Stereocontrolled synthesis of (2S*,3R*,4R*)-4-hydroxy-3-methylproline using a silicon assisted aza-[2,3]-Wittig sigmatropic rearrangement

Article abstract of DOI:10.1039/b007586h

Racemic synthesis of the non-proteinogenic amino acid (2S,3R,4R)-4-hydroxy-3-methylproline was discussed. Iodolactonization of an unstarurated amino acid derivative was done. Results showed that the silicon assisted aza-[2,3]-Wittig sigmatropic rearrangem

Full text of DOI:10.1039/b007586h

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Stereocontrolled synthesis of (2S*,3R*,4R*)-4-hydroxy-
3-methylproline using a silicon assisted aza-[2,3]-Wittig
sigmatropic rearrangement
1
James C. Anderson* and Alice Flaherty
School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD.
E-mail: j.anderson@nottingham.ac.uk
Received (in Cambridge, UK) 19th September 2000, Accepted 20th December 2000
First published as an Advance Article on the web 16th January 2001
The first racemic synthesis of the non-proteinogenic amino acid (2S,3R,4R)-4-hydroxy-3-methylproline (1) has
been achieved via iodolactonisation of an unnatural amino acid derivative 4. The relative stereochemistry was
derived from an efficient silicon assisted aza-[2,3]-Wittig sigmatropic rearrangement of 2.
There is an evergrowing interest in the synthesis, pharmacology
and conformational properties of non-proteinogenic amino
acids. Amongst these, metabolites of proline can exert dramatic
conformational changes in peptides,1 and are valuable
components of peptidomimetics.2 Naturally occurring
trans-4-hydroxyproline is found in various biologically active
Fig. 1 HyMePro.
peptides.3 A substituted derivative, (2S,3R,4R)-4-hydroxy-
3-methylproline (HyMePro, 1, Fig. 1), is an unusual proline
derived amino acid which is a component of a potent calcium
antagonist, the cyclic peptide scytonemin A, isolated from a
Scytonema sp. (strain U-3-3) (Scytonemataceae).4 The synthesis
of 1 would be difficult to achieve via the standard methods used
to synthesise 4-hydroxyproline derivatives.5 In this paper we
show that the silicon assisted aza-[2,3]-Wittig sigmatropic
rearrangement we have developed,6 can be used to provide
an unnatural amino acid precursor which, by standard mani-
pulations, can give 1 in high yield.
The rearrangement precursor 2 was prepared by the alkyl-
ation of the potassium anion of N-(tert-butoxycarbonyl)glycine
N,N-dimethylamide, with (Z)-2-(phenyldimethylsilyl)but-2-
enyl bromide in 97% yield. Treatment of 2 with KH and 0.5
equivalents of 18-crown-6 at 0 ЊC with warming to rt induced
a [2,3]-sigmatropic rearrangement to furnish 3 in greater than
1
20:1 diastereoselectivity by H NMR, in favour of the anti
diastereoisomer drawn (Scheme 1). The sense of diastereo-
selectivity is in accord with our transition state model13 and
Scheme 1
has been confirmed by single crystal X-ray crystallography.†
Protodesilylation was achieved under optimised conditions7
material). The two diastereoisomers were assigned based upon
comparison of the Boc deprotected materials with literature
data. Each diastereoisomer was deprotected with TFA–Et3SiH
t
employing a combination of BuOK–18-crown-6–TBAF to
give alkene 4 with no loss of diastereoselectivity in a 71%
yield. Partial hydrolysis of the amide by tBuOK may be dimin-
ishing this yield.8 The syn diastereoisomer can be prepared
in enantiomerically pure form by using Kazmaier’s [3,3]-
sigmatropic rearrangement of glycine ester enolates and has
been manipulated in a similar fashion to give peptides contain-
ing the all-cis diastereoisomer of 1.9
1
and their H NMR recorded. The C-4 stereochemistry was
assigned by analogy to butyrolactones prepared by Yoshida10
and other data.11 It is proposed that in this ring system
Jtrans = 0–4.4 Hz and Jcis = 7.3–8.5 Hz. The primary amine
resulting from deprotection of 5a possesses JH(2)–H(3) = 8.0 Hz
and JH(3)–H(4) = 3.0 Hz, to which we assign trans stereochemistry
across the C3–C4 bond. The diastereomeric primary amine
resulting from deprotection of 5b possesses JH(2)–H(3) = 7.0 Hz
and JH(3)–H(4) = 4.2 Hz, to which we assign cis stereochemistry
across the C3–C4 bond. These assignments were confirmed by
the conversion of 5a into 1. We expected to form diastereo-
isomer 5a according to the work of Yoshida10 (transition state
6, Fig. 2). The alternate diastereoisomer 5b could be formed
due to the transannular stereoelectronically stabilised transition
state structure 7 (Fig. 2), similar to those put forward by
Ohfune12 to account for the cis selectivity in the lactonisation
of 2-aminopent-4-enoic acid derivatives.
Iodolactonisation of 4 with I2 in DME–H2O gave a 3:1 mix-
ture of 5a:5b in 59% and 20% yield respectively (14% starting
† Crystal data for 3: C21H34N2O3Si, M = 390.59, monoclinic, space
group: P2(1)/c, µ = 0.123 mmϪ1
,
R1 = 0.0407, wR2 = 0.1140,
a = 10.0044(6), b = 21.5554(13), c = 10.6645(7) Å, β = 91.963(1)Њ,
U = 2298.4(2) Å3, temperature of data collection 150(2) K, Z = 4, 5315
independent reflections (of 12413 measured), R(int) = 0.0370. We thank
Dr C. Wilson, University of Nottingham, for this structure determin-
ation. CCDC reference number 148999. See http://www.rsc.org/
suppdata/p1/b0/b007586h/ for crystallographic files in CIF or other
electronic format.
DOI: 10.1039/b007586h
J. Chem. Soc., Perkin Trans. 1, 2001, 267–269
This journal is © The Royal Society of Chemistry 2001
267

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amide (1.51 g, 7.47 mmol)) in THF (5 mL ϩ 5 mL wash) was
added, via cannula, to a stirred suspension of KH (1.19 g, 8.94
mmol, 1.2 equiv. of a 35% dispersion in mineral oil, washed
twice with hexane) in THF (15 mL) at 0 ЊC. After stirring for
1 h, (Z)-2-(phenyldimethylsilyl)but-2-enyl bromide (2.0 g,
7.47 mmol, 1.0 equiv.) in THF (5 mL ϩ 5 mL wash) was added
and the reaction stirred for a further 1 h followed by 14 h at
rt. Saturated aq. NaHCO3 was added, and the THF removed in
vacuo. Saturated aq. NaHCO3 was added, extracted with Et2O,
dried (MgSO4) and concentrated in vacuo to give 2 as an off
white powder (2.81 g, 97%), no further purification was neces-
sary. Mp 71–73 ЊC; IR νmax (thin film) 2973, 1698, 1666 cmϪ1; 1H
NMR δ 0.27 (6H, s), 1.29 (9H, s), 1.54 (3H, br d, J = 6.1), 2.73
(3H, s), 2.75 (3H, s), 3.49–3.97 (4H, m), 5.92 (1H, q, J = 7.0),
7.15–7.21 (3H, m), 7.35–7.40 (2H, m); 13C NMR δ Ϫ1.5, 17.8,
28.3, 35.6, 36.1, 46.3, 54.5, 79.9, 127.8, 128.8, 133.6, 133.9,
136.7, 139.5, 164.2, 172.1; MS (EIϩ) 390 (Mϩ); Anal. Calcd. for
C21H34N2O3Si: C, 64.58; H, 8.78; N, 7.18. Found C, 64.28; H,
8.79; N, 6.98%.
Fig. 2 Transition state models 6 and 7 to account for the formation of
5a and 5b respectively.
Deprotection of 5a followed by treatment with 0.5 M KOH
in THF until pH 912 and purification by Dowex-50Wx4-100
ion exchange resin gave racemic HyMePro (1) in 85% yield over
2 steps (Scheme 1).‡
The silicon assisted aza-[2,3]-Wittig rearrangement is flexible
enough to allow other substituted alkenes and migrating groups
in precursors 2.6 This methodology can deliver unique allyl
glycine derivatives which have the potential to become build-
ing blocks for more elaborate amino acids as demonstrated
in this paper. Enantioselective variants are currently being
investigated.
(2S*,3R*)-N,N-Dimethyl-2-(tert-butoxycarbonylamino)-3-
methyl-4-(phenyldimethylsilyl)pent-4-enamide (3)
Experimental
Precursor 2 (70 mg, 0.179 mmol) in THF (0.3 mL ϩ 0.2 mL
wash) and then 18-crown-6 (18-C-6) (23 mg, 0.089 mmol, 0.5
equiv.) were added to a stirred suspension of KH (50 mg, 0.43
mmol, 2.4 equiv. of a 35% dispersion in mineral oil washed
twice with hexane) in THF (0.4 mL) at 0 ЊC. After 10 min the
reaction was warmed to rt for 2 h before the reaction was cooled
to 0 ЊC and quenched with pH 7 buffer (2 mL). The mixture was
then extracted with Et2O, the combined organics washed with
H2O, brine, dried (MgSO4) and concentrated in vacuo to give a
clear oil which was purified by flash-column chromatography
(30% EtOAc–light petroleum) to give 3 (66 mg, 94%) as a clear
oil which crystallised on standing as an inseparable ratio of
General details
General experimental details are as published.13
(Z)-2-(Phenyldimethylsilyl)but-2-enyl bromide
To a solution of DIBAL (6.72 mL, 38.0 mmol, 1.1 equiv.) in
Et2O (18 mL) at 0 ЊC was added, via syringe, alkynyl silane 3
(6.0 g, 34 mmol). The mixture was warmed to rt, refluxed for 1 h
and then cooled to 0 ЊC followed by the addition of MeLi (37.6
mL of a 1 M solution in THF, 38.0 mmol, 1.1 equiv.) via
syringe. The mixture was stirred at rt for 1 h, cooled to 0 ЊC and
added via cannula to a stirred suspension of paraformaldehyde
(7.97 g, 0.272 mol, 8 equiv.) in Et2O (18 mL) at 0 ЊC. After
stirring at rt for 14 h, the mixture was poured into ice-cold 1 M
HCl (50 mL), the mixture separated and the aqueous phase was
extracted with Et2O. The combined organic layers were washed
with brine, dried (MgSO4), and concentrated in vacuo to give
allylic alcohol (Z)-2-(phenyldimethylsilyl)but-2-en-1-ol as a
colourless clear oil (92%, 6.44 g) which was judged >95% pure
1
diastereoisomers (>20:1 by H NMR). Mp 52–54 ЊC; IR νmax
(thin film) 3299, 2966, 1705, 1641 cmϪ1; 1H NMR δ 0.34 (3H, s),
0.36 (3H, s), 0.84 (3H, d, J = 7.0), 1.33 (9H, s), 2.57 (1H, br dq,
J = 7.0), 2.85 (3H, s), 2.97 (3H, s), 4.49 (1H, dd, J = 9.5, 9.2),
4.69 (1H, br d, J = 9.2), 5.50 (1H, d, J = 3.4), 5.78 (1H, d,
J = 1.5), 7.27–7.29 (3H, m), 7.46–7.49 (2H, m); 13C NMR
δ Ϫ2.5, Ϫ2.4, 18.4, 28.4, 35.7, 37.5, 42.9, 52.7, 60.4, 79.2, 127.9,
128.1, 129.2, 134.2, 137.8, 151.3, 155.1, 172.5; MS (CIϩ) 391
(MHϩ). Anal. Calcd. for C21H34N2O3Si: C, 64.58; H, 8.78; N,
7.18. Found C, 64.13; H, 8.97; N, 7.21%.
1
by H NMR and used directly in the next step. IR νmax (thin
film) 3324, 2955, 1620 cmϪ1; 1H NMR δ 0.45 (6H, s), 1.45 (1H,
br s), 1.66 (3H, dt, J = 7.0, 1.2), 4.15 (2H, quintet, J = 1.2), 6.42
(1H, qt, J = 7.0, 1.2), 7.30–7.61 (5H, m); 13C NMR δ Ϫ1.4, 17.9,
69.3, 127.9, 128.9, 133.8, 138.2, 139.1, 140.6; MS (CIϩ) 224
(MNH4ϩ); Anal. Calcd. for C12H18OSi: C, 69.84; H, 8.74. Found
C, 69.81; H, 8.85%. To a solution of PPh3 (7.61 g, 29.0 mmol,
1.07 equiv.) in CH2Cl2 (25 mL) at Ϫ20 ЊC was added, via
syringe, Br2 (1.49 mL, 29.0 mmol, 1.07 equiv.). After 20 min
Et3N (2.93 g, 29.0 mmol, 1.07 equiv.) was added and after a
further 20 min, (Z)-2-(phenyldimethylsilyl)but-2-en-1-ol (5.39
g, 27.1 mmol) was added also via syringe. After stirring for 10
min the mixture was warmed to rt and adsorbed onto silica.
Silica gel filtration afforded allylic bromide (Z)-2-(phenyl-
dimethylsilyl)but-2-enyl bromide as a colourless clear oil (6.53
(2S*,3R*)-N,N-Dimethyl-2-(tert-butoxycarbonylamino)-3-
methylpent-4-enamide (4)
To a stirred solution of 3 (45 mg, 0.12 mmol) and 18-C-6 (43
mg, 0.16 mmol, 1.4 equiv.) in THF (0.25 mL) was added tBuOK
(18.2 mg, 0.16 mmol, 1.4 equiv.). After 2 h at rt the mixture was
cooled to 0 ЊC and quenched by the addition of NH4Cl
(0.3 mL). The aqueous phase was extracted with Et2O; the
combined organics washed with brine, dried (MgSO4) and
concentrated in vacuo. The crude product was placed under
nitrogen and treated with TBAF (0.6 mL of a 1 M solution, 0.6
mmol, 5 equiv.). After stirring for 24 h the reaction mixture was
diluted with EtOAc, washed with H2O, brine, dried (MgSO4)
and concentrated in vacuo. Purification by column chrom-
atography (30% EtOAc–hexane) gave 4 (21 mg, 71%) as a
crystalline solid, mp 43–45 ЊC; IR νmax (thin film) 3304, 2974,
g, 90%). IR νmax (thin film) 2957, 1606 cmϪ1; H NMR δ 0.50
1
(6H, s), 1.62 (3H, d, J = 7.0), 4.15 (2H, m), 6.58 (1H, q, J = 7.0),
7.30–7.61 (5H, m); 13C NMR δ Ϫ1.2, 17.7, 33.2, 127.7, 129.0,
134.2, 139.6, 139.9, 140.8; MS (EIϩ) 270 (Mϩ, 81Br); HRMS
C12H17BrSi calcd 270.0262, found 270.0259.
1
1704, 1642, 1252 cmϪ1; H NMR δ 1.06 (3H, d, J = 6.8), 1.42
(9H, s), 2.51–2.53 (1H, br m), 2.97 (3H, s), 3.12 (3H, s), 4.56
(1H, dd, J = 9.2, 6.4), 5.04 (1H, dt, J = 6.1, 1.2), 5.10 (1H, br s),
5.26 (1H br d, J = 8.8), 5.68 (1H, ddd, J = 7.6, 2.1, 1.2); 13C
NMR δ Ϫ16.5, 28.3, 35.7, 37.4, 41.1, 53.9, 79.4, 116.2, 138.6,
155.7, 171.5; MS (FABϩ) 257 (MHϩ). Anal. Calcd. for
C13H24N2O3: C, 60.89; H, 9.44; N, 10.93. Found C, 60.83; H,
9.75; N, 10.43%.
(Z)-N,N-Dimethyl-{N-tert-butoxycarbonyl-N-[2-(phenyldimeth-
ylsilyl)but-2-enyl]amino}acetamide (2)
A solution of N-(tert-butoxycarbonyl)glycine N,N-dimethyl-
‡ The spectral data of 1 were identical to those reported for the natural
product (ref. 4).
268
J. Chem. Soc., Perkin Trans. 1, 2001, 267–269

View Article Online
(2S*,3R*,4RS*)-2-(tert-Butoxycarbonylamino)-3-methyl-4-
(iodomethyl)-ꢀ-butyrolactone (5a and 5b)
trated in vacuo to remove the solvent and any excess TFA. The
crude material was subsequently dissolved in THF (0.5 mL)
and basified to pH 9 with 0.5 M KOH. After stirring at rt for 4 h
the reaction mixture was washed with Et2O (2 × 1 mL). The
aqueous layer was separated and treated with Dowex-
50Wx4-100 ion exchange resin (0.5 × 10 cm column), eluting
with 1 M NH3 to give 1 (12.3 mg, 85%) as a white powder. Mp
To a stirred solution of 4 (70 mg, 0.27 mmol) in DME–H2O,
1:1 (1.0 ml), was added I2 (76 mg, 0.3 mmol, 1.1 equiv.) at rt.
After stirring for 2 h the mixture was diluted with Et2O (2 mL)
and washed with satd. aq. Na2S2O3, NaHCO3 and brine. The
organics were dried (MgSO4) and concentrated in vacuo. Purifi-
cation by column chromatography (20% ethyl acetate–hexane)
gave, in order of elution the 4S* isomer 5b (19 mg, 20%) as a
white powder, mp 92–94 ЊC, IR νmax (thin film) 3358, 2976,
1
259–262 ЊC (lit.4 255–260 ЊC); H NMR (D2O) δ 1.24 (3H, d,
J = 6.9), 2.32 (1H, ddq, J = 10.8, 6.9, 3.7), 3.36 (1H, dd,
J = 12.7, 0.8), 3.54 (1H, dd, J = 12.7, 3.7), 3.76 (1H, d, J = 10.9),
4.44 (1H, t, J = 3.6); 13C NMR (D2O) δ 11.6, 43.6, 52.8, 64.9,
73.1, 174.5; MS (EIϩ) 146 (MHϩ), HRMS C6H12NO3 calcd.
146.0817, found 146.0815.
1
1779, 1692, 1530 cmϪ1; H NMR δ 0.85 (3H, d, J = 7.1), 1.47
(9H, s), 3.09 (1H, t, J = 9.8), 3.14–3.15 (1H, br m), 3.44 (1H, dd,
J = 9.9, 5.8), 4.63 (1H, br t, J = 5.7), 4.65–4.68 (1H, br m), 5.03
(1H, br s); 13C NMR δ 6.5, 28.6, 37.9, 56.6, 80.2, 81.2; MS
(FABϩ or EIϩ) unsatisfactory (see MS for deprotected 5b);
followed by the 4R* isomer 5a (57 mg, 59%) as a white powder,
mp 101–103 ЊC; IR νmax (thin film) 3334, 2976, 1783, 1693, 1518
cmϪ1; 1H NMR δ 1.05 (3H, d, J = 7.2), 1.46 (9H, s), 2.91 (1H, br
m), 3.31 (1H, dd, J = 10.5, 8.2), 3.38 (1H, dd, J = 10.6, 5.2),
Acknowledgements
The authors thank the EPSRC and Merck Sharp and Dohme
for financial support.
4.35–4.37 (1H, br m), 4.58–4.62 (1H, br m), 4.95 (1H, br s); 13
NMR δ 4.3, 14.0, 28.3, 37.6, 52.8, 80.9, 84.8, 155.6, 174.3; MS
(FABϩ) 356 (MHϩ); HRMS C11H19NO4I calcd. 356.0359, found
356.0351; and 4 (10 mg, 14%).
C
References
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Assignment of C-4 stereochemistry
The two diastereoisomers of 5 were Boc deprotected under
standard conditions and their 1H NMR spectra recorded.
Iodolactone 5a (17 mg, 0.048 mmol) in DCM (0.25 mL) and
Et3SiH (1 drop) was treated with TFA (0.007 mL, 0.91 mmol,
1.9 equiv.) at rt. After stirring for 4 h at rt the reaction was
diluted with DCM (3 mL) and washed with 1 M NaOH (2 mL).
The organics were dried (MgSO4) and concentrated in vacuo to
give the 4R* primary amine (10 mg, 82%); IR νmax (thin film)
1
3379, 2920, 1777 cmϪ1; H NMR δ 1.14 (3H, d, J = 7.2), 1.58
(2H, s), 2.64 (1H, ddq, J = 7.8, 7.2, 3.0), 3.31 (1H, dd, J = 10.6,
7.3), 3.37 (1H, dd, J = 10.6, 5.2), 3.88 (1H, d, J = 8.0), 4.25 (1H,
ddd, J = 7.4, 5.2, 3.0).
Iodolactone 5b (10 mg, 0.028 mmol) in DCM (0.14 mL) and
Et3SiH (1 drop) was treated with TFA (3 drops) at rt. After
stirring for 3 h the reaction was worked up as above to give the
4S* primary amine (7 mg, 98%); IR νmax (thin film) 3368, 2917,
6 J. C. Anderson, A. Flaherty and M. E. Swarbrick, J. Org. Chem.,
2000, 65, 9152.
7 J. C. Anderson and A. Flaherty, J. Chem. Soc., Perkin Trans. 1, 2000,
3025.
1
1778; H NMR δ 0.96 (3H, d, J = 7.2), 2.88 (1H, ddq, J = 7.2,
7.1, 4.5), 3.12 (1H, dd, J = 9.9, 9.8), 3.45 (1H, dd, J = 10.1, 5.8),
3.96 (1H, d, J = 7.0), 4.61 (1H, ddd, J = 9.9, 5.6, 4.3); MS (EIϩ)
256 (MHϩ), HRMS C6H11NO2I calcd. 255.9835, found
255.9926.
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(2S*,3R*,4R*)-4-Hydroxy-3-methylproline (1)
Iodolactone 5a (35 mg, 0.099 mmol) in DCM (0.5 mL) and
Et3SiH (2 drops) was treated with TFA (0.023 mL, 0.295 mmol,
3 equiv.) at rt. After stirring for 2 h the reaction was concen-
J. Chem. Soc., Perkin Trans. 1, 2001, 267–269
269