Asymmetric synthesis of anti-homopropargylic alcohols from aldehydes and chiral sulfonimidoyl substituted bis(allyl)titanium complexes through generation and elimination of novel chiral alkylidenecarbene (dimethylamino)sulfoxonium ylides

Article abstract of DOI:10.1021/ja020570u

A new method for the asymmetric synthesis of anti-configured homopropargylic alcohols 1 is described, which features the addition of chiral sulfonimidoyl substituted bis(allyl)titanium complexes 3 to aldehydes, the methylation of sulfonimidoyl substituted homoallylic alcohols 2 at the N-atom, and the elimination of alkenyl (dimethylamino)sulfoxonium salts 7 with LiN(H)tBu. The reaction of isopropyl, cyclohexyl, and methyl substituted allylic titanium complexes 3a-c with benzaldehyde, p-bromobenzal-dehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, (E)-3-phenylpropenal, and phenylpropynal afforded with high regio- and diastereoselectivities the anti-configured sulfonimidoyl substituted homoallylic alcohols 2a-j, respectively. Only one allylic unit of the titanium complexes 3a-c was transferred in the case of unsaturated aldehydes, and the starting allylic sulfoximines 2a-g were recovered in approximately 50% yield. The methylation of the silyl protected alkenyl sulfoximines 6a-j with Me₃OBF₄ gave in practically quantitative yields the (dimethylamino)sulfoxonium salts 7a-j, respectively. Salts 7a-e, 7g, 7h, and 7j delivered upon treatment with 2 equiv of LiN(H)tBu the enantio- and diastereomerically pure saturated and unsaturated alkynes 9a-e, 9g, 9h, and 9j, respectively, in high yields. Besides the alkynes the sulfinamide 8 (96% ee) was isolated. Aminosulfoxonium salts 9f and 9i, which carry a CC triple bond, also suffered an elimination under these conditions but did not yield the corresponding diynes. Elimination of salts 7a-e, 7g, 7h, and 7j proceeds most likely through deprotonation at the α-position with formation of the novel alkylidenecarbene aminosulfoxonium ylides 19a-e, 19g, 19h, and 19j, respectively. The ylides 19a-e, 19g, 19h, and 19j presumably eliminate sulfinamide 8 with generation of the chiral nonracemic β-siloxyalkylidene)carbenes 20a-e, 20g, 20h, and 20j, which suffer a 1,2-H-shift with formation of alkynes 9. Support for the formation of the putative alkylidenecarbenes 20 as intermediates comes from the elimination of the β-methyl substituted aminosulfoxonium salt 24, which delivered the enantio- and diastereomerically pure 2,3-dihydrofuran derivative 28 upon treatment with LiN(H)tBu in high yield. Here, the putative β-siloxyalkylidene)carbene 26 suffers a 1,5-O,Si bond insertion rather than a 1,2-Me shift. Methylation of the alkenyl sulfoximine 6a at the α-position with formation of 13 was achieved through deprotonation of the former with formation of the α-lithioalkenyl sulfoximine 11a and its treatment Mel. Reaction of the α-methylated alkenyl aminosulfoxonium salt 14a with LiN/Pr₂ at low temperatures gave the enantio- and diastereomerically pure anti-configured homoallenylic alcohol derivative 15, while reaction of the salt with LiN/Pr₂ or LiN(H)tBu at higher temperatures afforded the enantio- and diastereomerically pure nonterminal homopropargylic alcohol derivative 17. Deprotonation of the alkenyl (dimethylamino)sulfoxonium salts 7a and 7b with nBuLi afforded the novel alkylidenecarbene aminosulfoxonium ylides 19a and 19b, respectively, which upon treatment with Mel yielded the methylated aminosulfoxonium salts 14a and 14b, respectively.

Full text of DOI:10.1021/ja020570u

Published on Web 08/08/2002
Asymmetric Synthesis of anti-Homopropargylic Alcohols from
Aldehydes and Chiral Sulfonimidoyl Substituted
Bis(allyl)titanium Complexes through Generation and
Elimination of Novel Chiral Alkylidenecarbene
(Dimethylamino)sulfoxonium Ylides
Leleti Rajender Reddy, Hans-Joachim Gais,* Chang-Wan Woo, and Gerhard Raabe
Contribution from the Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen
Hochschule (RWTH) Aachen, Professor-Pirlet-Strasse 1, D-52056 Aachen, Germany
Received April 22, 2002
Abstract: A new method for the asymmetric synthesis of anti-configured homopropargylic alcohols 1 is
described, which features the addition of chiral sulfonimidoyl substituted bis(allyl)titanium complexes 3 to
aldehydes, the methylation of sulfonimidoyl substituted homoallylic alcohols 2 at the N-atom, and the
elimination of alkenyl (dimethylamino)sulfoxonium salts 7 with LiN(H)tBu. The reaction of isopropyl,
cyclohexyl, and methyl substituted allylic titanium complexes 3a-c with benzaldehyde, p-bromobenzal-
dehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, (E)-3-phenylpropenal, and phenylpropynal afforded
with high regio- and diastereoselectivities the anti-configured sulfonimidoyl substituted homoallylic alcohols
2a-j, respectively. Only one allylic unit of the titanium complexes 3a-c was transferred in the case of
unsaturated aldehydes, and the starting allylic sulfoximines 2a-g were recovered in approximately 50%
yield. The methylation of the silyl protected alkenyl sulfoximines 6a-j with Me3OBF4 gave in practically
quantitative yields the (dimethylamino)sulfoxonium salts 7a-j, respectively. Salts 7a-e, 7g, 7h, and 7j
delivered upon treatment with 2 equiv of LiN(H)tBu the enantio- and diastereomerically pure saturated and
unsaturated alkynes 9a-e, 9g, 9h, and 9j, respectively, in high yields. Besides the alkynes the sulfinamide
8 (96% ee) was isolated. Aminosulfoxonium salts 9f and 9i, which carry a CC triple bond, also suffered an
elimination under these conditions but did not yield the corresponding diynes. Elimination of salts 7a-e,
7g, 7h, and 7j proceeds most likely through deprotonation at the R-position with formation of the novel
alkylidenecarbene aminosulfoxonium ylides 19a-e, 19g, 19h, and 19j, respectively. The ylides 19a-e,
19g, 19h, and 19j presumably eliminate sulfinamide 8 with generation of the chiral nonracemic
(â-siloxyalkylidene)carbenes 20a-e, 20g, 20h, and 20j, which suffer a 1,2-H-shift with formation of alkynes
9. Support for the formation of the putative alkylidenecarbenes 20 as intermediates comes from the
elimination of the â-methyl substituted aminosulfoxonium salt 24, which delivered the enantio- and
diastereomerically pure 2,3-dihydrofuran derivative 28 upon treatment with LiN(H)tBu in high yield. Here,
the putative (â-siloxyalkylidene)carbene 26 suffers a 1,5-O,Si bond insertion rather than a 1,2-Me shift.
Methylation of the alkenyl sulfoximine 6a at the R-position with formation of 13 was achieved through
deprotonation of the former with formation of the R-lithioalkenyl sulfoximine 11a and its treatment MeI.
Reaction of the R-methylated alkenyl aminosulfoxonium salt 14a with LiNiPr2 at low temperatures gave the
enantio- and diastereomerically pure anti-configured homoallenylic alcohol derivative 15, while reaction of
the salt with LiNiPr2 or LiN(H)tBu at higher temperatures afforded the enantio- and diastereomerically pure
nonterminal homopropargylic alcohol derivative 17. Deprotonation of the alkenyl (dimethylamino)sulfoxonium
salts 7a and 7b with nBuLi afforded the novel alkylidenecarbene aminosulfoxonium ylides 19a and 19b,
respectively, which upon treatment with MeI yielded the methylated aminosulfoxonium salts 14a and 14b,
respectively.
Introduction
of alcohols 1 stems from the fact that terminal alkynes are
among the most versatile functional groups for the further
Enantio- and diastereomerically pure homopropargylic alco-
hols of type 1 (Scheme 1) constitute an interesting class of
compounds,1 which have frequently served as important building
blocks in natural product syntheses.2 The high synthetic utility
elaboration of a carbon skeleton.1-3 Asymmetric synthesis of
alcohols 1 from aldehydes with the concurrent formation of the
two stereogenic C-atoms has been accomplished mainly by two
(1) (a) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173. (b) O’Malley,
S. J.; Leighton, J. L. Angew. Chem. 2001, 113, 2999; Angew. Chem., Int.
Ed. 2001, 40, 2915.
* To whom correspondence should be addressed. E-mail: gais@
RWTH-Aachen.de.
9
10.1021/ja020570u CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 10427-10434
10427

A R T I C L E S
Reddy et al.
Scheme 1 . Retrosynthesis and Synthesis of anti-Homopropargylic
Alcohols
one-carbon homologation following conversion to the corre-
sponding aldehydes (eq 3).2i,l,o,7 While both methods are
imaginative and efficient, their enantio- and diastereoselectivities
tend to be variable and the allylic metal method requires the
oxidative cleavage of a double bond, which imposes restriction
upon R1 and R2. In addition, the large majority of applications
of both methods have been confined so far to the synthesis of
methyl substituted homopropragylic alcohols 1 (R1 ) Me).8
Further routes leading to alcohols 1 include the addition of chiral
nonracemic titanated allylic carbamates6d,e or chlorine substituted
allylic boronates6a,b,i to aldehydes followed by the elimination
of the corresponding aminocarbonyloxy2n,9 or chlorine10 sub-
stituted homoallylic alcohols, the ring opening of chiral oxiranes
by alkynylmetal reagents,2a-e,g,h,n,3a-c the ring opening of chiral
propargylic oxiranes with organometal reagents,11 the base-
catalyzed ring opening of chiral methylene oxetanes,12 and the
substitution of chiral bromoallenols with organometal reagents.11
While the regioselective ring opening of oxiranes by alkynyl-
metal reagents is restricted to hydroxyalkyl substituted oxiranes,
the other routes have been so far applied only to the synthesis
of racemic homopropargylic alcohols11 or even only to that of
one particular derivative of rac-1 where R1 ) Me.9,10,12 Thus
the scope of these routes for the synthesis of nonracemic
alcohols 1, which will crucially depend on the availability of
the chiral nonracemic starting material13 and the variability of
the substituents, has yet to be determined. Therefore, we felt
that it would be desirable to have a method which allows the
asymmetric synthesis of alcohols 1, carrying a wide range of
groups R1 and R2 including unsaturated and highly branched
ones, from aldehydes. We have recently shown that chiral
sulfonimidoyl substituted bis(allyl)titanium complexes 3 (R1 )
Me, Et, iPr, cC6H11, Ph) add with very high regio- and dia-
stereoselectivity to aliphatic aldehydes and benzaldehyde to give
enantio- and diastereomerically pure sulfonimidoyl functional-
ized homoallylic alcohols of type 2,14,15 which have served for
example as starting material for the asymmetric synthesis of
methods.4 The first method entails the synthesis of chiral
nonracemic allenylic metal compounds from the corresponding
chiral nonracemic propargylic alcohols and the addition of the
former to aldehydes (eq 2),2q-x,5 and the second method
encompasses the allylation of aldehydes with a chiral non-
racemic allylic metal reagent with formation of the correspond-
ing homoallylic alcohols,6 which are then converted to 1 by a
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Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 299.
(i) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera,
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(7) For a synthesis of syn-configured 1 through an aldol-type reaction of an
aldehyde with a chiral nonracemic enolate with formation of the â-hydroxy
carbonyl derivative and its one-carbon homologation following conversion
to the corresponding aldehyde, see: Toyota, M.; Yamamoto, N.; Nishikawa,
Y.; Fukumoto, K. Heterocycles 1995, 40, 115.
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9
10428 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002

anti-Homopropargylic Alcohol Asymmetric Synthesis
A R T I C L E S
Scheme 2. Synthesis of Sulfonimidoyl Substituted Homoallylic
â-substituted and â,â-disubstiuted â-amino acids and of 1,3-
amino alcohols having three contiguous stereogentic C-atoms.16
The allylic sulfoximines required for the synthesis of titanium
complexes 3 and ent-3 are readily accessible from the corre-
sponding aldehydes and (S)- or (R)-N,S-dimethyl-S-phenylsul-
foximine, respectively.14c Thus, provided an efficient alkenyl
sulfoximine to alkyne conversion could be devised (eq 1), the
homoallylic alcohols 2 should serve as versatile starting material
for the asymmetric synthesis of the 1,2-disubstituted homopro-
pargylic alcohols 1. A further prerequisite would be that not
only alkyl and aryl substituted derivatives of 2 but also those
containing unsaturated groups can be secured with high
selectivities from the titanium complexes 3 and aldehydes. In
this paper we describe a new method for the asymmetric
synthesis of anti-homopropargylic alcohols of type 1 based on
the addition of titanated allylic sulfoximines 3 to aliphatic,
aromatic, and other unsaturated aldehydes and the generation
and elimination of novel alkylidenecarbene aminosulfoxonium
ylides derived from sulfoximines 2.
Alcohols from Aldehydes and Sulfonimidoyl Substituted
Bis(allyl)titanium Complexes
Results and Discussion
Sulfonimidoyl Substituted Homoallylic Alcohols. Up to
now only the reaction of bis(allyl)titanium complexes 3 with
aliphatic aldehydes and benzaldehyde had been studied.14
Although mono(allyl)titanium complexes derived from allyl and
crotyl sulfoximine carrying an additional chiral substituent at
the N-atom have been reported to react not only with saturated
aldehydes but also with propenal with high selectivities,15
diminished selectivities have been observed in the reaction of
chiral allylic boron reagents with unsaturated aldehydes as
compared to saturated aldehydes.17 It was therefore of interest
to see whether unsaturated aldehydes, such as for example (E)-
3-phenylpropenal and phenylpropynal, would also react with
the allylic titanium reagents with high selectivities. Included
into the reactivity study of 3 with aldehydes were p-chloro-
benzaldehyde and p-bromobenzaldehyde in order to see whether
an elimination of the corresponding p-chlorophenyl and p-
bromophenyl substituted homoallylic alcohol 2 (R2 ) pClC6H4,
pBrC6H4) with bases with formation of 1 (R2 ) pClC6H4,
pBrC6H4) without a concomitant aryne formation or halogen-
metal exchange, depending on the base used, could be ac-
complished. The enantiomerically pure allylic sulfoximines
4a-c (Scheme 2) were prepared from (S)-N,S-dimethyl-S-
phenylsulfoximine18 and the corresponding aldehydes in good
yields by the addition-elimination-isomerization route ac-
cording to the one-pot procedure described recently.14c Reaction
of allylic sulfoximines 4a-c with 1.1 equiv of nBuLi in
tetrahydrofuran (THF) and titanation of the thus formed lithiated
allylic sulfoximines with 1.1 equiv of ClTi(OiPr)3 gave the
isopropyl, cyclohexyl, and methyl substituted bis(allyl)titanium
complexes 3a-c, respectively, together with equimolar amounts
of Ti(OiPr)4 which was found previously to be essential for the
reaction of the titanium complexes with aldehydes to occur.14c
Treatment of titanium complexes 3a-c, which were not isolated,
with 1.5 equiv, based on sulfoximines 4a-c, of benzaldehyde,
p-bromobenzaldehyde, p-chlorobenzaldehyde, p-methoxybenz-
aldehyde, (E)-3-phenylpropenal, and phenylpropynal at -78 °C
proceeded in each case with high regio- and diastereoselectivity
and gave the mono(allyl)titanium complexes 5a-j containing
the homoallylic alcohols 2a-j, respectively, as alkoxy ligands.
Titanium complexes 5a-j did not further react with the
aldehydes at low temperatures and gave upon hydrolysis the
diastereomerically pure anti-homoallylic alcohols 2a-j together
with the starting allylic sulfoximines 4a-c. Homoallylic alcohols
2a-j and allylic sulfoximines 4a-c, which were readily
separated by crystallization and chromatography, could be
obtained in 45-48% and 40-50% isolated yield, respectively.
We had found previously that reaction of mono(allyl)titanium
complexes of type 5 with aldehydes occurs only at higher
temperatures and proceeds with lower selectivities than that of
the titanium complexes of type 3.14c However, in the case of
alkyl substituted complexes 5 (R1, R2 ) alkyl) high selectivities
were attained in the reaction with saturated aldehydes when
ClTi(OiPr)3 was added to the reaction mixture.14c Surprisingly,
this modification was not successful in the case of the reaction
of titanium complexes 5a-j with aromatic and unsaturated
aldehydes. It seems that the selectivities of the reaction of mono-
(allyl)titanium complexes of type 5 with unsaturated aldehydes
in the presence of ClTi(OiPr)3 are generally lower than that of
the reaction of bis(allyl)titanium complexes 3 with saturated
aldehydes.19 In summary, in reactions of bis(allyl)titanium
complexes of type 3 with aliphatic aldehydes in the presence
of ClTi(OiPr)3 both allylic units can be utilized, whereas in the
reaction with unsaturated aldehydes it is only one unit which
can be transferred and half of the starting allylic sulfoximine is
recovered. Assignment of the anti-configuration of alcohols
2a-j was made on the basis of the NMR data in comparison
(15) For the highly selective synthesis of 2 (R1 ) H, Me) bearing a chiral
substituent at the N-atom, see: (a) Reggelin, M.; Weinberger, H. Angew.
Chem. 1994, 106, 489; Angew. Chem., Int. Ed. Engl. 1994, 33, 444. (b)
Reggelin, M.; Weinberger, H.; Gerlach, M.; Welcker, R. J. Am. Chem.
Soc. 1996, 118, 4765. (c) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(16) Gais, H.-J.; Loo, R.; Das, P.; Raabe, G. Tetrahedron Lett. 2000, 41, 2851.
(17) (a) Roush, W. R.; Park, J. C. J. Org. Chem. 1990, 55, 1143. (b) Ganesh,
P.; Nicholas, K. M. J. Org. Chem. 1997, 62, 1737.
(18) (a) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909. (b) Johnson,
C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. (c) Fusco, R.;
Tericoni, F. Chim. Ind. (Milan) 1965, 47, 61.
(19) Reddy, L. R.; Gais, H.-J.; Roder, D. Unpublished results.
9
J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10429

A R T I C L E S
Reddy et al.
Figure 2. Reaction of sulfonimidoyl substituted bis(allyl)titanium com-
plexes with aldehydes.
Figure 1. Structure of 2e in the crystal.
complexes (S,S)-3a-c, and (3) the reaction occurs through the
chairlike six-membered transition states TS-A.14c,15c These TS’s
feature, besides a coordination of the aldehyde to the Ti-atom,
pseudoequatorial R1 and R2 groups and a pseudoaxial sulfon-
imidoyl group which is coordinated through the N-atom to the
Ti-atom and whose phenyl group adopts the exo-position. It
seems surprising that the sulfonimidoyl group should adopt a
pseudoaxial position in the TS-A. However, for the reactions
of aldehydes with a number of allylic metal reagents, which
bear a heteroatom based substituent at the R-position, transition-
state models featuring a pseudoaxial position of that substituent
have been proposed to account for the selective formation of
the (Z)-configured homoallylic alcohol.6 The origin of this effect
is, however, a matter of debate. The alternative Si,Si,Z mode of
bond formation between the aldehydes and the (R,R)-configured
complexes (R,R)-3a-c via the analogous transition state TS-B
is considered to be less favorable because here the phenyl group
of the sulfonimidoyl group, which is coordinated to the Ti-atom,
resides in the sterically more encumbered endo-position.
Interestingly, in the reaction of bis(allyl)titanium complexes 3
with N-sulfonyl R-imino esters, which leads to (S,R,E)-
configured homoallylic amines and requires Si,Re,E processes,
the (R,R)-configured complexes (R,R)-3 seem to be the faster
reacting ones.22 The essential role exerted by Ti(OiPr)4 in the
addition of 3a-c to the aldehydes may be that of providing for
a free coordination site at the Ti-atom of the six-coordinate
complexes, which is required for the coordination of the
aldehyde through complexation of the sulfonimidoyl group of
one allylic moiety.
with previous structure determinations of further derivatives of
2.14c A final proof of the absolute configuration of the allylic-
homoallylic alcohol 2e was provided by X-ray crystal structure
analysis (Figure 1). The hydroxy sulfoximine 2e features in the
crystal an intermolecular hydrogen bond between the hydroxy
group and the N-atom of the sulfonimidoyl group.14c Finally,
silylation of the homoallylic alcohols 2a-j afforded the
triethylsilyl ethers 6a-j, respectively, in high yields.
Stereochemical Consideration. According to NMR spec-
troscopy the bis(allyl)titanium complexes 3a-c are configura-
tionally labile with regard to the CR-atoms and exist in solution
mainly as equilibrium mixtures of the C2-symmetric cis,cis,-
trans-configured octahedral complexes (R,R)-3a-c and (S,S)-
3a-c (Figure 2).14,20a,b According to NMR spectroscopy and
crystal structure analysis of a derivative of 3, bearing two phenyl
groups at the γ-position,14c the allylic sulfoximine ligands of
the titanium complexes are coordinated most likely in a bidentate
fashion via the CR-atom and the N-atom to the Ti-atom.
Equilibration of the diastereomeric complexes (R,R)-3a-c and
(S,S)-3a-c is fast at low temperatures20a,b and proceeds perhaps
through a reversible 1,3-C/N-shift of the Ti-atom containing
group of the type that has unequivocally been demonstrated for
the mono(allyl)titanium tris(diethylamino) complexes derived
from 4a-c. 14c,20a,c Formation of (S,R,Z)-configured homoallylic
alcohols 2a-j entails Re,Re,Z processes of the aldehydes with
the titanium complexes 3a-c. This can be rationalized on the
basis of the Curtin-Hammett principle21 by assuming that (1)
the equilibration of the bis(allyl)titanium complexes (R,R)-3a-c
and (S,S)-3a-c is faster than their reaction with the aldehydes,
(2) the aldehydes react preferentially with the (S,S)-configured
Terminal Homopropargylic Alcohols. Treatment of alkenyl
sulfoximines 6 with nBuLi or MeLi did not lead to an
elimination of N-methyl phenylsulfinamide with formation of
alkynes 9. Instead, a quantitative lithiation of 6 at the R-position
(20) (a) Gais, H.-J.; Schleusner, M.; Bruns, P. Unpublished results. (b)
Schleusner, M. Ph.D. Thesis, RWTH Aachen, 2002. (c) Bruns, P. Ph.D.
Thesis, RWTH Aachen, 2002.
(21) Seeman, J. I. Chem. ReV. 1983, 83, 83.
(22) Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem. Soc. 2002,
124, 7789.
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anti-Homopropargylic Alcohol Asymmetric Synthesis
A R T I C L E S
Table 1. Asymmetric Synthesis of anti-Homopropargylic Alcohols from Aldehydesa,b
1
2
compd
R
R
2 yield (%)
2 dr
6 yield (%)
7 yield (%)
9 yield (%)
1 yield (%)
a
b
c
d
e
f
g
h
i
iPr
Ph
48 (84)
48 (87)
48 (87)
48 (87)
48 (80)
47 (96)
48 (80)
45 (90)
45 (87)
48 (92)
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
98
98
97
98
97
97
96
98
96
97
92
96
98
96
98
95
96
96
97
99
95
89
90
92
90
c
90
90
c
85
97
98
92
97
c
97
97
c
iPr
iPr
iPr
iPr
iPr
cC6H11
cC6H11
cC6H11
Me
pBrC6H4
pClC6H4
pMeOC6H4
PhCHdCH
PhCtC
pBrC6H4
PhCHdCH
PhCtC
j
pBrC6H4
91
98
a Isolated yields. b Numbers in parentheses refer to yields based on recovered sulfoximine 4. c See text.
Scheme 3. Synthesis of Homopropargylic Alcohols through
Elimination of Alkenyl Aminosulfoxonium Salts
However, when the elimination of the p-bromophenyl substituted
salt 7b was carried out by using a large excess of LiN(H)tBu
(10 equiv), a mixture of the p- and m-tert-butylamino derivatives
of alkyne 9a in a ratio of 3:1 was isolated in 80% yield,
indicating not only an elimination but also an aromatic substitu-
tion through the aryne mechanism. Reaction of the salts 7f and
7i, which carry a triple bond, with 2 equiv of LiN(H)tBu did
not give the corresponding homopropargyl alcohol derivatives.
Instead a reaction product of yet unassigned structure was
isolated in each case, which according to NMR and IR
spectroscopy did not contain any triple bond and no dimethyl-
amino group (vide infra). In the elimination of salts 7a-e, 7g,
7h, and 7j besides alkynes 9a-e, 9g, 9h, and 9j, respectively,
(S)-N,N-dimethyl phenylsulfinamide (8) of 96% ee was isolated
in 80-90% yield as the second reaction product. Since (R)-
N,N-dimethyl tolylsulfinamide has already been successfully
converted in two steps into (R)-S-methyl-S-tolylsulfoximine with
high stereoselectivity,18b we are confident that sulfinamide 8
can be converted to (S)-S-methyl-S-phenylsulfoximine and thus
the chiral auxiliary be recycled. Deprotection of the silyl ethers
9a-e, 9g, 9h, and 9j gave finally the homopropargylic alcohols
1a-e, 1g, 1h, and 1j, respectively, in high yields (Table 1).
Nonterminal Homopropargylic Alcohols and Homoallen-
ylic Alcohols. The observation of a facile lithiation of alkenyl
sulfoximines 6 at the R-position led to the notion of a synthesis
of nonterminal homopropargylic alcohols via introduction of a
substituent at the R-position of 6 and a subsequent elimination
by the sequence of reactions described above. Treatment of the
alkenyl sulfoximines 6a and 6k14c with 1.2 equiv of MeLi at
-78 °C in ether gave the (Z)-configured R-lithioalkenyl
sulfoximines 10a and 10b, respectively, which upon warming
of the reaction mixture to -30 °C suffered a complete
isomerization to the (E)-isomers 11a and 11b, respectively
(Scheme 4). Protonation of 11a and 11b afforded quantitatively
the (E)-configured alkenyl sulfoximines 12a and 12b, respec-
tively. Treatment of lithioalkenyl sulfoximine 11a with MeI
furnished the R-methylated alkenyl sulfoximine 13 in 98% yield.
Methylation of sulfoximine 13 with Me3OBF4 at the N-atom
proceeded uneventfully and gave the aminosulfoxonium salt 14a
in 98% yield. Reaction of salt 14a with bases at different
temperatures took a differing but synthetically interesting course
(Scheme 5). Treatment of salt 14a with 3 equiv of LiNiPr2 at
-78 to -50 °C in THF afforded the homoallenylic alcohol
derivative 15 in 89% yield. Deprotection of the silyl ether 15
yielded the parent alcohol 16. Chiral nonracemic 1,2-disubsti-
tuted homoallenylic alcohols of type 15, whose asymmetric
synthesis has to the best of our knowledge not been described
yet,24 should be of considerable synthetic interest. When the
to the sulfonimidoyl group with formation of the corresponding
stable R-lithioalkenyl sulfoximines occurred (vide infra).14a
Therefore the sulfonimidoyl group of 6a-j was converted
through methylation to the (dimethylamino)sulfoxonium group,18b
which ought to be a better leaving group than the sulfonimidoyl
group.23 Treatment of the N-methyl alkenyl sulfoximines 6a-j
with Me3OBF4 afforded in practically quantitative yields the
aminosulfoxonium salts 7a-j, respectively (Scheme 3). We
were pleased to find that salts 7a-e, 7g, 7h, and 7j readily
afforded alkynes 9a-e, 9g, 9h, and 9j, respectively, in high
yields upon treatment with 2 equiv of LiN(H)tBu in THF at
-78 °C to room temperature and a subsequent aqueous quench
of the reaction mixtures. The complete conversion of salts 7a-
e, 7g, 7h, and 7j to alkynes 9a-e, 9g, 9h, and 9j, respectively,
required the use of 2 equiv of the base. For example treatment
of salt 7d with only 1 equiv of LiN(H)tBu in THF at -78 °C
and a subsequent aqueous workup led only to a 40% conversion
of the salt with formation of alkyne 9d. A competing substitution
of the p-bromophenyl and p-chlorophenyl substituted salts 7b
and 7c or alkynes 9b and 9c, respectively, with formation of
the corresponding arynes was not observed when only 2 equiv
of LiN(H)tBu were used in THF at -78 °C to room temperature.
(23) (a) Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970,
92, 6594. (b) Johnson, C. R.; Lockard, J. P.; Kennedy, E. R. J. Org. Chem.
1980, 45, 264.
9
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A R T I C L E S
Reddy et al.
Scheme 4. Synthesis of Lithioalkenyl Sulfoximines
Scheme 6. Mechanistic Scheme for the Formation of
Homopropargylic Alcohols from Alkenyl Aminosulfoxonium Salts
via Alkylidenecarbenes
about the question as to the mechanism of this elimination.
Because of the strong acidifying effect of the phenyl(dimeth-
ylamino)sulfoxonium group (pKa [MeS(O)(NMe2)PhBF4] )
14.4),25 salts 7 could perhaps react in the first step with the
lithium amide with formation of the alkylidenecarbene amino-
sulfoxonium ylides 19 (Scheme 6). In the second step, ylides
19 could suffer a heterolysis with elimination of sulfinamide 8
and formation of alkylidenecarbenes 20, which, in the last step,
could undergo a 1,2-H-shift with formation of alkynes 9. Finally,
alkynes 9 would be expected to consume the second equivalent
of the base to deliver acetylides 21, which would give alkynes
6 upon aqueous workup. To verify the putative deprotonation
of salts 7 with formation of the novel ylides 19 a number of
experiments were conducted with salts 7a and 7b. Treatment
of salt 7a with HNiPr2 at 0 °C in THF led to its quantitative
isomerization to the (E)-configured salt 22, which was inde-
pendently prepared by methylation of the alkenyl sulfoximine
12a with Me3OBF4 in quantitative yield (Scheme 7). This
observation may be rationalized by the formation of ylide 19a
as an intermediate on the way from the (Z)-isomer to the more
stable (E)-isomer. However, an isomerization pathway, which
involves the addition of the amine to the activated double
bond23b of 7a with formation of the corresponding ylide and a
subsequent elimination of the amine delivering salt 22, cannot
be excluded. Therefore a more definite confirmation for the
notion of a formation of ylides 19 upon reaction of salts 7 with
strong bases was sought. Treatment of salts 7a and 7b with 1
equiv of nBuLi at -100 °C in THF followed by the addition of
MeI resulted in the formation of the methyl substituted salts
14a and 14b, respectively, which were isolated in 94 and 46%
yield, respectively. Salt 14a was independently synthesized by
methylation of sulfoximine 13. These results unequivocally show
that salts 7a and 7b are able to yield with strong bases the
alkylidenecarbene aminosulfoxonium ylides 19a and 19b,
respectively.
Scheme 5. Synthesis of an Internal Homopropargylic Alcohol and
a Homoallenylic Alcohol from an Alkenyl Aminosulfoxonium Salt by
Choice of the Reaction Conditions
elimination of salt 14a was carried out by using either 3 equiv
of LiNiPr2 or 10 equiv of LiN(H)tBu at -78 °C and warming
the reaction mixture to room temperature, the nonterminal alkyne
17 was isolated in 36 and 72% yield, respectively, instead.
Deprotection of silyl ether 17 finally gave the homopropargylic
alcohol 18.
Alkylidenecarbene Aminosulfoxonium Ylides and Forma-
tion of a Chiral 2,3-Dihydrofuran Derivative. The facile
conversion of the alkenyl aminosulfoxonium salts 7a-e, 7g,
7h, and 7j to the alkynes 9a-e, 9g, 9h, and 9j, respectively,
which requires the use of 2 equiv of the lithium amide, brings
To obtain further insight into the mechanism of the elimina-
tion of salts 7, we studied the reaction of the â-methyl
substituted alkenyl aminosulfoxonium salt 24 with LiN(H)tBu
(Scheme 8). In this case the heterolysis of the alkylidenecarbene
ylide 25 derived from salt 24 should deliver the methyl
substituted (â-siloxyalkylidene)carbene 26. Previous studies of
(24) (a) Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736. (b)
Kimura, M.; Tanaka, S.; Tamaru, Y. Bull. Chem. Soc. Jpn. 1995, 68, 1689.
(c) Okamoto, S.; Sato, H.; Sato, F. Tetrahedron Lett. 1996, 37, 8865. (d)
Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2000,
122, 7138.
(25) Bordwell, F. G.; Branca, J. C.; Johnson, C. R.; Vanier, N. R. J. Org. Chem.
1980, 45, 3884.
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anti-Homopropargylic Alcohol Asymmetric Synthesis
A R T I C L E S
through sulfinate addition to (â-siloxybutynyl)iodonium salts,26c,d
had revealed an interesting and differing behavior of this type
of alkylidenecarbenes depending on the substituents of the
double bond. While (â-siloxyalkylidene)carbenes bearing a
H-atom at the â-position of the double bond underwent a 1,2-
H-shift with formation of alkynes, those carrying an alkyl group
at the â-position of the double bond suffered an intramolecular
1,5-O,Si bond insertion with formation of a 2,3-dihydrofuran
derivatives. Methylation of sulfoximine 23, which was prepared
with high regio- and diastereoselectivity from isobutyraldehyde
and the corresponding chiral nonracemic bis(allyl)titanium
complex,14c,27 with Me3OBF4 proceeded quantitatively and gave
salt 24. Treatment of salt 24 with 2 equiv of LiN(H)tBu at -100
°C in THF led to its rapid consumption with formation of the
sulfinamide 8. Remarkably, the enantio- and diastereomerically
pure 2,3-dihydrofuran derivative 28 was isolated in 90% yield
as the second elimination product and not the alkyne 17. On
the basis of these results, formation of alkynes 6 from salts 7
and of 2,3-dihydrofuran derivative 28 from salt 24 upon
treatment with LiN(H)tBu seems to proceed as follows. The
deprotonation of salts 7 and 24 gives ylides 19 and 25,
respectively, which both suffer a heterolysis to deliver the (â-
siloxyalkylidene)carbenes 20 and 26, respectively. While al-
kylidenecarbenes 20 preferentially undergo a 1,2-H-shift with
formation of alkynes 6, alkylidenecarbene 26 preferentially
undergoes a 1,5-O,Si bond insertion either concerted or via the
oxonium ylide 27, which suffers a [1,2]-silyl migration, to
deliver 2,3-dihydrofuran derivative 28. Thus, alkylidenecarbene
aminosulfoxonium ylides 19 seem to behave in this respect in
a manner similar to that of diazoalkenes,29 alkylidenecarbene
iodonium ylides,30 and alkylidenecarbene oxonium ylides,31
which readily yield alkynes through a 1,2-shift following
heterolysis to alkylidenecarbenes.3c,32 Formation of 2,3-dihy-
drofuran derivative 28 is also synthetically interesting since
asymmetric synthesis of 2,3-dihydrofurans has found much
attention recently,28 and enantio- and diastereomerically pure
2,3-dihydrofurans of type 28 are not readily accessible yet.28a
Scheme 7 . Synthesis of Alkylidenecarbene Aminosulfoxonium
Ylides
Scheme 8 . Elimination of an Alkenyl Aminosulfoxonium Salt with
Formation of a 2,3-Dihydrofuran Derivative
Conclusion
In this paper, we described a new method for the asymmetric
synthesis of anti-configured 1,2-disubstituted homopropargylic
alcohols 1, bearing the various groups R1 and R2, based on the
highly regio- and diastereoselective addition of chiral nonra-
cemic sulfonimidoyl substituted bis(allyl)titanium complexes 3
to aldehydes and a novel elimination of alkylidenecarbene
(dimethylamino)sulfoxonium ylides derived from homoallylic
(27) (a) Gais, H.-J.; Roder, D. Unpublished results. (b) Roder, D. Master Thesis,
RWTH Aachen, 2000.
(28) (a) Me´nez, P. L.; Fargeas, V.; Berque, I.; Poisson, J.; Ardisson, J.;
Lallemand, J.-Y.; Pancrazi, A. J. Org. Chem. 1995, 60, 3592. (b) Batsanov,
A. S.; Byerley, A. L. J.; Howard, J. A. K.; Steel, P. G. Synlett 1996, 4,
401. (c) Davies, H. M. L.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.;
Chruchill, D. G. J. Org. Chem. 1998, 63, 2641. (d) Ishitani, H.; Achiwa,
K. Heterocycles 1997, 46, 153. (e) Evans, D. E.; Sweeney, Z. K.; Rovis,
T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095.
(29) (a) Colvin, E. W.; Hamill, B. J. Chem. Soc., Perkin Trans. 1 1977, 869.
(b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837. (c)
Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992,
721.
(30) (a) Stang, P. J.; Wingert, H.; Arif, A. M. J. Am. Chem. Soc. 1987, 109,
7235. (b) Ochiai, M.; Takaoka, Y.; Nagao, Y. J. Am. Chem. Soc. 1988,
110, 6565. (c) Stang, P. J. Angew. Chem. 1992, 104, 281; Angew. Chem.,
Int. Ed. Engl. 1992, 31, 274.
(31) Sueda, T.; Nagaoka, T.; Satoru, G.; Ochiai, M. J. Am. Chem. Soc. 1996,
118, 10141.
(32) Stang, P. J. Chem. ReV. 1978, 78, 383.
chiral racemic (â-siloxyalkylidene)carbenes, which were gener-
ated either from â-siloxy ketones and Me3SiC(Li)N2,26a through
thermolysis of â-siloxy-R,â-expox-N-aziridinylimines,26b or
(26) (a) Miwa, K.; Aoyama, T.; Shiori, T. Synlett 1994, 461. (b) Kim, S.; Cho,
C. M. Tetrahedron Lett. 1995, 36, 4845. (c) Feldman, K. S.; Wrobleski,
M. L. J. Org. Chem. 2000, 65, 8659. (d) Feldman, K. S.; Wrobleski, M. L.
Org. Lett. 2000, 2, 2603.
9
J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002 10433

A R T I C L E S
Reddy et al.
alcohols carrying a (dimethylamino)sulfoxonium group. This
method should be particularly well-suited for the synthesis of
enantio- and diastereomerically pure homopropargylic alcohols
1 carrying sterically demanding and unsaturated substituents
since enantio- and diastereomerically pure functionalized anti-
homoallylic alcohols of type 2 can be obtained in a large variety
with high selectivities through addition of titanium complexes
3 to aliphatic, aromatic, and unsaturated aldehydes. Although
synthesis of homopropargylic alcohols 1 bearing two alkyl
groups has not yet been demonstrated, we have no doubt that
they can be made accessible by this method since the synthesis
of the corresponding homoallylic alcohols 2 (R1, R2 ) alkyl)
has already been described.14
Although the mechanism of the elimination of the alkyli-
denecarbene aminosulfoxonium ylides awaits further studies,
the available evidence points to a heterolysis of the novel
alkylidenecarbene aminosulfoxonium ylides 19 with formation
of chiral nonracemic (â-siloxyalkylidene)carbenes 20 which
suffer a 1,2-H-shift. Evidence for the operation of such a
mechanism was provided by the elimination of the methyl
substituted alkylidenecarbene ylide 20, which gave under 1,5-
O,Si bond insertion the 2,3-dihydrofuran 28 and not through a
1,2-Me-shift the alkyne 17. In this context it is tempting to
speculate that the failure to isolate in the elimination of salts 7f
and 7i the corresponding diynes might be due to an intramo-
lecular reaction of the corresponding carbenes involving the
triple bond at the γ,δ-position. The key alkylidenecarbene ylides
19 can be synthesized from the salts 7 upon treatment with
nBuLi at low temperatures and methylated at the R-position.
The elimination of the thus obtained R-methylated alkenyl
aminosulfoxonium salts, which can also be prepared through
methylation of the corresponding R-lithioalkenyl sulfoximines,
could perhaps also provide for an asymmetric synthesis of
homopropargylic alcohols with an internal triple bond and of
hitherto little explored homoallenylic alcohols. Formation of 2,3-
dihydrofuran derivative 28 suggests perhaps a new asymmetric
synthesis of synthetically interesting highly substituted 2,3-
dihydrofuran derivatives.
Acknowledgment. This work was financially supported by
the Deutsche Forschungsgemeinschaft (Collaborative Research
Center “Asymmetric Synthesis with Chemical and Biological
Methods”, SFB 380, and the Graduate College “Methods of
Asymmetric Synthesis”). We thank Daniel Roder for his help
with the synthesis of sulfoximine 23.
Supporting Information Available: Complete experimental
procedures and spectra and analytical data for all compounds
generated in the course of the investigations reported here,
including X-ray crystallographic data of 2e (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA020570U
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10434 J. AM. CHEM. SOC. VOL. 124, NO. 35, 2002