Enantioselective synthesis of bicyclic compounds via catalytic 1,4-addition-ring closing metathesis

Article abstract of DOI:10.1039/b100283j

A novel three step asymmetric annulation procedure comprises a tandem catalytic enantioselective 1,4-additionallylic substitution, Grignard addition and ring closing metathesis (RCM) sequence to provide [6,6], [7,6], [8,6] and [6,7] bicyclic products with

Full text of DOI:10.1039/b100283j

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Enantioselective synthesis of bicyclic compounds via catalytic 1,4-addition-ring
closing metathesis†
Robert Naasz, Leggy A. Arnold, Adriaan J. Minnaard and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh
4, NL-9747 AG Groningen, The Netherlands. E-mail: Feringa@chem.rug.nl; Fax: +(50)3634296
Received (in Cambridge, UK) 8th January 2001, Accepted 8th March 2001
First published as an Advance Article on the web 30th March 2001
A novel three step asymmetric annulation procedure com-
prises a tandem catalytic enantioselective 1,4-addition-
allylic substitution, Grignard addition and ring closing
metathesis (RCM) sequence to provide [6,6], [7,6], [8,6] and
[6,7] bicyclic products with ee’s of 93–97% in which the size
of both rings can easily be varied independent of each
other.
Novel routes to carbobicyclic compounds in enantiomerically
pure form continue to offer a synthetic challenge since
numerous products including terpenes and steroids show this
structural feature. A classical example is found in the synthesis
of (±)- -homo-19-nortestosterone starting from the readily
D
available Wieland–Miescher ketone for which an asymmetric
synthesis proceeds via the Hajos–Parrish version of the
Robinson annulation.1,2 In the pursuit of novel catalytic
asymmetric annulation strategies we focus on the construction
of enantiomerically pure carbobicyclic products with various
ring sizes.3
Since the pioneering work by the groups of Grubbs and
Schrock, ring closing metathesis (RCM) has become a powerful
tool for the synthesis of a variety of cyclic structures.4
Especially for medium sized and macrocyclic ring systems,
which are difficult or even impossible to make by other
methods, RCM proved to be highly valuable.5 As a result of the
remarkable tolerance of the Grubbs catalyst towards various
functional groups, RCM is increasingly applied in natural
product synthesis.6
We envisioned that by making use of a combination of RCM
and the copper–phosphoramidite based catalytic enantiose-
lective 1,4-addition developed in our laboratories, a variety of
enantiomerically pure bicyclic products would become readily
accessible. In these bicyclic products both ring sizes can easily
be varied, independent of each other. The following considera-
tions were made: (i) cyclic enones with different ring sizes and
substituents can be employed in the catalytic 1,4-addition with
enantioselectivities generally exceeding 96% in the products.
These products can subsequently act as templates onto which a
second ring can be annulated.7 (ii) The use of RCM for this
annulation would make different ring sizes in the second ring
possible.8
Scheme 1
Table 1 Tandem-1,4-addition-allylic substitution to cyclic enones.
Entry
Enone
n
R1
R
C.y. 2 (%)a ee 2 (%)b trans–cisc
1
2
3
4
5
6
1a
1b
1c
1d
1a
1a
1
2
3
1
1
1
H
H
H
Et 2a 88
Et 2b 86
Et 2c 79
96
—
97
—
96
93
9+1
d
d
e
—
196+1
e
Me Et 2d 82
—
H
H
Me 2e 92
Bu 2f 83
5.3+1
9+1
a Isolated yield after column chromatography. b Determined by chiral GC
(Chiraldex G-TA). c Determined by GC. d Not determined. e Only trans
detected.
By introducing a second terminal alkene moiety via the
1,2-addition of suitable Grignard reagents such as vinyl-, allyl-
and butenylmagnesium halides to 2a–f, the corresponding
dienes 4a–h are formed which are next converted to carbobi-
cyclic structures 6a-h by RCM as is shown in Scheme 2.
Table 2 summarizes the results of this new enantioselective
method for the preparation of carbobicyclic structures. As
expected, a reasonable selectivity was observed for the addition
To examine the viability of this approach we synthesized
2-allyl-3-alkylcycloalkanones 2a–f by a tandem 1,4-addition-
allylic substitution reaction.3,9
As is shown in Scheme 1 the zinc enolate resulting from the
catalytic 1,4-addition of dialkylzinc reagent to cycloalkenones
in the presence of phosphoramidite ligand (S,R,R)-3 (1 mol%)
and Cu(OTf)2 (0.5 mol%) was trapped stereo- and regio-
selectively by the Pd–allyl complex in situ generated from allyl
acetate and a catalytic amount of Pd(PPh3)4, giving dis-
ubstituted cycloalkanones 2a–f in good yields and with ee’s
ranging from 93 to 97% (Table 1). Furthermore a trans–cis ratio
of 9+1 or higher is observed in all cases except for 2e (entry 5).10
In the case of 2b and 2d complete diastereoselectivity towards
the trans isomer is found.
† Electronic supplementary information (ESI) available: NMR spectra and
detailed explanation. See http://www.rsc.org/suppdata/cc/b1/b100283j/
Scheme 2
DOI: 10.1039/b100283j
Chem. Commun., 2001, 735–736
This journal is © The Royal Society of Chemistry 2001
735

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Table 2 Grignard addition and RCM
Entry
R
R1
n
m
C.y. 4a (%) ee 4b (%)
Ring system C.y. 6d (%) ee 6b (%)
c
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Et
Et
Et
Et
Me
Bu
Et
H
H
H
Me
H
H
H
H
1
2
3
1
1
1
1
1
1
1
1
1
1
1
0
2
4a
4b
4c
4d
4e
4f
92
68d
95
70
82
92
64
98
—
96
97
—
—
—
—
—
6a
6b
6c
6d
6e
6f
[6,6]
[7,6]
[8,6]
[6,6]
[6,6]
[6,6]
[6,5]
[6,7]
60
100
43
79
46
68
96
96
97
97
96e
93
—
96
c
c
c
c
c
f
2a
2a
4g
4h
6g
6h
—
65
Et
a Isolated yield as a mixture of diastereomers. b Determined by chiral GC (Chiraldex G-TA). c Not determined. d Isolated yield of all-trans isomer after
column chromatography. e Determined by chiral HPLC after conversion into the p-nitrobenzoate ester. f Only a small amount ( < 10%) of cis-fused 6g was
detected by GC.
of the Grignard reagents to 2a–f in all cases and the major
isomer results from the attack of the Grignard reagent trans to
the allyl group leading to the all-trans isomer as the major
product (Scheme 2). Addition of allylmagnesium chloride (m =
1, entry 1) to a 90+10 trans–cis mixture of 2a yields three out of
four possible diastereomers of 4a in a ratio of 74:16:10 as
judged by GC. This result is explained as follows: addition of
the Grignard reagent to the trans compound (2R,3S)-2a
proceeds preferably trans to the allyl group but not with
complete selectivity accounting for 74% (1R,2R,3S)-1,2-dia-
llyl-3-ethylcyclohexanol (4a) and 16% (1S,2R,3S)-4a. The
relative configuration of the major isomer was determined by
COSY, HSQC and NOESY NMR experiments on the p-
nitrobenzoate ester of 6a.† Addition to the minor cis compound
(2S,3S)-2a accounts for the 10% of another isomer of 4a, most
probably (1S,2S,3S)-4a.
In the case of trans-2b the ratio of trans and cis addition is
80:20 and pure trans-4b (68%) could be isolated by column
chromatography. The addition to trans-2c proceeds with a
moderate selectivity giving a trans:cis ratio of 63+37. Addition
of butenylmagnesium bromide (m = 2) to a 9+1 trans–cis
mixture of 2a in THF at 0 °C required transmetallation to the
organocerium reagent to prevent enolization and to give
complete conversion to 4h as a mixture of 3 isomers (87+12+1)
with (1R,2R,3S)-4h as the major product (entry 8).11
[6,6], [7,6], [8,6] and [6,7] carbobicyclic skeletons and different
alkyl substituents have been prepared with ee’s ranging from
93–97%.
This work was supported by the Dutch Foundation for
Scientific Research (NWO).
Notes and references
1 R. K. Boeckman, Jr., J. Am. Chem. Soc., 1974, 96, 6179; G. Stork and
J. Singh, J. Am. Chem. Soc., 1974, 96, 6181.
2 Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615; Z. G.
Hajos and D. R. Parrish, Org. Synth., 1984, 63, 26; P. Buchsacher and
A. Fürst, Org. Synth., 1984, 63, 37.
3 R. Naasz, L. A. Arnold, M. Pineschi and B. L. Feringa, J. Am. Chem.
Soc., 1999, 121, 1104
4 Recent reviews on RCM: A. Fürstner, Angew. Chem., Int. Ed., 2000, 39,
3013; R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413.
5 For examples ranging from 5- to 19-membered rings see: A. Fürstner
and L. Ackermann, Chem. Commun., 1999, 95; 72-membered ring: K.
Akawa, T. Eguchi and K. Kakinuma, J. Org. Chem., 1998, 63, 4741.
6 Recent examples A. Fürstner, T. Gastner and H. Weintritt, J. Org.
Chem., 1999, 64, 2361; M. T. Crimmins and A. L. Choy, J. Am. Chem.
Soc., 1999, 121, 5653; M. Scholl and R. H. Grubbs, Tetrahedron Lett.,
1999, 40, 1425; K. C. Nicolaou, J. Y. Xu, S. Kim, J. Pfefferkorn, T.
Oshima, D. Vourloumis and S. Hosokawa, J. Am. Chem. Soc., 1998,
120, 8661.
7 B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; L. A. Arnold, R. Imbos,
A. Mandoli, A. H. M. De Vries, R. Naasz and B. L. Feringa,
Tetrahedron, 2000, 56, 2865; B. L. Feringa, M. Pineschi, L. A. Arnold,
R. Imbos and A. H. M. De Vries, Angew. Chem., Int. Ed. Engl., 1997,
36, 2620; A. H. M. De Vries, A. Meetsma and B. L. Feringa, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2374; For a recent general review on
enantioselective conjugate additions: M. P. Sibi and S. Manyem,
Tetrahedron, 2000, 56, 8033.
8 For examples of other annulations using RCM: S. C. Cho, P. H.
Dussault, A. D. Lisec, E. C. Jensen and K. W. Nickerson, J. Chem. Soc.,
Perkin Trans. 1, 1999, 193; J. S. Clark, G. P. Trevitt, D. Boyal and B.
Staman, Chem. Commun., 1998, 2629; S. Hölder and S. Blechert,
Synlett, 1996, 505; A. Fürstner and K. Langemann, J. Org. Chem., 1996,
61, 8746; C. A. Tarling, A. B. Holmes, R. E. Markwell and N. D.
Pearson, J. Chem. Soc., Perkin Trans. 1, 1999, 1695.
9 M. Kitamura, T. Miki, K. Nakano and R. Noyori, Tetrahedron Lett.,
1996, 37, 5141.
10 The relative configuration of the major isomer of 2a has previously been
determined: M. Kitamura, T. Miki, K. Nakano and R. Noyori, Bull.
Chem. Soc. Jpn., 2000, 73, 999.
11 For general information on the preparation and addition of organo-
cerium componds see: N. Takeda and T. Imamoto, Org. Synth., 1998,
76, 228.
12 D. J. Holt, W. D. Bark, R. R. Jenkins, D. L. Davies, S. Garratt, J.
Fawcett, D. R. Russell and S. Ghosh, Angew. Chem., Int. Ed., 1998, 37,
3298; B. Schmidt and T. Sattelkau, Tetrahedron, 1997, 53, 12 991; S. J.
Miller, S.-H. Kim, Z.-R. Chen and R. H. Grubbs, J. Am. Chem. Soc.,
1995, 117, 2108; S. J. Miller and R. H. Grubbs, J. Am. Chem. Soc., 1995,
117, 5855.
All dienes 4a–h readily undergo ring closure in benzene in the
presence of 7.5 mol% of Grubbs catalyst 5, except for 4g. In the
latter case formation of only a small amount of 6g was observed
(entry 7). GC analysis revealed that only the cis isomer of 4g
had been converted. The trans-fused 5,6-ring system is not
formed, most probably due to the strain in such a system.12
Formation of a six membered ring (entries 1–6) proceeded well
in all cases as 100% conversion was observed, indicating that
both cis- and trans-fused ring systems are readily formed.
Isomerically pure trans-diene 4b provided the 7,6-bicyclic
product in 100% isolated yield. In all other cases the major
isomer of the resulting carbobicyclic products from this
annulation protocol was isolated in moderate to good yield by
simple chromatographic procedures with ee’s ranging from 93
to 97%. For example, (1S,9R,9aR)-6a could be isolated in 60%
yield. Annulation of a seven membered ring by RCM was also
successful as (1S,4aR,9aR)-6h with an ee of 96% was isolated in
65% yield (entry 8).
In conclusion, new methodology for the synthesis of
enantiomerically pure carbobicyclic compounds has been
developed, based on an enantioselective tandem 1,4-addition–
allylic substitution, Grignard addition and RCM three step
sequence. In contrast to most methodologies for asymmetric
annulations, which are restricted to specific ring sizes, the
method presented here gives high enantioselectivities for the
construction of a variety of bicyclic structures. Products with
736
Chem. Commun., 2001, 735–736