Asymmetric synthesis of substituted homoallyl alcohols, halomethyl tetrahydrofurans, and chloro-amino sulfones from allyltitanium sulfoximines and α-hetero aldehydes

Article abstract of DOI:10.1021/ol0627606

Asymmetric syntheses of the iodomethyl-substituted bicyclic tetrahydrofuran 22 and the chloro-amino sulfone 30 from the allylic sulfoximine 15 and the α-hetero aldehydes 2 and 23, respectively, are described. Further examples for the asymmetric synthesis

Full text of DOI:10.1021/ol0627606

ORGANIC
LETTERS
2007
Vol. 9, No. 4
579-582
Asymmetric Synthesis of Substituted
Homoallyl Alcohols, Halomethyl
Tetrahydrofurans, and Chloro-amino
Sulfones from Allyltitanium Sulfoximines
and
r-Hetero Aldehydes
A. Rajender and Hans-Joachim Gais*
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule
(RWTH) Aachen, Landoltweg 1, 52074 Aachen, Germany
gais@rwth-aachen.de
Received November 13, 2006
ABSTRACT
Asymmetric syntheses of the iodomethyl-substituted bicyclic tetrahydrofuran 22 and the chloro-amino sulfone 30 from the allylic sulfoximine
15 and the -hetero aldehydes 2 and 23, respectively, are described. Further examples for the asymmetric synthesis of chloromethyl
r
tetrahydrofurans and chloro-amino sulfones are given. The synthesis of 30 features as key step the stereoselective Cl-substitution of a hydroxy
group under neighboring group participation by an aminosulfoxonium group which is converted to a sulfonyl group.
The asymmetric synthesis of tetrahydrofurans1,2 and â-amino
alcohols3,4 has attracted considerable attention. Tetrahydro-
furans5 and â-amino alcohols6 occur as structural motives
in a large number of natural products, and â-amino alcohols
have found application in the synthesis of chiral ligands and
auxiliaries.7 We describe in this paper asymmetric syntheses
of mono- and bicyclic halomethyl tetrahydrofurans of type
C and unsaturated chloro-amino sulfones of type A (Figure
1). While halomethyl tetrahydrofurans of type C are of
interest as starting materials for the synthesis of both new
muscarine analogs for the treatment of Alzheimer’s disease8
and tetrahydrofuran-containing macrocycles,5 halides A
should give access not only to the corresponding â-amino
alcohols but also to a number of other synthetically interest-
(1) For recent examples, see: (a) Mertz, E.; Tinsley, J. M.; Roush, W.
J. Org. Chem. 2005, 70, 8035. (b) Reddy, L. V. R.; Roy, A. D.; Raja, R.;
Shaw, A. K. Chem. Commun. 2006, 32, 3444. (c) Goeksel, H.; Stark, C. B.
W. Org. Lett. 2006, 8, 3433.
(2) For reviews, see: (a) Biovin, T. L. B. Tetrahedron 1987, 43, 3309.
(b) Katsuki, T. Curr. Org. Chem. 2001, 5, 663. (c) Gruttadauria, M.; Lo,
Meo, P.; Noto, R. Targets Heterocycl. Syst. 2001, 5, 31.
(3) For recent examples, see: (a) Garc´ıa-Delgado, N.; Reddy, K. S.; Sola`,
L.; Riera, A.; Perica`s, M. A.; Verdaguer, X. J. Org. Chem. 2005, 70, 7426.
(b) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097. (c) Sello, G.;
Orsini, F.; Bernasconi, S.; Di Gennaro, P. Tetrahedron: Asymmetry 2006,
17, 372.
(4) For reviews, see: (a) Reetz, M. Chem. ReV. 1999, 99, 1121. (b) Kolb,
H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis, 2nd
ed.; Beller, M., Bolm, C., Eds; Wiley-VCH: Weinheim, 2004; Vol. 2, p
309.
(6) For reviews, see: (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(b) Lee, H.-S.; Kang, S. H. Synlett 2004, 10, 1673.
(7) For reviews, see: (a) Fache, F.; Schulz, E.; Tommasino, L. M.;
Lemaire, C. Chem. ReV. 2000, 100, 2159. (b) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. ReV. 1996, 96, 835.
(5) For reviews, see: (a) Nicolaou, K. C.; Vourloumis, D.; Baran, P.
Angew. Chem., Int. Ed. 2000, 39, 44. (b) Bermejo, A.; Figade`re, B.; Zafra-
Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005,
22, 269. (c) Kang, E. J.; Lee, E. Chem. ReV. 2005, 105, 4348.
(8) (a) Hartung, J.; Kneuer, R. Tetrahedron: Asymmetry 2003, 14, 3019.
(b) Bikadi, Z.; Simonyi, M. Curr. Med. Chem. 2003, 10, 2611. (c) Popsavin,
V.; Popsavin, M.; Radic, L.; Beric, O.; Cirin-Novta, V. Tetrahedron Lett.
1999, 40, 9305.
10.1021/ol0627606 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/17/2007

aldehyde 19 with the titanium complexes derived from the
allyl sulfoximines 7 and 8 in the presence of an additional 1
equiv of ClTi(OiPr)3, which proceeded with high diastereo-
selectivity and gave the homoallylic alcohols 20 and 21,
respectively, in high overall yields. Next the cyclization of
the silyloxy-substituted homoallyl alcohols of type D with
formation of tetrahydrofurans of type B was investigated.
Treatment of the silyl ether 3 with either HF·pyridine in THF
or Bu4NF in THF led to a cleavage of the silyl group
followed by a highly diastereoselective cyclization, which
gave the tetrahydrofuran 4a in high yield. A similar treatment
of the cyclic silyloxy-substituted vinyl sulfoximines 9, 10,
and 16 resulted in a similarly highly diastereoselective
cyclication and afforded the bicyclic tetrahydrofurans 11a,
12a, and 17a, respectively, in high yields. The configuration
of 11a was determined by X-ray crystal structure analysis.
The application of sulfoximine-substituted tetrahydrofurans
of type B in, for example, the synthesis of muscarine agonists
requires the replacement of the sulfoximine group by a
halogen atom and their conversion to C. We had previously
shown that S-alkyl-N-methyl sulfoximines are readily con-
verted to the corresponding alkyl chlorides upon reaction
with a chloroformate.11 Thus treatment of the acyclic
sulfoximine 4b, which was obtained through silylation of
alcohol 4a (91%), with ClCO2CH(Cl)Me in CH2Cl2 at room
temperature cleanly afforded chloride 6 in good yield.
Similarly, reaction of the cyclic sulfoximines 11b and 12b,
obtained through silylation of alcohols 11a (98%) and 12a
(86%), respectively, with the chloroformate furnished the
bicyclic chloromethyl tetrahydrofurans 13 and 14, respec-
tively, in good yields. Finally, the reactivity of the function-
alized sulfoximine 17b, which was prepared through silyl-
ation of alcohol 17a (89%), was probed in order to get
information about the functional group tolerance of this
substitution. Treatment of sulfoximine 17b with the chloro-
formate gave chloride 18 in high yield. Eventually it was
found that iodides are also directly accessible from alkyl
sulfoximines.12 Treatment of sulfoximine 17b with phenyl
iodoformate13 in MeCN afforded iodide 22 in good yield.
The conversion of sulfoximines 4b, 11b, 12b, and 17b into
the corresponding halides upon reaction with a haloformate
involves an acyclation at the N-atom with formation of the
corresponding aminosulfoxonium salts carrying a methyl and
an ester group at the N-atom, followed by a nucleophilic
substitution of the aminosulfoxonium group by the halide
ion with formation of the corresponding halides and sulfi-
namides 5a and 5b, respectively. Sulfinamides 5a and 5b
were isolated in high yields. Since sulfinamide 5a of g98%
ee had already been converted to (S)-N,S-dimethyl-S-phen-
ylsulfoximine of g98% ee with good yield,11 recycling of
the chiral auxiliary is guaranteed.
Figure 1. Asymmetric synthesis of halomethyl tetrahydrofurans
and unsaturated chloro-amino sulfones.
ing derivatives. Key steps of the syntheses of A and C are
(1) a highly regio- and diastereoselective γ-hydroxyalkylation
of the allyltitanium sulfoximines F9 with R-hydroxy and
R-amino aldehydes of type E, (2) a highly diastereoselective
cyclization of homoallyl alcohols of type D (Het ) OH) with
formation of tetrahydrofurans of type B, (3) a substitution
of sulfoximines B with formation of halides C, and (4) a
novel one-pot stereoselective conversion of the hydroxy
sulfoximines D to chloro sulfones of type A. Although
sulfoximine-substituted tetrahydrofurans of type B, carrying
a functionalized chiral substituent at the N-atom, have been
previously prepared with high selectivity by a similar route,
their substitution with formation of halomethyl tetrahydro-
furans of type C or other functionalized tetrahydrofurans
proved not to be feasible.10
The allyl sulfoximines 1, 7, 8, and 15 (Scheme 1) were
prepared by the one-pot addition-elimination-isomerization
(AEI) route starting from the corresponding ketones and
enantiopure (S)-N,S-dimethyl-S-phenylsulfoximine in 78%,
86%, 83%, and 91% overall yield, respectively, as described
previously.9 The acyclic sulfoximine 1 was obtained as a
single E-isomer. Reaction of the allyltitanium sulfoximines
(cf. Figure 1) derived from sulfoximines 1, 7, 8, and 15 with
1.4 equiv of aldehyde 2 occurred with high diastereoselec-
tivity and furnished the silyloxy-substituted homoallylic
alcohols 3, 9, 10, and 16, respectively, in high overall yields.
The complete conversion of the intermediate allyltitanium
sulfoximines derived from 1, 7, 8, and 15 required the
presence of an additional 1 equiv of ClTi(OiPr)3.9a,b Therefore
it was gratifying to see that the presence of the Lewis acid
did not noticeably interfere in the reaction of the acetal-
substituted allyl sulfoximine 15. A similar situation was
encountered in the reaction of the acetal-protected chiral
Favorable results having been recorded in the hydroxy-
alkylation of complexes F with R-hydroxy aldehydes, their
reaction with R-amino aldehydes was studied. Treatment of
the allyltitanium sulfoximines derived from the allyl sulfox-
(9) (a) Gais, H.-J; Hainz, R.; Mu¨ller, H.; Bruns, P.; 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, 24, 3973. (b) Koep, S.;
Gais, H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243. (c) Ku¨pker,
K.; Diploma Thesis, RWTH Aachen 2005.
(10) (a) Reggelin, M.; Weinberger, H.; Heinrich, T. Liebigs Ann./Recueil
1997, 1881. (b) Reggelin, M.; Gerlach, M.; Vogt, M. Eur. J. Org. Chem.
1999, 1011. (c) Reggelin, M.; Junker, B.; Heinrich, T.; Slavik, S.; Bu¨hle,
P. J. Am. Chem. Soc. 2005, 128, 4023. (d) Reggelin, M.; Ku¨hl, J.; Kaiser,
J. P.; Bu¨hle, P. Synthesis 2006, 13, 2224.
(11) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org.
Chem. 2003, 8, 1500.
(12) Ko¨hler, F.; Gais, H.-J. Unpublished results.
(13) Hoffmann, H. M. R.; Iranshahi, L. J. Org. Chem. 1984, 49, 1174.
580
Org. Lett., Vol. 9, No. 4, 2007

Scheme 1. Reaction of Allyltitanium Sulfoximines with R-Hydroxy Aldehydes and Asymmetric Synthesis of Tetrahydrofurans
imines 1, 8, and 15 with aldehyde 23 in the presence of an
additional 1 equiv of ClTi(OiPr)3 proceeded with high
diastereoselectivity and gave the diastereopure homoallyl-
amino alcohols 24, 27, and 29, respectively, in high overall
yields (Scheme 2). Because of synthetic and mechanistic
reasons, the reactivity of aldehyde 31 and its enantiomer ent-
31 was also studied. Gratifyingly, reaction of the allyltitanium
sulfoximine derived from the seven-membered cyclic allyl
sulfoximine 8 with aldehydes 31 and ent-31 occurred in both
cases with high diastereoselectivity and gave the homoallyl
alcohols 32 and 34, respectively, in high overall yields. Thus
the chirality of the aldehyde has no influence upon the
stereoselectivity of the hydroxyalkylation. The configur-
ation of 32 was determined by X-ray crystal structure
analysis.
We had previously found that sulfoximine-substituted
homoallyl alcohols derived from F and unsubstituted alde-
hydes undergo upon reaction with a chloroformate an
acylation at the N-atom followed by a vinyl-allyl isomer-
ization and a subsequent substitution of the allylic amino-
sulfoxonium group by the Cl- ion to give the corresponding
allyl chloride.14 This prompted a study of the reactivity of
the amino-substituted homoallyl alcohols of type D (Het )
NR2) toward chloroformates. Surprisingly, treatment of the
acyclic sulfoximine 24 with ClCO2CH(Cl)Me gave â-chlo-
roamine 26 carrying a sulfonyl group instead of the sulfox-
imine group with high diastereoselectivity in good yield. In
addition to the chloro sulfone 26, the carbamate 25 was
isolated in similar yield. The generality of this novel
transformation was demonstrated by the reaction of the cyclic
sulfoximines 27, 29, and 32 with ClCO2CH(Cl)Me, which
gave with high diastereoselectivity the chloro-amino sulfones
28, 30, and 33, respectively, in good yields. The configuration
of the chloro sulfone 30 was determined by X-ray crystal
structure analysis.
The stereoselective transformations of the two functional
groups may be rationalized by the operation of a nucleophilic
substitution cascade as exemplified for sulfoximine 29 (cf.
Scheme 2). Sulfoximine 29 reacts with the chloroformate
through acylation at the N-atom to give the hydroxy
aminosulfoxonium salt 35. An intramolecular nucleophilic
attack of the hydroxy group of 35 at the S-atom is followed
by an elimination of 25 to furnish the cyclic oxosulfoxonium
(14) Tiwari, S. K.; Gais, H.-J.; Lindenmaier (nee Schneider), 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.
Org. Lett., Vol. 9, No. 4, 2007
581

Scheme 2. Reaction of Allyltitanium Sulfoximines with R-Amino Aldehydes and Asymmetric Synthesis of δ-Chloro-ꢀ-amino
Sulfones
salt 36. Salt 36 undergoes, as an O-alkylated sulfone, a facile
intramolecular nucleophilic substitution by the amino group
under inversion of configuration with formation of the
aziridinum salt 37. Then salt 37 reacts with the Cl- ion with
inversion of configuration15 to deliver the chloro-amino
sulfone 30. According to molecular model analyses the
high regioselectivity of the ring opening of 37 and the
corresponding aziridinium ions derived from 24 and 27
seems to be primarily due to a shielding of the Câ atom by
the sulfonyl group. In the case of the hydroxy sulfoximine
32, the Boc group could exert a similar neighboring group
effect leading to the intermediate formation of the oxazolium
salt 38. In summary, we have developed asymmetric
syntheses of halomethyl-substituted mono- and bicyclic
tetrahydrofurans and unsaturated chloro-amino-substituted
sulfones, a key step of which is the highly selective
hydroxyalkylation of allylsulfoximines with R-hydroxy and
R-amino aldehydes. The synthesis of the unsaturated chloro-
amino-substituted sulfones involves the stereoselective sub-
stitution of a hydroxy group by the Cl- ion under neighboring
group participation by an aminosulfoxonium group which
in turn is converted to a sulfonyl group.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 380 and GK 440).
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 15, 16, 17a,
1
17b, 18, 29, and 30 and copies of the H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) (a) Stamm, H. J. Am. Chem. Soc. 1999, 341, 319. (b) Weber, K.;
Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647. (c) O’Brien, P.; Towers,
T. D. J. Org. Chem. 2002, 67, 304.
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