Asymmetric modular synthesis of highly functionalized medium-sized carbocycles and lactones via ring-closing metathesis of sulfoximine-substituted trienes

Article abstract of DOI:10.1021/ja0651658

A modular asymmetric synthesis of medium-sized carbocycles and lactones has been developed that affords highly substituted 7-, 9-, and 11-membered rings. The key steps are (1) the highly diastereoselective synthesis of sulfoximine-substituted homoallylic

Full text of DOI:10.1021/ja0651658

Published on Web 11/11/2006
Asymmetric Modular Synthesis of Highly Functionalized Medium-Sized
Carbocycles and Lactones via Ring-Closing Metathesis of
Sulfoximine-Substituted Trienes
Michal Lejkowski, Hans-Joachim Gais,* Prabal Banerjee, and Cornelia Vermeeren
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule (RWTH) Aachen, Landoltweg 1,
52056 Aachen, Germany
Received July 19, 2006; E-mail: gais@rwth-aachen.de
The asymmetric synthesis of highly substituted medium-sized
Scheme 1
rings is a topic of considerable interest.1-3 Medium-sized carbo-
cycles and lactones for example are found as structural motifs in a
number of biologically relevant natural products.2-4 In this Communi-
cation we describe a new asymmetric synthesis of highly substituted
medium-sized carbocycles and lactones. Its key elements are the
modular synthesis of sulfoximine-substituted trienes starting from
enantiopure allylic sulfoximines and their ring-closing metathesis
(RCM).2,3
The successive treatment of the allylic sulfoximine 15 with nBuLi,
2.1 equiv of ClTi(OiPr)3, 2-butenal, 4-pentenal, and 2-methyl-
propanal at -78 °C afforded the corresponding sulfoximine-sub-
stituted homoallylic alcohols 2a, 2b, and 2c,5a each with g96% de
in 70-81% yield (Scheme 1). Their silylation (ClSiEt3, DMF, and
imidazol) furnished sulfoximines 3a, 3b, and 3c5a in 95-96% yield.
The lithiation of the Z-alkenyl sulfoximines5b,6 3a-c with nBuLi
at -78 °C occurred selectively at the R-position and gave the corres-
ponding Z-alkenyllithium derivatives which suffered at -30 °C a
complete isomerization to the E-configured alkenyllithium deriva-
tives5b,6 4a-c. Their treatment with allyl bromide furnished the
E-configured sulfoximine-substituted trienes 5a-c each as a single
Scheme 2
isomer in 75-92 overall yield based on 3a-c. The analogous
reaction of 4a and 4b with 4-pentanal proceeded efficiently but
was nearly unselective in regard to C-5 and gave the E-configured
allylic alcohols R-6a, S-6a, R-6b, and S-6b, respectively. Their
separation and silylation (ClSitBuMe2, DMF, and imidazol) afforded
the silyl ethers R-7a, S-7a, R-7b, and S-7b, respectively, in high
overall yield based on 3a-c. With the enantio- and diastereopure
sulfoximine-substituted trienes in hand, their RCM was studied.
Treatment of the 1,4,8-triene 5a (0.005 M) with 5 mol % of the
ruthenium complex 82 in toluene at reflux for 12 h gave the
7-membered carbocycle 9 in 96% yield (Scheme 2). A similar RCM
reaction of the 1,4,10-triene 5b with 8 furnished the Z-configured
nine-membered carbocycle 10 in 90% yield. Despite their congested
structure, the epimeric 1,6,10-trienes R-7a and S-7a also underwent
a facile RCM reaction. Thus treatment of R-7a and S-7a (0.005
M) with 5 mol % of 8 in CH2Cl2 at reflux for 12 h gave the
Z-configured nine-membered carbocycles R-11 and S-11, respec-
tively, in 90% and 80% yield. The configurations of R-11 and S-11
at C-1 were determined by NOE experiments. The treatment of
the 1,6,12-triene R-7b with 8 under the above conditions afforded
the Z-configured 11-membered carbocycle 12 in 70% yield and its
E-configured isomer 13 in 5% yield.7 The configurations of R-12
at C-1 was determined by NOE experiments.
The advantages offered by the modular synthesis of the sulfox-
imine-substituted trienes are demonstrated by the stereoselective
synthesis of triene 14 (Scheme 3) containing a tertiary C-atom.
Reaction of the alkenyllithium derivative 4a with propanal gave a
mixture of the epimeric allylic alcohols R-13 and S-14 in 80% yield.
Oxidation of the alcohols with Dess-Martin periodinane (DMP)
afforded enone 15 in 96% yield. The allylation of enone 15 with
allylmagnesium bromide gave the tertiary alcohol 16 with 96% de
in 90% yield. Thus, contrary to what was observed in the
hydroxyalkylation of 4a and 4b the sulfoximine group of enone
15 provided a high degree of asymmetric induction in the addition
to the carbonyl group. The treatment of the 1,5,9-triene 16 with 5
9
15378
J. AM. CHEM. SOC. 2006, 128, 15378-15379
10.1021/ja0651658 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 5
Scheme 4
of the 1,4,12-triene 23 with 8 furnished the Z-configured 11-
membered lactone 25 in 81% yield.
In summary, we have developed a highly flexible asymmetric
synthesis of functionalized medium-sized carbocycles and lactones
through RCM of sulfoximine-substituted trienes. Because of the
alkenyl sulfoximine moiety8 of the carbocycles and lactones, further
transformations can be envisioned including a Michael addition8
followed by a Cl-substitution of the sulfoximine group,6b a Ni-
catalyzed cross-coupling reaction with organometal reagents9 and
a migratory Cl-substitution of the sulfoximine group.10
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft (SFB 380) is gratefully acknowl-
edged. We thank Prof. S. Blechert for his collaboration in a study
of the RCM of sulfoximine-substituted dienes.
Supporting Information Available: Experimental procedures and
characterization data for 2a, 5a, 9, 17, 21, 23, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Yet, L. Chem. ReV. 2000, 100, 2963-3007. (b) Molander, G. A.;
Brown, G. A.; Storch de Gracia, I. J. Org. Chem. 2002, 67, 3459-3463.
(c) Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M.
A. H.; Matthews, I. R.; Wilson, F. X.; Witherington, J. Angew. Chem.,
Int. Ed. 2002, 41, 4313-4316. (d) Torres, E.; Chen, Y.; Kim, I. C.; Fuchs,
P. L. Angew. Chem., Int. Ed. 2003, 42, 3124-3131. (e) Baluenga, J.;
Alonso, J.; Fan˜ana´s, F. J. Chem.sEur. J. 2005, 11, 4995-5006. (f)
Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed. 2005,
44, 3895-3899. (g) Deng, L.; Giessert, A. J.; Gerlitz, O. O.; Dai, X.;
Diver, S. T.; Davies, H. M. L. J. Am. Chem. Soc. 2005, 127, 1342-1343.
(2) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036-2056. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003,
42, 4592-4633. (d) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199-2238.
(3) (a) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goodard, R.; Lehmann, C.
W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069. (b) Crimmins,
M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126, 10264-10266.
(4) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757-5821. (b)
Rigby, J. H. In Studies in Natural Products Synthesis; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, The Netherlands, 1993; Vol. 12, pp 233-
274. (c) Nicolaou, K. C.; Vourloumis, D.; Baran, P. Angew. Chem., Int.
Ed. 2000, 39, 44-122.
mol % of 8 in CH2Cl2 at reflux for 16 h furnished the eight-
membered carbocycle 17 in 90% yield. The S-configuration of 16
and 17 at C1 was tentatively assigned on the basis of model
considerations of the addition of the Grignard reagent to 15.
To demonstrate the synthetic potential of the sulfoximine-
substituted carbocycles, the 11-membered derivative 12 was treated
with AcOH/H2O in THF, which gave the allylic alcohol 18 in 96%
yield (Scheme 4). We ascribe the highly selective cleavage of the
tBuMe2Si group in the presence of the Et3Si group to a neighboring
effect exerted by the protonated sulfoximine group. Protonation of
sulfoximine 12 should give salt 12/AcOH in which the tBuMe2Si
group could be selectively activated toward a nucleophilic attack
by an intramolecular hydrogen bond. Oxidation of alcohol 18 with
DMP afforded enone 19 in 90%. An example for the facile
substitution of the sulfoximine group is provided by the cross-
coupling reaction of the alkenyl sulfoximine 9 with LiCuMe2 (3
equiv) in the presence of ClSiMe3, which gave the methylated
carbocycle 20 in 60% yield (95% based on recovered 9).
Because of the strong interest in the synthesis of medium-sized
lactones by RCM,1,2,3a their synthesis starting from the sulfoximine-
substituted diene 3c was probed. The esterification of alcohol 21,
obtained by desilylation of 5c (HF/pyridine, THF, 95%), with
acrylic acid and pent-4-enoic acid by using DCC/DMAP afforded
ester 22 in 47% yield (80% yield based on recovered 21) and ester
23 in 67% yield (97% yield based on recovered 21), respectively
(Scheme 5). The treatment of the 1,4,10-triene 22 (0.005 M) with
8 mol % of 8 in toluene at reflux for 16 h gave the Z-configured
9-membered lactone 24 in 87% yield. The similar RCM reaction
(5) (a) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe,
G.; Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.;
Loo, R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973-4009. (b)
Reddy, L. R.; Gais, H.-J.; Woo, C.-W.; Raabe, G. J. Am. Chem. Soc.
2002, 124, 10427-10434.
(6) (a) Gais, H.-J.; Mu¨ller, H.; Decker, J.; Hainz, R. Tetrahedron Lett. 1995,
36, 7433-7436. (b) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G.
Eur. J. Org. Chem. 2003, 1500-1526.
(7) Interestingly, the treatment of the 1,6,12-triene S-7b with 8 gave the
corresponding asymmetric and C2-symmetric 22-membered carbocycles
(32% and 38%) through a combination of CM and RCM reactions.
(8) Reggelin, M; Zur, C. Synthesis 2000, 1-64.
(9) (a) Erdelmeier, I.; Gais, H.-J. J. Am. Chem. Soc. 1989, 111, 1125-1126.
(b) Gais, H.-J.; Bu¨low, G. Tetrahedron Lett. 1992, 33, 461-464. (c) Gais,
H.-J.; Bu¨low, G. Tetrahedron Lett. 1992, 33, 465-468.
(10) Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu, G. S.; Raabe, G.; Reddy,
L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.; Iska, V. B. R. J. Am. Chem. Soc.
2006, 128, 7360-7373.
JA0651658
9
J. AM. CHEM. SOC. VOL. 128, NO. 48, 2006 15379