The influence of chiral auxiliaries and catalysts on the selectivity of intramolecular conjugate additions of pyrrole to N-tethered Michael acceptors

Article abstract of DOI:10.1039/b312552a

A series of pyrroles incorporating N-tethered acrylates and related groups has been prepared and examined for their capacity to undergo intramolecular Michael addition reactions to form, in a diastereo- or enantio-selective fashion, the corresponding 8-substituted tetrahydroindolizidine or homologues thereof.

Full text of DOI:10.1039/b312552a

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The influence of chiral auxiliaries and catalysts on the selectivity
of intramolecular conjugate additions of pyrrole to N-tethered
Michael acceptors
Martin G. Banwell,* Daniel A. S. Beck and Jason A. Smith*†
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200, Australia.
E-mail: mgb@rsc.anu.edu.au
Received 10th October 2003, Accepted 1st December 2003
First published as an Advance Article on the web 8th December 2003
A series of pyrroles incorporating N-tethered acrylates and
related groups has been prepared and examined for their
capacity to undergo intramolecular Michael addition reac-
tions to form, in a diastereo- or enantio-selective fashion,
the corresponding 8-substituted tetrahydroindolizidine or
homologues thereof.
A key step associated with our recently disclosed syntheses of
the racemic modifications of the alkaloids aspidospermidine
1
2
(
1) and rhazinal (2) was the AlCl -catalysed Michael addi-
3
3
tion of C2 within pyrrole 3 onto the N-tethered acrylate resi-
due thus producing the tetrahydroindolizidine 4. To the best of
our knowledge, conversion 3 4 represents the first example
of an intramolecular variant of a rather well-known inter-
Scheme 1 Reagents and conditions: (i) 160 ЊC, 12 h; (ii) CH N
2
2
(
excess), Et O, 18 ЊC, 3 h; (iii) DIBAL-H (1.0 mole eq.), THF, Ϫ78 ЊC,
2
1
h; (iv) (a) for 10: (MeO) P(O)CH CO 8-PM (1.1 mole eq.), LiHMDS,
2 2 2 2 2
2
2
2
4
molecular process. Of course, the utility of this variant would
CH Cl , 18 ЊC, 1 h; (b) for 11: (MeO) P(O)CH CO Me (1.1 mole eq.),
KHMDS, CH Cl , 18 ЊC, 1 h.
2 2
be greatly enhanced if it could be achieved in an enantio-
selective fashion. To this end we have examined the capacity of
certain chiral catalysts and auxiliaries to effect asymmetric
induction in the title processes and report the results of our
studies here.
Scheme 2 Reagents and conditions: (i) KH (2.0 mole eq.), THF, 18 ЊC,
6 h; (ii) (a) for 10: CH ᎐CHCO 8-PM (1.1 mole eq.), Grubbs’ 2nd gen.
1
2
2
catalyst (5 mole%), CH Cl , 40 ЊC, 24 h; (b) for 11: CH ᎐CHCO Me
(1.1 mole eq.), Grubbs’ 2nd gen. catalyst (5 mole%), CH
The substrates required for our study were initially generated
2
2
2
2
2
2
Cl
2
, 40 ЊC,
(
Scheme 1) by simple variations on the originally described
2
4 h; (iii) N-acryloyl oxazolidinone (1.0 mole eq.), Grubbs’ 2nd gen.
route to the “parent system” 3. Thus, reaction of the potassium
catalyst (10 mole%), CH Cl , 40 ЊC, 24 h; (iv) TBSOCH CH᎐
CH OTBS (2.0 mole eq.), Grubbs’ 1st gen. catalyst (10 mole%),
CH Cl , 40 ЊC, 24 h then TBAF (1.2 mole eq.), THF, 18 ЊC, 2 h;
2
2
2
salt of pyrrole (5) with γ-butyrolactone 6 gave, after acidic work
2
1,2
up, the previously reported acid 7 (95%). The readily derived
methyl ester 8 was reduced, with DIBAL-H, to the unstable
aldehyde 9 which was subjected to in situ Wadsworth–Horner–
2
2
(v) t-BuOOH (1.0 mole eq.), Ti(Oi–Pr)
ϩ)-tartrate (1.0 mole eq.), 4 Å molecular sieves, CH Cl , Ϫ20 ЊC, 24 h.
(1.0 mole eq.), diisopropyl
4
(
2
2
5
Emmons-type olefination with the relevant phosphonoacetate
7
8
thus affording the required substrates 10 (68% from 8, 4 : 1
mixture of E- and Z-isomers) and 11 (79% from 8, 10 : 1
mixture of E- and Z-isomers).
acrylate in the presence of Grubbs’ 2nd generation catalyst.
The latter step of these simple sequences was efficient (> 75%)
and proceeded with high E-selectivity such that serviceable
quantities of the target substrates could be obtained in just a
few steps from readily available starting materials. Simple
extensions of this approach provided cyclisation precursor 14
(83%, E-isomer only) and allylic alcohol 15 (76%, 8.5 : 1 mix-
ture of E- and Z-isomers). Subjection of the latter compound
An alternate and more expeditious route to compounds
1
5
1
0 and 11 involved (Scheme 2) N-alkylation of pyrrole with
-bromo-1-pentene (12) and then subjecting the product alkene
6
3 (84%) to an olefin cross metathesis (OCM) with the relevant
9
to Sharpless asymmetric epoxidation (SAE) using diisopropyl
(ϩ)-tartrate afforded epoxy-alcohol 16 (87%, 98% ee ) as
†
Current address: School of Chemistry, University of Tasmania,
10
Private Bag 75, Hobart, TAS 7001, Australia.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 – 1 5 9
157

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another potential cyclisation substrate. An OCM reaction
11
involving alkene 13 and acrolein diethyl acetal afforded prod-
uct 17 (75% of a 4 : 1 mixture of E- and Z-isomers). Analogous
treatment of the same precursor acetal with the readily avail-
able lower and higher homologues of alkene 13 afforded the
lower and higher homologues of 17, i.e. 18 and 19 respectively,
in essentially the same yields and E/Z ratios. Compounds 17–19
proved to be very unstable materials and were, therefore,
immediately subjected to the cyclisation reactions described
below.
Preliminary cyclisation studies were undertaken with the
(
Ϫ)-8-phenylmethyl ester E-10 which reacted with boron tri-
fluoride diethyl etherate in DCM at Ϫ20 ЊC to give the expected
1
product 20 in 82% yield and 90% de as judged by 500 MHz H
NMR analysis. Reaction of methyl ester E-11 under analogous
conditions gave (±)-21 in 95% yield. The initial assignment
of the R-configuration at C8 to the major diastereoisomeric
form of 20 followed from consideration of transition state
Scheme 3 Reagents and conditions: (i) Davis oxaziridine (1.1 mole eq.),
NaHMDS (1.1 mole eq.), THF, Ϫ78 ЊC, 0.5 h; (ii) LiBH (1.5 mole eq.),
4
12
structures
and was confirmed by chemical correlation
THF, 18 ЊC, 2 h; (iii) NaIO (1.3 mole eq.), THF–pH 7 aq. buffer, 0 ЊC,
4
studies (vide infra). Reaction of the unsaturated acetal 17 with
0.5 h then NaBH (1.5 mole eq.), EtOH, 0 ЊC, 0.25 h; (iv) H (4 atm.),
4
2
13
MacMillan’s organocatalyst in THF–water at Ϫ20 ЊC for 24 h
afforded the expected aldehyde 22 in 83% yield and 87% ee as
determined by chiral HPLC analysis of the derived alcohol
5% Rh on Al
2
O
3
(5 w/w%), (CF ) CHOH, 18 ЊC, 2 h.
3 2
cleaved with NaIO in aqueous buffer. The resulting and highly
4
14
2
3. That the sense of the asymmetric induction associated
sensitive aldehyde was immediately reduced, with NaBH , to
4
with the conversion 17 22 is the same as obtained for the
preceding process follows from the observation that each of the
products 20 and 22 is converted into the same enantiomeric
the alcohol 28 (78% from 27) which was obtained in 90% ee as
18
determined by chiral HPLC analysis. Hydrogenation of com-
pound 28 at 4 atm using rhodium on alumina as catalyst and
hexafluoroisopropanol as solvent then afforded a chromato-
15
form of the 1Њ-alcohol 23 (90%, 87% ee ) on reduction with
lithium aluminium hydride. This outcome is fully consistent
with the transition state structure expected to be involved
graphically separable mixture of (Ϫ)-tashiromine 29 {85%, [α]
D
13
19a
Ϫ35 (c 0.87, CHCl ), lit. [α]D Ϫ36.3 (c 0.88, CHCl )} and
3
3
19b
in the cyclisation of the iminium ion derived from 17. In a
similar manner the higher homologue of 17, viz. compound 19,
cyclised in the presence of MacMillan’s catalyst to give the
expected product 24 in 75% yield and 96% ee. Disappointingly,
the lower homologue of 17, viz. compound 18, failed to engage
in the hoped-for cyclisation process. Reaction of the N-acyl-2-
oxazolidinone 14 with the box ligand [Cu((R,R)-Bz-box)]-
(Ϫ)-epi-tashiromine 30 {5%, [α] Ϫ0.96 (c 0.31, ethanol), lit.
D
[α]D (of enantiomer) ϩ1.1 (ethanol)}. The NMR spectral data
derived from compounds 29 and 30 were in excellent agreement
19c,d
with those reported
in the literature.
20
Tanis and Raggon have previously shown that pyrroles can
act as effective terminators in epoxide-initiated cationic cyclis-
ation sequences but, to date, no study involving enantio-
merically enriched substrates appears to have been undertaken.
Consequently, the final aspects of the present study involved
16
(
SbF6)2 in hexafluoroisopropanol–dichloromethane at Ϫ78 ЊC
for 2 h gave product 25 (94%) which upon reduction with
lithium borohydride afforded alcohol 23 in 91% yield albeit
in only 26% ee. In dramatic contrast, when the first step of
the same sequence was carried out with the [Cu((R,R)-Ph-
21
examination of the indium trichloride-promoted cyclisation
of epoxy-alcohol 16. In the event an 84% yield of compound
ent-27 (70% de) was obtained. Using the same protocol (oxid-
ative cleavage/reductive work-up) as employed previously
(Scheme 3), this diol was converted into the 8-hydroxymethyl-
tetrahydroindolizidine ent-28 (52% yield, 70% ee). These results
suggest that the conversion 16 27 definitely does not proceed
with strict inversion of configuration at the relevant carbon of
the epoxide ring.
16
box)](SbF6)2 ligand then ent-25, rather than 25, was obtained
in 95% yield and 88% ee.
The foregoing results demonstrate that chiral substrates,
auxiliaries and/or catalysts can all be employed in the prepar-
ation of enantiomerically enriched 8-substituted tetrahydro-
indolizidines, and higher homologues thereof, from pyrroles
incorporating N-tethered Michael acceptors and other electro-
philes. Our efforts are now focused on using such methods for
the enantioselective construction of quaternary carbon centres
as seen, for example, at C8 in compound 4. Results will be
reported in due course.
Acknowledgements
The absolute stereochemistry of the cyclisation products 20,
2, 25 and ent-25 was established through a chemical corre-
We thank the Institute of Advanced Studies (IAS) for financial
support including the provision of a post-Doctoral Fellowship
to JAS. DASB is the grateful recipient of an APA PhD Scholar-
ship. The skilful assistance of Mr Tony Herlt with chiral HPLC
analyses is warmly acknowledged.
2
lation study (Scheme 3) involving conversion of the last of these
into an indolizidine-type natural product of known configur-
ation. Thus, the enolate derived from N-acyl-2-oxazolidinone
17
ent-25 was reacted with the Davis oxaziridine to give the
α-hydroxylated derivative 26 as a ca. 1 : 1 mixture of
diastereoisomers. Reduction of compound 26 with lithium
borohydride then afforded the vic-diol 27 (63% from ent-25,
References
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M. G. Banwell and J. A. Smith, J. Chem. Soc., Perkin Trans. 1, 2002,
2613.
1
: 1 mixture of diastereoisomers) which was immediately
1
58
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 – 1 5 9

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2
3
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13 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123,
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14 This ee was determined using a Diacel AS-Chiralpak 46 × 250 mm
column with 5 : 95 v/v isopropanol–hexane as the eluting solvent
Ϫ1
(flow rate of 0.7 ml min ); R (major enantiomer): 12.2 min; (minor
t
enantiomer): 14.8 min.
15 This ee was determined using a Diacel AS-Chiralpak 46 × 250 mm
4
5
See, for example, R. Lueoend and R. Neier, Helv. Chim. Acta, 1991,
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7
4, 91 and references cited therein.
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t
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whilst commercially available trimethyl phosphonoacetate was used
for the conversion 9 11.
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6
7
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18 This ee was determined using a Diacel AS-H-Chiralpak 46 ×
250 mm column with 5 : 95 v/v isopropanol–hexane as the eluting
Ϫ1
solvent (flow rate of 1.0 ml min ); R (major enantiomer): 15.3 min;
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8
9
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5
974. For reviews see; (b) A. Pfenninger, Synthesis, 1986, 89;
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(
1
1
0 This ee was determined using a Diacel AS-Chiralpak 46 × 250 mm
column with 1 : 9 v/v isopropanol–hexane as the eluting solvent
Ϫ1
(
flow rate of 0.7 ml min ); R (major enantiomer): 24.8 min; (minor
t
enantiomer): 21.9 min. The illustrated absolute stereochemistry for
9
1
6 was initially assigned using the Sharpless mnemonic but
subsequently confirmed by chemical correlation studies (see text).
1 This material was purchased from TCI, Japan.
1
1
ing related applications of InCl see: (b) J. S. Yadav, S. Abraham,
3
2 (a) E. J. Corey and H. E. Ensley, J. Am. Chem. Soc., 1975, 97, 6908;
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(
b) B. Mezrhab, F. Dumas, J. d’Angelo and C. Riche, J. Org. Chem.,
1
994, 59, 500.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 – 1 5 9
159