Ring-closing metathesis of chiral allylamines. Enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline

Article abstract of DOI:10.1021/jo025832p

The ring-closing metathesis (RCM) of two types of unsaturated chiral allylamines III, easily available from enantiomerically enriched epoxy alcohols, has been studied. Fully protected allylamines IIIa [¹R = CH₂-(CH₂)_n-CH=CH₂; ²R = Boc; ³R = PMB] have been prepared from unsaturated epoxy alcohols, whereas bis-allylamines IIIb (¹R = Ph, ²R = allyl, ³R = Boc or PMB) have been prepared from 2,3-epoxy-3-phenylpropanol. Both types have been subjected to RCM to provide either cyclic allylamine I or II. The synthetic potential of these intermediates has been demonstrated by the enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline.

Full text of DOI:10.1021/jo025832p

Rin g-Closin g Meta th esis of Ch ir a l Allyla m in es. En a n tioselective
Syn th esis of (2S,3R,4S)-3,4-Dih yd r oxyp r olin e
Rube´n Mart´ın, Montserrat Alco´n, Miquel A. Perica`s, and Antoni Riera*
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB),
Parc Cientı´fic de Barcelona and Departament de Qu´ımica Orga`nica, Universitat de Barcelona,
c/ J osep Samitier, 1-5, 08028-Barcelona, Spain
ariera@pcb.ub.es
Received April 17, 2002
The ring-closing metathesis (RCM) of two types of unsaturated chiral allylamines III, easily
available from enantiomerically enriched epoxy alcohols, has been studied. Fully protected
2
3
allylamines IIIa [1R ) CH2-(CH2)n-CHdCH2; R ) Boc; R ) PMB] have been prepared from
unsaturated epoxy alcohols, whereas bis-allylamines IIIb (1R ) Ph, R ) allyl,3R ) Boc or PMB)
2
have been prepared from 2,3-epoxy-3-phenylpropanol. Both types have been subjected to RCM to
provide either cyclic allylamine I or II. The synthetic potential of these intermediates has been
demonstrated by the enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline.
1
2
In tr od u ction
in R (IIIa ) or R (IIIb) (Figure 1). These allylamines, in
turn, would be readily accessible in enantiopure form by
deoxygenation of 3-amino-1,2-diols IV,11,12 arising from
the regioselective ring-opening of Sharpless13 epoxy al-
cohols V with appropriate nitrogen nucleophiles. We
describe herein the successful application of this strategy
to the stereoselective preparation of several cyclic amines
of structures I and II from enantiomerically enriched
epoxy alcohols. Moreover, the synthetic potential of those
intermediates is illustrated by the development of an
Polyhydroxylated cyclic amines are widespread in
nature and exhibit multiple biological activities. Many
of them such as polyhydroxypyrrolidines,1 polyhydroxy-
piperidines,2,3 or aminocyclitols4 are potent glycosidase
inhibitors5,6 with potential therapeutic importance. Al-
though the most usual access to these compounds is by
functional group manipulation from carbohydrates, the
development of practical asymmetric synthesis leading
to them is a subject of great interest.
(2) Selected synthesis of 1-deoxymannojirimycin: (a) Bernotas, R.
C.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123-1126. (b) Pederson,
R. L.; Kim, M.-J .; Wong, C.-H. Tetrahedron Lett. 1988, 29, 4645-4648.
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45, 327-336. (d) Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R.
Tetrahedron 1989, 45, 319-326. (e) Baxter, E. W.; Reitz, A. B. J . Org.
Chem. 1994, 59, 3175-3185. (f) Park, K. H.; Yoon, Y. J .; Lee, S. G. J .
Chem. Soc., Perkin Trans. 1 1994, 2621-2623. (g) Xu, Y.-M.; Zhou,
W.-S. J . Chem. Soc., Perkin Trans. 1 1997, 741-746. (h) Wu, X.-D.;
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sumura, S. Chem. Commun. 1999, 7, 41-42. (n) Shirai, M.; Okamoto,
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Dihydroxylation of unsaturated cyclic amines is a
convenient entry to many polyhydroxylated alkaloids.
Since ring-closing metathesis (RCM)7,8 has emerged as
one of the most powerful reactions for the preparation of
cycloalkenes, we envisaged that cyclic amines9,10 of
generic structures I and II could be prepared from
allylamines III bearing an appropriate unsaturated chain
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Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999
10.1021/jo025832p CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002
6896
J . Org. Chem. 2002, 67, 6896-6901

Sumthesis of (2S,3R,4S)-3,4-Dihydroxyproline
this event, by blocking both NH of the amino group we
intended to avoid the potential deleterious effect of the
secondary amine in the RCM, since it is known that a
basic amine can inactivate the catalyst.15 Aminodiols
2a -c bearing a fully protected amino group were deoxy-
genated with the Corey-Hopkins protocol.12 Thus, thiono-
carbonates 3a -c were prepared in high yield by treat-
ment with thiophosgene in the presence of 4-(dimethyl-
amino)pyridine and subsequently heated at 60 °C in 1,3-
dimethyl-2-phenylphosphazolidine. In this way the py-
rolysis took place smoothly affording bis-allylamines 4a -
c. With the bis-olefinic amines in hand, the RCM was
performed with 2% mol of benzylidene (bis(tricyclohexyl)-
phosphine)ruthenium(II) dichloride (Grubbs’s catalyst).7
The cyclopentene and cyclohexene amines 5b and 5c
were obtained in excellent yield in what represents a
straightforward synthesis of these intermediates of high
enantiomeric purity. Not surprisingly, the attempted
cyclization of 4a completely failed. In this case, most
probably due to the strain of the cyclobutane ring, the
starting material was completely recovered. Our pro-
jected preparation of enantiopure heterocyclic amines II
involved chiral allylamines IIIb bearing an allyl frag-
ment directly bonded to the amino group. We envisaged
that these compounds could be easily prepared by using
allylamine as a nucleophile in the epoxide ring-opening.
We selected 2,3-epoxy-3-phenylpropanol (6) as starting
material for two reasons: it is readily available in
enantiopure form and the phenyl group is a known
precursor of a carboxylic group. Thus, epoxyalcohol 6 of
>99% ee was prepared from cinnamyl alcohol by Sharp-
less epoxidation.13a Two well-established protecting groups
for the amino function, p-methoxybenzyl (PMB) and tert-
butoxycarbonyl (Boc), were selected. The PMB group was
tried first because the corresponding allylamines bearing
it (i.e. N-allyl-p-methoxybenzylamine) are still very nu-
cleophilic and consequently offered the advantage that
they could be directly used as nucleophiles in the epoxide
ring-opening. According to our expectations, the treat-
ment of epoxy alcohol 6 with N-allyl-p-methoxybenzyl-
amine under Sharpless conditions afforded aminodiol 7a
in excellent yield (Scheme 2). However, due to the
difficulties encountered in the dihydroxylation and in the
deprotection of the PMB (vide infra), the Boc-protected
aminodiol 7b was also prepared. The poor reactivity of
N-Boc-allylamine prevented its introduction by nucleo-
philic ring opening so epoxide 6 was treated with allyl-
F IGURE 1. Retrosynthetic analysis of cyclic allylamines.
enantioselective synthesis of protected (2S,3R,4S)-3,4-
dihydroxyproline from (2S)-N-Boc-2-phenyl-2,5-dihydro-
pyrrole
Resu lts a n d Discu ssion
Our approach to enantiopure dialkylaminocycloalkenes
(I) is based on the preparation of chiral allylamines IIIa
derived from unsaturated allyl alcohols. To this end,
epoxy alcohols 1a -c of high enantiomeric excess (91-
94% ee) were prepared by Sharpless catalytic epoxidation
of the corresponding alkadienols and converted in high
yield to the known N-Boc-N-(4′-methoxybenzyl)-3-amino-
1,2-diols 2a -c by our previously described procedure,
involving regioselective ring-opening with 4-methoxy-
benzylamine and subsequent protection with Boc2O.14 In
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Fleet, G. W. J . Tetrahedron: Asymmetry 2000, 11, 1645-1680.
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7325. (b) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc.
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1995, 34, 1833-1836. (d) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc.
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Int. Ed. Engl. 2000, 39, 2073-2077.
(8) Selected approaches to azasugars by RCM: (a) Huwe, C. M.;
Blechert, S. Synthesis 1997, 61-67. (b) White, J . D.; Hrnciar, P.;
Yokochi, A. F. T. J . Am. Chem. Soc. 1998, 120, 7359-7360. (c) Pandit,
U. K.; Overkleeft, H. S.; Borer, B. C.; Biera¨ugel, H. Eur. J . Org. Chem.
1999, 959-968. (d) Phillips, A. J .; Abell, A. D. Aldrichim. Acta 1999,
32, 75-89
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Tetrahedron Lett. 1989, 30, 5709-5712. (c) Tamao, K.; Nakagawa, Y.;
Ito, Y. J . Org. Chem. 1990, 55, 3438-3439. (d) Braun, H.; Felber, H.;
Kreâe, G.; Ritter, A.; Schmidtchen, F. P.; Schneider, A. Tetrahedron
1991, 47, 3313-3328. (e) Cho, C.-G.; Posner, G. H. Tetrahedron Lett.
1992, 33, 3599-3602. (f) Blond, A.; Platzer, N.; Guy, A.; Dhotel, H.;
Serva, L. Bull. Soc. Chim. Fr. 1996, 133, 283-293. (g) Brimble, M. A.;
Lee, C. K. Y. Tetrahedron: Asymmetry 1998, 9, 873-884. (h) Donohoe,
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9, 818-823. (b) Wang, C. J .; Calabrese, J . C. J . Org. Chem. 1991, 56,
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J . Org. Chem, Vol. 67, No. 20, 2002 6897

Mart´ın et al.
SCHEME 1
SCHEME 2
catalytic amount of OsO4 took place in excellent yield and
with complete facial selectivity, anti to the phenyl group.
After protection of the diol as an acetonide, the phenyl
group was oxidized with NaIO4 and a catalytic amount
of ruthenium trichloride19 to afford the protected 3,4-
dihydroxyproline 14b. This compound showed the same
rotatory power as the product prepared from Zanardi and
co-workers and their spectra were completely coincident.16c
In summary, chiral allylamines III prepared by deoxy-
genation of 3-amino-1,2-diols have been tested in RCM
reactions. Doubly olefinic compounds IIIa have been
readily prepared from unsaturated epoxy alcohols, and
their RCM has provided cyclic allylamines I in excellent
yields and high enantiomeric purity. On the other hand,
starting from 2,3-epoxycinnamyl alcohol, a nucleophilic
ring opening by allylamines followed by a deoxygenation
protocol afforded bis-allylamines IIIb, which upon RCM
provided unsaturated pyrrolidines II also in excellent
yields. One of these pyrrolidines has been used in the
preparation of enantiomerically pure fully protected
(2S,3R,4S)-3,4-dihydroxyproline.
amine in the presence of titanium tetraisopropoxide and
the resulting aminodiol 8 was protected with Boc2O to
afford 7b in good yield.
Both aminodiols 7a and 7b were submitted to the
Corey-Hopkins protocol12 with the same reaction condi-
tions as in the preparation of 4a -c, but the intermediate
thionocarbonates were not characterized but used directly
in the pyrolysis step. In both cases the deoxygenation
took place in good yields affording bis-allylamines 10a ,b.
These amines were treated with Grubbs’s catalyst in CH2-
Cl2 at room temperature. In both cases pyrrolidines 11a ,b
were obtained in excellent yields. The enantiomeric
purity of 11a ,b was checked by DSC and, as expected,
was in both cases >99%. These compounds, like other
related dehydropyrrolidines, are useful intermediates in
the synthesis of heterocyclic compounds and some of
them such as 11b have already been prepared.10 To
further demonstrate their potential, we have used them
as precursors in the synthesis of an important biologically
active amino acid: 3,4-dihydroxyproline.16,17 The key
steps for this synthesis would be the dihydroxylation of
the double bond and the oxidation of the phenyl ring.
After much experimentation we could neither dihydroxy-
late18 the p-methoxybenzyl derivative 11a nor deprotect
the PMB group in acceptable yield. Gratifyingly, however,
the dihydroxylation of 11b10e with K3Fe(CN)6 and a
Exp er im en ta l Section
Gen er a l Meth od s. Optical rotations were measured at
room temperature (23 °C) (concentration in g/100 mL). Infrared
spectra were recorded with NaCl film. 1H NMR were obtained
at 200 or 300 MHz with tetramethylsilane as internal stan-
dard. 13C NMR were obtained at 50.3 or 75.4 MHz in DCCl3,
(16) (a) Fleet, G. W. J .; Son, J . C. Tetrahedron 1988, 44, 2637-2647.
(b) Ikota, N. Chem. Pharm. Bull. 1993, 41, 1717-1721. (c) Zanardi,
F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.; Cornia, M.; Casiraghi,
G. Tetrahedron: Asymmetry 1996, 7, 1167-1180.
(17) (a) Dho, J . C.; Fleet, G. W. J .; Peach, J . M.; Prout, K.; Smith,
P. W. Tetrahedron Lett. 1986, 27, 3203-3204. (b) Taylor, S. W.; Waite,
J . H.; Ross, M. M.; Shabanowitz, J .; Hunt, D. F. J . Am. Chem. Soc.
1994, 116, 10803-10804. (c) Baldwin, J . E.; Field, R. A.; Lawrence, C.
C.; Lee, V.; Robinson, J . K.; Schofield, C. J . Tetrahedron Lett. 1994,
35, 4649-4652. (d) Behr, J .-B.; Defoin, A.; Mahmood, N.; Streith, J .
Helv. Chim. Acta 1995, 78, 1166-1177. (e) Weir, C. A.; Taylor, C. M.
J . Org. Chem. 1999, 64, 1554-1558.
(18) (a) Minato, M.; Yamamoto, K.; Tsuji, J . J . Org. Chem. 1990,
55, 766-768. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483-547.
(19) Carlsen, P. H. J .; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
6898 J . Org. Chem., Vol. 67, No. 20, 2002

Sumthesis of (2S,3R,4S)-3,4-Dihydroxyproline
SCHEME 3
and referenced to the solvent signal. Chemical shifts are
recorded in ppm. Signal multiplicities have been assigned by
DEPT experiments. Chromatographic separations were carried
out with NEt3 pretreated (2.5% v/v) SiO2 (70-230 mesh).
Compounds 2a -c14 and 613a were prepared according to known
procedures. All other compounds are novel except 11b10e and
14b.16c
with hexanes/ethyl acetate mixtures to afford 75 mg of 5b (99%
yield). [R]D -91.7 (c 1.0, CHCl3). IR (film) ν 3000, 2950, 1700,
1620, 1520, 1460, 1410 cm-1 1H NMR (200 MHz, CDCl3) δ
.
7.13 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 5.87 (m,
1H), 5.5 (m, 1H), 5.3 (broad, 1H), 4.21 (s broad, 2H), 3.78 (s,
3H), 2.25 (m, 2H), 1.55 (m, 2H), 1.41 (s broad, 9H). 13C NMR
(50 MHz, CDCl3) δ 158.1 (C), 155.8 (C), 134.2 (CH), 132.4 (C),
130.8 (2CH), 127.8 (CH), 113.4 (2CH), 79.5 (C), 62.4 (CH), 55.2
(CH3), 46.0 (CH2), 31.3 (2CH2), 28.4 (3CH3). HRMS calcd for
(4S,1′S)-N-(ter t-Bu toxyca r bon yl)-N-(4-m eth oxyben zyl)-
4-(1′-a m in obu t-3′-en yl)[1,3]d ioxola n e-2-th ion e (3a ). To a
stirred solution of 2a (1.25 g, 3.57 mmol) and 4-DMAP (1.05
g, 8.57 mmol) in dichloromethane (14.3 mL) at 0 °C under
nitrogen was added thiophosgene (95%, 350 µL, 4.28 mmol).
After 1 h of stirring at 0 °C, silica gel (7.14 g) was added and
the mixture was allowed to warm to 25 °C. Solvent was
removed in vacuo, and the remaining solid was loaded onto a
column of silica gel (21.4 g) and eluted with 20% ethyl acetate
in hexane to afford 1.17 g of thionocarbonate 3a (84% yield)
as an oil. [R]D +43.7 (c 2.0, CHCl3). IR (film) ν 3100, 2977,
1750, 1692, 1613, 1586, 1515, 1459, 1395, 1291 cm-1. 1H NMR
(200 MHz, CDCl3) δ 7.17 (d broad, 2H), 6.87 (d, J ) 8.4 Hz,
2H), 5.7 (m, 1H), 5.25-5.1 (m, 2H), 5.1 (m, 1H), 4.5-3.8 (m,
5H), 3.8 (s, 3H), 2.61 (m, 2H), 1.5 (s, 9H). 13C NMR (50 MHz,
CDCl3) δ 159.3 (C), 155 (C), 133.1 (CH), 129.2 (CH), 118.6
(CH2), 114.3 (CH), 82.8 (CH), 81.0 (C), 71.8 (CH2), 58.9 (CH),
55.2 (CH3), 50.3 (CH2), 33.8 (CH2), 28.3 (CH3). MS (CI-NH3)
m/e 295 (83%), 394 (M + 1, 2%), 395 (M + 2, 12%), 411 (M +
18, 100%).
C
18H26NO3 (M + 1) 304.1913, found 304.1921.
(2R,3R)-3-[Allyl(4-m eth oxyben zyl)a m in o]-3-p h en ylp r o-
p a n e-1,2-d iol (7a ). To a solution of (2R,3S)-2,3-epoxy-3-phen-
ylpropanol (6; 2.2 g, 14.65 mmol) in anhydrous dichlo-
romethane (55 mL) at room temperature was added titanium
tetraisopropoxide (13.3 mL, 44 mmol) dropwise under nitrogen.
The mixture was briefly stirred at room temperature for 30
min, allyl(4-methoxybenzyl)amine (5.2 g, 29.3 mmol) was
added, and the mixture was heated for 15 h at 65 °C. Then
the reaction mixture was allowed to reach room temperature
and quenched with 23.5 mL of a 10% aqueous solution of
sodium hydroxide saturated with sodium chloride. Stirring was
maintained for an additional 4 h at room temperature and the
mixture was filtered through a pad of Celite and washed with
dichloromethane. The aqueous layer was extracted with
dichloromethane and the combined organic phases were
washed with brine. The organic layer was dried and evapo-
rated. The resulting residue was purified by column chroma-
tography eluting with hexanes/ethyl acetate mixtures to afford
(3S)-N-(ter t-Bu toxyca r bon yl)-N-(4-m eth oxyben zyl)-(1-
vin ylbu t-3-en yl)a m in e (4a ). A suspension of thionocarbonate
3a (1.68 g, 4.27 mmol) in 1,3-dimethyl-2-phenyl-1,3,2-diaza-
phospholidine (2.3 mL, 12.8 mmol) was stirred under nitrogen
for 20 h at 45 °C. After cooling to 25 °C, the contents were
directly chromatographed on silica gel (elution with 2% ethyl
acetate in hexane) to afford 850 mg of olefin 4a (63% yield) as
an oil. [R]D -20.2 (c 1.4, CHCl3). IR (film) ν 3080, 2977, 1690,
7a (4.46 g, 93% yield) as a colorless oil. [R]23 -123.14 (c 1.1,
D
CHCl3). IR (NaCl) ν 3407, 3064, 1613, 1514, 1454 cm-1
.
1H
NMR (300 MHz, CDCl3) δ 7.41-7.19 (m, 7H), 6.88 (d, J ) 8,8
Hz, 2H), 5.82 (m, 1H), 5.21 (m, 2H), 4.38 (m, 1H), 3.81 (m,
9H), 3.39 (m, 1H), 2.92 (d, J ) 16.3 Hz, 1H), 2.59 (dd, J )
16.3, 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 158.8 (C), 135.7
(CH), 133.9 (C), 131.4 (C), 130.1 (CH), 129.9 (CH), 128.5 (CH),
128.0 (CH), 118.4 (CH2), 114.0 (CH), 68.8 (CH), 66.7 (CH), 66.5
(CH2), 55.2 (CH3), 53.9 (CH2), 53.2 (CH2). MS (CI-NH3) m/z
(%) 328(100) [M + 1]+, 345 (41) [M + 18]+. HRMS calcd for
1
1613 cm-1. H NMR (200 MHz, CDCl3) δ 7.17 (d, J ) 8.5 Hz,
2H), 6.82 (d, J ) 8.5 Hz, 2H), 5.95-5.55 (m, 2H), 5.15-4.95
(m, 4H), 4.3 (m, 3H), 3.79 (s, 3H), 2.4 (m, 2H), 1.43 (s, 9H).
13C NMR (50 MHz, CDCl3) δ 158.4 (C), 156 (C), 137.3 (CH),
135.1 (CH), 131.7 (C), 128.6 (CH), 116.9 (CH2), 116.2 (CH2),
113.5 (CH), 79.7 (C), 58.6 (CH), 55.2 (CH3), 47.9 (CH2), 36.8
(CH2), 28.4 (CH3). MS (CI-NH3) m/e 235 (M + 18, 100%), 318
(M + 1, 74%), HRMS calcd for C19H27NO3 317.2003, found
317.1991.
C
20H25NO3 327.1834, found 327.1819.
(2R,3R)-3-Allyla m in o-3-p h en ylp r op a n e-1,2-d iol (8). To
a solution of (2R,3S)-2,3-epoxy-3-phenylpropanol (6) (1.00 g,
6.66 mmol) in anhydrous dichloromethane (24 mL) at room
temperature was added titanium tetraisopropoxide (6 mL, 20
mmol) dropwise under nitrogen. The mixture was stirred for
15 min and allylamine (1.5 mL, 20 mmol) was added dropwise.
Then, the mixture was stirred for 8 h at 65 °C. The reaction
was allowed to cool to room temperature and quenched with
23.5 mL of a 10% aqueous solution of sodium hydroxide
saturated with sodium chloride. Stirring was maintained for
an additional 6 h at room temperature and the mixture was
(1S)-N-(ter t-Bu toxyca r bon yl)-N-(p-m eth oxyben zyl)cy-
clop en t-2-en yla m in e (5b). To a Schlenk flask containing a
solution of 4b (82 mg, 0.25 mmol) in anhydrous dichlo-
romethane (1.54 mL) was added benzylidene (bis(tricyclohexyl)-
phosphine)ruthenium(II) dichloride (8 mg, 0.03 mmol) under
argon. After 1 h of stirring at room temperature, air was
bubbled for 3 h. The solvent was removed in vacuo and the
crude product was purified by column chromatography eluting
filtered through
a pad of Celite, washing with dichlo-
romethane. The aqueous layer was extracted with dichlo-
J . Org. Chem, Vol. 67, No. 20, 2002 6899

Mart´ın et al.
romethane and the combined organic phases were washed with
brine, dried (sodium sulfate), and evaporated. The residue was
purified by column chromatography eluting with hexanes/ethyl
acetate mixtures yielding 8 as a yellow solid (1.32 g, 97% yield).
(C), 131.34 (CH), 128.24 (CH), 127.21 (CH), 126.67 (CH),
124.61 (CH), 79.54 (CH), 64.93 (C), 48.13 (CH2), 28.28 (CH3).
MS (CI-NH3) m/z (%) 246 (90) [M + 1]+, 263 (100) [M + 18]+.
Purity by DSC: 99.5% (mp 81.01 °C). Anal. Calcd for C15H19
-
[R]23 -67.04 (c 1.1, CHCl3). Mp 63-65 °C. IR (NaCl) ν 3315,
NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.45; H, 7.72; N,
5.65.
D
1641, 1603, 1496, 1463 cm-1
.
1H NMR (300 MHz, CDCl3) δ
7.37-7.26 (m, 5H), 5.91-5.77 (m, 1H), 5.17-5.07 (m, 2H),
3.88-3.81 (m, 2H), 3.58 (d, J ) 5 Hz, 2H), 3.21 (dd, J ) 13.6,
5.6 Hz, 1H), 3.03 (dd, J ) 13.2, 7.5 Hz, 1H), 2.71 (br s, 3H).
13C NMR (75 MHz, CDCl3) δ 139.2 (C), 136.0 (CH), 128.5 (CH),
127.7 (CH), 127.6 (CH), 116.4 (CH2), 73.5 (CH), 65.3 (CH), 64.4
(CH2), 49.7 (CH2). MS (CI-NH3) m/z (%) 208 (100) [M + 1]+,
225 (25) [M + 18]+. Anal. Calcd for C12H17NO2: C, 69.54; H,
8.27; N, 6.76. Found: C, 69.33; H, 8.15; N, 6.72.
(2R,3R,4S)-N-ter t-Butoxycar bonyl-3,4-dihydr oxy-2-ph en -
ylp yr r olid in e (12b). To a solution of 11b (0.1 g, 0.41 mmol)
in tBuOH (3 mL) and H2O (3 mL) were added potassium
hexacyanoferrate (0.403 g) and K2CO3 (0.167 g). The mixture
was stirred for 15 min at room temperature and a solution of
t
OsO4 (0.1 mL, 0.051 mM in BuOH) was added slowly. After
24 h of stirring the reaction was complete by TLC. Et2O (2
mL) was added and the aqueous layer was extracted with ethyl
ether. The combined organic layers were washed with brine
and dried (MgSO4). The solvent was removed in vacuo to give
(2R,3R)-3-ter t-Bu toxycar bon ylam in o-3-ph en ylpr opan e-
1,2-d iol (7b). To a solution of 8 (1.1 g, 6.28 mmol) in MeOH
(25 mL) at room temperature were added Boc2O (1.4 g, 7.54
mmol) and NaHCO3(18.84 mmol). The reaction mixture was
placed for 12 h in a ultrasonic bath being monitored by TLC.
The mixture was filtered through a pad of Celite and washed
with Et2O. The organic phase was dried and evaporated and
the crude product was purified by column chromatography
eluting with hexanes/ethyl acetate mixtures to yield 7b as a
white solid (1.55 g, 95% yield). [R]23D -57,4 (c 1.1, CHCl3). Mp
12b (0.113 g, 99% yield) as a colorless oil. [R]23 -16.2 (c 1.6,
D
CHCl3). IR (NaCl) ν 3434, 2979, 1700, 1399 cm-1
.
1H NMR
(300 MHz, CDCl3, 55 °C) δ 7.33-7.15 (m, 5H), 4.61 (br s, 1H),
4.22 (dd, J ) 7.3, 3.3 Hz, 1H), 3.99 (m, 1H), 3.73 (dd, J ) 11.7,
5.7 Hz, 1H), 3.64 (br s, 1H), 3.21 (br s, 2H), 1.24 (s, 9H).13
C
NMR (75 MHz, CDCl3, 55 °C) δ 154.8 (CO), 140.2 (C), 128.5
(CH), 127.1 (CH), 125.7 (CH), 80.0 (CH), 69.6 (CH), 66.9 (CH),
61.4 (C), 51.4 (CH2), 28.2 (CH3). MS (CI-NH3) m/z (%) 280
44-45 °C. IR (NaCl) ν 3387, 2997, 1689, 1614, 1461, 1411 cm-1
.
(86) [M + 1]+, 297 (100) [M + 18]+. Anal. Calcd for C15H21
-
1H NMR (300 MHz, CDCl3) δ 7.41-7.25 (m, 5H), 5.58-5.39
(m, 1H), 5.16 (d, J ) 9.1 Hz, 1H), 4.96-4.83 (m, 2H), 4.16 (br
s, 1H), 3.72-3.26 (m, 5H), 2.63 (br s, 1H), 1.49 (s, 9H). 13C
NMR (75 MHz, CDCl3) δ 155.6 (CO), 136.8 (C), 134.4 (CH),
129.6 (CH), 128.5 (CH), 127.9 (CH), 117.0 (CH2), 81.2 (CH),
69.9 (CH), 62.9 (CH2), 59.8 (C), 47.0 (CH2), 28.4 (CH3). MS (CI-
NH3) m/z (%) 308 (100) [M + 1], 325 (34) [M + 18]+. Anal.
Calcd for C17H25NO4: C, 66.43; H, 8.2; N, 4.56. Found: C,
66.47; H, 8.06; N, 4.39.
NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.67; H, 7.61; N,
5.05.
(2R,3R,4S)-N-ter t-Butoxycar bonyl-3,4-dihydr oxy-2-ph en -
ylp yr r olid in e Isop r op ylid en e Aceta l (13b). To a solution
of 12b (0.1 g, 0.36 mmol) in acetone (5 mL)were added 2,2-
dimethoxypropane (0.11 mL, 0.54 mmol) and a p-TsOH‚H2O
(ca. 6 mg). When the reaction was complete by TLC (ca. 3 h)
the mixture was concentrated and purified by column chro-
matography eluting with hexanes/ethyl acetate mixtures to
afford 13b (0.11 g, 96% yield) as a white solid. [R]23 -48.14
(1S)-N -Allyl-N -(t er t-b u t oxyca r b on yl)-1-p h e n yla llyl-
a m in e (10b). To a solution of 7b (1.4 g, 4.55 mmol) and 4-
(dimethylamino)pyridine (1.33 g, 10.94 mmol) in anhydrous
dichloromethane (25 mL) at 0 °C was added thiophosgene (0.47
mL, 5.46 mmol) slowly under nitrogen. The reaction mixture
was stirred for 2 h, at which time TLC showed the reaction to
be complete. Evaporation of the solvent (using a KOH trap)
afforded a crude product (9b) that was used without further
purification in the next step.
D
(c 1.4, CHCl3). Mp 98-100 °C. IR (NaCl) ν 2981, 1700, 1603
1
cm-1. H NMR (300 MHz, CDCl3, 55 °C) δ 7.39-7.19 (m, 5H),
5.11 (br, 1H), 4.78 (t, J ) 5.2 Hz, 1H), 4.69 (d, J ) 6 Hz, 1H),
4.01 (d, J ) 12.3 Hz, 1H), 3.65 (br s, 1H), 1.54 (s, 6H), 1.29 (s,
9H).13C NMR (75 MHz, CDCl3, 55 °C) δ 154.53 (CO), 140.35
(C), 128.67 (CH), 127.24 (CH), 125.79 (CH), 112.05 (CH), 87.45
(CH), 79.86 (CH), 78.94 (C), 67, 37 (C), 52.76 (CH2), 28.27
(CH3), 27.13 (CH3), 25.21 (CH3). MS (CI-NH3) m/z (%) 320
(23) [M + 1]+, 327 (100) [M + 18]+. Anal. Calcd for C18H25
-
In a 50-mL round-bottomed flask, the crude thiocarbonate
(1.44 g, 4.12 mmol) and freshly distilled 1,3-dimethyl-2-phenyl-
[1,3,2]diazaphospholidine (2.4 mL, 12.41 mmol) were placed
under nitrogen. The reaction mixture was warmed to 65 °C
for 24 h. The residual crude was directly purified by column
chromatography eluting with hexanes/ethyl acetate mixtures
to yield 10b (0.86 g, 72% overall yield from 7b) as a colorless
oil. [R]23D -43.59 (c 1.3, CHCl3). IR (NaCl) ν 2982, 1691, 1461,
NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.89; H, 7.94; N,
4.46.
(2S,3R,4S)-N-ter t-Bu t oxyca r b on yl-3,4-d ih yd r oxyp r o-
lin e Isop r op ylid en e Aceta l (14b). A 50-mL, three-necked,
round-bottomed flask equipped with a wide-bore gas outlet
(because the generation of carbon dioxide) was charged with
13b (100 mg, 0.32 mmol), carbon tetrachloride (2.2 mL),
acetonitrile (2.2 mL), water (4.5 mL), and sodium bicarbonate
(0.45 g, 5.35 mmol). The mixture was briefly stirred until both
phases were clear. Sodium periodate (1.22 g, 6.28 mmol) was
added and the mixture stirred for 15 min. Ruthenium trichlo-
ride hydrate (8 mg, 10% mol) was added and the mixture
vigorously stirred for 55 h. Then, diethyl ether (3 mL) was
added (a deep black color appeared at this point) at 0 °C with
vigorous stirring. After 10 min the organic phase was sepa-
rated and the aqueous layer extracted with ether. The
combined organic layers were washed with brine, dried,
filtered, and concentrated. The crude product was purified by
column chromatography eluting with methanol/dichloromethane
mixtures to afford pure 14b (53 mg, 59% yield) as a colorless
oil. [R]23D -44.1. (c 0.07, CHCl3). IR (NaCl) ν 3433, 1745, 1581
cm-1. 1H NMR (300 MHz, CDCl3) δ 7.19 (bs, 1H), 4.78 (m, 2H),
4.43 (m,1H), 3.77 (m, 2H), 1.48 (s, 9H), 1.42 (s, 3H), 1.29 (s,
3H).13C NMR (75 MHz, CDCl3) δ 172.3 (CO), 154.1 (CO), 111.8
(CH), 82.3 (CH), 81.4 (CH), 80.3(C), 66.9 (C), 52.1 (CH2), 28.5
(CH3), 26.8 (CH3), 25.1 (CH3). MS (CI-NH3) m/z (%) 288 (47)
[M + 1]+, 305 (100) [M + 18]+. Anal. Calcd for C13H21NO6: C,
54.35; H, 7.37; N, 4.88. Found: C, 54.27; H, 7.41; N, 4.81.
1402, 1373, 1264 cm-1 1H NMR (300 MHz, CDCl3) δ 7.39-
.
7.29 (m, 5H), 6.23-6.11 (m, 1H), 5.62 (br s, 1H), 5.39-5.22
(m, 2H), 5.01 (d, J ) 11.2 Hz, 2H), 3.86-3.69 (m, 3H), 1.46 (s,
9H).13C NMR (75 MHz, CDCl3) δ 155.55 (CO), 140.09 (C),
135.71 (CH), 135.3 (CH), 128.25 (CH), 127.71 (CH), 127.2 (CH),
117.83 (CH2), 115.9 (CH2), 79.92 (CH), 61.88 (C), 47.72 (CH2),
28.37 (CH3). MS (CI-NH3) m/z (%) 274 (100) [M + 1]+, 291
(41) [M + 18]+. HRMS (CI) calcd for C17H23NO2 (M+) 273.1729,
found 273.1746.
(2S)-N-ter t-Bu toxyca r bon yl-2-p h en yl-2,5-d ih yd r op yr -
r ole (11b). To a solution of 10b (0.72 g, 2.64 mmol) in
anhydrous dichloromethane was added Grubbs’s catalyst (0.11
g, 5% mol) dropwise under nitrogen. The resulting mixture
was stirred at room temperature. When the reaction was
complete by TLC (ca. 1 h), the reaction mixture was concen-
trated and chromatographed eluting with hexanes/ethyl ac-
etate mixtures to afford 11b (0.63 g, 99% yield) as a white
solid. [R]23D -280.5 (c 1.0, CHCl3). IR (NaCl) ν 3021, 1705, 1645
1
cm-1. H NMR (300 MHz, CDCl3, 55 °C) δ 7.32-7.19 (m, 5H),
5.87 (s, 1H), 5.73 (s, 1H), 5.37 (s, 1H), 4.33 (s, 2H), 1.21 (s,
9H).13C NMR (75 MHz, CDCl3, 55 °C) δ 154.67 (CO), 140.14
6900 J . Org. Chem., Vol. 67, No. 20, 2002

Sumthesis of (2S,3R,4S)-3,4-Dihydroxyproline
and 11a and; 1H NMR and 13C NMR spectra of compounds
4a , 4b, 4c, 5b, 5c, 7a , 10a , 11a , 8, 10b, 11b, 12b, and 13b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support from CIRIT
(2000SGR-00019) and from DGICIT (PB98-1246) is
gratefully acknowledged. R.M. thanks CIRIT (Gener-
alitat de Catalunya) for a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of compounds 3b, 4b, 3c, 4c, 5c, 10a ,
J O025832P
J . Org. Chem, Vol. 67, No. 20, 2002 6901