Stereoselective synthesis of functionalized pyrrolidines via a [3 + 2]-annulation of N-Ts-α-amino aldehydes and 1,3-bis(silyl)propenes

Article abstract of DOI:10.1021/ja0647102

An efficient protocol for stereoselective synthesis of densely functionalized pyrrolidines by a [3 + 2]-annulation of N-Ts-α-amino aldehydes and 1,3-bis(silyl)propenes is described. Copyright

Full text of DOI:10.1021/ja0647102

Published on Web 09/09/2006
Stereoselective Synthesis of Functionalized Pyrrolidines via a
[3 + 2]-Annulation of N-Ts-r-Amino Aldehydes and 1,3-Bis(silyl)propenes
Per Restorp,† Andreas Fischer,‡ and Peter Somfai*,†
Organic Chemistry and Inorganic Chemistry, KTH Chemical Science and Engineering, 100 44 Stockholm, Sweden
Received July 12, 2006; E-mail: somfai@kth.se
Scheme 1
The stereoselective synthesis of functionalized pyrrolidines is a
topic of considerable interest, due to their great abundance in natural
products1 and wide applications as chiral ligands2 and organocata-
lysts3 in asymmetric synthesis. Consequently, significant efforts
have been devoted to the development of efficient routes to
substituted pyrrolidines. Recent examples include 1,3-dipolar cy-
cloadditions of azomethine ylides to electron-deficient alkenes,4
reduction of pyrroles,5 intramolecular hydroaminations,6 and an-
nulation reactions of allyl-,7 vinyl-,8 and allenesilanes.9 However,
Table 1. Optimization of the [3 + 2]-Annulationa
the efficient construction of polysubstituted pyrrolidines with well-
defined stereochemistry and derivatizable functional groups remains
a challenge in organic synthesis. The Lewis acid promoted addition
of allylsilanes to aldehydes is an important method for stereose-
lective C-C bond formation.10 Allylsilanes can also function as
synthetic equivalents of 1,2-7a,11 or 1,3-dipoles7b,c,12 in annulation
reactions to activated CdX π-bonds, due to the efficient σfp
hyperconjugative stabilization of â-silyl carbocations by adjacent
C-Si bonds.10 Herein, we report an efficient procedure for
stereoselective construction of densely functionalized pyrrolidines
A by a Lewis acid promoted [3 + 2]-annulation of silanes B and
N-Ts-R-amino aldehydes C (Scheme 1). In this approach, silane B
functions as a 1,2-dipole equivalent, which after a stereoselective
addition to C yields intermediate D. The subsequent annulation, to
afford A, exploits the nucleophilicity of the sulfonamide nitrogen
toward the â-silyl cation for cyclization. This approach provides a
straightforward entry to polyhydroxylated pyrrolidines, which are
common subunits in a variety of biologically active alkaloids.1
Initial focus was directed toward investigating the effect of
different silicon substituents on the [3 + 2]-annulation. Gratifyingly,
treatment of N-Ts-valinal (1a)13 with silane 2a14 (SiR′3 ) SiMe3)
and BF3‚OEt2 in CH2Cl2 at -78 °C afforded pyrrolidine 3a in good
yield and excellent stereoselectivity (Table 1, entry 1). Interestingly,
silane 2a functions only as a 1,2-dipole equivalent, and no 1,2-
silyl migration7b,c,12 to give piperidines was observed. Silane 2b15
(SiR′3 ) SiiPr3) failed to participate in the [3 + 2]-annulation, the
reason probably being increased steric hindrance (entry 2). The
synthetic utility of this transformation would be greatly increased
if the silyl moieties in 3 could be transformed into hydroxy groups
via a Tamao-Fleming oxidation,16 a process which requires an
activating group on silicon. Alkylsilanes have been shown to be
resistant toward oxidation, but in contrast, the dimethylphenylsilyl
group is a known hydroxyl group synthon.16 However, treatment
of silane 2c17 (SiR′3 ) SiMe2Ph) and aldehyde 1a with BF3‚OEt2
afforded pyrrolidine 3b in low yield, although still as a single
diastereomer (entry 3). Instead, a pyrrolidine lacking the C4 Si
moiety could be isolated as the major product. To circumvent this
problem, other monodentate and chelating Lewis acids were
screened,18 none of which yielded pyrrolidine 3b. To our delight,
the aluminum-based Lewis acids afforded pyrrolidine 3b as a single
entry
1 (R)
2 (SiR
′
)
Lewis acid
yield of 3 (%)b
drc
3
1
2
3
4
5
6
7
a (Ts)
a (Ts)
a (Ts)
a (Ts)
a (Ts)
b (Cbz)
c (Bz)
a (SiMe3)
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
Me2AlCl
MeAlCl2
MeAlCl2
MeAlCl2
a (77)
>98:2
b (SiiPr3)
c (SiMe2Ph)
c (SiMe2Ph)
c (SiMe2Ph)
c (SiMe2Ph)
c (SiMe2Ph)
b (15)
b (25)
b (67)
>98:2
>98:2
>98:2
a For experimental details, see Supporting Information. b Isolated yield.
c Determined by H NMR analysis of the crude reaction mixtures.
1
diastereomer with no sign of desilylation (entries 4 and 5).
Competing elimination to the corresponding diene was, however,
observed,19 and the optimal result was obtained using MeAlCl2 as
Lewis acid, furnishing pyrrolidine 3b in 67% (entry 5).20 Finally,
the effect of nitrogen protecting groups was studied, but neither
NHCbz (entry 6) nor NHBz (entry 7) resulted in pyrrolidine
formation.
With optimized conditions at hand, we turned our attention to
the nature of the N-Ts-R-amino aldehydes, and 1a,d-h13 were
selected for further investigation (Table 2). The [3 + 2]-annulation
with silane 2c proceeded with excellent levels of diastereoselection
regardless of the nature of the R groups, and 1H NMR analysis of
the crude reaction mixtures could in each case only detect the
formation of a single diastereomer. Aldehydes 1a,d-h afforded
densely functionalized pyrrolidines 3b,d-h, substituted with a C3
hydroxyl and latent C4 hydroxyl and C5 hydroxymethyl groups,
which are possible to synthetically differentiate for selective
functionalization. In addition, pyrrolidines 3e-h contain a C2
substituent amenable for further synthetic transformations.
X-ray crystallographic analysis of 3b showed its relative stere-
ochemistry to be (2S*,3R*,4R*,5R*).21 The stereochemistry of
pyrrolidines 3a,d-h was assigned in analogy to 3b.
We have previously demonstrated that excellent levels of
chelation-controlled diastereoselection can be achieved in nucleo-
philic additions to R-NHTs aldehydes by using a monodentate Lewis
acid.22 The stereochemical outcome in such additions can be
† Organic Chemistry.
‡ Inorganic Chemistry.
9
12646
J. AM. CHEM. SOC. 2006, 128, 12646-12647
10.1021/ja0647102 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stereoselective [3 + 2]-Annulation of Silane 2c and
N-Ts-R-Amino Aldehydes 1a,d-ha
Scheme 2
entry
1 (R)
yield of 3 (%)b
drc
polyhydroxylated alkaloids is underway in our laboratory and will
be reported in due course.
1
2
3
4
5
6
a (iPr)
d (Me)
e (Ph)
b (67)
d (33)d
e (69)
f (57)
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
Acknowledgment. Financial support from the Royal Institute
of Technology, the Swedish Research Council, and the Knut and
Alice Wallenberg foundation is gratefully acknowledged.
f (CH2OTBS)
g (CH2CH2dCH2)
h (CH2CH2OTBDPS)
g (35)d
h (61)
Supporting Information Available: Experimental procedures and
spectral data characterizations of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a For experimental details, see Supporting Information. b Isolated yield.
1
c Determined by H NMR analysis of the crude reaction mixtures. d Low
yield due to instability of the aldehyde.
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Figure 1. Rationalization of the stereoselectivity.
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CdO moieties followed by nucleophilic attack on the sterically
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C3 relative stereochemistry in pyrrolidine 3b (Figure 1). It has
previously been argued that, in Lewis acid promoted additions of
crotylstannanes to aldehydes, syn-synclinal arrangements are the
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C4-C5 bond rotation.
The pyrrolidine structural motif is a common subunit in a variety
of polyhydroxylated alkaloids,1 which are of great importance due
to their potential chemotherapeutic utilities, such as anti-HIV and
anticancer agents. To demonstrate the applicability of the developed
[3 + 2]-annulation methodology to the synthesis of this important
class of compounds, we report a straightforward synthesis of DGDP
(5),24 which is a potent inhibitor of glucosidases as well a
substructure in more complex pyrrolizidine alkaloids (Scheme 2).
Desilylation of pyrrolidine 3f followed by a stereospecific Tamao-
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afforded DGDP in only three steps from 3f.
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In conclusion, we have developed an efficient approach to
pyrrolidines, containing four contiguous stereocenters by a highly
stereoselective [3 + 2]-annulation of 1,3-bis(silyl)propenes, which
functions as a 1,2-dipole equivalent, and N-Ts-R-amino aldehydes.
The application of this methodology in the total synthesis of
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