Synthesis of (+)-DGDP and (-)-7-epialexine

Article abstract of DOI:10.1039/b815332a

The partial reduction of electron deficient pyrroles is an extremely versatile method that allows us to prepare substituted pyrrolidines and pyrrolizidines with trans-diol stereochemistry on the five membered ring. The 2008 Royal Society of Chemistry.

Full text of DOI:10.1039/b815332a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of (+)-DGDP and (-)-7-epialexine†
Timothy J. Donohoe,* Matthew D. Cheeseman, Timothy J. C. O’Riordan and Jessica A. Kershaw‡
Received 2nd September 2008, Accepted 3rd September 2008
First published as an Advance Article on the web 19th September 2008
DOI: 10.1039/b815332a
The partial reduction of electron deficient pyrroles is an ex-
tremely versatile method that allows us to prepare substituted
pyrrolidines and pyrrolizidines with trans-diol stereochem-
istry on the five membered ring.
As part of a programme designed to explore and exploit the
partial reduction of heterocycles, we have developed a short, four
step sequence to prepare enantiopure mono-acetate 1, Scheme 1,
starting from commercially available N-Boc pyrrole.1 The key steps
in this route are a diastereoselective partial reduction reaction
and a subsequent enzymatic desymmetrisation. Compound 1
has proven to be very useful in the synthesis of a wide array
of natural products and compounds with important biological
activity,2 notably the pyrrolizidine alkaloids, Scheme 1. One of
the limitations of an otherwise extremely flexible route was the
requirement to incorporate cis-C3,4-diol stereochemistry, which
was installed by diastereoselective dihydroxylation of alkene 1. We
now report a solution to the problem of introducing trans-C3,4-
diol stereochemistry from a cyclic pyrroline, thus allowing access
to a widely occurring stereochemical motif.3
Scheme 2 Synthesis of DGDP 4.
grounds and confirmed by NOE analysis of 2) using a dioxirane
generated in situ.5 The acetate group of 2 was then allowed to
participate in a highly regio- and stereoselective ring opening
reaction at C4 following epoxide activation with BF3·OEt2.6
Under these conditions, the N-Boc group was also cleaved and
the (putative) intermediate 3 formed; however, the addition of
methanol to the reaction mixture had the desired effect of cleaving
the acetate-derived protecting groups in situ and formed DGDP
4 directly.7 The result of this approach is an exceptionally short
route to the target compound (6 steps and 34% overall yield). The
spectroscopic data exhibited by our synthetic sample matched
exactly those in the literature;8 furthermore, we confirmed the
structure of our material by X-ray crystallographic analysis.9
Next we attempted to prepare one of the more complex
pyrrolizidine alkaloids that have the same trans-C3,4-diol substitu-
tion pattern around the pyrrolidine ring. The synthetic challenges
to be addressed are as follows: the protection of the free alcohol
of 1 without cleavage of the labile OAc group, acetate mediated
epoxide opening without cleavage of the N-Boc group and finally
an appropriate protecting group strategy to allow for subsequent
chain extension and formation of the second ring.
Scheme 1 Synthesis of polyhydroxylated pyrrolizidines from 1.
The essence of our approach can be highlighted in the short
(6 step) synthesis of the glycosidase inhibitor (+)-2,5-dideoxy-2,5-
imino-D-glucitol (DGDP 4) Scheme 2.4 Thus, compound 1 was
epoxidised with high anti-stereoselectivity (rationalised on steric
Therefore, we embarked upon a route that was related to that
described above. Following benzyl protection of 1,10 to allow for
discrimination between hydroxyl groups later on, the product was
reacted under the previously described epoxidation conditions to
give epoxide 5 as a single diastereoisomer and in excellent yield
over two steps, Scheme 3. The ring opening reaction of epoxide
5 was performed at -50 ◦C so as to prevent N-Boc removal
under the reaction conditions. The resulting mixture of mono-
acetate regioisomers was deprotected by the addition of basic
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: timothy.
donohoe@chem.ox.ac.uk; Tel: +44 (0)1865 275649
† Electronic supplementary information (ESI) available: Details of ex-
perimental procedures, NMR data for all new compounds and X-ray
crystallographic data. CCDC reference number 695945. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b815332a
‡ Author to whom correspondence regarding the X-ray crystal structure
should be addressed.
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data for our sample matched that previously reported in the
literature.14
To conclude, this paper reports an epoxidation–intramolecular
ring opening approach to enable the trans-dihydroxylation of
pyrroline 1. The result is an extremely efficient route to trans-
C3,4-diol configured pyrrolidines. The monocyclic target DGDP
4 was synthesised in only six steps (34% overall yield). More
complex targets with trans-C3,4-diol stereochemistry, such as the
bicyclic 7-epialexine 11, can also be made via this chemistry (17
steps and 10% overall yield). As such, this work complements our
earlier studies on routes to pyrrolizidine alkaloids with cis-C2,5-
and trans-C2,5-stereochemistry, which were restricted to the cis-
C3,4-diol array. Consequently, we now have access to almost every
possible stereochemical arrangement within the pyrrolidine ring
and this leads to exciting possibilities for the flexible syntheses of
pyrrolizidines with important biological activity.
Acknowledgements
We thank the EPSRC for funding this work and Merck for
unrestricted support. We would also like to thank the Oxford
Chemical Crystallography Service for instrumentation.
Notes and references
1 (a) T. J. Donohoe, C. L. Rigby, R. E. Thomas, W. F. Nieuwenhuys,
F. L. Bhatti, A. R. Cowley, G. Bhalay and I. D. Linney, J. Org. Chem.,
2006, 71, 6298; (b) T. J. Donohoe, C. E. Headley, R. P. C. Cousins and
A. Cowley, Org. Lett., 2003, 5, 999; (c) T. J. Donohoe, R. E. Thomas,
M. D. Cheeseman, C. L. Rigby, G. Bhalay and I. Linney, Org. Lett.,
2008, 10, 3615.
2 For a description of the biological activity of polyhydroxylated
pyrrolizidine natural products and their epimers see: (a) R. J. Nash, P. I.
Thomas, R. D. Waigh, G. W. J. Fleet, M. R. Wormald, P. M. Lilley and
D. J. Watkin, Tetrahedron Lett., 1994, 35, 7849; (b) A. Kato, E. Kano, I.
Adachi, R. J. Molyneux, A. A. Watson, R. J. Nash, G. W. J. Fleet, M. R.
Wormald, H. Kizu, K. Ikeda and N. Asano, Tetrahedron: Asymmetry,
2003, 14, 325; (c) T. Yamashita, K. Yasuda, H. Kizu, Y. Kameda, A. A.
Watson, R. J. Nash, G. W. J. Fleet and N. Asano, J. Nat. Prod., 2002,
65, 1875; (d) A. Kato, I. Adachi, M. Miyauchi, K. Ikeda, T. Komae,
H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash, M. R. Wormald,
G. W. J. Fleet and N. Asano, Carbohydr. Res., 1999, 316, 95; (e) N.
Asano, H. Kuroi, K. Ikeda, H. Kizu, Y. Kameda, A. Kato, I. Adachi,
A. A. Watson, R. J. Nash and G. W. J. Fleet, Tetrahedron: Asymmetry,
2000, 11, 1; (f) N. Asano, Glycobiology, 2003, 13, 93R; (g) T. Cox, R.
Lachmann, C. Hollak, J. Aerts, S. van Weely, M. Hrebicek, F. Platt, T.
Butters, R. Dwek, C. Moyses, I. Gow, D. Elstein and A. Zimran, Lancet,
2000, 355, 1481; (h) F. M. Platt, G. R. Neises, G. Reinkensmeier, M. J.
Townsend, V. H. Perry, R. L. Proia, B. Winchester, R. A. Dwek and T.
Butters, Science, 1997, 276, 428.
3 For examples of the synthesis of polyhydroxylated pyrrolizidines with
trans-C3,4-diol stereochemistry see: (a) M. Dressel, P. Restorp and P.
Somfai, Chem.–Eur. J., 2008, 14, 3072; (b) H. Yoda, H. Katoh and K.
Takabe, Tetrahedron Lett., 2000, 41, 7661; (c) J. Behr, A. Esard and G.
Guillerm, Eur. J. Org. Chem., 2002, 1256; (d) D. Koch, S. Maechling and
S. Blechert, Tetrahedron, 2007, 63, 7112; (e) D. Chikkanna, O. V. Singh,
S. B. Kong and H. Han, Tetrahedron, 2005, 46, 8865; (f) J. Calveras,
J. Casas, T. Parella, J. Joglar and P. Clapes, Adv. Synth. Catal., 2007,
349, 1661; (g) I. Izquierdo, M. T. Plaza, R. Robles and F. Franco,
Tetrahedron: Asymmetry, 2001, 12, 2481.
Scheme 3 Synthesis of (-)-7-epialexine 11.
methanol, which formed triol 6.11 Protection of 6 as a tris-OTES
ether was followed by the direct and selective oxidation of the
primary OTES group by reaction under Swern conditions and
gave aldehyde 7.12 The addition of allylmagnesium bromide to
aldehyde 7 gave a secondary alcohol as a 6 : 1 mixture of (partially
separable) diastereoisomers. The major product had arisen from
chelation control (to the N-Boc) and our attempts to reverse
this stereoselectivity and produce the Felkin–Anh isomer were
unsuccessful.13
Following protection of the alcohol as TES-ether 8 the alkene
was cleaved with ozone and then reduced with NaBH4. This
step could not be performed as a one-pot procedure following
ozonolysis because of TES group migration to the primary alcohol
during purification. The resulting primary hydroxyl group was
activated (Ms2O) to furnish 9 and TESOTf was then employed to
deprotect the N-Boc group in order to prevent facile TES-ether
deprotection under Lewis acidic conditions. Subsequent addition
of methanol to the reaction mixture resulted in cyclisation to give
pyrrolizidine 10. Finally, global deprotection of the crude benzyl
ether 10 was carried out under acidic hydrogenolysis conditions to
provide (-)-7-epialexine 11 as a colourless oil. The spectroscopic
4 For a description of the biological activity of DGDP see: (a) Y. Minami,
C. Kuriyama, K. Ikeda, A. Kato, K. Takebayashi, I. Adachi, G. W. J.
Fleet, A. Kettawan, T. Okamotoe and N. Asanoa, Bioorg. Med. Chem.,
2008, 16, 2734; (b) I. Gautier-Lefebvre, J. Behr, G. Guillerm and M.
Muzard, Eur. J. Med. Chem., 2005, 40, 1255;(c) C. Wong, L. Provencher,
J. Porco, S. Jung, Y. Wang, L. Chen, R. Wang and D. H. Steensma,
J. Org. Chem., 1995, 60, 1492; (d) Y. Wang, Y. Takaoka and C. Wong,
Angew. Chem., Int. Ed. Engl., 1994, 33, 1242.
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5 For an example when similar conditions have been used to epoxidise
trans-C2,5-pyrrolines see: B. M. Trost, A. Aponick and B. N. Stanzl,
Chem.–Eur. J., 2007, 13, 9547.
6 For an example where BF3·OEt2 has been used to initiate an intramolec-
ular epoxide ring-opening reaction see: F. E. McDonald, F. Bravo, X.
Wang, X. Wei, M. Toganoh, J. R. Rodriguez, B. Do, W. A. Neiwert and
K. I. Hardcastle, J. Org. Chem., 2002, 67, 2525.
7 BF3·OEt2 has previously been shown to be an efficient reagent for N-
Boc deprotection see: M. Bohno, K. Sugie, H. Imase, Y. B. Yusof,
Y. Oishi and N. Chida, Tetrahedron, 2007, 63, 6977. For an example
where the combination of BF3·OEt2 and methanol has facilitated OAc
deprotection see:; X. Zhu, L. He, G. Yang, M. Lei, S. Chen and J. Yang,
Synlett, 2006, 20, 3510.
10 For an example of Ag2O mediated benzyl protection on a compound
with a potentially labile OAc group see: S. Sano, T. Miwa, K. Hayashi,
K. Nozaki, Y. Ozaki and Y. Nagao, Tetrahedron Lett., 2001, 42, 4029.
11 Following basic aqueous work-up of the epoxide ring-opening reaction,
a 1 : 1 mixture of acetate regioisomers at the C4- and C5-hydroxyl was
formed.
12 For an example of the oxidation of primary OTES-ethers under
Swern conditions in the presence of secondary OTES-ethers see: W. T.
Lambert, G. H. Hanson, F. Benayoud and S. D. Burke, J. Org. Chem.,
2005, 70, 9382.
13 All attempts at reagent controlled asymmetric allylation resulted in
either recovered starting material or decomposition possibly due to the
Lewis acidic conditions required for these reactions. Our previously
successful Luche-type allylation reaction (see Ref. 1c) on this type of
aldehyde and which was selective for the Felkin–Ahn diastereomer
failed to give any of the desired product.
14 (a) G. W. J. Fleet, M. Haraldson, R. J. Nash and L. E. Fellows,
Tetrahedron Lett., 1988, 29, 5441; (b) W. H. Pearson and J. V. Hines,
J. Org. Chem., 2000, 65, 5785; (c) A. Romero and C. Wong, J. Org.
Chem., 2000, 65, 8264. Our synthetic sample contains a minor amount
of a diastereoisomer which originates from the allyl addition to 7.
8 E. W. Baxter and A. B. Reitz, J. Org. Chem., 1994, 59, 3175.
9 Single crystal X-ray diffraction data for 4: C6H13NO4; Mr = 163.17;
˚
orthorhombic (P212◦121); a = 5.9247(2), b = 7.2417(3), c = 17.4475(9) A;
3
˚
a = b = g = 90 ; V = 748.58(6) A ; T = 150(2) K; Z = 4;
m = 0.121 mm-1; Dcalc = 1.448 g cm-3; Reflections collected = 1703;
independent reflections = 1018 (Rint = 0.031); R values [I > 2s(I), 796
reflections]: R1 = 0.0382, wR2 = 0.0911. See supplementary information
for details†.
3898 | Org. Biomol. Chem., 2008, 6, 3896–3898
This journal is
The Royal Society of Chemistry 2008
©