Syntheses of structurally diverse amino acids, including δ-hydroxylysine, using the acyl nitroso Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2010.02.076

By virtue of its ability to introduce amino and hydroxy functionalities in a 1,4-relationship with fully controlled relative stereochemistry, the acyl nitroso Diels-Alder (ANDA) reaction is ideally suited to the synthesis of structurally diverse, includin

Full text of DOI:10.1016/j.tetlet.2010.02.076

Tetrahedron Letters 51 (2010) 2160–2163
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Syntheses of structurally diverse amino acids, including d-hydroxylysine,
using the acyl nitroso Diels–Alder reaction
*
Lee Bollans, John Bacsa, Daniel A. O’Farrell, Scott Waterson, Andrew V. Stachulski
The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
By virtue of its ability to introduce amino and hydroxy functionalities in a 1,4-relationship with fully
controlled relative stereochemistry, the acyl nitroso Diels–Alder (ANDA) reaction is ideally suited to the
synthesis of structurally diverse, including hydroxylated, amino acids. The major issue to be tackled is that
of regiochemistry in the ANDA addition to unsymmetrical dienes. The transformation of three diverse
types of ANDA adducts into amino acids is described, in particular, the synthesis of d-hydroxylysine, an
important constituent of collagen, as a single (2SR, 5SR) diastereoisomer in protected form.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 18 December 2009
Revised 30 January 2010
Accepted 15 February 2010
Available online 18 February 2010
The nitroso Diels–Alder reaction was described by Wichterle in
19471 and has been frequently employed by synthetic chemists in
pursuit of a wide variety of structures. An especially attractive
feature of this reaction is that it introduces nitrogen and oxygen
substituents in a single step with a complete control of relative
1,4-stereochemistry. With appropriate substitution in the diene
employed, therefore, the reaction should be ideally suited to the
synthesis of hydroxy amino acids (and other amino acids) as single
diastereoisomers.
For an unsymmetrical diene, two products are possible (Scheme
1), termed ‘proximal (P)’ and ‘distal (D)’ by Boger,2 according to the
disposition of the O atom with respect to the side-chain (X or Y) of
highest atomic number. From a synthetic point of view, the reac-
tivity of the nitroso group is maximised by attachment to strongly
electron-withdrawing groups, particularly via sp2 centres, for
example, acyl groups. Henceforth this variant will be referred to
as the acyl nitroso Diels–Alder (ANDA) reaction. In particular, the
benzyloxycarbonyl and t-butoxycarbonyl nitroso dienophiles
(ZN@O and BocN@O),3 readily prepared in situ by oxidation of
the corresponding hydroxylamines, are of great value because they
combine high reactivity with mild conditions required to release
the free amine later.
X
Y
X
X
R
O
N
O
N
N
O
+
+
R
R
Y
Y
P
D
Scheme 1. Proximal (P) and distal (D) nitroso adducts from an unsymmetrical
diene (X>Y).
tronic character, a P/D mixture is predicted and the authors4 com-
mented: ‘a delicate balance of electronic and steric factors will
affect the result’.
We recently published5 a study on the ANDA adducts of sorbate
ester (e.g., 2) and sorbic alcohol derivatives—synthetically attrac-
tive because of the extra functionality built-in. We demonstrated,
inter alia, a convenient synthesis of 5-methylornithine 3 as a single
diastereoisomer from 2. We now report the extension of our
studies to other amino acid syntheses: we were particularly inter-
ested in the important hydroxyamino acid, (2S,5R)-d-hydroxyly-
The predictability of obtaining P or D adducts is clearly para-
mount for synthesis. A seminal theoretical study by Leach and
Houk4 showed that frontier orbital considerations are most signif-
icant. For any 1-substituted diene 1, the highest HOMO coefficient
will be located at C(4): hence the nitroso N bonds to this position.
When substituents X and Y (Scheme 1) are close in their elec-
sine
4 which is a
significant constituent of collagen,6 and
frequently O-glycosylated as a mono or disaccharide.7
CO2Et
CO2H
CO2H
CO2Me
CO2R
1
4
NH2
NH2
NH2
OH
* Corresponding author. Current address: Glycobiology Institute, University of
Oxford, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK. Tel.:
+44 (0) 151 794 3542; fax: +44 (0) 151 794 3588.
CO2R
H2N
PhthN
E-mail addresses: stachuls@liv.ac.uk, andrew.stachulski@bioch.ox.ac.uk (A.V.
Stachulski).
1
2
3
4
5
6
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.076

L. Bollans et al. / Tetrahedron Letters 51 (2010) 2160–2163
2161
sponding hydroxylamines: in common with other sorbic alcohol
derivatives,5 an organic oxidant (Bun4N+ IO4ꢀ) in CH2Cl2 gave a
better yield than NaIO4 in aq MeOH. The P and D adducts 11a
and 12a from BocN@O resulted in a total yield of 87% and a
45:42 ratio. Although it was in a sense disappointing that the de-
sired distal isomer 12a was marginally the minor product, the
isomers were easily separated and a single crystal X-ray struc-
tural analysis confirmed the structure of 12a (Fig. 1). We have
described5 the use of 1H–15N HSQC NMR as a useful tool for dis-
tinguishing P:D pairs: as noted therein, this technique has been
applied to 11b/12b, giving results consistent with the X-ray data
for 12a.
Similarly, reaction of 10a with ZN@O gave a separable mixture
of 11b and 12b (79%, P:D = 42:37). We were surprisingly unable to
effect a direct oxidation of the primary alcohol in 12a or 12b under
various conditions, although the proximal isomer 11b was easily
oxidised to the carboxylic acid using TEMPO-PhI(OAc)214,15 in very
satisfactory yield (61%). Instead, hydrogenation of 12b effected
deprotection of the Z group, saturation of the C@C bond and N–O
cleavage. Without isolation, the intermediate amine was treated
with Boc2O and Na2CO3 to afford the bis-Boc protected diol 13
(30%). Finally, selective oxidation of 13 using TEMPO-PhI(OAc)2
proceeded satisfactorily and bis-Boc d-hydroxylysine (2SR,5SR) 14
Superficially it would appear that a sorbate derivative such as 5
with a built-in protected amino group is an ideal precursor of 4, but
there are two critical issues to address:
1. The conjugated ester group has a strong directing effect4 in the
ANDA and the undesired P adduct is overwhelmingly preferred.
2. A second electron-withdrawing group on the diene can easily
shut down the ANDA reaction altogether: thus diesters of
muconic acid such as 6 fail to react.8
Regarding point 1, it is possible to enforce the D adduct, wholly
or in part, by using a tethered intramolecular ANDA in cases where
the intermolecular reaction gives largely the P adduct, as shown by
Russell and co-workers9 and Sparks et al.10 It was noteworthy in
the latter case that extending the length of the tether again led
to a regioisomeric mixture: further, introduction and removal of
a tether inevitably generate extra steps. Point 2 is demonstrated
by the complete unreactivity of phthalimide 5 (prepared in two
steps from methyl sorbate8) under our standard ANDA conditions.5
However, since sorbic alcohol derivatives react well under ANDA
conditions, and the free alcohols give appreciable D regioisom-
er,5,11 we aimed for a protected amino-alcohol related to 5 as a
suitable substrate, and this allowed us to prepare 4 in a protected
form as follows.
Successive Wittig reactions of Boc glycinal 7a (Scheme 2) with
stabilised phosphoranes afforded diene 9a via enal 8a, which was
generally not isolated but reacted directly.12 It is important to note
that ester 9a, like 5, was unreactive in the ANDA reaction in our
hands. DIBAL-H reduction of 9a afforded the desired alcohol 10a
in a satisfactory yield together with a little (ca. 5%) of the partially
reduced aldehyde. We also studied the corresponding series with
benzyloxycarbonyl (Z) protection (7b–10b), though the yields
were not as good, particularly in the DIBAL-H step; aldehyde 7b
was conveniently prepared by oxidation of Z-aminoethanol with
trichloroisocyanuric acid and TEMPO.13 Incidentally, we could
not effect a satisfactory selective reduction of the ester functional-
ity in phthalimide derivative 5.
Alcohol 10a reacted well in the ANDA reaction (Scheme 3)
with either BocN@O or ZN@O generated in situ from the corre-
Figure 1. Single crystal X-ray structure of compound 12a (CCDC 765959).
i)
ii)
RHN
CO2R'
RHN
CHO
RHN
CHO
7a, 7b
8a, 8b
9a, 9b
iii)
RHN
CH2OH
10a, 10b
Scheme 2. Synthesis of diene intermediates for d-hydroxylysine. Series a: R = Boc, R0 = Me; Series b: R = Z, R0 = Et. Reagents and conditions: [Series a] (i) Ph3P@CHCHO, THF,
reflux, 88%; (ii) Ph3P@CHCO2Me, THF, trace PhCO2H, 20 °C, combined yield for steps (i) and (ii) 67%; (iii) Bui2AlH, THF, ꢀ78 °C to ꢀ40 °C, 64%; [Series b]: (i), Ph3P@CHCHO, THF,
reflux, (ii) Ph3P@CHCO2Et, THF, trace PhCO2H, 20 °C, combined yield for steps (i) and (ii) 58%; (iii) Bui2AlH, THF, ꢀ78 °C to ꢀ40 °C, 38%.
OH
OH
HO
HO
CO H
2
O
i)
ii), iii)
iv)
NHBoc
OH
O
N
NHBoc
OH
N
O
OR
+
O
OR
BocNH
BocNH
BocNH
BocNH
BocNH
10a
11a, 11b
12a, 12b
13
14
11a, 12a: R = But; 11b, 12b: R = PhCH2
Scheme 3. Completion of the d-hydroxylysine synthesis. Reagents and conditions: (i) BocNHOH or ZNHOH, Bun4N+ IO4ꢀ, CH2Cl2, combined isomers 87% [Boc], 79% [Z]; (ii) (on
12b) H2–Pd, THF; (iii) Boc2O, aq THF, Na2CO3, 30% for steps (ii) and (iii); (iv) TEMPO, PhI(OAc)2, aq MeCN, 22%.

2162
L. Bollans et al. / Tetrahedron Letters 51 (2010) 2160–2163
Boc
CO2R
CO2Me
NHBoc
CO2H
NH2
N
Boc
O
i)
v)
ii)
iv)
N
O
OH
OH
CO2R
CO2Me
CO2H
R = H
iii)
R = Me
17
18a (R = H), 18b (R = Me)
19
15
Scheme 4. Synthesis of 2-amino-5-hydroxyadipic acid. Reagents and conditions: (i) BocNHOH, NaIO4, 70%; (ii) RuCl3, NaIO4, PhMe/EtOAc/H2O, 44%; (iii) TMSCHN2, 100%; (iv)
SmI2, THF, 80%; (v) aq HCl, heat, 100%.
resulted in 22% yield. Commercial
L
-d-hydroxylysine [viz. of (2S,5R)
being the removal of SmI2 traces: the ring-opened product 19
was obtained in high yield. Finally, heating 19 in aq HCl at reflux
afforded the desired diacid 15 as its HCl salt, essentially
quantitatively.
stereochemistry] was converted into bis-Boc derivative 14 for
comparison and fully characterised: see Supplementary data.
Previous syntheses of 4 have almost invariably proceeded via
chiral pool intermediates, especially glutamic acid: for example,
Allevi and Anastasia16 reported a synthesis in 10 steps, involving
diastereoisomer separation. The problem with this approach has
been control of the relative stereochemistry between C(2) and
Finally we describe an amino acid synthesis from an
x-phenyl
ANDA adduct. This synthesis exploits an important feature of the
reaction, namely the greater and reversed directing effect of a
phenyl group, compared to alkyl, in unsymmetrical dienes
(Scheme 1).4,11 Thus, where X = CH2OR, Y = Ph the D adduct is
strongly favoured: Kouklovsky has reported similar examples.11
We obtained the requisite diene (Scheme 5) by Wittig homologa-
tion of cinnamaldehyde 20 using Ph3P@CHCO2Me (Ph3P@CHCHO
did not react) followed by DIBAL-H reduction of known25 ester
21: the air-sensitive alcohol 2225 was obtained in an excellent
yield but was best used at once. Under standard ANDA conditions
(ZNHOH, NaIO4, and aq THF) compound 23 was obtained in a sat-
isfactory yield as the D adduct only; the mass balance was mainly
C(5) of the
but since chiral versions of the ANDA are well known, using, for
example, mandelic acid derivatives,18
-Cl nitroso sugars or cam-
a
-amino acid.17 Our synthesis clearly lacks a resolution,
a
phor-derived nitroso derivatives, this aspect could be addressed:
as noted above, the ANDA reaction ensures correct relative 2,5-
stereochemistry.
We now describe the conversion of other types of ANDA ad-
ducts into
a-amino acids, firstly 2-amino-5-hydroxyadipic acid
15,19 a known metabolite of 4 resulting from a PLP-mediated trans-
amination and obtainable from a symmetrical ANDA adduct21
(Scheme 4).
unreacted 22.
ꢀ
Interestingly, the use of organic-soluble periodate (Bun4N+ IO4
)
Thus cyclohexa-1,3-diene was reacted with BocN@O and the
product 17 subjected to oxidative cleavage to afford the dicar-
boxylic acid 18a reported by Procter and co-workers21c Cleavage
of the N–O bond in compounds such as 18a without the loss of
the N-protecting group has been performed in many ways, for
example, using Mo(CO)6/NaBH4, Raney nickel-H2 or with
SmI2.22–24 To improve solubility, the diacid was first converted
into the dimethyl ester 18b in a quantitative yield. SmI2 reduc-
tion then proceeded very well in THF, the only significant issue
in CH2Cl2 gave no reaction here, being consistent with a lower
intrinsic reactivity of all these -phenyl dienes compared to their
x
sorbate counterparts. Thus neither ester 21 nor the O-acetate of
22 would react under our standard ANDA conditions.26 Adduct
23 crystallised in a form suitable for a single crystal X-ray analysis,
confirming its D-regiochemistry (Fig. 2). Here again, 1H–15N HSQC
NMR gave the same conclusion.5 Oxidation of 23 using TEMPO-
PhI(OAc)2 afforded the acid 24 in an excellent yield, but we could
not selectively reduce the N–O bond with SmI2 in this case (cf.
i)
ii)
Ph
Ph
Ph
CHO
CH2OH
CO2Me
OH
21
22
Boc
20
OH
CO2H
Z
Boc
iii)
N
O
N
H
v)
vi)
N
H
Ph
23
Ph
27
Ph
28
iv)
O
OH
O
OH
Z
SmI2
THF
N
O
NHZ
OH
Ph
24
Ph
Scheme 5. Synthesis of homologated phenylalanine analogues via the ANDA reaction. Reagents and conditions: (i) Ph3P@CHCO2Me, PhMe, 20 °C, 80%; (ii) Bui2AlH, CH2Cl2,
0 °C, 91%; (iii) ZNHOH, NaIO4, aq THF, 0 °C, 50%; (iv) TEMPO, PhI(OAc)2, aq MeCN, 80%; (v) Pd/C, H2, THF, then Boc2O, Na2CO3, 59%; (vi) TEMPO, PhI(OAc)2, aq MeCN, 25%.

L. Bollans et al. / Tetrahedron Letters 51 (2010) 2160–2163
2163
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.076.
References and notes
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Synlett 1989, 9–14; (b) Kawabata, T.; Itoh, K.; Hiyama, T. Tetrahedron Lett. 1989,
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4. Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192–5200.
5. Bollans, L.; Bacsa, J.; Iggo, J. A.; Morris, G. A.; Stachulski, A. V. Org. Biomol. Chem.
2009, 7, 4531–4538.
6. Wang, C. G.; Luosujarvi, H.; Heikkinen, J.; Ristell, M.; Uitto, L.; Myllyla, R. Matrix
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7. (a) Taylor, M. R.; Drickamer, K. Introduction to Glycobiology; Oxford University
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F. R. J. Clin. Invest. 1977, 59, 819.
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Figure 2. Single crystal X-ray structure of ANDA adduct 23 showing the noticeable
intermolecular H bond (CCDC 725212).
10. Sparks, S. M.; Chow, C. P.; Zhu, L.; Shea, K. J. J. Org. Chem. 2004, 69, 3025–3035.
11. Calvet, G.; Blanchard, N.; Kouklovsky, C. Synthesis 2005, 3346–3354.
12. For the use of catalytic benzoic acid in the Wittig reaction with the stabilised
phosphorane, see: Ruchardt, C. Angew. Chem., Int. Ed. Engl. 1963, 2, 619.
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Scheme 4, 18b?19). We believe a more appropriate protecting
group could solve this issue (and retain the extra functionality)
as the sorbate-derived ANDA adduct 25 was smoothly reduced to
268 (80%), and Keck et al. reported SmI2 reductions where benzylic
OH groups were retained.24
14. For
a comprehensive review of TEMPO-based oxidations, see: Vogler, T.;
Studer, A. Synthesis 2008, 1979–1993.
15. (a) Threlfall, R.; Davis, A.; Howarth, N. M.; Fisher, J.; Cosstick, R. Chem.
Commun. 2008, 585–587; (b) Zhao, M. Z.; Li, J.; Mano, E.; Song, Z. G.;
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17. See also: (a) Bloemhoff, W.; Kerling, K. E. T. Recl. Trav. Chim. Pays-Bas 1975, 94,
182–185; (b) Via Williams glycine template methodology: van der
Nieuwendijk, A. M. C. H.; Kriek, N. M. A. J.; Brussee, J.; van Boom, J. H.; van
der Gen, A. Eur. J. Org. Chem. 2000, 3683–3691; (c) A more recent approach
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CO2Et
CO2Et
OH
O
N
SmI2
THF
NHBoc
Boc
Me
Me
25
26
Instead (Scheme 5), exhaustive hydrogenation of 23, including
hydrogenolysis of the benzylic alcohol, followed by reprotection
afforded amino-alcohol 27 in a satisfactory yield. Finally, TEM-
PO-PhI(OAc)2 oxidation afforded the known Boc amino acid
28;27,28 the Me ester of 28 was previously made via Heck
chemistry.20
In summary, we have demonstrated syntheses of three structur-
ally diverse a-amino acids 14, 15 and 28 as single diastereoisomers
using the ANDA reaction. Careful attention to the reactivity and
regiochemical preference of each diene, particularly when unsym-
metrical, is essential. In particular a novel, concise synthesis of the
important collagen constituent d-hydroxylysine in a protected
form is shown.
18. Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992, 33, 3583–3586;
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as in a later correction: Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett.
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6117–6125; (b) Collier, P. N.; Patel, I.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43,
3401–3405.
21. For some examples of symmetrical dienes in the ANDA, see: (a) Shireman, B. T.;
Miller, M. J. J. Org. Chem. 2001, 66, 4809–4813; (b) Shireman, B. T.; Miller, M. J.;
Jonas, M.; Wiest, O. J. Org. Chem. 2001, 66, 6046–6056; (c) Pepper, A. G.; Procter,
G.; Voyle, M. Chem. Commun. 2002, 1066–1067; (d) King, S. B.; Ganem, B. J. Am.
Chem. Soc. 1994, 116, 562.
22. Gouverneur, V.; Ghosez, L. Tetrahedron Lett. 1991, 32, 5349–5352.
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11772.
25. Cao, X.-P. Tetrahedron 2002, 58, 1301–1307.
26. D.A. O’Farrell, S. Waterson. M. Chem. projects, University of Liverpool, 2007–
2008 and 2008–2009.
Acknowledgements
27. Ueda, K.; Waki, M.; Izumiya, N. Int. J. Pept. Protein Res. 1987, 30, 33–39.
28. In retrospect, we believe that the rather low yields obtained in the oxidations
of 13 to 14 and 27 to 28 may have been due to the batch of TEMPO employed.
As given above, a similar oxidation of 23 to 24, using a new batch of TEMPO
and performed later, gave a very good yield of 80%, and this is probably the
expected yield for the other TEMPO oxidations.
We are grateful to the EPSRC for a DTA award to L.B. and the
University of Liverpool for consumables grants to D.O’F. and S.W.
(M. Chem. projects, 2007–8 and 2008–9). We also thank Professor
Richard Taylor (University of York) for valuable discussions on
diene synthesis.