Asymmetric synthesis of α-amino aldehydes from sulfinimine (N-sulfinyl imine)-derived α-amino 1,3-dithianes. Formal synthesis of (-)-2,3-trans-3,4-cis-dihydroxyproline

Article abstract of DOI:10.1016/j.tetlet.2006.02.092

Hydrolysis of sulfinimine-derived N-sulfinyl α-amino 1,3-dithianes with aqueous 1,3-dibromo-5,5-dimethylhydantoin affords the corresponding N-tosyl α-amino aldehydes in good yield and high enantiomeric purity. These aldehydes can be reduced to amino alcoh

Full text of DOI:10.1016/j.tetlet.2006.02.092

Tetrahedron Letters 47 (2006) 2743–2746
Asymmetric synthesis of a-amino aldehydes from sulfinimine
(N-sulfinyl imine)-derived a-amino 1,3-dithianes.
Formal synthesis of (ꢀ)-2,3-trans-3,4-cis-dihydroxyproline
Franklin A. Davis,* Tokala Ramachandar, Jing Chai and Eduardas Skucas
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA
Received 30 January 2006; revised 14 February 2006; accepted 14 February 2006
Available online 3 March 2006
Abstract—Hydrolysis of sulfinimine-derived N-sulfinyl a-amino 1,3-dithianes with aqueous 1,3-dibromo-5,5-dimethylhydantoin
affords the corresponding N-tosyl a-amino aldehydes in good yield and high enantiomeric purity. These aldehydes can be reduced
to amino alcohols and undergo the Wittig reaction to give allylic amines without epimerization. The utility of this methodology is
illustrated in a formal synthesis of (ꢀ)-2,3-trans-3,4-cis-dihydroxyproline.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of a-amino aldehydes not requiring amino
acids, these methods lack generality, are restricted by
the availability of the chiral starting materials, and are
often multistep.1,3 Therefore concise methods for the
asymmetric synthesis of enantiopure N-protected a-ami-
no aldehydes that do not necessitate a-amino acids as
precursors are of considerable value.
a-Amino aldehydes are extremely valuable chiral build-
ing blocks that have been widely used in the asymmetric
synthesis of a-amino acids, a-amino alcohols, 1,2-diam-
ines, allylic amines, heterocycles, and natural products.1
Their participation in aldol reactions, cycloaddition
reactions with 1,3-dienes, and reactions with various
organometallic reagents add to their versatility and util-
ity as chiral synthons.1 However, a-amino aldehydes are
notoriously unstable and easily racemized; therefore they
require an N-protecting group. The choice of this group
is critical for stability of the amino carbonyl moiety and
for success in subsequent transformations as most in-
volve reaction with basic types of nucleophiles. Although
a number of N-protecting groups have been shown to be
useful for this purpose—the choice depending on the
substituents (Boc, Cbz, dibenzyl, Fmoc, PhFl)—the
amino aldehydes are generally not purified prior to use
because of their sensitivity to racemization.1,2
Recently, we introduced a new and general method
for the asymmetric synthesis of N-protected a-amino
ketones involving the addition of 2-lithio-2-substituted-
1,3-dithianes to enantiopure sulfinimines (N-sulfinyl
imines) (S)-1 (Scheme 1).4–6 The resulting a-amino
S
R'
Li
1)
O
S
S
p-Tolyl
NH
S
2) aq. NH4Cl
O
S
H
R'
S
R
-78 oC, THF
p-Tolyl
N
R
(SS,S)-2
( )-1
S
PhI(O2CCF3)2
CH3CN/H2O
Often a-amino aldehydes are prepared from N-pro-
tected a-amino acids by employing a reduction step fol-
lowed by reoxidation, and as such the preparation is
limited by the availability of the amino acid.1 Although
a few procedures have been devised for the asymmetric
H3O+
O
S
NH2
p-Tolyl
NH
R'
S
R
S
R'
R
O
Keywords: a-Amino aldehydes; a-Amino alcohols; Allylic amines;
a-Amino 1,3-dithianes; Sulfinimines; Asymmetric synthesis.
Corresponding author. Tel.: +1 215 204 0477; fax: +1 215 204
0478; e-mail: fdavis@temple.edu
)-4
(SS,S
R = alkyl, aryl
(S)-3 (>96% ee)
*
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.092

2744
F. A. Davis et al. / Tetrahedron Letters 47 (2006) 2743–2746
1,3-dithioketals 2 were formed in good yield with excel-
lent diastereoselectivity. Acid hydrolysis gave the enan-
tiomerically pure free amine 3, which leaves the keto
group protected and provides unique opportunities for
functional group manipulation. Furthermore, we dis-
covered that it was possible to hydrolyze the thioketal
moiety without affecting the N-sulfinyl group by using
the Stork reagent bis(trifluoroacetoxy)-iodobenzene.7
The resulting N-sulfinyl a-amino ketone proved to be
unusually stable and attests to the impressive amine pro-
tecting group ability of the sulfinyl moiety.6 Here, we
present a new and general procedure for the asymmetric
synthesis of N-protected a-amino aldehydes from N-sul-
finyl a-amino 1,3-dithioacetals.
and extraction with methylene chloride, concentration
resulted in a solid. The proton NMR spectrum of this
material, which was remarkably clean, exhibited
absorption at d 9.4 ppm, which suggested that the
desired a-amino aldehyde 7a had indeed been formed.
Less than 2–3% of the succinimide by-product was
detected by NMR. On the other hand, the methyl pro-
tons attributed to the p-toluenesulfinyl group had
shifted downfield from 2.23 in 6a to 2.31 ppm. This
suggested that the p-toluenesulfinyl group had been
oxidized, under the hydrolysis conditions, to give the
N-tosyl a-amino aldehyde 8a. Attempts at chromato-
graphic purification of 8a resulted in decomposition.
In an effort to find evidence that the N-sulfinyl group
in 7a had been oxidized, the N-sulfinyl group in (+)-
6a was replaced with a tosyl group to give (S)-(ꢀ)-
10. This was easily accomplished by treating (+)-6a
with TFA/MeOH to give the amino 1,3-dithioacetal
(+)-9 in 95% yield. Reaction of (+)-9 with p-toluene-
sulfonyl chloride in Et3N afforded (S)-(ꢀ)-10 in 82%
yield. Subsequent hydrolysis of 10 using the NBS pro-
tocol gave a product whose proton NMR was identical
to that obtained on hydrolysis of (+)-6a (Scheme 2).
2. Synthesis of a-amino 1,3-dithianes and a-amino
aldehydes
Addition of 1.5 equiv of the preformed ꢀ78 °C THF
solution of 2-lithio-1,3-dithiane to sulfinimines
(S)-(+)-N-(benzylidene)-p-toluenesulfinamide (5a), (S)-
(+)-N-(isobutylidene)-p-toluenesulfinamide (5b), and (S)-
(+)-N-(2,2-dimethylpropylidene)-p-toluenesulfinamide
(5c) gave the corresponding N-sulfinyl a-amino-1,3-
dithianes (SS,S)-(+)-6a (73%, 82% de), (SS,S)-(+)-6b
(70%, 72% de) and (SS,S)-(+)-6c (72%, 96% de) in
good yield and de (Scheme 2). Chromatography gave
the pure diastereoisomers. However, when (+)-6a
(R = Ph) was treated with the Stork reagent, decompo-
sition occurred and the corresponding aldehyde 7a was
not detected in the proton NMR of the crude reaction
mixture (Scheme 2). When the hydrolysis of (+)-6a was
carried out using 5 equiv of NBS in aqueous acetone
for 10 min, followed by quenching with sodium sulfite,
Having established that N-tosyl a-amino aldehyde (S)-8
was formed under the reaction conditions, it was neces-
sary to determine its enantiomeric purity. This was
accomplished by reduction of the crude aldehyde with
5 equiv of NaBH4 to give the known 1,2-amino alcohol
(S)-(+)-11, which was then transformed to its Mosher
ester (Scheme 3). The literature specific rotation of (S)-
(+)-118 and its Mosher ester indicated that the enantio-
meric purity of the amino alcohol was >97% ee. This
means the enantiomeric purity of the intermediate a-
amino aldehyde 8a is better than 97% ee. Similar results
were observed for 8b and for 8c.
The yields given for the amino alcohols (S)-11 are over-
all yields for several steps including oxidation, hydro-
lysis, and reduction beginning with the N-sulfinyl
a-amino 1,3-dithiane 6. The fact that these overall yields
ranged from 42% for R = t-Bu to 70% for Ph suggest
that the intermediate N-tosyl a-amino aldehydes (S)-8
are formed in good yield and in high enantiomeric
purity. In these studies we observed that hydrolysis
with 2 equiv of 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH) resulted in much improved yields of the a-
amino aldehydes 8 over NBS. Importantly, none of
S
S
H
Li
1)
O
S
p-Tolyl
NH
S
2) aq. NH4Cl
O
S
H
H
S
R
-78 oC, THF
p-Tolyl
R
N
(SS,S)-6
(S)-(+)-5a: R = Ph
(S)-(+)-5b: R = i-Pr
(S)-(+)-5c: R = t-Bu
1) 5 eq NBS
2) Na2SO3
O
S
Ts
PhI(O2CCF3)2
CH3CN/H2O
NH
p-Tolyl
NH
H
H
R
Ph
6a
O
S
O
O
Ts
R
1) 2 equiv DBDMH
2) Na2SO3
p-Tolyl
NH
S
NH
(SS,S)-7a
( )-8
S
H
S
H
R
1) 2 eq NBS
2) Na2SO3
O
( )-8
Ts
S
(SS,S)-(+)-6
NH
S
NH2
Ts-Cl/Et3N
H
TFA/MeOH
(95%)
H
S
Ts
Ph
Ph
S
(S)-(+)-11a: R = Ph (70%)
(S)-(+)-11b: R = i-Pr (58%)
(S)-(+)-11c: R = t-Bu (42%)
NaBH4
NH
S
(SS,S)-6a
OH
(82%)
R
(>97% ee)
(S)-(-)-10
( )-(+)-11
S
(S)-(+)-9
Scheme 2.
Scheme 3.

F. A. Davis et al. / Tetrahedron Letters 47 (2006) 2743–2746
2745
the 5,5-dimethylhydantoin by-products were detected in
the proton NMR of the crude reaction mixture.
(S)-(ꢀ)-14 was obtained in 60% yield for the three steps.
The diene, (S)-(ꢀ)-15, prepared from (ꢀ)-14 and allyl
bromide, was subjected to ring-closing metathesis
employing the Grubbs second-generation catalyst to
give the unsaturated pyrrolidine (ꢀ)-16 in 85% yield.
Dihydroxylation of (ꢀ)-16 with K3Fe(CN)6/cat. OsO4
occurred exclusively anti to the phenyl group affording
diol (ꢀ)-17, which, upon protection as the acetonide
by reaction with dimethoxy propane, gave (ꢀ)-18 in
79% isolated yield. Reductive removal of the N-tosyl
group was accomplished with Na/liq NH3 and, without
purification, the secondary amino group was Boc
protected to give (ꢀ)-19. (2R,3R,4S)-(ꢀ)-N-tert-butoxy-
carbonyl-3,4-dihydroxy-2-phenyl-pyrrolidine isopropyl-
idene acetal (19) has been transformed by Riera and
co-workers via RuCl3/NaIO4 oxidation of the phenyl
group to the carboxylic acid, to produce the proline,12a
which on hydrolysis gave (ꢀ)-2,3-trans-3,4-cis-
dihydroxyproline (20).14a Intermediate (ꢀ)-19 can also
be used in the construction of the azasugar (+)-2-
(hydroxymethyl)pyrrolidne-3,4-diol (21).12b
Our studies suggest that the N-tosyl group is a particu-
larly effective protecting group for a-amino aldehydes.
We attribute this effect to its ability to stabilize anions
at nitrogen and thus inhibiting base-catalyzed epimer-
ization. Interestingly there are very few examples of an
N-arylsulfonyl group being used to protect an a-amino
aldehyde,9,10 with the possible exception of Rapoport,
who demonstrated the utility of N-arylsulfonyl protect-
ing groups in many transformations of amino acids
including modifications of the carboxyl group to give
a-amino ketones.10 Removal is effected without epimeri-
zation via reduction with sodium naphthalide or cleav-
age with HBr in HOAc.11 In our studies, we have
found that Na/NH3 (liq) is particularly effective for
removal of this protecting group.4
3. Formal synthesis of (ꢀ)-2,3-trans-3,4-cis-dihydroxy-
proline
Polyhydroxy pyrrolidines and prolines (azasugars) are
common constituents of many biologically active natu-
ral products and are potent glycosides inhibitors.12 As
such they may be useful in treating cancer, diabetes,
and various viral infections. To illustrate the utility of
our new a-amino 1,3-dithiane derived a-amino alde-
hydes, we present a concise formal asymmetric synthesis
of (ꢀ)-2,3-trans-3,4-cis-dihydroxyproline (20), a natu-
rally occurring amino acid isolated from the marine
mussel Mytilus edulis.13,14
4. Summary
In summary, hydrolysis of sulfinimine-derived N-sulfinyl
a-amino 1,3-dithianes with aqueous NBS, or better with
1,3-dibromo-5,5-dimethylhydantoin, affords the corre-
sponding N-tosyl a-amino aldehydes in good yield and
in high enantiomeric purity. Because a-amino acids are
not required as precursors and because of the great
structural diversity of available sulfinimines,6 this proto-
col represents an important new method for the enantio-
selective synthesis of valuable a-amino aldehyde chiral
building blocks for asymmetric synthesis. The N-tosyl
a-amino aldehydes are sufficiently stable to epimeriza-
tion to undergo further elaboration such as reduction
to amino alcohols and in the Wittig reaction to produce
allyl amines.15
Our synthesis begins with the epimer of (SSS)-(+)-6a,
(RSR)-(ꢀ)-12, which is hydrolyzed to give the crude N-
tosyl a-amino aldehyde (R)-13 (Scheme 4). On treatment
with the Wittig reagent generated from methyl triphen-
ylphosphonium bromide and KHMDS, allylic amine
O
S
Br
1) 2 equiv DBDMH
2) Na2SO3
Ts
Ph
p-Tolyl
NH
S
Ph3PCH3Br/
KHMDS
Ts
NH
K2CO3/DMF
Ts
NH
H
S
N
H
Ph
Ph
(60%)
Ph
(60% 3 steps)
O
(S)-(-)-14
( )-(-)-15
S
(R)-13
HO
(RS,R)-(-)-12
1) Na/Liq NH3
2) Boc2O
cat. OsO4
K3Fe(CN)6
OH
OMe
O
O
O
TsOH
O
OMe
Grubbs II
(85%)
Ph
(81%)
Ph
N
(67% 2 steps)
N
(79%)
Ph
N
Ph
Ts
(2R,3R,4S)-(-)-17
OH
N
Ts
Ts
Boc
(S)-(-)-16
(2R,3R,4S)-(-)-18
HO
(2R,3R,4S)-(-)-19
HO
OH
ref. 12a, 14a
HO2C
N
N
H
H
OH
(+)-2-(hydroxymethyl)
pyrrolidine-3,4-diol (21)
(-)-2,3-trans-3,4-cis-
dihydroxyproline (20)
Scheme 4.

2746
F. A. Davis et al. / Tetrahedron Letters 47 (2006) 2743–2746
1993, 32, 578; (b) Gryko, D.; Urbanczyk-Kipkowska, Z.;
Acknowledgements
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11. Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53,
2367.
We thank the National Institute of General Medical Sci-
ences, for generous support of this work (GM 57870).
12. For leading references, see: (a) Martin, R.; Alcon, M.;
Pericas, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896; (b)
Kumareswaran, R.; Hassner, A. Tetrahedron: Asymmetry
2001, 12, 3409.
References and notes
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asymmetric synthesis of (ꢀ)-20, see: (a) Zanardi, F.;
Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.; Cornia,
M.; Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167;
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2000, 1046; (g) Lee, B. W.; Jeong, I.-Y.; Yang, M. S.;
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Chem. 2002, 67, 4466; (i) Ref. 12a.
2. Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109,
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3. (a) Bringmann, G.; Geisler, J.-P. Synthesis 1989, 608; (b)
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Alexakis, A.; Lensen, N.; Tranchier, J.-P.; Mangeney, P.;
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15. Selected compound properties: (+)-6a: 172–174 °C (dec.);
20
20
½aꢁD +69.8 (c 1.0, CHCl3); (+)-6b: mp 94–96 °C; ½aꢁD +51.8
20
(c 1.1, CHCl3); (+)-6c: colorless oil, ½aꢁD +15.4 (c 1.91,
20
CHCl3); (+)-9: viscous liquid, ½aꢁD +39.4 (c 1.0, CHCl3);
20
(ꢀ)-10: mp 121–122 °C; ½aꢁD ꢀ61.2 (c 0.52, CHCl3); (+)-
20
11a: mp 105–106 °C [lit.8 mp 106 °C]; ½aꢁD +79.2 (c, 1.0,
25
CHCl3), [lit.8 ½aꢁD +81.5 (c, 1.0, CHCl3); (+)-11b: mp 89–
20
90 °C [lit.16 mp 88–89 °C]; ½aꢁD +30.7 (c 0.5, CHCl3),
4. Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6,
3393.
25
[lit.16 ½aꢁD +29.4 (c, 0.837, CHCl3); (+)-11c: mp 111–
20
5. For a related study, see: Xu, X.; Liu, J.-Y.; Chen, D.-J.;
Timmons, C.; Li, G. Eur. J. Org. Chem. 2005, 1805.
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Zhou, P.; Chen, B.-C.; Davis, F. A. In Advances in Sulfur
Chemistry; Rayner, C. M., Ed.; JAI Press: Stamford, CT,
2000; Vol. 2, pp 249–282; (b) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (c) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003; (d)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han,
Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93.
112 °C; ½aꢁD +10.3 (c 1.45, CHCl3); (ꢀ)-12: mp 173 (dec),
25
25
½aꢁD ꢀ68.6 (c, 0.7, CHCl3); (ꢀ)-14; colorless liquid, ½aꢁD ꢀ
25
49.4 (c, 0.7, CHCl3), [lit.17 ½aꢁD ꢀ50.2 (c, 1.32, CHCl3); (ꢀ)-
20
15: viscous liquid, ½aꢁD ꢀ67.4 (c 1.15, CHCl3); (ꢀ)-16:
20
viscous liquid, ½aꢁD ꢀ37.4 (c 1.0, CHCl3); (ꢀ)-17: viscous
20
liquid, ½aꢁD ꢀ24.9 (c 0.8, CHCl3); (ꢀ)-18: viscous liquid,
20
½aꢁD ꢀ28.9 (c 0.5, CHCl3); (ꢀ)-19: mp 99 °C, [lit.12a mp 98–
25
25
100 °C]; ½aꢁD ꢀ49.4 (c, 0.7, CHCl3), [lit.12a ½aꢁD ꢀ48.14 (c,
1.4, CHCl3).
16. Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Otaka, A.;
Tamamura, H.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga,
T.; Chounan, Y.; Yamamoto, Y. J. Org. Chem. 1995, 60,
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8. Hoppe, I.; Hoffmann, H.; Garner, I.; Kretteck, T.; Hoppe,
D. Synthesis 1991, 1157.
9. For use of N-arylsulfonyl protecting groups, see: (a)
Braun, M.; Opdenbusch, K. Angew. Chem., Int. Ed. Engl.
17. Kurose, N.; Takahashi, T.; Koizumi, T. J. Org. Chem.
1996, 61, 2932.