An oxidation and ring contraction approach to the synthesis of (±)-1-deoxynojirimycin and (±)-1-deoxyaltronojirimycin

Article abstract of DOI:10.1021/ol902533b

"Chemical Equation Presented" A reaction sequence involving the chemoselective olefinic oxidation of W(1)-benzyl-2,7-dihydro-1H-azepine with m-CPBA in the presence of HBF₄ and BnOH followed by ring contraction facilitates the stereoselective pr

Full text of DOI:10.1021/ol902533b

ORGANIC
LETTERS
2010
Vol. 12, No. 1
136-139
An Oxidation and Ring Contraction
Approach to the Synthesis of
(()-1-Deoxynojirimycin and
(()-1-Deoxyaltronojirimycin
Sharan K. Bagal,† Stephen G. Davies,*,‡ James A. Lee,‡ Paul M. Roberts,‡
Angela J. Russell,‡ Philip M. Scott,‡ and James E. Thomson‡
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K., and Pfizer Global R&D, Sandwich,
Kent CT13 9NJ, U.K.
steVe.daVies@chem.ox.ac.uk
Received November 2, 2009
ABSTRACT
A reaction sequence involving the chemoselective olefinic oxidation of N(1)-benzyl-2,7-dihydro-1H-azepine with m-CPBA in the presence of
HBF4 and BnOH followed by ring contraction facilitates the stereoselective preparation of either of the epoxide diastereoisomers of (2RS,3SR)-
N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine by simple modification of the reaction conditions. Epoxide ring opening, functional
group interconversion, and deprotection allow the synthesis of (()-1-deoxynojirimycin and (()-1-deoxyaltronojirimycin.
Polyhydroxylated piperidines have received considerable at-
tention from the synthetic community due to their glycosidase
inhibitory properties,1 which give them great potential in the
treatment of a variety of disorders including cancer and HIV.2
As part of an ongoing research program directed toward the de
novo preparation of imino and amino sugars and their deriva-
tives,3 we recently reported the ammonium-directed oxidation
of 3-(N,N-dibenzylamino)cyclohex-1-ene 1 upon treatment with
m-CPBA in the presence of Cl3CCO2H.4 Regioselective in situ
ring opening of the intermediate epoxide 2 gave trichloroacetate
ester 3, which underwent transesterification to give diol 4 in
quantitative yield and 95:5 dr (Scheme 1). Herein, the applica-
tion of this methodology to the stereoselective synthesis of (()-
1-deoxynojirimycin (and its diastereoisomer (()-1-deoxyal-
tronojirimycin) using a strategy reliant on oxidation of N(1)-
benzyl-2,7-dihydro-1H-azepine and ring contraction is reported.
N(1)-Benzyl-2,7-dihydro-1H-azepine 10 was prepared ac-
cording to a modification of the procedure reported by Walsh
and co-workers.5 Methylation of (Z,Z)-hexa-2,4-dienedioic
(3) For selected recent examples, see: (a) Aciro, C.; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2008, 6, 3762. (b) Davies, S. G.; Durbin, M. J.; Goddard, E. C.;
Kelly, P. M.; Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D. Org. Biomol.
Chem. 2009, 7, 761. (c) Aciro, C.; Davies, S. G.; Kurosawa, W.; Roberts,
P. M.; Russell, A. J.; Thomson, J. E. Org. Lett. 2009, 11, 1333. (d) Bond,
C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa, W.;
Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J.
Org. Chem. 2009, 74, 6735.
† Pfizer Global R&D.
‡ University of Oxford.
(1) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645. Davis, B. G. Tetrahedron: Asymmetry 2009,
20, 652.
(2) For instance, see: Cross, P. E.; Baker, M. A.; Carver, J. P.; Dennis,
J. W. Clin. Cancer Res. 1995, 1, 935. Qian, X.; Moris-Varas, F.; Fitzgerald,
M. C.; Wong, C.-H. Bio. Med. Chem. 1996, 4, 2055. Nakagawa, K.; Kubota,
H.; Tsuzuki, T.; Kariya, J.; Kimuro, T.; Oikawa, S.; Miyazawa, T. Biosci.
Biotechnol. Biochem. 2008, 72, 2008. Winchester, B. G. Tetrahedron:
Asymmetry 2009, 20, 645.
(4) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.
10.1021/ol902533b  2010 American Chemical Society
Published on Web 12/02/2009

Scheme 1
.
Ammonium-Directed Dihydroxylation of
Scheme 3
.
Oxidation of N(1)-Benzyl-2,7-dihydro-1H-azepine 10
by m-CPBA in the Presence of HBF4
3-(N,N-Dibenzylamino)cyclohex-1-ene 1
acid 5 (cis,cis-muconic acid) with MeI and K2CO3 gave
dimethyl (Z,Z)-hexa-2,4-dienedioate 6 in 91% yield. DIBAL-H
reduction of 6 followed by treatment of the resultant diol 7
with PBr3 gave dibromide 8 in 83% yield over the two steps.
Addition of benzylamine to 8 furnished a chromatographi-
cally separable 14:86 mixture of 9 and 10, which were
isolated in 7 and 62% yield, respectively. The overall yield
of 10 from 5 (four steps) was 47%6 (Scheme 2).
m-CPBA under analogous conditions gave 13 exclusively,
which was isolated in 50% yield (Scheme 3). The relative
configuration within 13 was unambiguously established by
single-crystal X-ray analysis (Figure 1), and the relative
Scheme 2. Preparation of N(1)-Benzyl-2,7-dihydro-1H-azepine 10
Figure 1. Chem3D representation of the single-crystal X-ray
structure of 13 (some H atoms omitted for clarity).
Initial studies into the olefinic oxidation of 10 employing in
situ N-protection by treatment with Cl3CCO2H in a CH2Cl2/
BnOH mixture under the previously reported conditions4 gave
incomplete conversion to a chromatographically inseparable
mixture of products. However, when the acid protecting agent
was changed to HBF4, complete conversion to a mixture of
monobenzyl protected diol 12 and monobenzyl protected diol
epoxide 13 was noted. Optimization of the reaction conditions
revealed that use of 1.5 equiv of m-CPBA gave an 85:15
mixture of 12:13 from which 12 was isolated as a single
diastereoisomer, albeit in only 29% yield due to its incompat-
ibility with chromatographic media. Employing 4 equiv of
configuration within 12 was established by chemical correlation:
resubjection of 12 to the oxidation reaction conditions promoted
conversion to 13 as a single diastereoisomer in 62% isolated
yield. These results are consistent with a mechanism involving
epoxidation of the double bond followed by highly regioselec-
tive ring opening of the intermediate epoxide 11 by BnOH at
C(4), which is both remote from the destabilizing influence of
the electron-withdrawing, protonated nitrogen atom in the late
transition state7 and an activated allylic site.8 In the presence
of excess m-CPBA, the intermediate monobenzyl protected diol
12 is further oxidized in a diastereoselective manner to give
the monobenzyl protected diol epoxide 13 (Scheme 3).
(5) Walsh, J. G.; Furlong, P. J.; Gilheany, D. G. J. Chem. Soc., Perkin
Trans. 1 1999, 3657.
(7) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737. Addy, J. K.;
Parker, R. E. J. Chem. Soc. 1963, 915.
(6) Walsh et al. reported that 10 is unstable and “decomposed too fast
to allow for 13C analysis” (see ref 5). In our hands, however, 10 proved
stable and could be stored for several months under argon in a freezer
without any detectable degradation.
(8) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry -
Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons Inc.:
New York, 2001; p 434.
Org. Lett., Vol. 12, No. 1, 2010
137

17:15, with purification giving 17 in 98:2 dr (Scheme 4). The
observation of epoxide 15 as the minor diastereoisomeric
product of this reaction confirms the stereochemical assignment
of tetrahydropyridine 16.
Scheme 4
.
Ring Contraction of Tetrahydroazepine 12 and
Azepane 13
Treatment of 15 with Cl3CCO2H followed by 2 M aq
NaOH effected regioselective ring opening of the epoxide
and hydrolysis of the resultant trichloroacetate ester to give
19 as a single diastereoisomer. The relative configuration
within 19 was unambiguously established by single-crystal
X-ray analysis (Figure 3); this analysis also unambiguously
Treatment of azepane 13 with MsCl promoted ring contrac-
tion9 to give piperidine 15 in 76% isolated yield as a single
diastereoisomer (Scheme 4). The relative configuration within
15 was unambiguously established by single-crystal X-ray
analysis (Figure 2). This stereochemical outcome is consistent
Figure 3. Chem3D representation of the single-crystal X-ray
structure of 19 (some H atoms omitted for clarity).
established the regioselectivity of epoxide ring opening [i.e.,
1
attack of Cl3CCO2H occurs exclusively at C(5)]. H NMR
3J coupling constant analysis of 19 was indicative of an
analogous solution phase conformation. Examination of the
favored solid-state conformation of 15 revealed that attack
of Cl3CCO2H at C(5) would give rise to trans-diaxial ring
opening11 via a chair-like transition state 18 with the C(2)-
and C(3)-substituents in pseudoequatorial sites. Ring opening
of epoxide 17 gave an 88:12 mixture of 20:19, and
chromatographic purification gave 20 in 60% yield and 99:1
dr. The relative configuration within 20 was assigned by 1H
NMR 3J coupling constant analysis, assuming a chair
conformation. This stereochemical outcome is also consistent
with ring opening proceeding preferentially via attack of
Cl3CCO2H at C(5). However, this results in either a
disfavored chair-like transition state which places the C(2)-
chloromethyl and C(3)-benzyloxy substituents in pseudoaxial
sites or a disfavored twist-boat-like transition state, which
may therefore account for the lower levels of regioselectivity
observed. The regioselectivity of ring opening of epoxides
15 and 17 parallels our previous observations,3,4 as well as
those of Wolinsky12 and Crotti13 in related systems, insofar
as ring opening occurs preferentially at the carbon atom
Figure 2. Chem3D representation of the single-crystal X-ray
structure of 15 (some H atoms omitted for clarity).
with a mechanism involving initial mesylation of the free
hydroxyl group followed by intramolecular SN2-type displace-
ment of the mesylate by the nitrogen atom to give an
intermediate aziridinium ion 14. Attack of the chloride ion at
the least hindered site furnishes the six-membered ring 15
exclusively. Treatment of tetrahydroazepine 12 with MsCl gave
tetrahydropyridine 16 as a single diastereoisomer in 76% yield
after purification. The relative configuration within 16 was
initially assigned on the basis of this transformation proceeding
via formation and ring opening of the corresponding aziridium
ion. The olefinic oxidation of tetrahydropyridine 16 using
m-CPBA/Cl3CCO2H returned starting material under a range
of conditions, although use of F3CCO3H/F3CCO2H10 promoted
conversion to a 98:2 mixture of the diastereoisomeric expoxides
(10) Gil, L.; Compe`re, D.; Guilloteau-Bertin, B.; Chiaroni, A.; Marazano,
C. Synthesis 2000, 2117.
(11) Fu¨rst, A. Plattner, P. A. 12th Internat. Congr. Pure & Appl. Chem.;
New York, 1951; p 409.
(12) Wolinsky, J.; Thorstenson, J. H.; Killinger, T. A. J. Org. Chem.
1978, 43, 875.
(13) Calvani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994,
50, 12999.
(9) Liu, T.; Zhang, Y.; Bleriot, Y. Synlett 2007, 6, 905.
138
Org. Lett., Vol. 12, No. 1, 2010

remote from the exocyclic heteroatom (in this case oxygen).
In the case of 17, the preferential attack at C(5) may be
promoted by both steric13 and electrostatic14 effects associ-
ated with the exocyclic C(3)-benzyloxy substituent, although
hydrogen-bonded delivery of the nucleophile by the endocy-
clic (protonated) nitrogen atom may also play a role in
determining the regioselectivity of attack15 (Scheme 5).
Scheme 6
.
Functional Group Interconversion of Piperidines 19
and 20
Scheme 5. Ring Opening Reactions of Epoxides 15 and 17
Scheme 7. Deprotection of Piperidines 22 and 24
Treatment of 19 with AgBF4 in CH2Cl2 promoted ring
closure to aziridinium 21. Treatment of 21 with NaOAc in
DMF gave 22 as a single diastereoisomer in 74% yield (two
steps) after chromatography. The relative configuration
within 22 was assigned on the basis of 1H NMR 3J coupling
constant analysis. This two-step conversion of 19 to 22 could
be effected in one-pot upon treatment of 19 with AgOAc in
DMF, giving 22 in 85% isolated yield. An analogous series
of transformations applied to 20 (99:1 dr) gave 24 (99:1 dr),
either in a single chemical operation or in two steps via the
intermediacy of aziridinium 23 (Scheme 6).
Transesterification of 22 was achieved upon treatment with
K2CO3 in MeOH and was followed by global hydrogenolytic
N- and O-debenzylation mediated by Pearlman’s catalyst
[Pd(OH)2/C] to give (()-1-deoxyaltronojirimycin, which was
isolated as its hydrochloride salt 2616 in 51% yield over the
two steps, and in >99:1 dr (Scheme 7). Similar treatment of
24 gave (()-1-deoxynojirimycin which was isolated as its
hydrochloride salt 2817 in 45% yield (over two steps) and
in 99:1 dr after chromatography (Scheme 7).
In conclusion, the oxidative functionalization of N(1)-
benzyl-2,7-dihydro-1H-azepine on one or both of the olefin
moieties and subsequent ring contraction facilitates the
preparation of both epoxide diastereoisomers of (2RS,3SR)-
N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperi-
dine. A further sequence of transformations gives (()-1-
deoxynojirimycin and (()-1-deoxyaltronojirimycin. This
strategy is reliant on N-protection during the oxidative steps
being achieved in situ by protonation and demonstrates the
utility of our recently reported protocol for the synthesis of
molecules with function. Further applications of this useful
transformation, as well as studies into the development of
an asymmetric variant, are ongoing.
Acknowledgment. The authors would like to thank Pfizer
for a CASE studentship (P.M.S.) and the Oxford Chemical
Crystallography Service for the use of their X-ray diffracto-
meters.
(14) Miljkovic´, M.; Gligorijevic´, M.; Glisˇin, D. J. Org. Chem. 1974,
3223.
(15) For a related example, see: Quick, J.; Khandelwal, Y.; Meltzer,
P. C.; Weinberg, J. S. J. Org. Chem. 1983, 48, 5199.
(16) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; Reddy, J. P. J.
Org. Chem. 2004, 69, 4760.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Fleet, G. W. J.; Carpenter, N. M.; Petursson, S.; Ramsden, N. G.
Tetrahedron Lett. 1990, 31, 409. Ermert, P.; Vasella, A. HelV. Chim. Acta
1991, 74, 2043. Somfai, P.; Marchand, P.; Torsell, S.; Lindstro¨m, U. M.
Tetrahedron 2003, 59, 1293.
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