Stereodivergent and regioselective synthesis of 3,4-cis- and 3,4-trans-pyrrolidinediols from α-amino acids

Article abstract of DOI:10.1021/ol049237g

Highly stereodivergent Woodward-Prevost reaction applied to iodoacetates derived from homochiral α-amino acids afforded enantiopure 3,4-cis- and 3,4-trans-pyrrolidinediol derivatives, with control over the protecting group, allowing for differential prote

Full text of DOI:10.1021/ol049237g

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2273-2276
Stereodivergent and Regioselective
Synthesis of 3,4-cis- and
3,4-trans-Pyrrolidinediols from r-Amino
Acids
Jin Hyo Kim, Marcus J. C. Long,† Jun Young Kim, and Ki Hun Park*
DiVision of Applied Life Science (BK21 program), Department of Agricultural
Chemistry, Gyeongsang National UniVersity, Jinju 660-701, South Korea, and
Chemistry Research Laboratory, UniVersity of Oxford, 12 Mansfield Road,
Oxford OX1 3TA, U.K.
khpark@gshp.gsnu.ac.kr
Received April 26, 2004
ABSTRACT
Highly stereodivergent Woodward−Prevost reaction applied to iodoacetates derived from homochiral r-amino acids afforded enantiopure
3,4-cis- and 3,4-trans-pyrrolidinediol derivatives, with control over the protecting group, allowing for differential protection.
Enantiopure 3,4-pyrrolidinediols have been extensively
exploited both because of their wide-ranging pharmacological
properties and also due to their serving as important
functional units for further manipulation in organic synthesis.
For example, many 1,4-dideoxy-1,4-iminopentositols,1
swanisonine,2 (-)-anisomycine,3 lentiginosine,4 and dihy-
droxyproline5 are included in these series. Therefore, a
number of synthetic strategies have been devoted to their
stereoselective synthesis from both carbohydrate6 and non-
carbohydrate sources,7 the latter mostly involve the use of
aldolization, epoxidation, or dihydroxylation for selective
hydroxylation. These methodologies are ideally suited to the
preparation of a single stereoisomer of the target 3,4-
pyrrolidinediol, but they all either have limited stereodiver-
gent approach or require many tedious protection and
deprotection steps. Obviously, homochiral R-amino acids are
the most suitable starting material to synthesize an enan-
tiopure 3,4-pyrrolidinediol, but only a few examples have
been reported.8 The main reason for the paucity of examples
in this area is that although the stereoselective installation
of 3-hydroxy group has been extensively studied, and highly
(6) From carbohydrates, see: (a) Taylor, C. M.; Barker, W. D.; Weir,
C. A.; Park, J. H. J. Org. Chem. 2002, 67(13), 4466.(b) Taylor, C. M.;
Weir, C. A. Org. Lett. 1999, 1, 787. (c) Kim, J. H.; Yang, M. S.; Lee, W.
S.; Park, K. H. J. Chem. Soc., Perkin Trans. 1 1998, 2877. (d) Fleet, G. W.
J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1(2), 119.
(7) From non-carbohydrates, see: (a) Shi, Z.-C.; Lin, G.-Q. Tetrahe-
dron: Asymmetry 1995, 6 (12), 2907. (b) Ono, M.; Suzuki, K.; Akita, H.
Tetrahedron Lett. 1999, 40, 8223. (c) Delair, P.; Brot, E.; Kanazawa, A.;
Greene, A. E. J. Org. Chem. 1999, 64, 1383. (d) Iida, H.; Yamazaki, N.;
Kibayashi, C. J. Org. Chem. 1986, 51, 1069. (e) Martin, R.; Alcon, M.;
Pericas, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896. (f) Madhan, A.;
Venkateswara Rao, B. Tetradedron Lett. 2003, 44 5641.
* To whom correspondence should be addressed. Tel: +82-55-751-
5472. Fax: +82-55-757-0178.
† University of Oxford.
(1) (a) Elbein A. D. Annu. ReV. Biochem. 1987, 56, 496.
(2) (a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055. (b) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R.
Aust. J. Chem. 1979, 32, 2257.
(3) Sobin, B. A.; Tanner, F. W. J. Am. Chem. Soc. 1954, 76, 4053.
(4) Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886.
(5) Taylor, S. W.; Waite, J. H. In Prolyl Hydroxylase, Protein Disulfide
Isomerase, and Other: Structurally Related Proteins; Guzman, N. A., Eds.;
Marcel Dekker: New York, 1998; p 97.
(8) (a) Huang, Y.; Dalton, D. R. J. Org. Chem. 1997, 62, 372. (b) Hulme,
A. N.; Rosser, E. M. Org. Lett. 2002, 4, 265.
10.1021/ol049237g CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/03/2004

effective methodologies now exist to generate such deriva-
tives as single diastereoisomers from R-amino aldehydes,9
the installation of the 4-hydroxy group has proved much
more difficult and no general stereoselective methodology
currently exists for this purpose (Figure 1). This report
then Swern) in 73% overall yield.18 Subsequent installation
of the vinyl moiety could have been achieved stereoselec-
tively,9,19 but in this case a simple Grignard reaction was
preferred because, fortunately, both of the allyl alcohols could
be easily isolated as single diastereomers by chromatography
on silica gel. The stereoselective iodoamination of allyl
acetate (1a-e) afforded a minimum 25:1 ratio of cis and
trans isomers of iodoacetates, and the single trans isomer
(2a-e) was used for the subsequent Woodward-Prevost
reaction (Table 1).
Table 1. a
Figure 1.
describes the rational design of a chiral synthon for applica-
tion of Woodward-Prevost reaction to 3,4-cis- and 3,4-trans-
pyrrolidinediols stereodivergently.
entry
conditions
time (h)
yieldb (%)
dec (%)
As first noted by Winstein,10 R-haloacetates in the presence
of metal carboxylates are easily transformed to the corre-
sponding cis or trans diols by stereoselective nucleophilic
displacement at the R-carbon.11 This reaction refined by
1
2
3
4
5
toluene, rt
>100
76
75
85
94
68
trace
>95
>95
>95
>95
d
toluene, 60 °C
toluene, reflux
CH2Cl2, reflux
THF, 60 °C
4
24
12
12
Woodward and Prevost13 involves the in situ generation
of R-iodoacetate in a one-pot reaction. Although it has proved
to be powerful methodology for stereoselective dihydroxy-
lation, the vast majority of the examples suffer from a number
of problems, such as poor facial selectivity of epi-iodination
in cyclic substrates,14 low reactivity of the haloacetate due
to steric constraints,15 and low yields.16 However, many of
the associated flaws can be circumvented by preforming the
R-haloacetate and treating this species with the required
Lewis acid. We previously reported that iodoamination of
allyl acetate gives a novel iodoacetate precursor with high
yield and stereoselectivity via endocyclization (Scheme 1).17
a The reactions were all run at 0.2 M concentration. b Isolated yield.
1
c Determined by H NMR integration. d Not determined.
Initially, precursor 2a was chosen as a substrate on which
to test the utility, both with respect to the diversity and
selectivity, of the Woodward-Prevost reaction in this system.
Compound 2a was treated with silver(I) salts under a range
of reaction conditions, while varying the solvent and tem-
perature (Scheme 2). It was found that low polarity solvent
and vigorous conditions gave optimal results in this reaction.
Thus iodoacetate was treated with AgOAc at reflux for 4 h
in dry toluene to give the expected 3,4-trans-diacetate 5 as
the sole product in 94% yield via intermolecular substitution
at the C4-position (vida infra). Both yield and selectivity
were very sensitive to the water content of reaction mixture.
Diacetate 5 could subsequently be converted to the trans-
3,4-diol 3a, as proved by NOESY data, in >95% de by
treatment with LiAlH4 in 98% yield. Synthesis of the C4
epimer 4a was attempted using Woodward-type conditions
on the same starting material 2a. Hence, treatment of 2a with
AgBF4 in wet toluene at room temperature for 12 h yielded
two isomeric hydroxy acyl compounds 6 and 7, which were
separable by chromatography on silica in a 1:1 ratio in 72%
yield. Treatment of these monoacyl derivatives with LiAlH4
Scheme 1
The required starting materials were easily prepared from
commercially available phenylalanine, tyrosine, serine, va-
line, and alanine, which were esterified with MeOH/TMSCl,
protected with Pf, and then reduced to aldehyde (LiAlH4,
(9) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141. (b) Lee, B. W.; Lee J. H.; Jang, K. C.; Kang, J. E.
K.; Kim, J. H.; Park, K. M.; Park, K. H. Tetrahedron Lett. 2003, 44, 5905.
(c) Vuljanic, T.; Kihlberg, J.; Somfai, P. J. Org. Chem. 1998, 63, 279.
(10) Winstein S.; Buckles R. E. J. Org. Chem. 1942, 64, 2769.
(11) For other example of carbohydrates as neighboring groups, see: (a)
Shoji M.; Yamaguchi J.; Kakeya H.; Osada H.; Hayashi Y. Angew Chem.,
Int. Ed. 2002, 41, 3192. (b) Xiao D.; Vera M. D.; Liang B.; Joullie M. J.
Org. Chem. 2001, 66, 2734. (c) Imperato F. J. Org. Chem. 1976, 41, 3478.
(12) Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80,
209.
(14) (a) Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801.
(b) Whitesell, J. K.; Minton, M. A. J. Am. Chem. Soc. 1987, 109, 6403.
(15) Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D.; Welzel, P.
Tetrahedron 2000, 56, 1345.
(16) Kamano, P. Y.; Pettit, G. R.; Tozawa, M.; Komeichi, Y.; Inoue,
M. J. Org. Chem. 1975, 40, 2136.
(17) Lee, W. S.; Jang, K. C.; Kim, J. H.; Park, K. H. Chem. Commun.
1999, 251.
(18) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96 (6), 1825
(19) (a) Maurer, P. J.; Knudsen, C. G.; Palkowitz, A. D.; Rapoport, H.
J. Org. Chem. 1985, 50 (3), 325. (b) Roemmele, R. C.; Rapoport, H. J.
Org. Chem. 1989, 54 (8), 1866.
(13) Prevost C. Compt. Rend. 1933, 196, 1129.
2274
Org. Lett., Vol. 6, No. 13, 2004

Scheme 2
yielded the same product C3, C4 cis-pyrolidinediol 4a, as
Table 2. Preparation of 3,4-trans- and cis-Pyrrolidinediolsa
proved by NOESY data, demonstrating that the two mono-
acyl species, derived from collapse of the ortho ester type
intermediate, differed only in the position of the acyl group,
not in the stereochemistry of the diol framework. Accord-
ingly, both diastereoisomers of a homochiral pyrrolidinediol
(3a and 4a) were synthesized using a remarkably stereodi-
vegent strategy from R-amino acids. To test the versitility
of this methodology with respect to its steric and electronic
demands, a range of C2 position substituted precursors 2b-e
were screened. The compounds (2b-e) were all subjected
to the optimized Prevost reaction conditions, used in the
model substrate, and rewardingly the results were all
similar: in all cases the all-trans derivatives were isolated
as the sole product in excellent yield. Table 2 shows that
methyl (entry 9), the smallest group, was big enough to afford
high regio- and stereoselectivity. These imply that many
chiral R-amino acids will be able to generate either diaste-
reomer of 3,4-pyrrolidine-diol in a stereoselective manner.
Furthermore, as previously shown, the cis-diols (4b-e) were
simply obtained by treatment of AgBF4 and H2O in toluene
and reaction of the diesters with LiAlH4. The relative
entry
R group
2a (Bn)
product
yieldb (%) dec (%)
1
2
3
4
5
6
7
8
9
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
94
72
92
68
87
64
95
75
97
73
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
2a (Bn)
2b (p-methoxybenzyl)
2b (p-methoxybenzyl)
2c (CH2OBn)
2c (CH2OBn)
2d (i-Pr)
2d (i-Pr)
2e (CH3)
2e (CH3)
10
a The reactions were all run at 0.2 M concentration. Path A: AgOAc,
toluene, reflux; LAH, THF, 0 °C. Path B: AgBF4, toluene/water (10/1),
rt; LAH, THF, 0 °C. b Two-step yield. c Determined by 1H NMR inte-
gration.
1
stereochemistry of each product was determined using H
NMR data based on both coupling constant values and
NOESY experiments.
Mechanistically, the observations broadly agree with the
overall scheme of the Woodward-Prevost-type reaction
(Figure 2). The stereoselectivity in the case of the formation
of 3,4-cis systems arises from the trapping of the cyclic cation
the data above, this process can give either 3- or 4-acetoxy
species with equal probability. In the case of the 3,4-trans
compounds, the initial mechanism of the reaction is the same.
However, reversible addition to the cyclic intermediate
allows for the thermodynamic product to be formed in an
SN2 reaction at either the C3 or C4 position, but in this
system the R group is set up optimally to shield attack at
the 3-position, due to 1, 2 steric strain. The ability to syn-
thesize a differentilly protected 3,4-pyrrolidinediol is one of
the most attractive aspects of this was attempted using
AgOBz. As shown in Scheme 3, treatment of iodoacetate
2b with silver benzonate in toluene at reflux for 5 h gave
3-O-acetyl-4-O-benzoyl diol 8 in 94% yield. The posi-
tions of C3 and C4 protons were supported by HMBC
correlation.
Figure 2.
derived from neighboring group participation of the acetate
group, by water. This process is irreversible, and the
intermediate is hydrolyzed to hydroxyacetate. As shown in
With this result proving the principle of differential
protection, a short route to anisomycine derivative 11 was
Org. Lett., Vol. 6, No. 13, 2004
2275

Scheme 3
Scheme 4
attempted. Iodoacetate 2a was refluxed with silver trifluo-
roacetate to give monoacetate 10 in 83% yield directly
(Scheme 4). The trifluoroacetyl group in intermediate 9 was
completely removed in the course of silica chromatography.
The N-Pf groups in compound 10 was removed by hydro-
genation with 10% Pd/C in ethyl acetate at room temperature
for 3 h to give target compound 11 in 89% yield. Hence,
application of Woodward conditions to iodoacetate 2a
allowed the synthesis of compound 11 using straightforward
steps in excellent yield, thus removing the protection/
deprotection and chiral induction step previously required.
In conclusion, we have successfully developed an excellent
highly stereodivergent method for approaching 3,4-pyrro-
lidinediols.
utility of the 2,3-cis isomers previously synthesized by the
group are currently underway.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) through the
Regional Animal Industry Research Center at Jinju National
University, Jinju, Korea. We are also grateful for the financial
support of the Brain Korea 21 program.
This representative example demonstrates the inherent
synthetic potential of this methodology: after simple depro-
tection of Pf group in 3c and 4c, 1,4-dideoxy-1,4-imino-L-
arabinitol and 1,4-dideoxy-1,4-imino-L-ribitol will be gen-
erated, respectively. Both efforts to prepare other biologically
important 3,4-pyrrolidinediols and also research into the
Supporting Information Available: Experimental pro-
cedures, product characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL049237G
2276
Org. Lett., Vol. 6, No. 13, 2004