Heck reactions of amino acid building blocks: Application to the synthesis of pyrrololine analogues

Article abstract of DOI:10.1016/S0040-4039(02)00512-9

Heck reactions of unsaturated amino acid building blocks are described which allow access to homo- and bis-homophenylalanine derivatives and to γ,δ-unsaturated amino acids. Preliminary synthetic studies utilising this chemistry for the preparation of pyrr

Full text of DOI:10.1016/S0040-4039(02)00512-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3401–3405
Heck reactions of amino acid building blocks: application to the
synthesis of pyrrololine analogues
Philip N. Collier,a Ian Patelb and Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bAstraZeneca, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
Received 7 February 2002; accepted 8 March 2002
Abstract—Heck reactions of unsaturated amino acid building blocks are described which allow access to homo- and bis-
homophenylalanine derivatives and to g,d-unsaturated amino acids. Preliminary synthetic studies utilising this chemistry for the
preparation of pyrrololine and deoxypyrrololine analogues are also reported. © 2002 Elsevier Science Ltd. All rights reserved.
discovered that by employing catalytic palladium(II)
acetate and tri-n-butylphosphine with a slight excess of
iodobenzene and potassium carbonate in DMF, the
desired Heck coupling product 6 could be obtained
from N-Boc alkene 1 after 1 h at 100°C in 72% yield
{Table 1, entry i: [h]D −71.5 (c 1.9, CHCl3); lit.7 [h]D
−71.3 (c 1.1, CHCl3)}. The regiochemical and stereo-
chemical outcome of the reaction was as expected,
giving the terminally-substituted, E-alkene 6 (J 16.0
Hz). The corresponding N-Cbz protected alkene 2
There has been considerable recent interest in the
design of new synthetic routes for the preparation of
non-proteinogenic a-amino acids and their derivatives
for use in biological studies or as chemical building
blocks.1–4 We have recently described the hydrobora-
tion of the amino acid-derived alkenes 1, 2 and 3 with
9-BBN, and the subsequent Suzuki coupling of the
derived triorganoboranes; this chemistry has been used
to prepare novel homophenylalanines, bis-homophenyl-
alanines, and related derivatives.2,3 Herein, we report
the utilisation of alkenes 1, 2 and 3 in Heck coupling
reactions. Crisp et al. have also reported Heck coupling
reactions of unsaturated amino acids and their deriva-
tives.4 For example,
-vinylglycine-derivatives 4 and 5
L
underwent efficient Heck coupling reactions with a
number of vinyl triflates, although aromatic halides and
triflates gave less predictable results, especially in sys-
tems containing additional electron-withdrawing
substituents.
Initial studies were carried out on the Heck coupling
reactions of alkenes 1 and 2 with a range of aryl
halides, as shown in Scheme 1 and Table 1.5,6 We
Scheme 1.
* Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00512-9

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P. N. Collier et al. / Tetrahedron Letters 43 (2002) 3401–3405
Table 1. Heck coupling reactions of alkenes 1 and 2
Entry
P
ArX
Product
[h]D (in CHCl3)
Yield (%)
i
ii
iii
iv
v
Boc (1)
Cbz (2)
Cbz (2)
Cbz (2)
Cbz (2)
Cbz (2)
PhI
PhI
PhBr
6
7
7
8
9
−71.5 (c 1.9)
−94.7 (c 2.2)
−94.7 (c 2.2)
−95.9 (c 0.6)
−123.8 (c 1.0)
−109.6 (c 2.3)
72
80
77
78
85
82
4-MeO-C6H4I
4-MeO2C-C6H4Br
2-O2N-C6H4I (2 equiv.)
vi
10
underwent coupling with iodobenzene and bromobenz-
ene giving adduct 7 in even higher yields (Table 1,
entries ii and iii, 80 and 77%, respectively), and the
remaining reactions were therefore carried out using
compound 2. Heck coupling on this system was shown
to be compatible with electron-donating and electron-
withdrawing substituents (Table 1, entries iv–vi). The
coupling with 2-nitro-iodobenzene required slightly
more forcing conditions (110°C, overnight with 2 equiv.
of aryl iodide) for the reaction to proceed to completion,
but the desired product 10 was obtained in 82% yield
(Table 1, entry vi).
acids 13 and 14, respectively, by reduction followed by
our hydrolysis–oxidation–methylation
published2
sequence (Scheme 2). Reduction of the N-Boc-protected
oxazolidine 6 was achieved using standard hydrogen–
Pd/C conditions to give 11 quantitatively, while reduc-
tion of the N-Cbz compound 10 was performed in 83%
yield using diimide generated from 2,4,6-tri-iso-propyl-
benzenesulfonyl hydrazide (TPSH) by the action of base.
The unsaturated Heck coupling products could also be
transformed into novel amino acid precursors and
homochiral synthetic building blocks (Scheme 3). For
example, dibromocyclopropanation8 of alkene 8 gave
adduct 15, while oxazolidine cleavage in 8 under acidic
conditions furnished styrenyl amino alcohol 16 {[h]D
−62.5 (c 0.2, EtOH)}.
The Heck coupling adducts can be easily transformed
into homophenylalanine derivatives. Thus, adducts 6
and 10 can be readily converted into protected amino
Scheme 2.
Scheme 3.

P. N. Collier et al. / Tetrahedron Letters 43 (2002) 3401–3405
Table 2. Heck coupling reactions of alkene 3
Entry ArX Product [h]D (in CHCl3) Yield (%)
3403
Next, we investigated the Heck coupling reactions of
protected allylglycine 3 with a range of aromatic
iodides and bromides (Scheme 4). We were delighted
to observe the efficient formation of the corresponding
g,d-unsaturated amino acid products, in protected
form, under the same reaction conditions as before
(Table 2). As before, reasonable yields were obtained
in coupling with a range of aromatic iodides and bro-
mides, including examples containing electron-donat-
i
PhI
1-Br-Naphthalene 18
4-MeO-C6H4I 19
4-MeO2C-C6H4Br 20
3-O2N-C6H4I 21
17
+32.7 (c 2.1)
+28.5 (c 0.8)
+38.1 (c 1.3)
+32.7 (c 0.7)
+34.4 (c 0.9)
79
67
74
66
70
ii
iii
iv
v
ing
and
electron-withdrawing
substituents.
Hydrogenation of the alkene double bond in adduct
20 gave the known3 bis-homophenylalanine derivative
22, which displayed an optical rotation in good agree-
ment with the reported value {[h]D +15.7 (c 0.7,
CHCl3); lit.3 [h]D +16.2 (c 1.5, CHCl3)}.
and 30 (Scheme 6). Coupling of N-SEM diiodopyrrole
32 with vinyl glycinol 29 gave the required double
adduct in only 14% yield (22% based on recovered
starting material), which underwent diimide reduction
to give 33. With the SEM-protected alkene 30, the key
Heck coupling reaction proceeded in an unoptimised
21% yield (33% based on recovered starting material)
giving pyrrole 34 after alkene reduction. Although
optimisation is obviously required, compounds 33 and
34 are valuable intermediates for the synthesis of
pyrrololine 23 and deoxypyrrololine 24.
We next investigated applications of this Heck
methodology. Pyrrololine 23 and deoxypyrrololine 24
are important cross-linking agents in human bone col-
lagen and have become attractive synthetic targets due
to their novel structural features and practical applica-
tions in the diagnosis of osteoporosis and other bone
diseases.9 We decided to explore the use of our Heck
coupling for the introduction of the pyrrole C-3 and
C-4 amino acid side chains.
In conclusion, a range of Heck coupling reactions
have been successfully accomplished using amino acid-
derived alkenes 1, 2, 3, 29 and 30. The majority of
these processes proceed in good yields, even with elec-
The first approach utilised 3,4-diiodo-N-methylpyrrole
26, readily obtained by iodination of N-TIPS pyrrole
25 using the procedure of Muchowski et al.10 (Scheme
5). The double Heck coupling reaction with alkene 2
proceeded in an unoptimised yield of 20%, giving
adduct 27, an ideal precursor for the preparation of
N-truncated pyrrololine analogues.
tron-deficient
systems
(thereby
complementing
existing4 procedures), and provide a route to a range
of non-proteinogenic amino acids and related com-
pounds. Work is in progress to optimise the double
Heck coupling with diiodopyrroles and to apply it to
the total synthesis of pyrrololine 23 and deoxypyrrolo-
line 24.
A second double Heck approach was explored which
employed the protected vinyl glycinol derivatives 2911
Scheme 4.

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P. N. Collier et al. / Tetrahedron Letters 43 (2002) 3401–3405
Scheme 5.
Scheme 6.
4. (a) Crisp, G. T.; Glink, P. T. Tetrahedron 1992, 48,
Acknowledgements
3541–3556; see also (b) Itaya, T.; Shimomichi, M.; Ozasa,
M. Tetrahedron Lett. 1988, 29, 4129–4132. For related
Suzuki approaches see Refs.
2 and 3; for Stille
We thank AstraZeneca and the University of York for
studentship support (P.N.C.).
approaches, see: (c) Crisp, G. T.; Glink, P. T. Tetra-
hedron 1994, 50, 3213–3234; (d) Kazmaier, U.; Schauß,
D.; Raddatz, S.; Pohlman, M. Chem. Eur. J. 2001, 7,
456–464 and references cited therein. Note added in
proof: For Heck reactions of protected allyl glycines, see:
Gurjar, M. K.; Talukdar, A. Synthesis 2002, 315–316.
5. All new compounds were fully characterised by NMR
spectroscopy and by HRMS etc.
6. Typical procedure: To the alkene (1 equiv., 0.15–0.38
mmol) in anhydrous, degassed DMF (1 mL per 0.1 mmol
alkene) was added in rapid succession potassium carbon-
ate (1.1 equiv.), palladium acetate (0.1 equiv.), tri-n-
butylphosphine (0.2 equiv.) and the aryl halide (1.1
equiv.) at rt under nitrogen. The mixture was covered by
aluminium foil, heated (usually to 100°C) and monitored
by TLC until complete (usually 1–3 h). The reaction
mixture was cooled and saturated aq. NaCl (10 mL per
0.1 mmol alkene) and Et2O (10 mL per 0.1 mmol alkene)
were added. The aqueous layer was re-extracted with
References
1. (a) Chrystal, E.; Bey, P.; Rando, R. R. J. Neurochem.
1979, 32, 1501–1507; (b) Walsh, C. Tetrahedron 1982, 38,
871–909 and references cited therein; (c) Lowe, P. N.;
Rowe, A. F. Comp. Biochem. Physiol., B: Comp. Biochem.
1987, 88B, 223; (d) Angst, C. Pure Appl. Chem. 1987, 59,
373–380.
2. (a) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K.
Tetrahedron Lett. 1999, 40, 5263–5266; (b) Collier, P. N.;
Patel, I.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42,
5953–5954; (c) Collier, P. N.; Campbell, A. D.; Patel, I.;
Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002,
67, 1802–1815 and references cited therein.
3. Collier, P. N.; Campbell, A. D.; Patel, I.; Taylor, R. J. K.
Tetrahedron Lett. 2000, 41, 7115–7119.

P. N. Collier et al. / Tetrahedron Letters 43 (2002) 3401–3405
3405
Et2O (10 mL per 0.1 mmol alkene). The combined
organic layers were washed with H2O (10 mL per 0.1
mmol alkene), dried, filtered and concentrated in vacuo
to give the crude product which was purified by flash
column chromatography eluting with petroleum ether–
EtOAc mixtures to afford the Heck coupling product
(yields based on alkenes).
8. De Frutos, P.; Ferna´ndez, D.; Ferna´ndez-Alvarez, E.;
Bernabe´, M. Tetrahedron 1992, 48, 1123–1130.
9. Adamczyk, M.; Johnson, D. D.; Reddy, R. E. J. Org.
Chem. 2001, 66, 11–19 and references cited therein.
10. Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.;
Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. J. Org.
Chem. 1990, 55, 6317–6328.
11. Sabat, M.; Johnson, C. R. Org. Lett. 2000, 2, 1089–
1092.
7. Reginato, G.; Mordini, A.; Caracciolo, M. J. Org. Chem.
1997, 62, 6187–6192.