3), 28.2 (OCMe3), 32.8 (C(2)), 54.8
(N(CH2Ph)2), 62.5 (C(3)), 75.2 (C(4)), 80.1 (OCMe3), 127.0, 127.4,
127.5, 127.9, 128.1, 128.3, 129.0, 129.1 (o-Ph, m-Ph, p-Ph), 139.9,
144.3 (i-Ph), 172.6 (C(1)).
General procedure 1b for lithium amide conjugate addition
BuLi (as a solution in hexanes) was added dropwise via syringe to
a stirred solution of the requisite amine in THF at −78 ◦C. After
stirring for 30 min, a solution of the requisite a,b-unsaturated
◦
carbonyl compound in THF at −78 C was added dropwise via
cannula. The reaction mixture was allowed to warm to −50 ◦C
over 12 h, quenched with sat. aq. NH4Cl and allowed to warm to
rt over 15 min. The reaction mixture was concentrated in vacuo
and the residue was partitioned between DCM and 10% aq. citric
acid. The organic layer was separated and the aqueous layer was
extracted twice with DCM. The combined organic extracts were
washed sequentially with sat. aq. NaHCO3 and brine, dried and
concentrated in vacuo.
tert-Butyl (3RS,4SR,aSR)- and (3RS,4RS,aSR)-3-[N-benzyl-
N-(a-methylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)-4-phenyl-
butanoate (3RS,4SR,aSR)-anti-31 and (3RS,4SR,aSR)-syn-32.
Following general procedure 1b, BuLi (3.20 mL, 2.00 mmol),
(RS)-N-benzyl-N-(a-methylbenzyl)amine (633 mg, 3.00 mmol)
in THF (10 mL), and (RS,E)-26 (696 mg, 2.00 mmol) in THF
(10 mL) gave a 92 : 8 mixture of anti-31 : syn-32. Purification via
flash column chromatography (eluent hexane–EtOAc, 20 : 1) gave
a 92 : 8 mixture of anti-31 : syn-32 as a pale yellow oil (1.01 g,
General procedure 2 for lithium amide conjugate addition and MeI
quench
91%); C35H49NO3Si requires C, 75.1; H, 8.8; N, 2.5%; found C,
+
=
75.3; H, 9.1; N, 2.3%; mmax (film) 1718 (C O); m/z (CI ) 560 ([M +
BuLi (as a solution in hexanes) was added dropwise via syringe to
a stirred solution of the requisite amine in THF at −78 ◦C. After
stirring for 30 min, a sol◦ution of a,-b-unsaturated carbonyl
compound in THF at −78 C was added dropwise via cannula.
After stirring for a further 2 h at −78 ◦C, the reaction mixture
was quenched with MeI and allowed to warm to rt over 12 h,
then quenched with sat. aq. NaHCO3. The reaction mixture was
concentrated in vacuo and the residue was partitioned between
DCM and 10% aq. citric acid. The organic layer was separated and
the aqueous layer was extracted twice with DCM. The combined
organic extracts were washed sequentially with sat. aq. NaHCO3
and brine, dried and concentrated in vacuo.
H]+, 35%), 338 (100), 282 (37), 178 (47), 105 (88), 91 (74).
Data for anti-31: dH (400 MHz, CDCl3) −0.28 (3H, s, SiMeA),
−0.10 (3H, s, SiMeB), 0.77 (9H, s, SiCMe3), 0.89 (3H, d, J 7.1 Hz,
C(a)Me), 1.46 (9H, s, OCMe3), 1.76 (1H, dd, J 16.6, 2.3 Hz,
C(2)HA), 2.28 (1H, dd, J 16.6, 8.9 Hz, C(2)HB), 3.60 (1H, q, J
7.1 Hz, C(a)H), 3.63 (1H, d, J 15.2 Hz, NCHA), 3.80 (1H, d,
J 15.2 Hz, NCHB), 4.00–4.06 (1H, m, C(3)H), 4.41 (1H, d, J
8.1 Hz, C(4)H), 7.08–7.45 (15H, m, Ph); dC (100 MHz, CDCl3)
−4.9 (SiMeA), −4.6 (SiMeB), 18.2 (SiCMe3), 18.5 (C(a)Me), 25.9
(SiCMe3), 28.2 (OCMe3), 34.6 (C(2)), 51.2 (NCH2), 57.5, 59.3
(C(3), C(a)), 77.8 (C(4)), 79.8 (OCMe3), 127.0, 127.1, 127.4, 127.9,
128.1, 128.3, 128.6 (o-Ph, m-Ph, p-Ph), 141.1, 141.4, 145.4 (i-Ph),
172.1 (C(1)).
General procedure 3 for desilylation and concomitant lactonisation
Data for syn-32: dH (400 MHz, CDCl3) −0.26 (3H, s, SiMeA),
−0.01 (3H, s, SiMeB), 0.65 (3H, d, J 7.1 Hz, C(a)Me), 0.81 (9H, s,
SiCMe3), 1.45 (9H, s, OCMe3), 1.50 (1H, dd, J 16.7, 2.2 Hz,
C(2)HA), 2.43 (1H, dd, J 16.7, 10.6 Hz, C(2)HB), 3.54–3.63 (3H,
m, C(3)H, C(a)H, NCHA), 4.39 (1H, d, J 14.7 Hz, NCHB), 4.84
(1H, d, J 2.5 Hz, C(4)H), 7.09–7.49 (15H, m, Ph).
TBAF was added to a solution of the requisite c-silyloxy-b-amino
ester in THF and heated at 50 ◦C for 24 h. The reaction mixture
was then allowed to cool to rt and poured into brine. The resultant
mixture was extracted with EtOAc (3 × 25 mL) and the combined
organic extracts were dried and concentrated in vacuo. The residue
was then dissolved in PhMe and TFA was added. The resultant
suspension was stirred at rt for 24 h before being concentrated in
vacuo. The residue was then partitioned between sat. aq. NaHCO3
(50 mL) and EtOAc (25 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc (2 × 25 mL). The
combined organic extracts were dried and concentrated in vacuo.
tert-Butyl (3R,4S,aS)-3-[N-benzyl-N-(a-methylbenzyl)amino]-
4-(tert-butyldimethylsilyloxy)-4-phenylbutanoate anti-31. Fol-
lowing general procedure 1b, BuLi (0.91 mL, 0.57 mmol),
(S)-N-benzyl-N-(a-methylbenzyl)amine (250 mg, 1.18 mmol)
in THF (2.5 mL), and (R,E)-26 (200 mg, 0.57 mmol) in THF
(2.5 mL) gave anti-31 in >98% de. Purification via flash column
chromatography (eluent hexane–EtOAc, 20 : 1) gave anti-31 as a
colourless oil (306 mg, 95%, >98% de); C35H49NO3Si requires C,
75.1; H, 8.8; N, 2.5%; found C, 74.9; H, 9.1; N, 2.2%; [a]2D1 +50.3
(c 1.1 in CHCl3).
tert-Butyl (3RS,4SR)- and (3RS,4RS)-3-(N,N-dibenzylamino)-
4-(tert-butyldimethylsilyloxy)-4-phenylbutanoate (3RS,4SR)-anti-
28 and (3RS,4RS)-syn-29. Following general procedure 1a, BuLi
(1.60 mL, 1.00 mmol), dibenzylamine (394 mg, 2.00 mmol) in
THF (5 mL), and (RS,E)-26 (348 mg, 1.00 mmol) in THF (5 mL)
gave an 88 : 12 mixture of anti-28 : syn-29. Purification via flash
column chromatography (eluent hexane–EtOAc, 20 : 1) gave an
88 : 12 mixture of anti-28 : syn-29 as a pale yellow oil (524 mg,
tert-Butyl (3S,4S,aR)- and (3R,4S,aR)-3-[N-benzyl-N-(a-
methylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)-4-phenylbuta-
noate (3S,4S,aR)-anti-33 and (3R,4S,aR)-syn-32. Following
general procedure 1b, BuLi (0.91 mL, 0.57 mmol), (R)-N-benzyl-
N-(a-methylbenzyl)amine (250 mg, 1.18 mmol) in THF (2.5 mL),
and (R,E)-26 (200 mg, 0.57 mmol) in THF (2.5 mL) gave an
11 : 89 mixture of anti-33 : syn-32. Purification via flash column
96%); C34H47NO3Si·HCl requires C, 70.1; H, 8.3; N, 2.4%; found
+
=
C, 70.1; H, 8.4; N, 2.3%; mmax (film) 1718 (C O); m/z (CI ) 546
([M + H]+, 12%), 324 (36), 91 (100).
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chromatography (eluent hexane–EtOAc, 20 : 1) gave an 11 : 89
mixture of anti-33 : syn-32 as a colourless oil (301 mg, 94%);
C35H49NO3Si requires C, 75.1; H, 8.8; N, 2.5%; found C, 75.05; H,
X-Ray crystal structure determination for 39
Data were collected using an Enraf–Nonius j-CCD diffractometer
with graphite monochromated MoKa radiation using standard
procedures at 190 K. The structure was solved by direct methods
(SIR92), all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.29
+
+
=
8.9; N, 2.3%; mmax (film) 1714 (C O); m/z (CI ) 560 ([M + H] ,
48%), 338 (100), 282 (30), 178 (37), 105 (56), 91 (45).
Data for anti-33: dH (400 MHz, C6D6) −0.17 (3H, s, SiMeA),
0.07 (3H, s, SiMeB), 0.79 (3H, d, J 7.1 Hz, C(a)Me), 0.88 (9H, s,
SiCMe3), 1.41 (9H, s, OCMe3), 1.70 (1H, dd, J 16.8, 2.1 Hz,
C(2)HA), 2.62 (1H, dd, J 16.8, 10.7 Hz, C(2)HB), 3.63 (1H, d,
J 15.2 Hz, NCHA), 4.58 (1H, d, J 15.2 Hz, NCHB), 3.72 (1H, q,
J 7.1 Hz, C(a)H), 3.90 (1H, app dt, J 10.7, 2.3 Hz, C(3)H), 5.14
(1H, d, J 2.3 Hz, C(4)H), 7.06–7.72 (15H, m, Ph); dC (100 MHz,
C6D6) −5.5 (SiMeA), −4.6 (SiMeB), 18.0 (SiCMe3), 18.5 (C(a)Me),
25.8 (SiCMe3), 28.1 (OCMe3), 33.7 (C(2)), 53.2 (NCH2), 57.0, 57.1
(C(3), C(a)), 78.3 (C(4)), 80.1 (OCMe3), 126.5, 127.0, 127.1, 127.4,
127.6, 128.1, 128.2, 128.4, 128.5 (o-Ph, m-Ph, p-Ph), 141.4, 141.6,
144.4 (i-Ph), 172.5 (C(1)).
X-Ray crystal structure data for 39. [C36H51NO3Si]: M =
1147.78, triclinic, space group P1, a = 11.4449(2), b = 11.8000(2),
3
−1
˚
˚
c = 14.6478(2) A, V = 1722.68(5) A , Z = 2, l = 0.10 mm ,
colourless block, crystal dimensions = 0.1 × 0.1 × 0.1 mm. A
total of 7805 unique reflections were measured for 5 < h < 27 and
6098 reflections were used in the refinement. The final parameters
were wR2 = 0.082 and R1 = 0.066 [I > 3.0r(I)].
(4R,5S,aS)-4-[N-Benzyl-N-(a-methylbenzyl)amino]-5-phenyl-
tetrahydro-2-furanone 45. Following general procedure 3, TBAF
(868 mg, 2.75 mmol) and anti-31 (280 mg, 0.50 mmol) in
THF (10 mL) gave the crude reaction product. Purification via
sequential flash column chromatography (eluent hexane–EtOAc,
6 : 1) and recrystallisation from hexane–DCM (1 : 1) at −30 ◦C gave
45 as a white crystalline solid (123 mg, 66%, >98% de); C25H25NO2
requires C, 80.8; H, 6.8; N, 3.8; found: C, 80.45; H, 6.8; N, 3.5%;
tert-Butyl (2S,3R,4S,aS)- and (2R,3R,4S,aS)-2-methyl-3-[N-
benzyl-N-(a-methylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)-
4-phenylbutanoate (2S,3R,4S,aS)-39 and (2R,3R,4S,aS)-40.
Following general procedure 2, BuLi (4.80 mL, 3.00 mmol), (S)-
N-benzyl-N-(a-methylbenzyl)amine (1.27 g, 6.00 mmol) in THF
(15 mL), (R,E)-26 (1.04 g, 3.00 mmol) in THF (15 mL) and MeI
(5.82 mL, 18.0 mmol) gave a 73 : 27 mixture of 39 : 40. Purification
via flash column chromatography (eluent hexane–EtOAc, 25 :
1) gave a 73 : 27 mixture of 39 : 40 as a white solid (1.53 g,
89%). Fractional crystallisation from MeCN at 20 ◦C gave 39 as a
colourless solid (>98% de). Concentration of the mother liquors
gave a 20 : 80 mixture of 39 : 40 as a colourless oil.
◦
mp 122–124 C; [a]D21 −124.0 (c 0.6 in CHCl3); mmax (KBr) 1780
=
(C O); dH (400 MHz, CDCl3) 1.15 (3H, d, J 7.0 Hz, C(a)Me),
2.05 (2H, dd, J 18.1, 8.6 Hz, C(2)HA), 2.29 (2H, dd, J 18.1, 8.2 Hz,
C(2)HB), 3.73–3.93 (4H, m, C(4)H, C(a)H, NCH2), 5.25 (1H, d,
J 6.9 Hz, C(5)H), 7.15–7.49 (15H, m, Ph); dC (100 MHz, CDCl3)
18.2 (C(a)Me), 29.6 (C(3)), 50.6 (NCH2), 57.4, 62.0 (C(4), C(a)),
84.1 (C(5)), 126.1, 127.6, 127.8, 128.5, 128.8, 129.0 (o-Ph, m-Ph,
p-Ph), 139.0, 139.7, 141.4 (i-Ph), 176.0 (C(2)); m/z (CI+) 372 ([M +
H]+, 89%), 268 (97), 237 (54), 146 (84), 105 (77), 91 (100).
Data for 39: C36H51NO3Si requires C, 75.3; H, 9.0; N, 2.7%;
◦
found C, 75.4; H, 9.2; N, 2.7%; mp 95–97 C; [a]2D1 +66.5 (c 1.0
=
in CHCl3); mmax (film) 1718 (C O); dH (400 MHz, CDCl3) −0.33
(3H, s, SiMeA), −0.04 (3H, s, SiMeB), 0.68 (9H, s, SiCMe3), 0.86
(3H, d, J 7.1 Hz, C(2)Me), 1.26 (3H, d, J 7.1 Hz, C(a)Me), 1.55
(9H, s, OCMe3), 2.79 (1H, qd, J 7.1, 1.8 Hz, C(2)H), 3.64 (1H,
q, J 7.1 Hz, C(a)H), 3.75 (1H, d, J 14.8 Hz, NCHA), 4.16 (1H,
d, J 14.8 Hz, NCHB), 4.43 (1H, dd, J 9.5, 1.8 Hz, C(3)H), 4.65
(1H, d, J 9.5 Hz, C(4)H), 7.07–7.44 (15H, m, Ph); dC (100 MHz,
CDCl3) −4.7 (SiMeA), −4.6 (SiMeB), 12.6, 18.4 (C(2)Me, C(a)Me),
18.2 (SiCMe3), 25.9 (SiCMe3), 28.4 (OCMe3), 40.1 (C(2)), 52.3
(NCH2), 57.0, 61.7 (C(3), C(a)), 75.0 (C(4)), 79.8 (OCMe3), 126.8,
127.0, 127.7, 127.8, 128.0, 128.3, 128.5, 129.2 (o-Ph, m-Ph, p-Ph),
141.1, 141.7, 145.3 (i-Ph), 174.5 (C(1)); m/z (CI+) 574 ([M + H]+,
32%), 352 (100), 296 (39), 192 (55), 105 (87), 91 (96).
(3R,4R,5S,aS)-3-Methyl-4-[N -benzyl-N -(a-methylbenzyl)-
amino]-5-phenyl-tetrahydro-2-furanone 50. From 39. Following
general procedure 3, TBAF (678 mg, 2.15 mmol) and 39 (410 mg,
0.72 mmol) in THF (10 mL) gave the crude reaction product.
Purification via flash column chromatography (eluent hexane–
EtOAc, 6 : 1) gave 50 as a colourless oil (235 mg, 85%, >98%
de).
From 40. Following general procedure 3, TBAF (678 mg,
2.15 mmol) and 40 (283 mg, 0.49 mmol) in THF (10 mL)
gave the crude reaction product. Purification via flash column
chromatography (eluent hexane–EtOAc, 6 : 1) gave 50 as a yellow
oil (129 mg, 68%, >98% de).
=
Data for 40: mmax (film) 1714 (C O); dH (400 MHz, CDCl3) −0.33
(3H, s, SiMeA), −0.02 (3H, s, SiMeB), 0.79 (9H, s, SiCMe3), 1.11
(3H, d, J 7.3 Hz, C(2)Me), 1.17 (3H, d, J 6.9 Hz, C(a)Me), 1.38
(9H, s, OCMe3), 2.79 (1H, app quintet, J 7.2 Hz, C(2)H), 3.63
(1H, app t, J 6.5 Hz, C(3)H), 3.89 (1H, q, J 6.9 Hz, C(a)H), 3.96
(1H, d, J 15.6 Hz, NCHA), 4.09 (1H, d, J 15.6 Hz, NCHB), 4.90
(1H, d, J 6.2 Hz, C(4)H), 7.02–7.37 (15H, m, Ph); dC (100 MHz,
CDCl3) −4.8 (SiMeA), −4.4 (SiMeB), 16.5, 20.4 (C(2)Me, C(a)Me),
18.2 (SiCMe3), 26.0 (SiCMe3), 28.0 (OCMe3), 42.0 (C(2)), 52.4
(NCH2), 60.0, 65.6 (C(3), C(a)), 77.8 (C(4)), 79.5 (OCMe3), 126.5,
126.9, 127.3, 127.9, 128.1, 128.4, 128.7 (o-Ph, m-Ph, p-Ph), 142.4,
144.2, 144.9 (i-Ph), 175.5 (C(1)); m/z (CI+) 574 ([M + H]+, 63%),
352 (100), 296 (44), 192 (83), 105 (46), 91 (84).
Data for 50: [a]D21 −42.5 (c 0.55 in CHCl3); C26H27NO2 requires
C, 81.0; H, 7.1; N, 3.6; found: C, 81.05; H, 7.2; N, 3.5%; mp 109–
110 ◦C, mmax (KBr) 1767 (C O); dH (400 MHz, CDCl3) 1.00 (3H, d,
=
J 7.1 Hz, C(3)Me), 1.08 (3H, d, J 6.9 Hz, C(a)Me), 2.77 (1H, dq,
J 10.2, 7.1 Hz, C(3)H), 3.45 (1H, dd, J 10.2, 8.4 Hz, C(4)H), 3.86
(1H, d, J 14.6 Hz, NCHA), 3.94 (1H, d, J 14.6 Hz, NCHB), 3.98
(1H, q, J 6.9 Hz, C(a)H), 5.07 (1H, d, J 8.4 Hz, C(5)H), 7.15–7.49
(15H, m, Ph); dC (100 MHz, CDCl3) 14.0, 18.3 (C(3)Me, C(a)Me),
37.8 (C(3)), 50.6 (NCH2), 58.2, 69.9 (C(4), C(a)), 81.9 (C(5)H),
127.3, 127.4, 127.9, 128.3, 128.5, 128.7 (o-Ph, m-Ph, p-Ph), 138.2,
140.2, 143.3 (i-Ph), 177.8 (C(2)); m/z (CI+) 386 ([M + H]+, 100%),
282 (61), 251 (31), 105 (37), 91 (42).
3930 | Org. Biomol. Chem., 2007, 5, 3922–3931
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2006, 71, 5694; S. Hanessian, G. J. Reddy and N. Chahal, Org. Lett.,
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Acknowledgements
The authors would like to thank GlaxoSmithKline for financial
support (J.W.B.C.)
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