Asymmetric synthesis of α-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

Article abstract of DOI:10.1021/ol0485971

(Chemical Equation Presented) N-Sulfinyl α-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable α-amino 1,3-dithioketal

Full text of DOI:10.1021/ol0485971

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3393-3395
Asymmetric Synthesis of r-Amino
1,3-Dithioketals from Sulfinimines
(N-Sulfinyl Imines). Synthesis of
(2S,3R)-(−)-3-Hydroxy-3-methylproline
Franklin A. Davis,* Tokala Ramachandar, and Hu Liu
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received July 20, 2004
ABSTRACT
N-Sulfinyl r-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal
of the N-sulfinyl or the thioketal groups affords stable r-amino 1,3-dithioketals and N-sulfinyl r-amino ketones, respectively. This new sulfinimine-
derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(−)-3-hydroxy-3-methylproline.
The asymmetric syntheses of R-amino ketones 1 is currently
receiving a great deal of attention because of the value of
these building blocks in the asymmetric syntheses of
heterocyclic compounds and natural products.1 Generally
enantiopure R-amino ketones are prepared by reaction of
lithium and Grignard reagents with suitably N-protected
R-amino acid derivatives; however, these syntheses are
limited by the availability of the starting material.2,3 In
addition, while R-amino ketones are more stable than
R-amino aldehydes, racemization can occur on storage. The
harsh conditions necessary to remove the N-protecting group
can also be problematic.1,4
The keto group is then unmasked later in the synthetic
sequence. R-Amino 1,3-dithianes 2 are a class of compounds
that can be used in this manner because the dithioacetal group
is stable to both acidic and basic conditions (Scheme 1).5
Scheme 1
There is however, another way to think about the syntheses
and utilization of R-amino ketones, and that is to protect the
keto group and leave the amine free for further elaboration.
Although racemic R-amino 1,3-dithianes 2 have been
described,6 the only optically active examples were those
prepared from D-glucosamine.7 Furthermore, in only one
instance, a racemic example, was the 1,3-dithiane success-
(1) (a) Coppola, G.; Schuster, H. Asymmetric Synthesis: Construction
of Chiral Molecules Using Amino Acids; Wiley: New York, 1987. (b) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (c) Sardina, F. J.;
Rapoport, H. Chem. ReV. 1996, 96, 1825.
(2) For leading references to the asymmetric synthesis of R-amino
ketones, see: Paleo, M. R.; Calaza, M. I.; Sardina, F. J. J. Org. Chem.
1997, 62, 6862.
(3) For an alternative method, see: Myers, A. G.; Yoon, T. Tetrahedron
Lett. 1995, 36, 9429.
(4) For reviews on R-amino aldehydes and ketones, see: (a) Jurczak, J.;
Golebiowski, A. Chem. ReV. 1989, 89, 149. (b) Fisher, L. E.; Muchowski,
J. M. Org Prep. Proced. Int. 1990, 22, 399.
(5) For a review of the application of 1,3-dithianes in natural product
synthesis, see: Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59,
6147.
(6) (a) Wan, Y.; Angleson, J. K.; Kutateladze, A. G. J. Am. Chem. Soc.
2002, 124, 5610. (b) Mitkin, O. D.; Kurchan, A. N.; Wan, Y.; Schiwal, B.
F.; Kutateladze, A. G. Org. Lett. 2001, 3, 1841. (c) Page, P. C. B.; van
Niel, M. B.; Westwood, D. J. Chem. Soc., Chem. Commun. 1987, 775.
10.1021/ol0485971 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/14/2004

fully deprotected to give the ketone moiety.8 We describe
here a general method for the asymmetric synthesis of
R-amino 1,3-dithianes 2 and the utility of this new sulfin-
imine-derived chiral building block for the asymmetric
synthesis of R-amino ketones 1 and the polyoxypeptin amino
acid (2S,3R)-(-)-3-hydroxy-3-methylproline (14).
Synthesis of R-Amino-1,3-dithianes. Addition of 1.5
equiv of a preformed -78 °C THF solution of 2-lithio-2-
methyl-1,3-dithiane to sulfinimines (S)-(+)-N-benzylidene-
p-toluenesulfinamide (3a) and (S)-(+)-N-isobutylidene-p-
toluenesulfinamide (3b) readily gave the corresponding
N-sulfinyl R-amino-1,3-dithianes (SS,S)-(+)-4a and (SS,S)-
(+)-4b (Scheme 2).9,10 The diastereoselectivities, determined
N-sulfinyl groups in sulfinamides, TFA/H2O, also works (see
below).8 A chiral shift reagent experiment indicated that the
C-N stereocenter in (+)-5a was not compromised in the
deprotection step.
Unless R-amino ketones are suitably N-protected, they are
unstable and generally cannot be isolated.1,4 Consequently,
a method for the selective hydrolysis of the dithioketal
moiety, in the presence of the N-sulfinyl group in (+)-4, is
required if N-sulfinyl R-amino 1,3-dithianes are to be useful
chiral building blocks (Scheme 1). It is unlikely that the
N-sulfinyl group would survive most of the traditional
methods for thioketal hydrolysis, i.e., mercury(II) salts and
oxidative conditions.12 However, we found that bis(trifluo-
roacetoxy)iodobenzene [PhI(O2CCF3)2], described earlier by
Stork and Zhao for selective thioacetal hydrolysis, proved
to be ideal for this purpose.13 Treatment of 4a,b with 2 equiv
of PhI(O2CCF3)2 in acetonitrile-water afforded methyl
ketones (SS,S)-(-)-6a and (SS,S)-(-)-6b in 72 and 60%
isolated yields (Scheme 2). The fact that racemization was
not detected in 6 further illustrates the unique nitrogen
protecting group abilities of the sulfinyl group.9
Scheme 2
Chelation-control arguments, based on six-membered
chairlike transition states where the metal ion is chelated to
the sulfinyl oxygen, have been used to rationalize the chiral
recognition for the addition of enolates, Grignard reagents,
DIBAL-H, and Et2AlCN to sulfinimines.9d,14 On the other
hand, steric arguments have been evoked to explain the
stereochemical preference in additions of benzyl Grignard,
R-metallo phosphonates, 1,3-dipoles, and glycine iminoester
enolates to sulfinimines.9d,14 The absolute configuration of
the newly created stereogenic center in (+)-4 was determined
to be (S)- by m-CPBA oxidation of 6a to (S)-(+)-7, which
has a known absolute configuration (Scheme 3).15 This
Scheme 3
1
by H NMR on the crude reaction mixtures, were excellent
(92-97% de), and the yields of the major diastereoisomers,
isolated by flash chromatography, were very good (76-
84%).
Selective removal of the N-sulfinyl group in (+)-4 can be
accomplished in several ways. Treatment of the N-sulfinyl
R-amino 1,3-dithianes 4 with the Dess-Martin periodinane
(DMP) reagent afforded the corresponding amino 1,3-
dithianes (S)-(+)-5a and (S)-(+)-5b in 76 and 71% yield,
respectively (Scheme 2).11 The usual method for removing
(7) (a) Barton, D. H. R.; Gateau-Olesker, A.; Anaya-Mateos, J.; Cleophax,
J.; Gero, S. D.; Chironi, A.; Riche, C. J. Chem. Soc., Perkin Trans. I 1990,
3211. (b) Anaya, J.; Barton, D. H. R.; Gero, S. D.; Grande, M.; Hernando,
J. I. M.; Laso, N. M. Tetrahedron: Asymmetry 1995, 6, 609.
(8) Padwa, A.; Dharan, M.; Smolanoff, J.; Wetmore, S. I. J. Am. Chem.
Soc. 1973, 95, 1954.
(9) For reviews on the chemistry of sulfinimines, see: (a) 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) Davis, F. A.;
Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, in press.
assignment means that 2-methyl-2-lithio-1,3-dithiane addi-
tions to sulfinimines fall into the chelation-control category
and may go through a transition state such as TS-1 (Scheme
3).
(11) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 4, 575.
These workers reported the used DMP as a selective method for removal
of thioketals and thioacetals.
(10) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
3394
Org. Lett., Vol. 6, No. 19, 2004

(-)-3-Hydroxy-3-methylproline. The aim of new syn-
thetic methodology is to solve important problems in
synthesis. To highlight the utility of our new chiral building
block, we employed an R-amino 1,3-dithiane in the asym-
metric synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline
(14). This nonproteinogenic amino acid is a key component
of the polyoxypeptins, a 19-membered cyclic hexadepsipep-
tide antibiotic reported to be a potent inducer of apoptosis
in human pancreatic andenocarcinoma ASPC-1 cells.16,17
Scheme 4
Our synthetic strategy was to use the phenyl group as a
masked carboxylic acid and to construct the pyrrolidine
heterocycle directly from a substituted dithiane and benz-
aldehyde-derived sulfinimine (R)-(-)-3a. To this end, a
preformed -78 °C solution of 1.5 equiv of dilithio species
8, prepared from 2-(2-hydroxyethyl)-1,3-dithiane,18 was
added to (R)-(-)-3a at -78 °C (Scheme 4). Addition of Ts-
Cl and quenching gave pyrrolidine (-)-9 in 91% de and 70%
isolated yield of the major diastereoisomer for the single-
flask reaction. Next, the N-sulfinyl group was removed (TFA/
H2O) and replaced with a tosyl group in one operation. The
thioketal in (+)-10 was hydrolyzed with PhI(O2CCF3)2
affording the 3-oxo pyrrolidine (R)-(-)-11 in 78% yield. The
ketone, on treatment with excess methylmagnesium bromide,
gave alcohol (-)-12 as a single isomer in 85% yield.
Oxidation of the phenyl group to the carboxylic acid (-)-
12 was easily affected by RuCl3/NaIO4. To facilitate isola-
tion, the acid was immediately converted to the methyl ester
(2S,3R)-(-)-13 with TMSCHN2. Attempts to remove the
N-tosyl group in the crude acid resulted in low conversions
to (-)-14 (20-30%). Alternatively, the somewhat longer
sequence involving hydrolysis of the methyl ester in (-)-13
and then reductive removal of the N-tosyl group with Na/
liquid NH3 gave (2S,3R)-(-)-3-hydroxy-3-methylproline (14)
in 72% yield (Scheme 4).19 Recognizing that a number of
the 10 steps are one-flask transformations, we consider our
synthesis of this amino acid to be one of the most concise
to date.
In summary, sulfinimines and lithio-1,3-dithianes afford
N-sulfinyl-R-amino-1,3-thianes 4 in high de and good yields.
This new sulfinimine-derived chiral building block can be
selectivly deprotected to give either R-amino-1,3-dithianes
5 or N-sulfinyl R-amino ketones 6 as stable entities. The
synthetic utility of N-sulfinyl-R-amino-1,3-thianes is il-
lustrated by the asymmetric synthesis of the polyoxypeptins
amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline (14).
(12) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; p 297.
(13) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(14) For leading references, see: (a) Davis, F. A. Lee, S.; Yan, H.; Titus,
D. D. Org. Lett. 2001, 3, 1757. (b) Reference 9d of this article.
(15) Adam, W.; Roschmann, K. J.; Saha-Moller, C. R. Eur. J. Org. Chem.
2000, 557.
(16) Umezawa, K.; Nakasawa, K.; Uchihata, Y.; Otsuka, M. AdV. Enzyme
Acknowledgment. We thank the National Institute of
General Medical Sciences for generous support of this work
(GM 57870 and GM51982).
Regul. 1999, 39, 145.
(17) For earlier asymmetric syntheses of this amino acid, see: (a)
Noguchi, Y.; Uchiro, H.; Yamada, T.; Kobayashi, S. Tetrahedron Lett. 2001,
42, 5253. (b) Makino, K.; Kondoh, A.; Hamada, Y. Tetrahedron Lett. 2002,
43, 4695. (c) Qin, D.-G.; Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2002, 67,
1038. (d) Shen, J.-W.; Qin, D.-G.; Zhang, H.-W.; Yao, Z.-J. J. Org. Chem.
2003, 68, 7479. (e) Merio, P.; Revuelta, J.; Tejero, T.; Cicchi, S.; Goti, A.
Eur. J. Org. Chem. 2004, 776.
(18) Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33,
300.
(19) Properties of (-)-14 were consistent with literature values. See ref
17d of this article.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0485971
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3395