Asymmetric synthesis of homoallylic amines and functionalized pyrrolidines via direct amino-crotylation of in situ generated imines

Article abstract of DOI:10.1016/S0040-4020(00)00870-X

The asymmetric synthesis of functionalized homoallylic amines and silyl functionalized pyrrolidines through the Lewis acid promoted condensation of chiral (E)-crotylsilanes with sulfonyl imines and in situ generated N-acyl imines is described. We had anticipated that this bond construction could be used in the asymmetric synthesis of the N-terminal amino acid subunit of the nikkomycins. Aryl sulfonyl imines condense with chiral silane reagents in the presence of BF₃·OEt₂ to form homoallylic arylsulfonyl amines with useful levels of syn selectivity. For cases involving aryl N-acyl imines we have learned that the temperature controls the course of the reaction. For instance, at temperatures of -78°,C or below the major product is the pyrrolidine, while at higher temperatures (-30 to -20°C) the homoallylic amine is produced. For the cases studied, the [3+2]-annulation is limited to aryl imine derivatives, as alkyl- and branched- imines failed to produce the pyrrolidine derivatives: higher reaction temperatures promote the conversion of the annulation product to the homoallylic amines. In double stereodifferentiating reactions with in situ generated imines, good levels of selectivity were achieved in the formation of secondary amines beating syn-anti and syn-syn stereochemical triads. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00870-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10263±10274
Asymmetric Synthesis of Homoallylic Amines and Functionalized
Pyrrolidines via Direct Amino-Crotylation of
In Situ Generated Imines
*
Jennifer V. Schaus, Nareshkumar Jain and James S. Panek
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for Science and Engineering, 590 Commonwealth Avenue,
Boston University, Boston, MA 02215, USA
Received 7 February 2000; accepted 31 May 2000
AbstractÐThe asymmetric synthesis of functionalized homoallylic amines and silyl functionalized pyrrolidines through the Lewis acid
promoted condensation of chiral (E)-crotylsilanes with sulfonyl imines and in situ generated N-acyl imines is described. We had anticipated
that this bond construction could be used in the asymmetric synthesis of the N-terminal amino acid subunit of the nikkomycins. Aryl sulfonyl
imines condense with chiral silane reagents in the presence of BF3´OEt2 to form homoallylic arylsulfonyl amines with useful levels of syn
selectivity. For cases involving aryl N-acyl imines we have learned that the temperature controls the course of the reaction. For instance, at
temperatures of 2788C or below the major product is the pyrrolidine, while at higher temperatures (230 to 2208C) the homoallylic amine is
produced. For the cases studied, the [312]-annulation is limited to aryl imine derivatives, as alkyl- and branched- imines failed to produce
the pyrrolidine derivatives: higher reaction temperatures promote the conversion of the annulation product to the homoallylic amines. In
double stereodifferentiating reactions with in situ generated imines, good levels of selectivity were achieved in the formation of secondary
amines bearing syn±anti and syn±syn stereochemical triads. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
In studies directed toward the synthesis of nikkomycin B,6
which belong to a group of potent chitin synthetase
inhibitors with fungicidal, insecticidal, and acaricidal
activity (Fig. 1).7 We required the development of an
ef®cient method for the synthesis of enantiomerically
enriched homoallylic amines (b-amino acid synthons).
These chiral amines can be obtained from the addition of
chiral (E)-crotylsilane reagents to achiral and chiral in situ
generated imines.8 In this paper we report our results on the
asymmetric synthesis of homoallylic amines via direct
amino-crotylation of in situ generated N-acyl and N-sulfonyl
imines. In certain cases, functionalized pyrrolidines are
produced from these reactions through a [312]-annulation,
which involves the internal trapping of the intermediate
bridged-carbocation.
The development of ef®cient, practical asymmetric synthe-
ses of a- and b-amino acids has been an area of interest in
the past several years.1 The availability of these compounds
in an enantiomerically enriched form is important due to
their wide use as synthetic intermediates in the pharma-
ceutical and chemical industry. Various syntheses of natural
and unnatural nonproteinaceous amino acid derivatives
have already been established.2 a-Amino acids are
important pharmaceutical building blocks for their incor-
poration into enzyme inhibitors,3 as well as conformational
modi®ers in physiologically active peptides.4 The b-amino
acids are potentially valuable for the chemical synthesis of
peptidomimetics,5 functionalized b-lactams, and some
naturally occurring materials. Interest in biologically and
synthetically important amines with well-de®ned stereo-
chemistry has often contributed to the development of
new reaction methodology for their synthesis. Methodology
designed for the stereoselective synthesis of b-amino acid
synthons has evolved from simple diastereoselective
processes involving the use of enol derivatives and allyl-
metals in addition to chiral imines.1a
The retrosynthetic analysis of nikkomycin B, illustrated in
Fig. 1, resulted in the disconnection of the amide bond,
yielding two major fragments, the N-terminal amino-acid
3 and the polyoxin C 2. Further disconnection of 3 produced
homoallylic carbamate 4 where the trisubstituted ole®n
would serve as a precursor to an aryl ketone. This material
could be derived from the crotylation of b-benzyloxy
aldehyde 5 and (R)-b-aryl substituted crotylsilane 6j.
Synhomoallylic acylamine 4 possesses structural simi-
larities to the 1,2-syn-stereochemistry of the nikkomycins
and can serve as a precursor to the N-terminal amino acid
subunit 3. The versatility of these reagents has been
Keywords: asymmetric synthesis; homoallylic amines; pyrrolidines.
* Corresponding author. 11-617-353-2484; fax: 11-617-353-6466;
e-mail: panek@chem.bu.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00870-X

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J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
Figure 1. Retrosynthetic analysis of nikkomycin B.
illustrated by the synthesis of functionalized homoallylic
ethers, homoallylic alcohols, tetrahydrofurans, cyclo-
pentanes, D2-isoxazolines, silylsubstituted pyrrolidines,
allylic amines, and C-glycosides.9 The application of chiral
silanes in the synthesis of complex natural products has
recently been demonstrated in our laboratories.10
which should be applicable to the synthesis of the nikko-
mycins.
Synthesis of the chiral crotylsilanes
The synthesis of the silane reagents, summarized in Scheme
2, was initiated with an enzymatic resolution (Pseudomonas
lipase)11 of the racemic (E)-vinylsilanes which afforded the
pure (S,E)-vinylsilane 9 and the (R,E)-vinyl acetate 8 in high
enantiomeric purity after separation on SiO2. In the course
of our studies, we have learned that these (E)-vinyl silanes
are excellent substrates for the enzymatic resolution;
however, the corresponding (Z)-vinyl silanes showed no
reactivity. A LiAlH4 reduction or base catalyzed hydrolysis
(K2CO3, MeOH) of the (R)-acetate provided the desired
(R,E)-alcohol. The individual secondary allylic alcohols
were subjected to an ortho-ester Claisen rearrangement to
produce the chiral silane reagents (R)-6a/6b and (S)-6c/6d,
respectively. As anticipated, the sigmatropic rearrangement
was highly stereospeci®c (ee.96%) and highly stereo-
selective with respect to the con®guration of the trans-
double bond, which was exclusively produced.12
The Lewis acid promoted condensation between chiral (E)-
crotylsilanes and in situ generated achiral N-acylimines
produces the syn homoallylic N-acylamines or the N-acyl
pyrrolidines through a [312] annulation. Both reactions
occur with equally high levels of diastereoselectivity
(Scheme 1, Eqs. (1) and (2)). Raising the temperature
from 278 to 2208C can effect the opening of the resulting
pyrrolidine product. However, for the cases examined,
this annulation appears to be limited to aryl imine
derivatives as the alkyl and branched imines failed to
produce the pyrrolidine derivatives affording clean homo-
allylic amine products instead. Higher reaction temperatures
resulted in a direct and ef®cient conversion to the homo-
allylic amines. The scope of this methodology was extended
to produce homoallylic N-tosyl amines, and aryl imines,
Scheme 1. Asymmetric addition to in situ generated iminium ions.

J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
10265
Scheme 2. Preparation of chiral (E)-crotylsilanes.
Direct amino crotylation reactions
The N-tosyl iminium ions were generated in situ from
p-toluene-sulfonamide, the appropriate aldehyde, and silane
6c. In the presence of BF3´OEt2, the combination of reagents
cleanly afforded the N-tosyl homoallylic amines 13 with
high yields (71±90%) and high levels of diastereoselection
(10:1 to 30:1 syn±anti) (see Table 2).
Our initial attempts at the synthesis of homoallylic amines
was ®rst studied in the Lewis acid catalyzed addition of
chiral silane reagents to simple alkyl and aryl imines;
however, their lack of reactivity toward the nucleophilic
addition led to the examination of the more electrophilic
N-tosylimines 10.13 The initial results of this study are
summarized in Table 1.
While attempting to expand the scope of these reagents in
the synthesis of chiral amines, it was found that in situ
generated acyliminium ions, formed from aldehydes and
acetals with amines or carbamates, readily condensed with
the silane reagents to form homoallylic amines and, in
certain instances, pyrrolidines. Based on these results, an
In general, good to modest chemical yields were obtained
(not optimized) and, except for one case (entry 2) only the
unsubstituted silane reagents were examined.
Table 1. Diastereoselective addition reactions of N-tosylimines with (E)-crotylsilane
Entry
Sulfonyl imine
Silane
Lewis acid/conditions
Yield(%)a
dr (syn/anti)b
1
2
3
4
5
10a; RˆPh
10b; Rˆp-MeOPh
10b
10b
10c; RˆtBu
6a; (3R), XˆH
TiCl4/2788C!rt 20 h
SnCl4/08C!rt 24 h
11a; 64
11b; 82
11c; 42
11d: 67
11e; 70
.30:1
5:1
10:1
10:1
30:1
6e; (2S, 3S) XˆOMe
6a
6a
6a
BF3´OEt2/2108C!rt 16 h
BF3´OEt2/2108C!rt 40 h
TMSOTf/2208C!rt 12 h
a Yield was based on the amount of major diastereomer obtained after SiO2 chromatography.
1
b Ratios were determined by H NMR.
Table 2. Asymmetric synthesis of functionalized homoallylic N-tosyl imines
Entrya
Acetal/aldehyde
Yield (%)b
drc
1
2
3
12a; RˆPh
13a; 80
13b; 90
13c; 71
20:1
30:1
10:1
12b; RˆtBu
12c; RˆBnOCH2
a In all cases, silane 6c was used.
b Yield was based on the amount of major diastereomer obtained after puri®cation on SiO2.

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J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
Table 3. Asymmetric synthesis of functionalized homoallylic carbamates
Entry
Silane
Acetal/aldehyde
Yield (%)a
dr (syn/anti)b
1
2
3
4
5
6
7
8
9
10
6a; (3R), RˆH, XˆH
6e; (2S,2S), RˆH, XˆOMe
6f; (2R,2S), RˆH, XˆMe
6a; (3R), RˆH, XˆH
6a; (3R), RˆH, XˆH
6a; (3R), RˆH, XˆH
6a; (3R), RˆH, XˆH
6d; (3S), RˆMe, XˆH
6d; (3S), RˆMe, XˆH
6d; (3S), RˆMe, XˆH
12a; R0ˆPh
14a; 87
14b; 79
14c; 73
14d; 65
14e; 87
14f; 68
14g; 72
14h; 77
14i; 70
14j; 89
30:1
9:1
12a
12a
30:1
30:1
30:1
30:1
30:1
24:1
8:1
12d; R0ˆBnOCH2CH2
12c; R0ˆBnOCH2
12e; R0ˆPr
12f; R0ˆtBu
12c
12f
12a
1.2:1
a Yield was based on the amout of major diastereomer obtained after SiO2 chromatography.
b Ratios were determined by 1H NMR.
ef®cient procedure for the direct asymmetric amino-crotyl-
ation and a [312]-pyrrolidine annulation was developed.8
temperature the N-carbamoyl pyrrolidines are produced
from aryl acetals or aldehydes. On the other hand, only
acyclic homoallylic carbamates were detected and isolated
when the reaction was warmed to 2208C. Based on these
results, the scope of the reaction was extended to include the
use of b-methyl substituted silane (Table 3, entries 8
through 10). Those reactions produced the amines with
tri-substituted ole®ns.
Further efforts to probe the reactivity of in situ generated
iminium ions in the condensation with (E)-crotylsilanes led
us to investigate the use of N-acyl imine systems. We have
learned that the silane reagents can reliably be used in
highly diastereo- and enantioselective additions to in situ-
generated N-acyl imines under mild conditions
(278!2208C). It was shown that by lowering the reaction
In most cases high yields (ranging from 65 to 89%) and
Table 4. Asymmetric synthesis of functionalized pyrrolidones with methyl carbamate
Entry
Silane
Acetal/aldehyde
Yield (%)a
drb
1
2
3
4
6a; (3R) XˆH
12a; R1ˆR2ˆR3ˆH
12a
15a; 68
15b; 72
15c; 47
15d; 53
30:1
20:1
20:1
10:1
6e; (2S,3S) XˆOMe
6e
6e
12g; R1ˆR2ˆH, R3ˆCl
12h; R1ˆR2ˆOMe, R3ˆH
a Yield was based on the amount of major diastereomer obtained after SiO2 chromatography.
b Ratios were determined by 1H NMR.

J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
Table 5. Asymmetric synthesis of functionalized pyrrolidines with tert-butyl carbamate
10267
Entrya
Acetal/aldehyde
Yield (%)b
drc
1
2
3
12a; R1ˆR2ˆR3ˆH
16a; 89
16b; 74
16c; 78
30:1
30:1
30:1
12g; R1ˆR2ˆH, R3ˆOMe
12h; R1ˆR2ˆOMe, R3ˆH
a In all cases, silane 6c was used.
b Yield was based on the amount of major diastereomer obtained after SiO2 chromatography.
1
c Ratios were determined by H NMR.
useful levels of diastereoselection were obtained, and often
the anti diastereomer could not be detected by H NMR
consistent with the stereochemical outcome of the
Mukaiyama aldol.16 In an earlier report, we described the
results of double stereodifferentiating crotylation reactions
with chiral silane reagents. We learned that there is con-
siderable mechanistic homology with the Mukaiyama
aldol; the stereochemical course of these double stereo-
differentiating crotylation reactions is determined by the
local chirality of the individual reaction partners. We have
demonstrated that under non-chelation reaction conditions
the diastereomeric relationships between a-methyl and
b-alkoxy group of the chiral aldehyde does not reinforce
carbonyl p-facial selectivity.17
1
(depicted in the table as drˆ30:1). Only three cases did
not exhibit useful selectivity (entries 2, 9 and 10). The
difference in the level of selectivity observed in Table 3 is
perhaps best explained based on the size of the aldehyde or
acetal substituent used. For instance, this range can be
rationalized using a steric argument based on the proposed
open transition states (A and B). Thus, high levels of selec-
tivity are observed for the sterically demanding substituents
(entries 4 through 8) that preferentially react via transition
state A. However, the planar nature of the phenyl ring
allows for minimal interaction in either transition state A
or B, thereby accounting for the low levels of facial bias
with benzaldehyde (entries 2 and 10). The reaction was then
studied for the formation of pyrrolidines 15 utilizing methyl
carbamate; the results obtained are summarized in Table 4.
The addition of (E)-crotylsilanes to achiral in situ generated
iminium ions proved ef®cient as well as highly diastereo-
selective. This led us to study the amino crotylation process
with chiral imines. Based on the previous results with chiral
aldehydes,15b the prediction was made that a syn crotylation
will be favored when catalyzed with BF3´OEt2 (a mono
dentate Lewis acid), indicating that the silane reagent will
override the chirality associated with the aldehyde
(antiperiplanar transition state).
Based on the high levels of selectivity and on the high yields
obtained in the pyrrolidine formation utilizing methyl car-
bamate, tert-butyl carbamate was used, anticipating this
would be a more labile group, which would directly afford
the free pyrrolidines 16 (see Table 5).
The reaction using methylcarbamate as the amine source
was surveyed with the monodentate Lewis acid BF3´OEt2
and three different chiral aldehydes 12i±12k (Table 6). In
general, the reactions were high yielding (73±85%) with
levels of diastereoselectivity ranging from 4:1 to 30:1.
Based on the results of these experiments and our previous
efforts in this area with chiral a-substituted aldehydes,18 and
a-amino aldehydes,19 anti crotylation products were
obtained with TiCl4 (a bidentate Lewis acid) and an oxygen
protecting group that would enhance chelation (synclinal
transition state). This concept is illustrated in with entries
6 and 7 (Table 6). Accordingly, the stereochemistry of the
reaction of 12i and 12j are in expectation with previous
observations with chiral aldehydes.18,19
As anticipated, the annulation reaction with tert-butylcarba-
mate derived iminium ion took place with high levels of
diastereoselection and in high yields. For the examples
surveyed in this study, the deacylated pyrrolidines were
isolated rather than the N-carbamoyl systems, as the
intermediate product (amine or pyrrolidine) undergoes
deacylation under the reaction conditions.
Double stereodifferentiating addition reactions
Lewis acid promoted allyl- and crotylation reactions of
chiral a-substituted aldehydes have been extensively
studied and continue to be an active area of research.14 By
analogy, these reagents may be thought of as propionate and
acetate-enolate equivalents, for diastereo- and enantio-
selective construction of stereochemically well de®ned
homoallylic alcohols (b-hydroxy carbonyl synthons).
Because these reactions complement the enolate-based
aldol and aldol surrogates they belong to an important
group of organometallic reagents available for the control
of acyclic stereochemistry. During the course of this Lewis
acid catalyzed addition, the emerging hydroxyl bearing
stereocenter is generally controlled by the inherent
diastereofacial bias of the aldehyde.15 This reaction is
Stereochemical assignment
The stereochemical assignment of the diastereomers was
determined by measurement of the three-bond coupling
constants (3JH4, H5) after conversion to their oxazolidinones
(Scheme 3). Their individual synthesis required oxidative
cleavage of the trans ole®n of 17a, 17b and 17f, and subse-
quent reduction of the intermediate aldehyde to the corre-
sponding alcohol which was then cyclized in the presence of
K2CO3 (re¯uxing toluene) to afford the oxazolidinones

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J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
Table 6. Representative double stereodifferentiating reactions
a All reactions were run in 0.1 M CH2Cl2 with BF3´OEt2 as the Lewis acid. The iminium ion was generated in situ at 2788C and the reaction was stirred at
2358C for 24 to 30 h before being diluted with saturated aqueous NaHCO3.
Yield was based on the amount of major diastereomer obtained after SiO2 chromatography.
b
c
1
Ratios determined by H NMR.
The reaction also provided the free amine (ca. 35%) and debenzylated material (ca. 10%).
d
19a,19b. Oxazolidinone 19f was obtained directly from the
amino alcohol 17f in the presence of methylchloroformate
and trimethylamine. Stereochemical assignment for the
remaining crotylation products 17c, 17d, and 17e was
based on analogy with 17a and 17b, and with 17f in the
case of homoallylic carbamate 17g.
nones. The JH4, H5 coupling constants were determined to
be 1.6 and 1.8 Hz for the syn diastereomers 19a and 19b and
8.9 Hz for the anti crotylation product 19e. Those J values
are consistent with a 4,5-syn relationship between the emer-
ging methyl group from the silane reagent and the C±N
bond and a 4,5-anti relationship for 19e.
The stereochemical assignment of the homoallylic
carbamates was accomplished by homonuclear decoupling
experiments on the individual diastereomeric oxazolidi-
Summary
Asymmetric synthesis of functionalized homoallylic amines

J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
10269
Scheme 3. Stereochemical assignment.
and silyl functionalized pyrrolidines through the Lewis acid
promoted condensation of chiral (E)-crotylsilanes with in
situ generated N-acyl imines were found to be highly dia-
stereoselective. This methodology should be applicable to
the preparation of a wide range of amino acid synthon
equivalents, such as the one found in the nikkomycins.
We anticipate that the enhanced selectivity exhibited by
the chiral silane reagents in double stereodifferentiating
reactions will prove useful in the synthesis of natural
products bearing unusual amino acids.
calcium hydride. Unless otherwise noted, non aqueous
reactions were carried out in oven dried glassware under a
nitrogen atmosphere.
General procedure for the enzymatic resolution of the
racemic (E)-vinylsilanes
The racemic vinyl silane 7 was dissolved in pentane. To this
solution was added a crude extract of Pseudomonas lipase
AK (0.5 wt. equiv.), and freshly distilled vinyl acetate
(2.0 equiv.). The suspension was stirred at RT until the
1
reaction came to 50% completion as determined by H
NMR analysis of reaction aliquots. The resolution afforded
the pure (S,E)-vinylsilane alcohol and the (R,E)-vinyl
acetate in high enantiomeric purity after chromatographic
separation on SiO2. The K2CO3-mediated hydrolysis of the
(R)-acetate provided nearly enantiomerically pure (R,E)-
alcohol. Finally, the b-substituted (R,E)- and (S,E)-crotyl-
silanes were produced in high yield by an ortho-ester
Claisen rearrangement (MeC(OMe)3, cat. propionic acid,
PhMe, re¯ux) on the individual secondary allylic alcohols
(see procedure below). The results of the resolution and
Claisen rearrangements of the (S,E)- and (R,E)-vinylsilanes
are summarized in Table 2.
Experimental
1H NMR spectra were recorded on a Varian Unity
(400 MHz) spectrometer at ambient temperature. Data are
reported as follows: chemical shift in ppm from internal
standard
d
scale, multiplicity (bˆbroad, sˆsinglet,
dˆdoublet, tˆtriplet, qˆquartet, and mˆmultiplet), integra-
tion, and coupling constant (Hz). 13C NMR were recorded
on a Jeol (67.5 Hz) and Gemini Varian (150 Hz), spectro-
meters at ambient temperature. Chemical shifts are reported
in ppm from tetramethylsilane on the d scale, with the
solvent resonance employed as the internal standard
(deuterochloroform at 77.0 ppm). All 13C spectra were
recorded with complete proton decoupling. Difference
NOE (DNOE) were recorded with 1024 accumulated
transients each. The irradiation delay was set to 8 s. No
special precautions were taken in sample preparation prior
to recording the DNOE spectra (no degassing). Optical
rotations were recorded on a AUTOPOL III digital polari-
meter at 589 nm, and are reported as [a]D23 (concentration in
grams/100 mL solvent). High resolution mass spectra were
obtained on a Finnegen MAT-90 spectrometer.
General procedure for the ortho-ester Claisen rear-
rangement of enantiomerically pure (E)-vinylsilanes illus-
trated for (3S)-1-(dimethylphenyl)silyl-2-ethyl-1-buten-
3-ol
To a toluene solution of the chiral secondary alcohol (5.0 g,
20.7 mmol, 0.25 M), trimethyl orthoacetate (82.8 mmol,
10.5 mL, 4.0 equiv.) and a catalytic amount of propionic
acid (100 mL, 0.23 mmol) were added. The solution was
warmed to re¯ux for 16 h before the reaction mixture was
cooled to room temperature. The toluene was removed
under reduced pressure and the products puri®ed by ¯ash
chromatography on SiO2 (100% hexanes!5% EtOAc±
hexanes, gradient elution) to afford (R)-crotylsilane
(5.34 g, 89% yield, 96% ee) as a colorless oil.
Analytical thin layer chromatography was performed on
Whatman 0.25 mm silica gel 60-F plates. Flash chromato-
graphy was preformed as previously described.20 When
speci®ed as `anhydrous', solvents were distilled and/or
stored over 4 A sieves prior to use. Tetrahydrofuran
(THF) was distilled from sodium metal/benzophenone
ketyl. Dichloromethane (CH2Cl2) was distilled from
Ê
Representative procedure for the BF3´OEt2 promoted

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J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
imine additions illustrated for the reaction of silane 6b to
benzaldehyde dimethyl acetal and p-toluene sulfon-
amide. (5R,6R,3E)-Methyl-5-methyl-6-(N-tosylsulfon-
amide)-6-phenyl-hexenoate (13a). Table 2, entry 1. Into
a dry 10 mL round bottom ¯ask was dissolved benzaldehyde
dimethyl acetal (171 mg, 1.12 mmol) and the p-toluene
sulfonamide (202 mg, 1.18 mmol) in CH2Cl2 (1.1 mL,
1.0 M). The solution was cooled to 2788C and BF3´OEt2
(208 mL, 2 equiv.) was added via microsyringe. The
reaction mixture was stirred at 2788C for 30 min and the
silane reagent 6a (150 mg, 0.56 mmol) in CH2Cl2 (0.6 mL)
was added. The reaction was then stirred at 2358C for 48 h
before being diluted with saturated solution of NaHCO3
(5 mL). The resulting solution was then extracted with
CHCl3 (3£3 mL). The combined organic layers were dried
over MgSO4, and concentrated under reduced pressure. The
resulting clear yellow oil was ¯ushed through a short plug of
SiO2, eluting with 20±30% EtOAc±hexanes, to yield the
desired sulfonamide 13a as a colorless oil (173 mg,
to benzaldehyde dimethyl acetal and methyl carbamate.
(5R,6S,3E)-Methyl-5-methyl-6-(N-methylcarbamate)-6-
phenyl-hexenoate (14a). Table 3, entry 1, dr.30:1 syn±
anti, 87% yield. A 25 mL round bottom ¯ask equipped with
a magnetic stir bar and rubber septum was charged with
4 mL dry CH2Cl2, benzaldehyde dimethyl acetal (350 mg,
2.3 mmol, 1 equiv.) and methylcarbamate (174 mg,
2.31 mmol, 1 equiv.). The resulting solution was cooled to
2788C. To this mixture, BF3´OEt2 (572 mL, 4.638 mmol,
2.0 equiv.) was added under N2 at 2788C. The reaction
mixture was warmed to room temperature and stirred for
10 min (the reaction mixture becomes yellow and homo-
geneous). The reaction mixture was recooled to 2788C
and a solution of (E)-crotylsilane (524.8 mg, 2 mmol,
0.863 equiv.) in CH2Cl2 (1 mL) was added to this dropwise
over a period of 10 min. Then the reaction mixture was
immediately warmed to 2208C while being monitored by
TLC (20% EtOAc±petroleum ether). After 24 h the reaction
mixture was diluted with a saturated solution of NaHCO3
(10 mL) and extracted with EtOAc (3£10 mL). The
combined organic layers were dried with anhydrous
Na2SO4, ®ltered, and the solvent removed under reduced
pressure to afford crude 14a as light yellow oil. Chromato-
graphy on silica gel using 20% EtOAc±petroleum ether as
the eluant afforded pure 14a as a colorless oil (483.6 mg,
1
0.45 mmol, drˆ20:1 syn±anti, 80%). H NMR (CDCl3) d:
6.88±7.47 (m, 9H); 5.54 (m, 1H); 5.14 (m, 2H); 4.28 (dd,
1H, Jˆ5.2 Hz, Jˆ3.6 Hz); 3.71 (s, 3H); 2.79 (dd, 2H,
Jˆ1.2 Hz, Jˆ2.0 Hz); 2.54 (m, 1H); 2.31 (s, 3H); 0.865
(d, 3H, Jˆ6.8 Hz). 13C NMR (CDCl3) d: 172.2; 142.7;
138.2; 137.7; 134.8; 129.1; 127.8; 127.4; 126.9; 124.2;
61.7; 51.9; 42.7; 37.5; 21.3; 16.4. IR (neat) cm21: 3289;
1736; 1456; 1437; 1326; 1160. MS: CIMS1NH4 (NH3
gas) 388, 260, 155, 91. CIHRMS1NH4 calculated for
C21H25NO4S1Hˆ388.15; found 388.1559. [a]D23ˆ162.48
(CH2Cl2, c0.63).
1
87% yield). H NMR (CDCl3, 400 MHz) d 7.15±7.31 (m,
5H), 5.56 (m, 1H), 5.40 (bd, 1H, Jˆ8.4 Hz), 5.30 (dd, 1H,
Jˆ8.4 Hz, Jˆ15.6 Hz), 4.64 (t, 1H, Jˆ8.4 Hz), 3.68 (s, 3H),
3.62 (s, 3H), 3.01 (d, 2H, Jˆ10.8 Hz), 2.61 (m, 1H), 0.96 (d,
4H, Jˆ7 Hz); 13C NMR (67.5 MHz, CDCl3) d 172.1, 156.2,
139.9, 135.4, 128.0, 127.2, 127.1, 127.0, 123.5, 58.9, 52.0,
51.8, 41.9, 37.6, 16.5; IR (neat) cm21: 3325, 2980, 1710,
1540, 1480, 1360, 1250, 1180, 1020, 810; MS: CIMS1NH4
(NH3 gas) 309, 293, 292, 217, 164, 84, 82, 64;
CIHRMS1NH4 calculated for C16H22NO4ˆ292.1548;
found: 292.1569. [a]D23ˆ21048 (CH2Cl2, c 0.85).
(5R,6R,3E)-Methyl-5-methyl-6-(N-tosylsulfonamide)-6-
trimethyl-hexenoate (13b). Table 2, entry 2, dr.30:1 syn±
anti, 90% yield. 1H NMR (CDCl3) d:7.71 (d, 2H,
Jˆ8.0 Hz); 7.26 (d, 2H, Jˆ8.0 Hz); 5.32 (m, 1H); 5.09
(m, 1H); 4.35 (d, 1H, Jˆ10.0 Hz); 3.66 (s, 3H); 3.06 (dd,
1H, Jˆ2.0 Hz, Jˆ8.4 Hz); 2.85 (m, 2H); 2.42 (m, 1H); 2.40
(s, 3H); 0.87 (d, 3H, Jˆ6.8 Hz); 0.84 (s, 9H). 13C NMR
(CDCl3) d: 172.2; 142.7; 139.7; 139.2; 129.4; 127.1;
120.2; 66.1; 51.7; 37.5; 36.9; 36.2; 27.3; 21.4; 16.6. IR
(neat) cm21: 3359; 2962; 1738; 1641; 1437; 1305; 1159;
1095. MS: CIMS1NH4 (NH3 gas) 368, 310, 240, 236,
155. CIHRMS1NH4 calculated for C13H29NO4S1
Hˆ368.1817; found 368.1920. [a]D23ˆ114.28 (CH2Cl2,
c0.96).
(2S,5R,6S,3E)-Methyl-5-methyl-6-(N-methylcarbamate)-
2-methoxy-6-phenyl-hexenoate (14b). Table 3, entry 2,
1
drˆ9:1 syn±anti, 79% yield. H NMR (400 MHz, CDCl3)
d 7.1±7.3 (m, 5H), 5.61 (dd, 1H, Jˆ5.3, 15.6 Hz), 5.4 (m,
2H), 4.6 (b t, 1H, Jˆ7.4 Hz), 4.1 (d, 1H, Jˆ7.2 Hz), 3.65 (s,
3H), 3.54 (s, 3H), 3.25 (s, 3H), 2.6 (m, 1H), 0.9 (d, 3H,
Jˆ7 Hz); 13C NMR (67.5 MHz, CDCl3) d 171.3, 156.6,
140.4, 137.9, 128.7, 128.5, 127.5, 127.5, 126.4, 81.3, 59.53,
57.3, 52.5, 52.3, 42.2, 16.7; IR (neat) cm21 3360, 2960, 1720,
1530, 1470, 1440, 1350, 1305, 1240, 1180, 1080, 1040, 1020,
880, 820; CIMS (NH3 gas) 339, 322, 290, 215, 165, 164;
CIHRMS1NH4 calculated for C17H24NO5ˆ322.1654;
found 322.1666. [a]D23ˆ2708 (CH2Cl2, c 5.4).
(5R,6R,3E)-Methyl-5-methyl-6-(N-tosylsulfonamide)-7-
benzyloxy-heptenoate (13c). Table 2, entry 3, drˆ10:1
syn±anti, 71% yield. 1H NMR (CDCl3) d:7.67 (d, 2H,
Jˆ8.4 Hz); 7.26 (m, 7H); 5.36 (m, 2H); 4.82 (d, 1H,
Jˆ8.8 Hz); 4.29 (ABq, 2H, Jˆ6.0 Hz); 3.66 (s, 3H); 3.40
(dd, 2H, Jˆ6.4 Hz, Jˆ2.8 Hz); 3.11 (m, 2H); 2.92 (d, 1H,
Jˆ6.8 Hz); 2.44 (m, 1H); 2.39 (s, 3H); 0.96 (d, 3H,
Jˆ7.2 Hz). 13C NMR (CDCl3) d: 172.1; 143.1; 138.0;
137.7; 135.9; 128.5; 128.3; 127.7; 127.7; 127.6; 123.2;
73.1; 68.9; 57.4; 51.8; 37.6; 36.9; 21.5; 16.7. IR (neat)
cm21: 3422; 2100; 1643; 1454; 1437; 1330; 1162. MS:
CIMS1NH4 (NH3 gas) 432, 354, 352, 260, 217, 91.
CIHRMS1NH4 calculated for C23H29NO5S1Hˆ432.55;
found 432.2. [a]2D3ˆ112.28 (CH2Cl2, c0.90).
(2S,5R,6S, 3E)-Methyl-2, 5-dimethyl-6-phenyl-6-(N-methyl-
carbamate)hexenoate (14c). Table 3, entry 3, dr.30:1
syn±anti, 73% yield. H NMR (400 MHz, CDCl3) d 7.1±
1
7.3 (m, 5H), 5.46 (dd, 1H, Jˆ7.3 Hz, Jˆ15.6 Hz), 5.25 (m,
2H), 4.58 (t, 1H, Jˆ7.3 Hz), 3.63 (s, 3H), 3.60 (s, 3H), 3.04
(m, 1H), 2.53 (m, 1H), 1.12 (d, 3H, Jˆ7 Hz), 0.95 (d, 3H,
Jˆ6.7 Hz). 13C NMR (67.5 MHz, CDCl3) d 175.0, 156.2,
140.2, 132.6, 130.5, 128.06, 128.0, 127.1, 59.2, 52.0, 51.8,
42.3, 42.0, 17.1, 16.6; IR (neat) cm21 3360, 2960, 1723,
1530, 1475, 1460, 1350, 1305, 1240, 1180, 1080, 1040,
1020, 880, 820. MS: CIMS1NH4 (NH3 gas) 306.2, 232,
231, 199, 171, 165, 164, 144, 121, 120, 106, 77, 59, 42.
Representative procedure for the BF3´OEt2 promoted
imine additions illustrated for the reaction of silane 6a

J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
10271
CIHRMS1NH4 calculated for C17H23NO41Hˆ306.1705,
found 306.1733. [a]D23ˆ213.38 (CH2Cl2, c1.5).
Jˆ4.8 Hz); 2.50 (m, 1H); 1.58 (s, 3H); 1.07 (d, 3H,
Jˆ4.4 Hz). dr.12:1 13C NMR (CDCl3) d: 172.4; 157.0;
140.4; 138.1; 128.9; 128.3; 127.7; 127.6; 117.8; 73.2;
70.4; 53.4; 52.0; 51.7; 44.3; 33.2; 15.8; 12.4. IR (neat)
cm21: 3437, 2253, 1723, 1507, 1456, 1257, 909. MS:
CIMS1NH4 (NH3 gas) 91, 105, 208, 242, 350.
CIHRMS1NH4 calculated for C20H26NO5ˆ361.1889;
found: 361.1832. [a]D23ˆ110.78 (CH2Cl2, c1.6).
(5R,6S,3E)-Methyl-9-benzyloxy-5-methyl-6-(N-methyl-
carbamate)octenoate (14d). Table 3, entry 4, dr.30:1
syn±anti, 65% yield. H NMR (400 MHz, CDCl3) d 7.3
1
(m, 5H), 5.53 (m, 1H), 5.42 (dd, 1H, Jˆ8.3, 15.5 Hz),
4.92 (d, 1H, Jˆ9.7 Hz), 4.46 (s, 2H), 3.66 (s, 3H), 3.63 (s,
3H), 3.53 (m, 3H), 3.02 (d, 2H, Jˆ6.73 Hz), 2.34 (m, 1H),
1.95 (m, 1H), 1.5 (m, 1H), 1.01 (d, 3H, Jˆ6.8 Hz); 13C
NMR (67.5 MHz, CDCl3) d 172.7, 157.2, 138.6, 136.5,
128.7, 128. 127.9, 123.4, 73.6, 68.1, 53.4, 52.3, 52.1, 41.8,
38.1, 31.9. 17.1; IR (neat) cm21 3340, 2980, 1720, 1520,
1440, 1340, 1250, 1160, 1100, 1090, 1010, 980; MS:
CIMS1NH4 (NH3 gas) 350, 318, 292, 242, 164, 117, 116,
91; CIHRMS1NH4 calculated for C19H27NO51Hˆ
350.1967; found 350.2000. [a]D23ˆ1278 (CH2Cl2, c1.5).
(5R,6R,3E)-Methyl-5-methyl-6-(N-methylcarbamate)-4-
methyl-7-trimethyl-heptenoate (14i). Table 3, entry 9,
1
drˆ8:1 syn±anti, 70% yield. H NMR (CDCl3) d: 5.31 (t,
1H); 4.56 (br, 1H); 3.65 (s, 3H); 3.62 (s, 3H); 3.50 (dd, 1H,
Jˆ4.0, 6.0 Hz); 3.00 (d, 2H, Jˆ6.8 Hz); 2.45 (m, 1H); 1.60
(s, 3H); 2.45 (m, 1H); 1.60 (s, 3H); 0.97 (d, 3H, Jˆ2.8 Hz);
0.95 (s, 9H) dr.8:1 13C NMR (CDCl3) d: 172.7, 157.1,
143.2, 116.0, 60.1, 52.0, 51.6, 42.3, 33.4, 29.7, 27.2, 15.6,
14.3. IR (neat) cm21: 3055, 2987, 1727, 1517, 1435, 1422,
1266. MS: CIMS1NH4 (NH3 gas) 69, 76, 144, 154, 228,
286. CIHRMS1NH4 calculated for C15H27NO41Hˆ
286.1940; found 286.1980. [a]D23ˆ18.98 (CH2Cl2, c1.0).
(5R,6S,3E)-Methyl-9-benzyloxy-5-methyl-6-(N-methyl-
carbamate)heptenoate (14e). Table 3, entry 5, dr.30:1
syn±anti, 87% yield. H NMR (400 MHz, CDCl3) d 7.28
1
(m, 5H), 5.51 (m,1H), 5.4 (dd, 1H, Jˆ6.9 Hz, Jˆ15.2 Hz),
4.96 (d, 1H, Jˆ8.5 Hz), 4.43 (ABq, 2H, Jˆ11.7 Hz), 3.6 (s,
6H), 3.52 (m, 3H), 2.97 (d, 4H, Jˆ6.7 Hz), 2.47 (m, 1H),
0.99 (d, 3H, Jˆ6.9 Hz); 13C NMR (67.5 MHz, CDCl3) d
172.3, 156.8, 138.0, 136.6, 128.3, 127.6, 122.7, 70.0, 54.7,
52.0, 51.7, 38.9, 37.7, 16.9. IR (neat) cm21: 3325, 2960,
1710, 1550, 1480, 1360, 1250, 1180, 1030, 810.
[a]D23ˆ27.58 (CH2Cl2, c0.6).
(5R,6R,3E)-Methyl-5-methyl-6-(N-methylcarbamate)-4-
methyl-6-phenyl-hexenoate (14j). Table 3, entry 10,
1
drˆ1.2:1 syn±anti, 89% yield. H NMR (CDCl3) d: 7.08±
7.32 (m, 5H); 5.27 (t, 1H); 4.73 (t, 1H); 3.61 (s, 3H); 3.55 (s,
3H); 3.09 (d, 1H, Jˆ7.2 Hz); 2.96 (dd, 2H, Jˆ28.8, 2.8 Hz);
2.55 (t, 1H); 1.53 (s, 3H); 1.06 (d, 3H, Jˆ6.8 Hz). dr.2:1.
13C NMR (CDCl3) d: 182.7; 172.3; 156.5; 141.4; 139.6;
128.3; 128.2; 127.0; 126.9; 118.4; 57.8; 51.7; 47.9; 33.3;
16.6; 15.0; 14.2; 12.1. IR (neat) cm21: 3333; 2953; 1725;
1534; 1455; 1437; 1259; 1018. MS: CIMS1NH4 (NH3 gas)
59, 121, 164, 194, 306, 327. CIHRMS1NH4 calculated for
C17H23NO41Hˆ306.1627; found 306.1713. [a]D23ˆ115.58
(CH2Cl2, c1.3).
(5R,6S,3E)-Methyl-5,7-dimethyl-6-(N-methylcarbamate)-
octenoate (14f). Table 3, entry 6, dr.30:1 syn±anti, 68%
yield. 1H NMR (400 MHz, CDCl3) d 5.53 (m, 1H), 5.42 (dd,
1H, Jˆ8, 15.4 Hz), 4.42 (d, 1H, Jˆ10.3 Hz), 3.65 (s, 3H),
3.64 (s, 3H), 3.34 (m, 1H), 3.02 (d, 2H, Jˆ6.5 Hz), 2.24 (m,
1H), 1.8 (m, 1H), 0.97 (d, 3H, Jˆ6.7 Hz), 0.88 (d, 3H,
Jˆ6.7 Hz), 0.78 (d, 3H, Jˆ6.7 Hz); 13C NMR (67.5 MHz,
CDCl3) d 172.3, 157.43, 137.2, 121.6, 59.8, 52, 51.7, 39.8,
37.7, 29.4, 20.4, 16.5, 16.0; IR (neat) cm21 3340, 2980,
1740, 1520, 1240, 1180, 1110, 910, 740; MS: CIMS1NH4
(NH3 gas) 258, 202, 174, 130, 84, 64; CIHRMS1NH4
calculated for C13H23NO41Hˆ258.1705; found: 258.1690.
[a]D23ˆ119.08 (CH2Cl2, c1.0).
Representative experimental procedure for the
BF3´OEt2 promoted pyrrolidine annulation for the addi-
tion of silane 6a to benzaldehyde dimethyl acetal and
methyl carbamate as illustrated for 15a. (2S,3R,4S,5S)-
3-(Dimethylphenyl)silane-4-methyl-5-phenyl-pyrrolidine-
N-methylcarbamate-2-acetic acid methyl ester (15a).
Table 4, entry 1. A 25 mL round bottom ¯ask equipped
with magnetic stir bar and rubber septum was charged
with 2 mL dry CH2Cl2, benzaldehyde dimethyl acetal
(350 mg, 2.297 mmol, 1.0 equiv.) and methylcarbamate
(174 mg, 2.31 mmol, 1.0 equiv.). The resulting solution
was cooled to 2788C, and BF3´OEt2 (572 mL,
4.638 mmol, 2.01 equiv.) was added under N2. The reaction
mixture was warmed to room temperature and stirred for
10 min (the reaction mixture became yellow and homo-
geneous). The reaction mixture was recooled to 21008C
and a solution of (E)-crotylsilane (524.8 mg, 2 mmol,
0.863 equiv.) in CH2Cl2 was added to this dropwise over a
period of 10 min (20% EtOAc±petroleum ether). After
10 min the reaction mixture was warmed to 2858C while
being monitored by TLC (20% EtOAc±petroleum ether).
After 12 h the reaction mixture was diluted with a saturated
solution of NaHCO3 (10 mL) and extracted with EtOAc
(3£10 mL). The combined organic layers were dried with
anhydrous Na2SO4, ®ltered, and the solvent removed under
reduced pressure to afford crude 15a as light yellow oil.
Chromatography on silica gel using 20% EtOAc±petroleum
(5R,6S,3E)-Methyl-6-(N-methyl carbamate)-5, 7, 7-tri-
methyloctenoate (14g). Table 3, entry 7, dr.30:1 syn±
anti, 72% yield. H NMR (400 MHz, CDCl3) d 5.55 (m,
1
2H), 4.58 (d, 1H, Jˆ11 Hz), 3.66 (s, 3H), 3.65 (s, 3H),
3.44 (dd, 1H, Jˆ4, 11 Hz), 3.01 (m, 2H), 2.53 (m, 1H),
0.97 (d, 3H, Jˆ6.89 Hz), 0.92 (s, 9H); 13C NMR (67.5
MHz, CDCl3) d 172.9, 157.7, 140.1, 132.1, 120.6, 62.4,
52.5, 52.2, 38.1, 37.9, 36.2, 27.8, 27.7, 16.9; IR (neat)
cm21 3325, 2960, 1720, 1540, 1360, 1260, 1190, 1080,
1000, 805, 760; MS: CIMS1NH4 (NH3 gas) 289, 272,
240, 214, 144, 85; CIHRMS1NH4 calculated for
C14H25NO41Hˆ272.2861; found: 272.2818. [a]D23ˆ129.08
(CH2Cl2, c 0.2).
(5R,6R,3E)-Methyl-5-methyl-6-(N-methylcarbamate)-4-
methyl-7-benzyloxy-heptenoate (14h). Table 3, entry 8,
1
drˆ24:1 syn±anti, 77% yield. H NMR (CDCl3) d: 7.25±
7.34 (m, 5H); 5.40 (t, 1H); 4.93 (b, 1H); 4.46 (m, 2H); 3.74
(d, 2H, Jˆ2.8 Hz); 3.68 (s, 6H); 3.42 (m, 1H); 6.03 (d, 2H,

10272
J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
ether as the eluant afforded pure 15a (579.5 mg, theoretical
852 mg, dr.30:1 syn±anti, 68% yield). 1H NMR
(400 MHz, CDCl3) d 7.39(d, 2H, Jˆ7.3 Hz), 7.15 (m,
6H), 6.86 (d, 2H, Jˆ7.3 Hz), 4.57 (d, 1H, Jˆ4.4 Hz), 4.16
(dd, 1H, Jˆ5.5, 7.4 Hz) 3.68 (s, 3H), 3.33 (s, 3H), 2.52 (m,
2H), 1.85 (m, 2H), 0.51 (d, 3H, Jˆ6.8 Hz), 0.30 (s, 3H),
0.22 (s, 3H); 13C NMR (67.5 MHz, CDCl3) d 174.1, 153.1,
141.1, 137.2, 133.8, 129.3, 128.0, 127.6, 127.4, 126.4, 81.2,
57.1, 54.3, 51.6, 32.4, 30.5, 25.4, 12.8, 22.9, 24.63. IR
(neat) cm21 2905, 1715, 1655, 1420, 1300, 1210, 1190,
1080, 1000, 920, 880, 820; MS: CIMS1NH4 (NH3 gas)
426, 309, 292, 183, 164, 152, 106; CIHRMS1NH4 calcu-
lated for C24H31NSiO41Hˆ426.2100; found 426.2092.
[a]D23ˆ160.68 (CH2Cl2, c3.5).
(10S,2S,3R, 4S,5S)-3-(Dimethylphenyl)silane-4-methyl-2-
(10-methoxy)-5-phenyl-pyrrolidine-N-methyl carbamate-
2-acetic acid methyl ester (15b). Table 4, entry 2,
drˆ20:1 syn±anti, 72% yield. 1H NMR (CDCl3,
400 MHz) d 7.65 (d, 2H, Jˆ7 Hz), 7.25 (m, 6H), 6.83 (d,
2H, Jˆ7 Hz) 4.73 (d, 1H, Jˆ4.5 Hz), 4.71 (d, 1H,
Jˆ2.5 Hz), 4.55 (dd, 1H, Jˆ2.8, 10.5 Hz), 3.77 (s, 3H),
3.51 (s, 3H), 3.42 (s, 3H), 2.75 (dd, 1H, Jˆ2.5, 10.5 Hz),
2.18 (m, 1H), 0.68 (d, 3H, Jˆ7 Hz), 0.54 (s,3H), 0.49 (s,
3H); 13C NMR (67.5 MHz, CDCl3) d 173.7, 152.6, 142.6,
139.4, 134.1, 129.3, 128.5,128.4, 127.4, 126.4, 80.9, 79.4,
59.7, 55.2, 54.2, 51.3, 35.2, 32.9, 13.3, 24.0, 20.5; IR
(neat) cm21 2900, 1710, 1650, 1420, 1300, 1210, 1190,
1080, 1000, 920, 880, 820; MS: CIMS1NH4 (NH3 gas)
456, 424, 384, 314, 292, 290, 215, 164, 135, 111;
CIHRMS1NH4 calculated for C25H33NSiO51H456.2206;
found 456.2208. [a]D23ˆ124.98 (CH2Cl2, c0.4).
(10S,2S,3R,4S,5S)-5-(p-Chloro-phenyl)-3-dimethylphenyl-
silane-4-methyl-2-(10methoxy)-pyrrolidine-N-methyl car-
bamate-2-acetic acid methyl ester (15c). Table 4, entry 3,
drˆ20:1 syn±anti, 47% yield. 1H NMR (CDCl3, 400 MHz)
d 7.5 (m, 5H), 7.0 (d, 2H, Jˆ8.2 Hz), 6.31 (d, 2H,
Jˆ8.4 Hz), 4.38 (d, 1H, Jˆ2.5 Hz), 4.28 (m, 2H), 3.78 (s,
3H), 3.76 (s, 3H), 3.57 (s, 3H), 2.35 (dd, 1H, Jˆ2.5,
10.7 Hz), 1.8 (m, 1H), 0.45 (d, 3H, Jˆ7 Hz), 0.41 (s, 3H),
0.2 (s, 3H); 13C NMR (67.5 MHz, CDCl3) d 174, 152.3,
140.3, 139.2, 133.8, 129.33, 128.3, 128.1, 127.7, 81.0,
79.0, 60.1, 54.4, 54.1, 51.9, 34.7, 32.4, 13.0, 20.46 20.7;
IR (neat) cm21 2900, 1710, 1650, 1420, 1300, 1210, 1190,
1080, 1000, 920, 880, 820; MS: CIMS1NH4 (NH3 gas) 492,
490, 458, 332, 324, 249, 198, 135, 111, 89; CIHRMS1NH4
calculated for C25H33ClNSiO5ˆ491.1894; found 491.1879.
[a]D23ˆ156.88 (CH2Cl2, c2.5).
(10S,2S,3R, 4S,5S)-5-(2,3-Dimethoxy-phenyl)-3-(dimethyl-
phenyl)silane-4-methyl-2-(10methoxy)-pyrrolidin-N-methyl
carbamate-2-acetic acid methyl ester (15d). Table 4, entry
4, drˆ10:1 syn±anti, 53% yield. 1H NMR (CDCl3,
400 MHz) d 7.23±7.55 (m, 5H), 6.94 (t, 1H, Jˆ7.8 Hz),
6.77 (d, 1H, Jˆ7.8 Hz), 6.65 (d, 1H, Jˆ7.8 Hz), 4.96 (d,
1H, Jˆ5 Hz), 4.12 (d, 1H, 4.3 Hz), 4.05 (dd, 1H, Jˆ4.4,
8.2 Hz), 3.84 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H), 3.62 (s,
3H), 3.42 (s, 3H), 2.17 (m, 1H), 2.1 (dd, 1H, Jˆ4.3,
8.2 Hz), 0.47 (s, 3H), 0.40 (s, 3H), 0.33 (d, 3H, Jˆ7 Hz);
13C NMR (67.5 MHz, CDCl3) d 173.7, 153.1, 152.2, 146.25,
137.2, 135.3, 134.6, 134.5, 133.0, 127.6, 127.5, 123.4,
123.3, 120.9, 110.6, 79.9, 79.1, 60.3, 59.0, 55.7, 55.6,
54.3, 51.7, 51.3, 34.6, 31.7, 12.9, 21.85; IR (neat) cm21
2905, 1719, 1645, 1420, 1305, 1210, 1190, 1180, 1000,
920, 880, 820; MS: CIMS1NH4 (NH3 gas) 516, 350, 275,
224, 148; CIHRMS1NH4 calculated for C27H37NSiO71Hˆ
516.2416; found 516.2396. [a]D23ˆ175.48 (CH2Cl2, c1.1).
Representative experimental procedure for the
BF3´OEt2 promoted pyrrolidine annulations for the
addition of silane 6a to benzaldehyde dimethyl acetal
and tert-butyl carbamate as illustrated for 16a.
(2S,3R,4S,5S)-3-(dimethylphenyl)silane-4-methyl-5-phenyl-
pyrrolidine-2-acetic acid methyl ester (16a). Table 5,
entry 1. In a dry 10 mL round bottom ¯ask, 2,3-dimethoxy
benzaldehyde (34 mg, 0.21 mmol) and the tert-butylcarba-
mate (24 mg, 0.21 mmol) were taken up in dry CH2Cl2
(0.2 mL, 1.0 M). The solution was cooled to 2788C before
addition of BF3´OEt2 (47 mL, 2 equiv.). The reaction
mixture was then pulled out of the dry ice/acetone bath
and stirred for 10 min. The reaction is then cooled again
to 21008C and a solution of silane (50 mg, 0.188 mmol)
in CH2Cl2 (0.2 mL, 1.0 M) was added dropwise. The solu-
tion was then stirred overnight at 2858C before being
diluted with a saturated solution of NaHCO3 (3 mL) and
extracted with CHCl3 (3£1 mL). The combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure. Puri®cation on SiO2, eluting with
30!40% EtOAc±hexanes, afforded the desired pyrrolidine
as a colorless oil (67 mg, 0.15 mmol, dr.30:1 syn±anti,
1
78%). H NMR (CDCl3) d: 7.16±7.55 (m, 10H); 6.72 (d,
1H, Jˆ6.0 Hz); 5.15 (br, 1H); 4.60 (dd, 1H, Jˆ4.4, 7.2 Hz);
3.62 (s, 3H); 2.57 (dd, 2H, Jˆ10.4, 26.8 Hz); 2.13 (m, 1H);
1.83 (m, 1H); 0.59 (d, 3H, Jˆ7.2 Hz); 0.45 (s, 3H); 0.34 (s,
3H). 13C NMR (CDCl3) d: 201.4; 174.2; 153.6; 140.8;
138.3; 137.0; 133.9; 129.4; 127.0; 126.1; 80.2; 78.4; 56.7;
52.9; 51.8; 42.0; 32.5; 29.5; 29.3; 25.2; 24.7; 12.8. IR (neat)
cm21: 3408; 2977; 1702; 1456; 1411; 1309; 1119. MS:
CIMS1NH4 (NH3 gas) 352, 334, 284, 240, 143, 135.
CIHRMS1NH4 calculated for C22H29NO2Si1H368.1967;
found 368.2066. [a]D23ˆ236.18 (CH2Cl2, c1.65).
(2S,3R,4S,5S)-3-(Dimethylphenyl)silane-4-methyl-5-(p-
methoxy-phenyl)-pyrrolidine-2-acetic acid methyl ester
1
(16b). Table 5, entry 2, dr.30:1 syn±anti, 74% yield. H
NMR (CDCl3) d: 7.36±7.56 (m, 7H); 6.70 (dd, 2H, Jˆ2.0,
ˆ6.4 Hz); 5.10 (br, 1H); 4.38 (m, 1H); 4.11 (m, 1H); 3.77 (s,
3H); 3.62 (s, 3H); 2.56 (ABx, 2H, Jˆ6.4, 10.0, 6.4,
27.2 Hz); 2.08 (m, 1H); 1.80 (m, 1H); 0.58 (d, 3H,
Jˆ6.8 Hz); 0.45 (s, 3H); 0.34 (s, 3H). 13C NMR (CDCl3)
d: 201.4; 174.2; 153.6; 138.3; 137.0; 129.3; 129.0; 128.4;
128.2; 128.0; 127.7; 127.0; 126.1; 80.2; 56.7; 52.9; 51.8;
42.0; 32.5; 29.6; 29.4; 25.2; 24.7; 12.8; 23.1. IR (neat)
cm21
: 3427; 1702; 1456; 1360; 1268; 1026. MS:
CIMS1NH4 (NH3 gas) 68, 135, 207, 270, 314, 396, 426.
CIHRMS1NH4 calculated for C23H31NO3Si1H397.2073;
found 398.2151. [a]D23ˆ247.28 (CH2Cl2, c1.15).
(2S,3R,4S,5S)-3-(Dimethylphenyl)silane-4-methyl-5-(2,3-
dimethoxy-phenyl)-pyrrolidine-2-acetic acid methyl
ester (16c). Table 4, entry 3, dr.30:1 syn±anti, 78%
1
yield. H NMR (CDCl3) d: 6.80±7.53 (m, 8H); 6.48 (d,
1H, Jˆ7.6 Hz); 5.02 (br, 1H; 4.15 (dd, 1H, Jˆ5.2 Hz,
Jˆ2.8 Hz); 3.86 (s, 3H); 3.84 (s, 3H); 3.80 (s, 3H); 2.49
(ABx, 2H, Jˆ6.4, 9.6, 6.8, 39.2 Hz); 2.32 (m, 1H); 1.78

J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
10273
(m, 1H); 0.60 (d, 3H, Jˆ7.2 Hz); 0.45 (s, 3H); 0.40 (s, 3H).
13C NMR (CDCl3) d: 202.6; 202.5; 174.4; 153.7; 125.3;
134.0; 132.1; 129.3; 127.9; 123.8; 119.5; 111.8; 80.2;
60.6; 55.7; 51.8; 50.7; 32.3; 29.5; 24.7; 11.9. IR (neat)
cm21: 3406; 1707; 1480; 1354; 1268; 1169; 1123; 1006.
MS: CIMS1NH4 (NH3 gas) 83, 85, 135, 206, 292, 300,
344. CIHRMS1NH4 calculated for C24H33NO4Siˆ
427.2179; found 427.2150. [a]D23ˆ253.78 (CH2Cl2, c0.6).
(m, 2H); 3.43 (m, 1H); 3.01 (d, 2H, Jˆ6.8 Hz), 2.27 (m,
1H), 1.92 (m, 1H), 1.03 (m, 9H), 0.976 (d, 3H, Jˆ6.8 Hz),
0.77 (d, 3H, Jˆ6.8 Hz). 13C NMR (CDCl3) d: 172.2, 157.0,
137.3, 135.7, 135.6, 135.5, 133.7, 127.8, 127.7, 127.6,
121.8, 66.6, 55.5, 52.0, 51.6, 40.1, 37.7, 37.1, 36.7, 26.8,
16.7, 19.2, 17.0, 11.2. IR (neat) cm21: 3432, 2958, 1750,
1635. MS: CIMS1NH4 (NH3 gas) 256, 384, 434, 455, 480,
512. CIHRMS1NH4 calculated for C29H42NO5Si1Hˆ
512.2754; found 512.2826.
(5S,6S,7S,3E) Methyl-8-benzyloxy-5-methyl-6-(N-methyl
carbamate)-7-methyl-hexenoate (17a). Table 6, entry 1,
dr.30:1 syn±anti, 85% yield. H NMR (CDCl3) d: 7.25±
7.35 (m, 5H), 5.41 (m, 2H), 4.45 (s, 2H), 3.65 (s, 3H). 3.63
(s, 3H), 3.42 (m, 1H), 3.32 (m, 2H). 2.98 (d, 2H, Jˆ7.6 Hz),
2.24 (m, 1H), 1.89 (m, 1H); 1.05 (d, 3H, Jˆ7.2 Hz), 0.97 (d,
3H, Hˆ7.2).
(5S,6R,7S,3E) Methyl-8-benzyloxy-5-methyl-6-amino-7-
methyl-hexenoate (17f). Table 6, entry 6, dr.1:30 syn±
anti, 63% yield. H NMR (CDCl3) d: 7.29±7.34 (m, 5H),
1
1
5.58 (m, 2H), 4.49 (s, 2H), 3.65 (s, 3H), 3.55 (m, 1H), 3.46
(m, 1H), 3.05 (m, 2H, Jˆ6 Hz), 2.34 (m, 1H), 1.89 (m, 1H);
1.05 (d, 3H, Jˆ6.8 Hz), 0.97 (d, 3H, Jˆ6.8 Hz). 13C NMR
(CDCl3) d: 172.6, 135.5, 128.4, 127.7, 127.6, 122.4, 79.9,
(5R,6S,7S,3E) Methyl-7-benzyloxy-5-methyl-6-(N-methyl
carbamate)-7-methyl-heptenoate (17b). Table 6, entry 2,
75.4, 73.5, 51.7, 39.9, 37.9, 36.2, 17.9, 13.4. IR (neat) cm21
3460, 2964, 2931, 1737, 1454, 1275.
:
1
drˆ24:1 syn±anti, 82% yield. H NMR (CDCl3) d: 7.22±
7.34 (m, 5H); 5.40±5.57 (m, 2H); 4.63 (br, 1H); 4.50 (m,
4H); 3.79 (m, 1H); 3.66 (s, 3H); 3.63 (s, 3H); 3.61 (m, 1H);
2.99 (d, 3H, Jˆ6.4 Hz); 2.45 (m, 1H); 1.15 (d, 3H,
Jˆ6.8 Hz). 13C NMR (CDCl3) d: 182.7, 157.2, 137.0,
128.3, 127.7, 121.8, 74.8, 70.5, 57.2, 52.1, 37.8, 15.9,
15.3. IR (neat) cm21: 3428, 2113, 1646, 1540. MS:
CIMS1NH4 (NH3 gas) 49, 91, 132, 140, 214, 228, 242,
260, 350. CIHRMS1NH4 calculated for C19H27NO51
Hˆ350.1889; found 350.1999. [a]D23ˆ12.38 (CH2Cl2,
c0.7).
(5R,6R,7S,3E) Methyl-7-benzyloxy-5-methyl-6-(N-methyl
carbamate)-7-methyl-heptenoate (17g). Table 6, entry 7,
drˆ1:8 syn±anti 35% yield. 1H NMR (CDCl3) d: 7.27±7.48
(m, 5H); 5.56 (m, 2H); 4.63 (d, 1H, Jˆ11.6 Hz); 4.38 (d,
1H, Jˆ 11.6 Hz), 3.66 (s, 3H), 3.62 (s, 3H), 3.50 (m, 1H),
3.27 (m, 1H), 3.04 (2H, d, Jˆ6 Hz), 2.37 (m, 1H), 1.18 (d,
3H, Jˆ6 Hz), 1.12 (d, 3H, Jˆ6.8 Hz). 13C NMR (CDCl3) d:
171.2, 135.8, 133.4128.6, 127.2, 121.9, 99.470.8, 67.3, 51.2,
41.0, 38.3, 37.1, 19.5, 17.2, 14.9. IR (neat) cm21: 3433,
1653, 1457, 1252, 1018.
(5S,6R,7R,3E) Methyl-8-benzyloxy-5-methyl-6-(N-methyl
carbamate)-7-methyl-hexenoate (17c). Table 6, entry 3,
General procedure for the cyclization of the homoallylic
amine illustrated with 3-benzyloxy-2-(S)-methyl-pro-
pionyaldehyde
1
drˆ5:1 syn±anti, 87% yield. H NMR (CDCl3) d: 7.25±
7.35 (m, 5H), 5.38 (m, 1H), 4.97 (d, 1H Jˆ9.6 Hz), 4.63
(d, 1H, Jˆ11.6 Hz), 4.47 (d, 1H, Jˆ11.6 Hz), 3.68 (m, 1H),
3.65 (s, 3H), 3.64 (s, 3H), 3.32 (t, 1H, Jˆ9.6 Hz), 2.44 (m,
1H), 1.16 (d, 3H, Jˆ8 Hz), 0.99 (d, 3H, Jˆ8 Hz).). 13C
NMR (CDCl3) d: 172.25, 157.6, 137.3, 128.4, 128.3,
127.8, 127.7, 127.6, 122.6, 75.5, 73.2, 70.7, 66.3, 60.0,
52.1, 37.7, 17.7, 16.6, 15.8. IR (neat) cm21: 3450, 2133,
1655, 1530 MS: CIMS1NH4 (NH3 gas) 91, 132, 140,
228, 260, 350
Cleavage of ole®n 18a by ozonolysis and reduction of the
crude aldehyde yielded the corresponding crude alcohol
(20 mg, 0.067 mmol) which was taken up in toluene
(1.5 mL) and excess K2CO3 was added. The solution was
then heated until all the toluene evaporated followed by an
additional heating for 10 min. The residue was the diluted in
CH2Cl2 (2 mL) and ®ltered through a pad of Celitew. After
concentration under reduced pressure and puri®cation on
SiO2, the desired oxizolidinone 19a was obtained as a color-
less oil (12 mg, 0.045 mmol, 68%).
(5R,6S,7S,3E) Methyl-8-t-butyldimethylphenyloxy-5-
methyl-6-(N-methyl carbamate)-7methyl-heptanoate (17d).
1
Table 6, entry 4, dr.30:1 syn±anti, 73% yield. H NMR
1
Oxazolidinone (19a). H NMR (CDCl3) d: 7.25±7.37 (m,
(CDCl3) d: 7.34±7.65 (m, 10H); 5.61 (br, 1H); 5.34 (m,
2H); 3.80 (dd, 1H, Jˆ3.2, 7.2 Hz); 3.64 (s, 3H); 3.59 (s,
3H); 3.45 (m, 2H); 2.92 (d, 2H, Jˆ5.2 Hz); 2.29 (m, 1H);
1.77 (m, 1H); 1.06 (s, 9H); 1.01 (m, 6H). 13C NMR (CDCl3)
d: 172.2, 157.8, 137.5, 135.7, 132.8, 129.8, 127.8, 121.8,
65.5, 58.9, 51.9, 51.7, 41.2, 37.7, 35.2, 26.9, 19.1, 17.6,
15.9. IR (neat) cm21: 3428, 2961, 1727, 1643. MS:
CIMS1NH4 (NH3 gas) 256, 384, 434, 454, 480, 512.
CIHRMS1 NH4 calculated for C29H42NO5Si1H512.2754;
found 512.2824. [a]D23ˆ28.68 (CH2Cl2, c1.7).
5H), 6.63 (b, 1H), 4.52 (s, 2H), 4.27 (dd, 1H, J1ˆ2.4 Hz,
J2ˆ8.4 Hz), 4.08 (dd, 1H, J1ˆ2.0 Hz, J2ˆ8.8 Hz), 3.49 (dd,
1H, J1ˆ3.2 Hz, J2ˆ6.4 Hz), 3.35 (m, 2H), 1.96 (m, 1H),
1.85 (m, 1H), 1.05 (d, 3H, Jˆ6.8 Hz), 0.80 (d, 3H,
Jˆ7.2 Hz). 13C NMR (CDCl3) d: 169.3; 128.6; 128.0;
127.8; 75.9; 73.6; 72.5; 60.5; 34.3; 27.6; 13.0; 9.4.
1
Oxazolidinone (19b). H NMR (CDCl3) d: 7.33 (m, 5H);
5.55 (br, 1H); 4.50 (ABq, 2H, J1ˆ11.2 Hz, J2ˆ10.8 Hz);
4.23 (ABq, 2H, J1ˆ10.8 Hz, J2ˆ10.8 Hz); 3.40 (m, 2H);
2.03 (m, 1H); 1.21 (d, 3H, Jˆ2.0 Hz); 1.03 (d, 3H,
Jˆ6.8 Hz). 13C NMR (CDCl3) d: 169.3; 128.7; 128.1;
127.8; 75.6; 72.4; 70.9; 58.8; 29.8; 26.7; 14.9; 10.2.
(5R,6R,7R,3E) Methyl-8-t-butyldimethylphenyloxy-5-
methyl-6-(N-methyl carbamate)-7methyl-heptanoate (17e).
1
Table 6, entry 5, drˆ8:1 syn±anti, 80% yield. H NMR
1
Oxazolidinone (19e). H NMR (CDCl3) d: 7.53 (m, 5H);
4.68 (d, 1H, Jˆ12 Hz), 4.4 (d, 1H, Jˆ12 Hz), 4.24 (m, 1H),
(CDCl3) d: 7.35±7.65 (m, 10H); 5.46 (m, 1H); 5.36 (m,
1H); 4.53 (broad d, 1H); 3.65 (s, 3H); 3.62 (s, 3H); 3.55

10274
J. V. Schaus et al. / Tetrahedron 56 (2000) 10263±10274
9. (a) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57,
5790±5792. (b) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1994,
59, 2674±2675. (c) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991,
113, 9868±9870. (d) Panek, J. S.; Jain, N, F. J. Org. Chem. 1993,
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1999, 122, 1235±1236. (b) Oleandolide: Hu, T.; Takenaka, N.;
Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229±9230. (c) (2)-
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3.94 (m, 2H), 3.75 (m, 1H), 2.37 (m, 1H), 1.33 (d, 3H,
Jˆ6.4 Hz), 0.85 (d, 3H, Jˆ6.8 Hz).
Acknowledgements
The authors are grateful to B. J. Neubert for technical
assistance. Financial support was obtained from the NIH
(RO1 CA56304) and P®zer Central Research for under-
graduate research fellowships to J. V. S. and B. J. N.
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