Syntheses of the enantiomers of 1-deoxynojirimycin and 1- deoxyaltronojirimycin via chemo- and diastereoselective olefinic oxidation of unsaturated amines

Article abstract of DOI:10.1021/jo101756g

Oxidation of enantiomerically pure (R)-N(1)-1′-(1″-naphthyl) ethyl-2,7-dihydro-1H-azepine with m-CPBA in the presence of HBF₄ and BnOH gave (3S,4R,5S,6S,1′R)-N(1)-1′-(1″-naphthyl)ethyl-3- hydroxy-4-benzyloxy-5,6-epoxyazepane as the major product and as a single diastereoisomer after chromatography. Elaboration of this highly functionalized intermediate via ring contraction to (2S,3R,4S,5S,1′R)-N(1)-benzyl-2- chloromethyl-3-benzyloxy-4,5-epoxypiperidine followed by regioselective epoxide ring opening, functional group manipulation, and deprotection gave (+)-1-deoxyaltronojirimycin. Alternatively, resolution of (RS,RS)-N(1)-benzyl-3- hydroxy-4-benzyloxy-2,3,4,7-tetrahydro-1H-azepine or (3RS,4SR,5RS,6RS)-N(1)- benzyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane by preparative chiral HPLC and subsequent elaboration allows access to the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin, respectively.

Full text of DOI:10.1021/jo101756g

pubs.acs.org/joc
Syntheses of the Enantiomers of 1-Deoxynojirimycin and
1-Deoxyaltronojirimycin via Chemo- and Diastereoselective Olefinic
Oxidation of Unsaturated Amines
Sharan K. Bagal,‡ Stephen G. Davies,*,† James A. Lee,† Paul M. Roberts,†
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 September 10, 2010
Oxidation of enantiomerically pure (R)-N(1)-10-(100-naphthyl)ethyl-2,7-dihydro-1H-azepine with
m-CPBA in the presence of HBF4 and BnOH gave (3S,4R,5S,6S,10R)-N(1)-10-(100-naphthyl)ethyl-
3-hydroxy-4-benzyloxy-5,6-epoxyazepane as the major product and as a single diastereoisomer
after chromatography. Elaboration of this highly functionalized intermediate via ring contrac-
tion to (2S,3R,4S,5S,10R)-N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine followed
by regioselective epoxide ring opening, functional group manipulation, and deprotection gave
(þ)-1-deoxyaltronojirimycin. Alternatively, resolution of (RS,RS)-N(1)-benzyl-3-hydroxy-4-
benzyloxy-2,3,4,7-tetrahydro-1H-azepine or (3RS,4SR,5RS,6RS)-N(1)-benzyl-3-hydroxy-4-
benzyloxy-5,6-epoxyazepane by preparative chiral HPLC and subsequent elaboration allows access
to the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin, respectively.
Introduction
e.g., 5-amino-5-deoxy-D-glucopyranose [(þ)-nojirimycin, 1],2
1,5-dideoxy-1,5-imino-D-glucitol [(þ)-1-deoxynojirimycin, 2],3
and 1,5-dideoxy-1,5-imino-D-altroitol [(þ)-1-deoxyaltronojiri-
mycin, 3]3e,f (Scheme 1).
Polyhydroxylated piperidines are produced as secondary
metabolites in a vast array of different organisms, although
the majority originate in plants.1 They are widely known as
iminosugars (or azasugars) due to their inherent similarity to
monosaccharides (the difference being that the endocyclic
oxygen atom is replaced by a nitrogen atom) with the result
that many are named with reference to their “parent” sugar,
(3) (a) Murao, S.; Miyata, S. Agric. Biol. Chem. 1980, 44, 219. (b) Asano,
N.; Tomioka, E.; Kizu, H.; Matsui, K. Carbohydr. Res. 1994, 253, 235.
(c) Asano, N.; Oseki, K.; Tomioka, E.; Kizu, H.; Matsui, K. Carbohydr. Res.
1994, 259, 243. (d) Asano, N.; Yamashita, T.; Yasuda, K.; Ikeda, K.; Kizu,
H.; Kameda, Y.; Kato, A.; Nash, R. J.; Lee, H. S.; Ryu, K. S. J. Agric. Food
Chem. 2001, 49, 4208. (e) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002, 65,
1875. (f) Asano, N.; Yamauchi, T.; Kagamifuchi, K.; Shimizu, N.; Takahashi,
S.; Takatsuka, H.; Ikeda, K.; Chuakul, W.; Kettawan, A.; Okamoto, T. J. Nat.
Prod. 2005, 68, 1238.
(1) Magalhaes, A. F.; Santos, C. C.; Magalhaes, E. G.; Noguiera, M. A.
Phytochem. Anal. 2002, 13, 215.
(2) Ishida, N.; Kumagai, K.; Niida, T.; Tsuruoka, T.; Yumoto, H. J. Antibiot.,
Ser. A 1967, 20, 66. Inouye, S.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahedron 1968,
23, 2125.
DOI: 10.1021/jo101756g
r
Published on Web 11/02/2010
J. Org. Chem. 2010, 75, 8133–8146 8133
2010 American Chemical Society

Bagal et al.
JOCArticle
SCHEME 1
sugar processing enzymes in the proliferation of these
conditions.5
As part of an ongoing research program directed toward
the de novo preparation of imino and amino sugars and their
derivatives, we developed an ammonium-directed oxidation
protocol for a range of cyclic allylic6 and homoallylic6c
amines upon treatment with m-CPBA in the presence of
Cl3CCO2H.7 We recently disclosed the application of a
modification of this protocol as one of the key steps to
facilitate the stereoselective syntheses of (()-1-deoxy-
nojirimycin 2 and (()-1-deoxyaltronojirimycin 3.8-10 In this
synthesis, oxidation of N(1)-benzyl-2,7-dihydro-1H-azepine
4 in the presence of aqueous HBF4 and 1.5 equiv of
m-CPBA in a mixture of BnOH/CH2Cl2 (v/v 2:1) gave an
85:15 mixture of 5:8, from which 5 was isolated in 29% yield
and >99:1 dr, while use of 4 equiv of m-CPBA gave 8 in 50%
isolated yield and >99:1 dr. Ring contraction of 8 gave
piperidine epoxide 9 in 76% yield and >99:1 dr, while ring
contraction of 5 followed by further oxidation of the double
bond with F3CCO3H in the presence of F3CCO2H gave the
diastereoisomeric epoxide 7 in 62% yield over the two steps
and in 98:2 dr. Further manipulation of 7 and 9 via regiose-
lective epoxide ring-opening, functional group manipula-
tion, and deprotection gave (()-1-deoxynojirimycin 2 (in
99:1 dr) and (()-1-deoxyaltronojirimycin 3 (in >99:1 dr),
The biological activity of this class of compounds is wide
and varied, although most effects are attributed to their
ability to act as glycosidase inhibitors.4 Polyhydroxylated
piperidines act to inhibit these enzymes by mimicking the
saccharides that would usually be targeted by the enzyme.
The interaction of the mimic with the enzyme can be greater
than that of the desired target as the piperidine can become
protonated in the enzyme pocket, thereby mimicking the
postulated oxo-carbenium ion intermediate of glycosidic
bond cleavage. Due to their inherent biological activity both
naturally occurring and synthetic polyhydroxylated piper-
idines have been targeted and extensively tested as poten-
tial therapeutics for various conditions including HIV, can-
cer, diabetes, and hereditary diseases such as Gaucher’s
(lysosomal storage) disease, all exploiting the prevalence of
which were isolated as their hydrochloride salts 2 HCl and
3
3 HCl, respectively (Scheme 2).
3
We wished to develop an asymmetric version of this
versatile protocol. Our strategy in this area was 2-fold:
development of a practical resolution protocol for one of
the intermediates en route to either 2 or 3 would allow the
efficient preparation of the enantiomerically pure polyhy-
droxylated piperidines and their derivatives or, alternatively,
incorporation of a chiral N-protecting group on the nitrogen
atom would promote diastereoselective oxidation, and we
delineate herein our investigations within these areas.
(4) For a review on the biological activity of polyhydroxylated alkaloids,
see: Watson, A. A.; Fleet, G. W. J; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265.
(5) Wrodnigg, T. M.; Steiner, A. J.; Verberacher, B. J. Anti-Cancer Agents
Med. Chem. 2008, 8, 77. Nakagawa, K.; Kubota, H.; Tsuzuki, T.; Kariya, J.;
Kimura, T.; Oikawa, S.; Miyazawa, T. Biosci. Biotechnol. Biochem. 2008, 72,
2210.
Results and Discussion
Synthesis of Polyhydroxylated Piperidines Employing a
Resolution Protocol: Application to the Synthesis of
(þ)-1-Deoxynojirimycin. We first investigated the potential
for resolution of one of the synthetic intermediates in our pre-
viously reported routes to (()-1-deoxynojirimycin 2 and
(()-1-deoxyaltronojirimycin 3, which thus required prepara-
tion of the functionalized racemic tetrahydroazepine 5 and
racemic azepane 8. Upon scale up of our previously reported
oxidation protocol for dihydroazepine 4 using 1.5 equiv of m-
CPBA in the presence of aqueous HBF4 in BnOH/CH2Cl2,8
we noted (in addition to the formation of 5)11 the appearance
of an undesired by product in the 1H NMR spectrum of the
(6) (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751. (b) Aciro, C.;
Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 3762. (c) Bond, C. W.; Cresswell, A. J.; Davies,
S. G.; Kurosawa, W.; Lee, J. A.; Fletcher, A. M.; Roberts, P. M.; Russell,
A. J.; Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735.
(7) For a review, see: Kurosawa, W.; Roberts, P. M.; Davies, S. G. Yuki
Gosei Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.) 2010, in press.
(8) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136.
(9) For previous syntheses of 2, see: (a) Bernotas, R. C.; Ganem, B.
Tetrahedron Lett. 1985, 26, 1123. (b) Fleet, G. W. J.; Fellows, L. E.; Smith,
P. W. Tetrahedron 1987, 43, 979. (c) Iida, H.; Yamazaki, N.; Kibayashi, C.
J. Org. Chem. 1987, 52, 3337. (d) Straub, A.; Effenberger, F.; Fischer, P.
J. Org. Chem. 1990, 55, 3926. (e) Schaller, C.; Vogel, P.; Jager, V. Carbohydr.
Res. 1998, 314, 25. (f) Comins, D. L.; Fulp, A. B. Tetrahedron Lett. 2001, 42,
€
6839. (g) Somfai, P.; Marchand, P.; Torsell, S.; Lindstrom, U. M. Tetra-
hedron 2003, 59, 1293. (h) McDonnell, C.; Cronin, L.; O’Brien, J. L.;
Murphy, P. V. J. Org. Chem. 2004, 69, 3565. (i) Dhavale, D. D.; Markad,
S. D.; Karanjule, N. S.; Reddy, J. P. J. Org. Chem. 2004, 69, 4760.
(j) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi,
I. Tetrahedron 2004, 60, 8199. (k) Kato, A.; Kato, N.; Kano, E.; Adachi, I.;
Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano,
N. J. Med. Chem. 2005, 48, 2036. (l) Jadhav, V. H.; Bande, O. P.; Puranik,
V. G.; Dhavale, D. D. Tetrahedron: Asymmetry 2010, 21, 163. (m) Best, D.;
Wang, C.; Weymouth-Wilson, A. C.; Clarkson, R. A.; Wilson, F. X.; Nash,
R. J.; Miyauchi, S.; Kato, A.; Fleet, G. W. J. Tetrahedron: Asymmetry 2010,
21, 311. (n) Wennekes, T.; Meijer, A. J.; Groen, A. K.; Boot, R. G.; Groener,
J. E.; van Eijk, M.; Ottenhoff, R.; Bijl, N.; Ghauharali, K.; Song, H.; O’Shea,
T. J.; Liu, H.; Yew, N.; Copeland, D.; van den Berg, R. J.; van der Marel,
G. A.; Overkleeft, H. S.; Aerts, J. M. J. Med. Chem. 2010, 53, 689.
(10) For previous syntheses of 3, see: (a) Xu, Y.-M.; Zhou, W.-S. J. Chem.
Soc., Perkin Trans. 1 1997, 741. (b) Barili, P. L.; Berti, G.; Catelani, G.;
D’Andrea, F.; de Rensis, F.; Puccioni, L. Tetrahedron 1997, 53, 3407.
(c) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009. (d) Kazmaier,
U.; Grandel, R. Eur. J. Org. Chem. 1998, 1833. (e) Asano, K.; Hakogi, T.;
Iwama, S.; Katsumura, S. Chem. Commun. 1999, 41. (f) Singh, O. V.; Han., H.
Tetrahedron Lett. 2003, 49, 2387. (g) Ruiz, M.; Ruanova, T. M.; Blanco, O.;
ꢀ~
Nunez, F.; Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240. (h) van den
Nieuwendijk, A. M. C. H.; Ruben, M.; Engelsma, S. E.; Risseeuw, M. D. P.;
van den Berg, R. J. B. H. N.; Boot, R. G.; Aerts, J. M.; van der Marel, G. A.;
Overkleeft, H. S. Org. Lett. 2010, 12, 3957. Also see ref 9i-9n.
(11) Azepane 8 was also present in the crude reaction mixture (the ratio of
5:8 was 85:15); see ref 8.
8134 J. Org. Chem. Vol. 75, No. 23, 2010

Bagal et al.
JOCArticle
SCHEME 2a
aReagents and conditions: (i) HBF4 (40% w/w in H2O), m-CPBA (4 equiv), CH2Cl2, BnOH, rt, 24 h; (ii) HBF4 (40% w/w in H2O), m-CPBA
(1.5 equiv), CH2Cl2, BnOH, rt, 24 h; (iii) MsCl, Et3N, CH2Cl2, 0 °C, 1.5 h; (iv) F3CCO2H, F3CCO3H, CH2Cl2, 0 °C to rt, 6 h; (v) Cl3CCO2H, CH2Cl2, rt,
16 h, then NaOH (2 M, aq); (vi) AgOAc, DMF, 65 °C, 24 h; (vii) K2CO3, MeOH, rt, 16 h; (viii) H2, Pd(OH)2/C, MeOH, rt, 72 h, then HCl (aq).
SCHEME 3a
SCHEME 4a
aReagents and conditions: (i) HBF4 OEt2, m-CPBA (4 equiv), CH2Cl2,
BnOH, rt, 24 h; (ii) HBF4 OEt2, m-CPBA (1.5 equiv), CH2Cl2, BnOH, rt,
24 h.
3
3
of diol 11. Treatment of 4 with 5 equiv of HBF4 OEt2
3
followed by 1.5 equiv of m-CPBA resulted in oxidation to
a 75:25 mixture of (()-5 and (()-8, respectively. Purification
gave (()-5 as a single diastereoisomer in 42% yield after
chromatography on silica gel. Meanwhile, analogous oxida-
tion of 4 employing 4 equiv of m-CPBA gave oxidation of
both double bonds to give (()-8 as a single diastereoisomer,
which was isolated in 65% yield and >99:1 dr after silica gel
chromatography (Scheme 4).
aReagents and conditions: (i) HBF4 (40% w/w in H2O), m-CPBA (1.5
equiv), CH2Cl2, BnOH, rt, 24 h; (ii) chromatography; (iii) Cl3CCO2H,
m-CPBA, CH2Cl2, rt, 21 h, then NaOH (2 M, aq).
crude reaction mixture. Although this compound was not
isolated upon chromatography, it was assigned as diol 11:
given our previous observations concerning the production of
monobenzyl-protected diol 5 from the oxidation of dihydro-
azepine 4 by m-CPBA in the presence of aqueous HBF4 in a
solvent mixture of BnOH/CH2Cl2, in which BnOH acts as the
nucleophile to effect ring-opening of epoxide 10, wepostulated
that competitive ring-opening of10 by H2O would result inthe
formation of the diol 11. Indeed, oxidation of dihydroazepine
4 with m-CPBA in the presence of Cl3CCO2H and basic
aqueous workup (2 M aq NaOH) gave quantitative conver-
sion to 11 as a single diastereoisomer, which was isolated in
30% yield (Scheme 3).
After extensive experimentation, we subsequently found that
both (()-5 and (()-8 were amenable to resolution via prepara-
tive HPLC using a Chiralpak AD-H column. Thus, oxidation
of dihydroazepine 4 with 1.5 equiv of m-CPBA in the presence
of HBF4 OEt2 followed by chromatographic purification and
3
resolution enabled the preparation of (þ)-5 in 15% yield (out of
a maximum of 50% from 4) and >99% ee, and (-)-5 in 13%
yield (out of a maximum of 50% from 4) and >99% ee {for
(þ)-5, [R]25D þ82.8 (c 1.0 in CHCl3); for (-)-5, [R]25D -81.8
(c 1.0 in CHCl3)} (Scheme 5). Under analogous conditions but
using 4 equiv of m-CPBA in the oxidation reaction, (þ)-8 was
isolated in 11% yield (out of a maximum of 50% from 4) and
98% ee and (-)-8in 12% yield (out of a maximum of 50% from
4) and >99% ee {for (þ)-8, [R]25D þ52.4 (c 1.0 in CHCl3); for
(-)-8, [R]25D -56.4 (c 1.0 in CHCl3)} (Scheme 6).
In order to circumvent this problem, we modified our
experimental protocol to employ HBF4 OEt2 in place of
3
aqueous HBF4, which was found to give improved crude
mass return as well as complete suppression of the formation
The absolute configurations within (þ)-5 and (-)-5 could
not be assigned a priori; they were established as (þ)-(S,S)-5
J. Org. Chem. Vol. 75, No. 23, 2010 8135

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SCHEME 5a
SCHEME 6a
aReagents and conditions: (i) HBF4 OEt2, m-CPBA (4 equiv),
CH2Cl2, BnOH, rt, 24 h; (ii) chromatography; (iii) preparative chiral
HPLC (Chiralpak AD-H column).
aReagents and conditions: (i) HBF4 OEt2, m-CPBA (1.5 equiv),
CH2Cl2, BnOH, rt, 24 h; (ii) chromatography; (iii) preparative chiral
HPLC (Chiralpak AD-H column).
3
3
Having determined the absolute configurations within
(þ)-5 and (-)-5, the absolute configurations within (þ)-8
and (-)-8 were established via chemical correlation. Thus,
oxidation of (þ)-(S,S)-5 (>99% ee) with m-CPBA in the
and (-)-(R,R)-5 via chemical correlation to the enantiomers
of 1-deoxynojirimycin 2. Thus, ring contraction of (þ)-5 was
effected upon treatment with MsCl to give 6 in 75% yield
and>99:1 dr.12 Chemo- and diastereoselective oxidation of
the olefin within 6 was achieved upon treatment with
F3CCO3H in the presence of F3CCO2H, giving piperidine
epoxide 7 in 98:2 dr, which was isolated in 62% yield. Upon
treatment with Cl3CCO2H, epoxide ring-opening occurred
at C(5) with modest levels of regioselectivity13 [the ratio of
C(4):C(5) ring opened products in the crude reaction mixture
was 88:12], with saponification of the crude reaction mixture
with aqueous NaOH giving 12 in 51% isolated yield and 99:1
dr. Subsequent displacement of the chloride functionality with-
in 12 gave acetate ester 1312 and was followed by treatment
with K2CO3 in MeOH to effect transesterification to give 14,
with subsequent hydrogenolysis and acidification giving
presence of aqueous HBF414 gave (þ)-8 in >99% ee15 {[R]25
D
þ54.1 (c 1.0 in CHCl3)}, while oxidation of (-)-(R,R)-5(>99%
ee) gave (-)-8 in >99% ee16 {[R]25D -54.3 (c 1.0 in CHCl3)},
thus allowing the absolute configurations within (þ)-8 and
(-)-8 to be unambiguously assigned as (þ)-(3S,4R,5S,6S)-8
and (-)-(3R,4S,5R,6R)-8. We have previously demonstrated
the elaboration of (()-8 into (()-1-deoxyaltronojirimycin,8 and
therefore, elaboration of (þ)-(3S,4R,5S,6S)-8 via an analogous
series of reactions should culminate in the preparation of
(þ)-1-deoxyaltronojirimycin, while similar elaboration of
(-)-(3R,4S,5R,6R)-8 should permit the synthesis of (-)-1-deoxy-
altronojirimycin (Scheme 8).
Synthesis of Polyhydroxylated Piperidines Employing Dia-
stereoselective Olefinic Oxidation of an Enantiopure Substrate:
Application to the Synthesis of (þ)-1-Deoxyaltronojirimycin.
Having developed a route to the antipodes of 1-deoxynojirimycin
2 (and 1-deoxyaltronojirimycin 3) relying on resolution of func-
tionalized tetrahydroazepine 5 and azepane 8, we turned our
attention to the development of a de novo asymmetric
synthesis.17 Our strategy in this area centered on employing a
chiral N-protecting group as it was envisaged that this would
break the symmetry of the 7-membered ring, potentially allow-
ing diastereoselective oxidation. A range of N-substituted di-
hydroazepanes 19-22, all bearing a chiral N-protecting group
based upon the R-methylbenzyl scaffold, was prepared from
cis,cis-muconic acid 15. Methylation of 15 with MeI and K2CO3
gave diester 16 in 91% yield. Reduction of 16 with DIBAL-H
(þ)-1-deoxynojirimycin hydrochloride (þ)-2 HCl in 30% yield
3
from 12 [7% overall yield from (þ)-5 in 6 steps] and 99:1 dr.
Similar elaboration of (-)-5 gave a sample of (-)-1-deoxy-
nojirimycin hydrochloride (-)-2 HCl in 8% overall yield in six
3
steps, and 99:1 dr. The values of the specific rotations of our
samples of the antipodes of 2 {for (þ)-2 HCl, [R]25 þ31.0
D
(c 0.45 in H2O); lit.3a for sample isolated from natural source
3
[R]22D þ38.0 (c 1.0 in H2O); lit.9m [R]23D þ36.9 (c 1.1 in H2O);
for (-)-2 HCl, [R]25D -34.0 (c 0.45 in H2O); lit.9i [R]25D -46.0
3
(c 1.3 in H2O); lit.9m [R]24D -38.7 (c 1.0 in H2O)} allowed the
absolute configurations within (þ)-5 and (-)-5 to be unam-
biguously assigned as (þ)-(S,S)-5 and (-)-(R,R)-5, and the
absolute configurations within the synthetic intermediates 6, 7,
and 12-14 were therefore also unambiguously established.
Furthermore, given the enantiomeric purities of (þ)-5 and
(-)-5 (>99% ee in both cases), the enantiomeric purities of
(þ)-2 HCl, (-)-2 HCl, 6, 7, and 12-14 can be inferred as
(14) Aqueous HBF4 was used for these reactions as it was found to give
cleaner crude reaction mixtures than the analogous procedures using
HBF4 OEt2.
3
3
3
>99% ee (Scheme 7).
(15) The enantiomeric purity of (þ)-8 prepared in this manner was
inferred from the enantiomeric purity of the starting material (þ)-5
(i.e., >99% ee).
(12) This reaction presumably proceeds via the intermediacy of the
corresponding aziridinium ion; see ref 8.
(13) For a discussion concerning the regioselectivity of ring-opening, see
ref 8.
(16) The enantiomeric purity of (-)-8 prepared in this manner was
inferred from the enantiomeric purity of the starting material (-)-5
(i.e., >99% ee).
(17) Brown, J. M.; Davies, S. G. Nature 1989, 342, 631.
8136 J. Org. Chem. Vol. 75, No. 23, 2010

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SCHEME 7a
aReagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 °C, 1.5 h; (ii) F3CCO2H, F3CCO3H, CH2Cl2, 0 °C to rt, 6 h; (iii) Cl3CCO2H, CH2Cl2, rt, 16 h,
then NaOH (2 M, aq); (iv) AgOAc, DMF, 65 °C, 24 h; (v) K2CO3, MeOH, rt, 16 h; (vi) H2, Pd(OH)2/C, MeOH, rt, 72 h, then HCl (aq).
SCHEME 8a
SCHEME 9a
aReagents and conditions: (i) HBF4 (40% w/w in H2O), m-CPBA
(4 equiv), CH2Cl2, BnOH, rt, 24 h.
aReagents and conditions: (i) Mel, K2CO3, DMF, rt, 24 h; (ii) DIBAL-
H, CH2Cl2, 0 °C to rt, 16 h; (iii) PBr3, Et2O, 0 °C to rt, 7 h; (iv)
ArCH(Me)NH2, K2CO3, THF, rt, 24 h. bIsolated as a 93:7 mixture of
22:26. 2-Nap = 2-naphthyl. 1-Nap = 1-naphthyl. 2-Tol = 2-tolyl.
followed by treatment of the resultant diol 17 with PBr3 gave
dibromide 18 in 83% yield (two steps). Addition of a range of
chiral primary amines18 to 18 furnished, in each case, the
corresponding dihydroazepanes 19-22 as the major products,
along with the corresponding dihydropyrroles 23-26 as minor
products.19 Chromatography allowed isolation of 19-22 in
good yield (Scheme 9).
Cl3CCO2H (5 equiv) over 21 h6a proceeded to full conversion
to give a chromatographically inseparable 65:35 mixture of two
diastereoisomeric diols 27 and 31, which were assigned the
relative anti-configurations on the basis of the reaction proceed-
ing via epoxidation followed by stereospecific SN2-type epoxide
ring-opening.20 Under identical reaction conditions, oxidation
of 2-naphthyl substrate 20 and 2-tolyl substrate 22 gave incom-
plete conversion to chromatographically inseparable 65:35
The oxidation of N-R-methylbenzyl protected dihydro-
azepine 19 with m-CPBA (2 equiv) in the presence of
(18) Enantiopure (R)-R-methylbenzylamine (99% ee), (R)-1-(20-naphthyl)-
ethylamine, and (R)-1-(10-naphthyl)ethylamine (98% ee) are commercially avail-
able. A racemic sample of 1-(20-tolyl)ethylamine was prepared according to the
procedure outlined by Li et al. for the preparation of (RS)-1-(p-xylyl)-
ethylamine; see: Li, Y.; Selvaratnam, S.; Vittal, J. J.; Leung, P.-H. Inorg. Chem.
2003, 42, 3229.
(20) The absolute configurations within the major diastereoisomeric diols
27-30 resulting from these oxidation reactions were tentatively assigned as
(3S,4S,10R) by analogy to the stereochemical outcome observed upon
oxidation of 21 with HBF4 in the presence of BnOH, which gave the
corresponding (3S,4S,10R)-diastereoisomer 38 as the major product, the
stereochemistry of which was unambiguously established by single-crystal
X-ray analyses of derivatives and by chemical correlation to (þ)-1-deoxy-
altronojirimycin 3.
(19) Peak overlap and the presence of unidentified impurities in the 1H
NMR spectra of the crude reaction mixtures precluded the determination of the
dihydroazepine to dihydropyrrole product ratios. Dihydropyrroles 23-26 were
formed as single diastereoisomers of unknown relative configuration.
J. Org. Chem. Vol. 75, No. 23, 2010 8137

Bagal et al.
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SCHEME 10a
SCHEME 11a
aReagents and conditions: (i) HBF4 OEt2, m-CPBA (4 equiv), BnOH,
3
rt, 24 h; (ii) MsCl, Et3N, CH2Cl2, 0 °C, 1.5 h. 1-Nap = 1-naphthyl.
38 was assigned by subsequent chemical correlation with 35,
while the absolute configuration within 39 was assigned as the
alternative stereochemical outcome resulting from an epoxida-
tion step followed by an SN2-type ring-opening process. These
observations are consistent with the N-1-(10-napthyl)ethyl group
within 21 promoting the diastereoselective formation of the
intermediate epoxide 37 (in 80:20 dr), which undergoes ring-
opening via an SN2-type process upon attack of BnOH exclu-
sively at C(4), which is both distal to the protonated nitrogen
atom26 and an activated allylic position,27 to give an 80:20
mixture of the monobenzyl protected diols 38 and 39. Mean-
while, oxidation of the 80:20 mixture of 38 and 39 using aqueous
HBF414 and m-CPBA gave a crude reaction mixture containing
35 and a diastereoisomeric compound (assigned as 40) in the
ratio of 80:20, along with ∼10% of other unidentifiable pro-
ducts. Purification gave an 80:20 mixture of 35:40 in 60%
combined yield. This result suggests that 38 undergoes comple-
tely diastereoselective epoxidation to give 35 and that 39 under-
goes completely diastereoselective epoxidation to give 40. Given
that the analogous tetrahydroazepine 5 bearing an N-benzyl
group (which is incapable of promoting a diastereoselective
reaction) undergoes highly diastereoselective epoxidation to give
8 as a single diastereoisomer, these studies imply that the
configuration of the N-1-(10-naphthyl)ethyl group has little or
no effect in determining the facial selectivity of the epoxidation
reaction of 38 and 39 (Scheme 12).
There are four potential sites for oxidation within the ammo-
nium ions derived from dihydroazepines 19-22: two olefins,
each with two faces. Assuming that the chiral N-protecting
group acts as a steric block to oxidation at one of these sites, with
oxidation occurring with equal probability at the remaining
three sites, then the maximum diastereoselectivity attainable in
this scenario would be 67:33 (two of the three epoxides becom-
ing equivalent on deprotonation during basic aqueous workup):
essentially the same as observed experimentally for oxidation of
R-methylbenzyl 19, 2-naphthyl 20, and 2-tolyl 22 with m-CPBA
in the presence of Cl3CCO2H. In the case of 1-naphthyl 21,
however, an enhanced diastereoselectivity of 80:20 is noted for
both oxidation under m-CPBA/Cl3CCO2H conditions and
m-CPBA/HBF4/BnOH conditions and therefore these results
cannot be accounted for solely by invoking a sterically driven
process. Examination of the X-ray crystal structure of
1-naphthyl 2128 reveals that the 7-membered ring preferentially
aReagents and conditions: (i) Cl3CCO2H, m-CPBA, CH2Cl2, rt,
21 h, then NaOH (2 M, aq). 2-Nap = 2-naphthyl. 1-Nap = 1-naphthyl.
2-Tol = 2-tolyl.
mixtures of the corresponding anti-diols 28 and 32 and 30 and
34, respectively. Meanwhile, oxidation of 1-naphthyl substrate
21 gave incomplete conversion to an 80:20 mixture of the
diastereoisomeric anti-diols 29 and 33, with chromatographic
purification allowing partial separation of the diastereo-
isomers20,21 (Scheme 10).
Encouraged by these initial results, the oxidation of 1-naphthyl
substrate 21 was further investigated. Using our previously
optimized conditions for N-benzyl protected dihydroazepine
4, oxidation of 21 with 4 equiv of m-CPBA in the presence of
5 equiv of HBF4 OEt2 in BnOH22 gave quantitative conversion
3
to a mixture of products with the functionalized tetrahydro-
azepine 35 as the major component.23 Purification gave a sample
of 35 in 25% isolated yield and >99:1 dr. Treatment of 35 with
MsCl in the presence of Et3N effected ring contraction to give
piperidine 36 as a single diastereoisomer, which was isolated in
66% yield. Single-crystal X-ray analysis of 36 unambiguously
established its relative configuration, with the absolute (2S,3R,
4S,5S,10R)-configuration being assigned from the known
(R)-stereocenter of the 1-(10-naphthyl)ethyl group.24 Therefore,
the absolute (3S,4R,5S,6S,10R)-configuration within 35 could
also be confidently assigned. Given the known enantiomeric
purity of the (R)-(þ)-1-(10-naphthyl)ethylamine (98% ee)18 used
in the preparation of 21, the enantiomeric purities of 35 and 36
can be inferred as 98% ee (Scheme 11).
In order to investigate the origin of selectivity in the oxidation
of 21, the reaction was repeated using only 1.5 equiv of
m-CPBA, which gave incomplete (∼50%) conversion to a
chromatographically inseparable 80:20 mixture of two diastereo-
isomeric diols 38 and 39, which were isolated in 32% combined
yield and 80:20 dr.25 The absolute configuration within
(21) We also investigated N(1)-(10-phenyl-20-hydroxyethyl)-2,7-dihydro-
1H-azepine (derived from the reaction of phenylglycinol with dibromide 18)
as a potential substrate for the oxidation reaction, but all conditions
investigated returned only starting material or gave rise to a complex mixture
of products.
(22) Unlike N-benzyl-substituted dihydroazepine 4, N-1-(10-naphthyl)-
ethylamine-substituted dihydroazepine 21 was freely soluble in BnOH and
therefore the addition of CH2Cl2 to the reaction mixture to aid solubility was
not necessary; this modification to the experimental conditions did not affect
the reaction diastereoselectivity or efficiency.
(23) Following preparation of an authentic sample, 40 could also be
identified as a constituent of the crude reaction mixture; the ratio of 35:40 was
∼80:20.
(26) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737. Addy, J. K.;
Parker, R. E. J. Chem. Soc. 1963, 915.
(27) 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.
(28) Crystallographic data (excluding structure factors) have been depos-
ited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 788732.
(24) Crystallographic data (excluding structure factors) have been depos-
ited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 788733.
(25) Attempts to drive the reaction to full conversion of starting material
resulted in overoxidation to 35 and 40.
8138 J. Org. Chem. Vol. 75, No. 23, 2010

Bagal et al.
JOCArticle
SCHEME 12a
FIGURE 1. Newman projections along the N-C(10) bond of 21
in the preferred solid-state conformation and the corresponding
ammonium ion 41.
SCHEME 13a
aReagents and conditions: (i) Cl3CCO2H, CH2Cl2, rt, 16 h, then
NaOH (2 M, aq); (ii) AgOAc, DMF, 65 °C, 24 h. 1-Nap =1-naphthyl.
aReagents and conditions: (i) HBF4 OEt2, m-CPBA (1.5 equiv),
BnOH, rt, 24 h; (ii) HBF4 (40% w/w in H2O), m-CPBA (4 equiv),
BnOH, rt, 24 h. 1-Nap =1-naphthyl.
3
or no part in determining the facial selectivity of the ensuing
epoxidation reaction. Given the known conformational lability
of 7-membered rings,29a the origin of selectivity in the second
epoxidation reaction of 5 to 8, of 38 to 35, and of 39 to 40 is not
clear, although it may plausibly be a result of hydrogen-bonded
delivery of the oxidant, or epoxidation on the sterically most
accessible face, or a combination of both factors.
adopts an envelope-type conformation, with a near planar
arrangement of the six carbon atoms and the nitrogen atom
out of this plane. The chiral N-protecting group adopts a pseudo-
axial position, with the C(10)-H bond oriented directly over the
7-membered ring. 1H NMR NOE data was supportive of an
analogous solution phase conformation for ammonium ion 41
(prepared from 21 and F3CCO2H in CDCl3). When viewed as
a Newman projection along the N-C(10) bond, the 1-naphthyl
group shields the lower face of one of the olefins, presumably
blocking reaction at this site. The origin of enhanced diastereo-
selectivity in this case is consistent with selective epoxidation
occurring on the face of the olefin away from the 1-naphthyl
group within ammonium ion 41, with a rate acceleration for
oxidation at this site promoted by stabilization of the partial
positive charges that develop within the epoxidation transition
state on the olefinic carbons by interaction with the π-systemof
the 1-naphthyl group, resulting in the production of epoxide 37
as the major product (Figure 1). Regioselective ring-opening of
37 by BnOH gives 38, with further diastereoselective oxidation
of 38 giving 35. It may be assumed that after the first oxidation,
the conformation of the 7-membered ring switches from
envelope-like to chairlike,29 with the N-1-(10-naphthyl)ethyl
group occupying a pseudoequatorial position, being some-
what remote from the reaction site and therefore playing little
With a diastereo- and enantiomerically pure sample of
piperidine epoxide 36 in hand, its elaboration to (þ)-1-deoxy-
altronojirimycin 3 was pursued. Epoxide ring-opening upon
treatment of 36 with Cl3CCO2H proceeded exclusively at C(5)
to give trichloroacetate ester 42 as a single regio- and diastereo-
isomer, that could be isolated as a 98:2 mixture of 42:43 upon
workup using 0.1 M aqueous NaHCO3, followed by recrystal-
lization of the crude reaction mixture. Alternatively, workup
using 2 M aqueous NaOH effected ester hydrolysis to give diol
43 directly in 67% yield, >99:1 dr and 98% ee.30 The relative
configuration within 43 was assigned on the basis of 1H NMR
3J coupling constant analysis. Subsequent treatment of 43 with
AgOAc in DMF at 65 °C resulted in conversion to a 90:10
mixture of piperidine 45 and azepane 46. Chromatography
facilitated separation of this mixture, giving piperidine 45 in
60% yield, >99:1 dr and 98% ee,30 and azepane 46 in 7% yield,
>99:1 dr and 98% ee.30 This product distribution is consistent
with the reaction proceeding via the intermediacy of the
aziridinium ion 44, which may undergo ring-opening at either
the least substituted site (leading to piperidine 45) or the more
substituted site (leading to azepane 46).Therelativeconfiguration
(29) Both cycloheptene and cycloheptene oxide have been shown to favor
a chairtype conformation in solution; see: (a) Leong, M. K.; Mastryukov,
V. S.; Boggs, J. E. J. Mol. Struct. 1998, 445, 149. (b) Abraham, R. J.;
Castellazzi, I.; Sancassan, F.; Smith, T. A. D. J. Chem. Soc., Perkin Trans. 2
1999, 99.
(30) The enantiomeric purities of 43, 45, and 46 were inferred from the
enantiomeric purity of the (R)-(þ)-1-(10-naphthyl)ethylamine used to pre-
pare the original starting material 21 (i.e., 98% ee).
J. Org. Chem. Vol. 75, No. 23, 2010 8139

Bagal et al.
JOCArticle
SCHEME 14a
Elix UV-10 system. Organic solvents were used as supplied
(analytical or HPLC grade) without prior purification. Organic
layers were dried over MgSO4. Thin layer chromatography was
performed on aluminum plates coated with 60 F254 silica. Plates
were visualized using UV light (254 nm), iodine, 1% aqueous
KMnO4, or 10% ethanolic phosphomolybdic acid. Flash
column chromatography was performed either on Kieselgel
60 silica on a glass column or on an automated flash column
chromatography platform.
Melting points are uncorrected. IR spectra were recorded as
either a thin film on NaCl plates (film) or a KBr disk (KBr), as
stated. Selected characteristic peaks are reported in cm-1. NMR
spectra were recorded in the deuterated solvent stated. The field
was locked by external referencing to the relevant deuteron
aReagents and conditions: (i) K2CO3, MeOH, rt, 16 h; (ii) H2,
Pd(OH)2/C, MeOH, rt, 72 h, then HCl (aq). 1-Nap =1-naphthyl.
1
1
resonance. H-1H COSY and H-13C HMQC analyses were
within 45 was unambiguously established by single crystal
X-ray analysis, with the absolute (2R,3R,4S,5R,10R)-config-
uration being assigned from the known (R)-stereocenter of the
1-(10-naphthyl)ethyl group.31 This analysis also affirms the
relative configurations within 42 and 43 (and thereby also
confirms the regioselectivity of the ring-opening reaction).
The absolute (3R,4S,5S,6R,10R)-configuration within azepane
46 was assigned on the basis of an SN2-type ring-opening of
aziridinium 44 at the more substituted site (Scheme 13).
used to establish atom connectivity.
(þ)-(S,S)- and (-)-(R,R)-N(1)-Benzyl-3-hydroxy-4-benzyloxy-
2,3,4,7-tetrahydro-1H-azepine 5. HBF4 Et2O (4.07 mL, 29.7 mmol)
3
was added to a stirred solution of 4 (1.1 g, 5.94 mmol) in BnOH/
CH2Cl2 (v/v 2:1, 33 mL), and the resultant solution was stirred for 5
min at rt. m-CPBA (75%, 2.05 g, 8.91 mmol) was then added, and
the resultant solution was stirred for 24 h before the addition of solid
Na2SO3 (∼4 g) until starch-iodide paper indicated that no oxidant
remained. The mixture was diluted with CH2Cl2 (50 mL), and the
organic layer was washed with 2 M aq NaOH (2 ꢀ 100 mL). The
combined aqueous washings were extracted with CHCl3/iPrOH (v/v
3:1, 2 ꢀ 100 mL), and the combined organic extracts were dried and
concentrated in vacuo. The residue was then passed through a
Biotage SCX-2 scavenger column, eluting first with CH2Cl2/MeOH
(v/v 1:1), then 2 M NH3 in MeOH. The ammonia-containing eluent
was concentrated in vacuo to give a 75:25 mixture of 5:8. Purification
via flash column chromatography (gradient elution, 5f50% EtOAc
in 30-40 °C petroleum ether) gave (()-5 as a colorless oil (580 mg,
32%, >99:1 dr):33 IR νmax (film) 3450 (O-H), 3028, 2918 (C-H);
NMR δH (400 MHz, CDCl3) 2.88 (1H, dd, J = 13.4, 7.6 Hz,
C(7)HA), 3.04-3.29 (4H, m, C(2)H2, C(7)HB, OH), 3.69 (2H, AB
system, NCH2Ph), 3.85 (1H, td, J = 7.0, 3.7 Hz, C(3)H), 4.30-4.35
(1H, m, C(4)H), 4.55 (1H, d, J = 11.6 Hz, OCHAHBPh), 4.73 (1H,
d, J = 11.6 Hz, OCHAHBPh), 5.69-5.84 (2H, m, C(5)H, C(6)H),
7.25-7.42 (10H, m, Ph); NMR δC (100 MHz, CDCl3) 55.0 (C(7)),
59.3 (C(2)), 62.5 (NCH2Ph), 69.6 (C(3)), 71.6 (OCH2Ph), 80.2
(C(4)), 127.2, 127.8, 127.9, 128.4, 128.5, 128.9 (o,m,p-Ph), 130.0,
130.1 (C(5), C(6)), 138.1, 138.6 (i-Ph); MS m/z (ESIþ) 332 ([M þ
Finally, treatment of piperidine 45 with K2CO3 in MeOH
was followed by hydrogenolysis of the resultant triol 47 to
give (þ)-1-deoxyaltronojirimycin (3), which was isolated as
its hydrochloride salt (þ)-3 HCl in 71% yield (two steps)
3
and >99:1 dr (Scheme 14). The spectroscopic data of our
sample of (þ)-3 HCl were in excellent agreement with those
3
previously reported in the literature {[R]25 þ31.1 (c 0.5 in
D
MeOH); lit.9i [R]23 þ31.0 (c 2.0 in MeOH); lit.10f [R]25
D
D
þ33.2 (c 0.5 in MeOH)}. Given the enantiomeric purity of
the (R)-(þ)-1-(10-naphthyl)ethylamine (98% ee) used in the
preparation of 21, the enantiomeric purity of (þ)-3 HCl
3
prepared in this manner can be inferred as 98% ee.
Conclusion
In conclusion, oxidation of enantiomerically pure (R)-N(1)-
10-(100-naphthyl)ethyl-2,7-dihydro-1H-azepine with m-CPBA in
the presence of HBF4 and BnOH gave (3S,4R,5S,6S,10R)-N(1)-
10-(100-naphthyl)ethyl-3-hydroxy-4-benzyloxy-5,6-epoxyaze-
pane as the major product and as a single diastereoisomer
after chromatography. Elaboration of this highly functiona-
lized intermediate via ring contraction to (2S,3R,4S,5S,10R)-
N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine
followed by regioselective epoxide ring-opening, functional
group manipulation, and deprotection gave (þ)-1-deoxyaltro-
nojirimycin. Alternatively, resolution of (RS,RS)-N(1)-benzyl-
3-hydroxy-4-benzyloxy-2,3,4,7-tetrahydro-1H-azepine or
(3RS,4SR,5RS,6RS)-N(1)-benzyl-3-hydroxy-4-benzyloxy-
5,6-epoxyazepane by preparative chiral HPLC and subsequent
elaboration allows access to the enantiomers of 1-deoxynojirimy-
cin and 1-deoxyaltronojirimycin, respectively.
þ
Na]þ, 40%), 310 ([M þ H]þ, 100); HRMS (ESIþ) C20H24NO2
([M þ H]þ) requires 310.1802, found 310.1798. Preparative chiral
HPLC (Chiralpak AD-H [250 ꢀ 21.2 mm (i.d.)], mobile phase:
MeOH/EtOH [v/v 1:1]) gave (-)-(R,R)-5 as a colorless oil (240 mg,
13% from 4, >99:1 dr, >99% ee): [R]25D -81.8 (c 1.0 in CHCl3).
Anal. Calcd for C20H23NO2: C, 77.6; H, 7.5; N, 4.5. Found: C, 77.8;
H, 7.7; N, 4.6. Further elution gave (þ)-(S,S)-5 as a colorless oil
(280 mg, 15% from 4, >99:1 dr, >99% ee): [R]25D þ82.8 (c 1.0 in
CHCl3).
(þ)-(S,S)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-1,2,3,6-tetra-
hydropyridine 6. Et3N (0.35 mL, 2.49 mmol) and MsCl (0.14 mL,
1.87 mmol) in CH2Cl2 (12 mL) were added sequentially to a stirred
solution of (þ)-(S,S)-5 (385 mg, 1.24 mmol) in CH2Cl2 (12 mL) at
0 °C, and the resultant solution was stirred for 1.5 h at 0 °C before
being concentrated in vacuo. Purification via flash column chroma-
tography (gradient elution, 2f20% EtOAc in 30-40 °C petroleum
ether) gave (þ)-(S,S)-6 as a yellow oil (304 mg, 75% >99:1 dr,
Experimental Section
>99% ee):33 [R]25 þ49.6 (c 1.0 in CHCl3); IR νmax (film) 3063,
General Experimental Details. m-CPBA was supplied as a
70-77% slurry in water and titrated according to the procedure
of Swern32 immediately before use. Water was purified by an
D
3031, 2868 (C-H); NMR δH (400 MHz, CDCl3) 3.09-3.13 (2H, m,
C(6)H2), 3.15-3.21 (1H, m, C(2)H), 3.55 (1H, dd, J 11.3,
8.0, CHAHBCl), 3.71 (1H, d, J = 13.1 Hz, NCHAHBPh), 3.88
(1H, dd, J=11.3, 3.5 Hz, CHAHBCl), 4.01 (1H, d, J=13.1 Hz,
(31) Crystallographic data (excluding structure factors) have been depos-
ited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 788734.
(33) The synthesis of racemic 5-8 and 12 has previously been reported by
us; see ref 8.
(32) Swern, D. Org. React. 1953, VII, 392.
8140 J. Org. Chem. Vol. 75, No. 23, 2010

Bagal et al.
JOCArticle
NCHAHBPh), 4.11-4.15 (2H, m, C(3)H), 4.56-4.63 (2H, AB
system, OCH2Ph), 5.86-5.95 (2H, m, C(4)H, C(5)H), 7.26-7.46
(10H, m, Ph); NMR δC (100 MHz, CDCl3) 40.4 (CH2Cl), 48.4
(C(2)), 57.7 (NCH2Ph), 60.9 (C(6)), 70.9 (OCH2Ph), 71.7 (C(3)),
123.6 (C(5)), 127.2, 127.6, 127.9, 128.4, 128.9 (o,m,p-Ph), 129.1
(C(4)), 138.3, 138.5 (i-Ph); MS m/z (ESIþ) 330 ([M þ H]þ, 37Cl,
79), 328 ([M þ H]þ, 35Cl, 100); HRMS (ESIþ) C20H2335ClNOþ
([M þ H]þ) requires 328.1463, found 328.1462.
(þ)-(3S,4R,5S,6S)- and (-)-(3R,4S,5R,6R)-N(1)-Benzyl-3-
hydroxy-4-benzyloxy-5,6-epoxyazepane 8. Method A. HBF4
3
Et2O (0.56 mL, 4.04 mmol) was added to a stirred solution of 4
(500 mg, 2.70 mmol) in BnOH/CH2Cl2 (v/v 2:1, 15 mL), and the
resultant solution was stirred for 5 min at rt. m-CPBA (75%, 2.48 g,
10.8 mmol) was then added and the resultant solution was stirred
for 24 h before the addition of solid Na2SO3 (∼4 g) until
starch-iodide paper indicated that no oxidant remained. The
mixture was diluted with CH2Cl2 (50 mL), and the organic layer
was washed with 2 M aq NaOH (2 ꢀ 100 mL). The combined
aqueous washings were extracted with CHCl3/iPrOH (v/v 3:1,
2 ꢀ 100 mL), and the combined organic extracts were dried and
concentrated in vacuo. The residue was then passed through a
Biotage SCX-2 scavenger column, eluting first with CH2Cl2/
MeOH (v/v 1:1) and then 2 M NH3 in MeOH. The ammonia-
containing eluent was concentrated in vacuo. Purification via
flash column chromatography (eluent 30-40 °C petroleum
ether/EtOAc, 2:1) gave (()-8 as a beige solid (300 mg, 34%,
>99:1 dr):33 mp 51-53 °C; IR νmax (KBr) 3443 (O-H), 3062,
3029, 3002, 2914 (C-H); NMR δH (400 MHz, CDCl3) 2.42 (1H,
dd, J = 13.6, 8.6 Hz, C(2)HA), 2.65 (1H, br s, OH), 2.97 (1H, dd,
J = 14.9, 2.0 Hz, C(7)HA), 3.04 (1H, dd, J = 13.6, 2.8 Hz,
C(2)HB), 3.12 (1H, td, J = 4.7, 2.0 Hz, C(6)H), 3.24 (1H, dd, J =
14.9, 4.7 Hz, C(7)HB), 3.36 (1H, dd, J = 4.7, 2.7 Hz, C(5)H), 3.82
(2H, A2 system, NCH2Ph), 3.83-3.84 (1H, m, C(3)H), 3.96 (1H,
td, J = 8.5, 2.7 Hz, C(4)H), 4.7 (1H, d, J = 11.6 Hz, OCHA-
HBPh), 4.87 (1H, d, J = 11.6 Hz, OCHAHBPh), 7.25-7.45 (10H,
m, Ph); NMR δC (100 MHz, CDCl3) 52.0 (C(2)), 54.2, 54.3 (C(5),
C(6)), 57.2 (C(7)), 61.4 (NCH2Ph), 67.8 (C(4)), 71.6 (OCH2Ph),
81.2 (C(3)), 127.2, 127.9, 128.0, 128.4, 128.6, 128.8 (o,m,p-Ph),
137.8, 138.7 (i-Ph); MS m/z (ESIþ) 348 ([M þ þNa]þ, 15), 326
([M þ H]þ, 100); HRMS (ESIþ) C20H24NO3 ([M þ H]þ)
requires 326.1751, found 326.1747. Preparative chiral HPLC
(Chiralpak AD-H [250 ꢀ 21.2 mm (i.d.)], mobile phase: MeOH/
EtOH [v/v 1:1]) of an aliquot (150 mg) gave (-)-(3R,4S,5R,6R)-8
(-)-(R,R)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-1,2,3,6-
tetrahydropyridine 6. Et3N (0.35 mL, 2.49 mmol) and MsCl
(0.14 mL, 1.87 mmol) in CH2Cl2 (12 mL) were added sequen-
tially to a stirred solution of (-)-(R,R)-5 (385 mg, 1.24 mmol)
in CH2Cl2 (12 mL) at 0 °C, and the resultant solution was
stirred for 1.5 h at 0 °C before being concentrated in vacuo.
Purification via flash column chromatography (gradient elu-
tion, 2f20% EtOAc in 30-40 °C petroleum ether) gave
(-)-(R,R)-6 as a yellow oil (304 mg, 75% >99:1 dr, >99%
ee):33 [R]25D -49.5 (c 1.0 in CHCl3).
(þ)-(2S,3R,4R,5R)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-
4,5-epoxypiperidine 7. (F3CCO)2O (0.64 mL, 4.58 mmol) was
added to a stirred solution of H2O2 (35% solution in H2O, 0.18 mL,
1.83 mmol) and CH2Cl2 (2.5 mL) at 0 °C, and the resultant solution
was stirred for 1.5 h at rt. A solution of (þ)-(S,S)-6 (250 mg,
0.76 mmol) and CF3CO2H (0.14 mL, 1.91 mmol) in CH2Cl2
(5 mL) was then added, and the resultant mixture was allowed to
warm to rt over 6 h. Solid Na2SO3 (∼500 mg) was then added until
starch-iodide paper indicated that no oxidant remained. CH2Cl2
(20 mL) was then added, and the organic layers were washed with 2
M aq NaOH (2 ꢀ 100 mL). The combined aqueous layers were
extractedwithCHCl3/iPrOH (v/v 3:1, 2 ꢀ 50 mL), and the combined
organic extracts were dried and concentrated in vacuo. Purification
via flash column chromatography (gradient elution, 5f25% EtOAc
in 30-40 °C petroleum ether) gave (þ)-(2S,3R,4R,5R)-7 as a color-
less oil (159 mg, 62%, 98:2 dr, >99% ee):33 [R]25D þ16.0 (c 1.0 in
CHCl3); IR νmax (film) 3086, 3062, 3028, 3005, 2887, 2805 (C-H);
NMR δH (400 MHz, CDCl3) 2.86-2.94 (2H, m, C(2)H, C(6)HA),
3.11 (1H, app d, J = 14.2 Hz, C(6)HB), 3.27-3.31 (1H, m, C(3)H),
3.35 (1H, app d, J = 4.0 Hz, C(4)H), 3.61 (1H, d, J = 13.4 Hz,
NCHAHBPh), 3.77 (1H, dd, J = 11.6, 4.8 Hz, CHAHBCl), 3.83 (1H,
dd, J = 11.6, 6.6 Hz, CHAHBCl), 3.93 (1H, d, J = 13.4 Hz,
NCHAHBPh), 3.98 (1H, app d, J = 5.1 Hz, C(5)H), 4.60-4.69
(2H, AB system, OCH2Ph), 7.25-7.45 (10H, m, Ph); NMR δC (100
MHz, CDCl3) 41.1 (CH2Cl), 47.3 (C(6)), 51.4 (C(5)), 52.4 (C(4)),
56.8 (NCH2Ph), 60.8 (C(2)), 71.3 (C(3)), 72.1 (OCH2Ph), 127.3,
128.0, 128.1, 128.4, 128.5, 128.8 (o,m,p-Ph), 137.5, 138.1 (i-Ph); MS
m/z(ESIþ) 368([Mþ Na]þ,37Cl,18),366([Mþ Na]þ,35Cl, 48), 346
([M þ H]þ, 37Cl, 34), 344 ([M þ H]þ, 35Cl, 100); HRMS (ESIþ)
as a beige solid (51 mg, 12% from 4, >99:1 dr, >99% ee): [R]25
D
-56.4 (c 1.0 in CHCl3). Further elution gave (þ)-(3S,4R,5S,6S)-
8 as a beige solid (47 mg, 11% from 4, >99:1 dr, 98% ee): [R]25
D
þ52.4 (c 1.0 in CHCl3).
Method B. HBF4 (40% w/w in H2O, 0.13 mL, 8.56 mmol) was
added to a stirred solution of (þ)-(S,S)-5 (50 mg, 0.16 mmol) in
BnOH/CH2Cl2 (v/v 2:1, 1.5 mL), and the resultant solution was
stirred for 5 min at rt. m-CPBA (75%, 149 mg, 0.65 mmol) was
then added, and the resultant solution was stirred for 24 h before
the addition of solid Na2SO3 (∼500 mg) until starch-iodide
paper indicated that no oxidant remained. The mixture was
diluted with CH2Cl2 (50 mL), and the organic layer was washed
with 2 M aq NaOH (2 ꢀ 20 mL). The combined aqueous
washings were extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ 20
mL), and the combined organic extracts were dried and con-
centrated in vacuo. The residue was then passed through a
Biotage SCX-2 scavenger column, eluting first with CH2Cl2/
MeOH (v/v 1:1) and then 2 M NH3 in MeOH. The ammonia-
containing eluent was concentrated in vacuo. Purification via
flash column chromatography (eluent 30-40 °C petroleum
ether/EtOAc, 2:1) gave (þ)-(3S,4R,5S,6S)-8 as a beige solid
þ
C20H2335ClNO2 ([M þ H]þ) requires 344.1412, found 344.1406.
Anal. Calcd for C20H22ClNO2: C, 69.9; H, 6.45; N, 4.1. Found C,
70.0; H, 6.6; N, 4.0.
(-)-(2R,3S,4S,5S)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-
4,5-epoxypiperidine 7. (F3CCO)2O (0.76 mL, 5.49 mmol) was
added to a stirred solution of H2O2 (35% solution in H2O, 0.21
mL, 2.20 mmol) and CH2Cl2 (3 mL) at 0 °C, and the resultant
solution was stirred for 1.5 h at rt. A solution of (-)-(R,R)-6
(300 mg, 0.92 mmol) and CF3CO2H (0.17 mL, 2.29 mmol) in
CH2Cl2 (5 mL) was then added, and the resultant mixture was
allowed to warm to rt over6 h. Solid Na2SO3 (∼500 mg) was then
added until starch--iodide paper indicated that no oxidant
remained. CH2Cl2 (20 mL) was then added, and the organic
layers were washed with 2 M aq NaOH (2 ꢀ 100 mL). The
combined aqueous layers were extracted with CHCl3/iPrOH (v/v
3:1, 2 ꢀ 50 mL), and the combined organic extracts were dried
and concentrated in vacuo. Purification via flash column chro-
matography (gradient elution, 5f25% EtOAc in 30-40 °C
petroleum ether) gave (-)-(2R,3S,4S,5S)-7 as a colorless oil
(36 mg, 62%, >99:1 dr, >99% ee): [R]25 þ54.1 (c 1.0 in
D
CHCl3).
Method C. HBF4 (40% w/w in H2O, 0.13 mL, 8.56 mmol) was
added to a stirred solution of (-)-(R,R)-5 (50 mg, 0.16 mmol) in
BnOH/CH2Cl2 (v/v 2:1, 1.5 mL), and the resultant solution was
stirred for 5 min at rt. m-CPBA (75%, 149 mg, 0.65 mmol) was
then added, and the resultant solution was stirred for 24 h before
the addition of solid Na2SO3 (∼500 mg) until starch-iodide
paper indicated that no oxidant remained. The mixture was
diluted with CH2Cl2 (50 mL), and the organic layer was washed
with 2 M aq NaOH (2 ꢀ 20 mL). The combined aqueous
washings were extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ 20 mL),
(174 mg, 58%, 98:2 dr, >99% ee):33 [R]25 -15.5 (c 1.0 in
D
CHCl3).
J. Org. Chem. Vol. 75, No. 23, 2010 8141

Bagal et al.
JOCArticle
and the combined organic extracts were dried and concentrated
in vacuo. The residue was then passed through a Biotage SCX-2
scavenger column, eluting first with CH2Cl2/MeOH (v/v 1:1)
and then 2 M NH3 in MeOH. The ammonia-containing eluent
was concentrated in vacuo. Purification via flash column chro-
matography (eluent 30-40 °C petroleum ether/EtOAc, 2:1) gave
(-)-(3R,4S,5R,6R)-8 as a beige solid (35 mg, 61%, >99:1 dr,
>99% ee): [R]25D -54.3 (c 1.0 in CHCl3).
ether) gave (þ)-(2R,3S,4S,5R)-12 as a colorless oil (65 mg, 50%,
99:1 dr):12 [R]25D þ26.9 (c 1.0 in CHCl3).
(þ)-(2R,3R,4R,5S)-2-Hydroxymethyl-3,4,5-trihydroxypiperidine
Hydrochloride [(þ)-1-Deoxynojirimycin hydrochloride] 2 HCl. Step
3
1. AgOAc (21 mg, 0.12 mmol) was added to a stirred solution of
(-)-(2S,3R,4R,5S)-12 (30 mg, 0.08 mmol) in DMF (1 mL), and the
resultant suspension was stirred for 24 h at 65 °C. The reaction mixture
was then allowed to cool to rt before the addition of H2O
(4 mL). The mixture was extracted with Et2O (3 ꢀ 2 mL), and the
combined organic extracts were washed with H2O (3 ꢀ 6 mL) before
being dried and concentrated in vacuo to give (2R,3R,4R,5S)-13 as a
colorless oil (20 mg) that was used without purification.
(RS,RS)-1-Benzyl-2,3,4,7-tetrahydro-1H-azepine-3,4-diol 11.
Cl3CCO2H (1.54 g, 9.45 mmol) was added to a stirred solution
of 4 (350 mg, 1.89 mmol) in CH2Cl2 (3.5 mL), and the resultant
solution was stirred for 5 min at rt. m-CPBA (75%, 870 mg, 3.78
mmol) was then added, and the resultant solution was stirred for
21 h before the addition of solid Na2SO3 (∼500 mg) until starch-
iodide paper indicated that no oxidant remained. The mixture
was diluted with CH2Cl2 (50 mL), and the organic layer was
washed with 2 M aq NaOH (2 ꢀ 50 mL). The combined aqueous
washings were extracted with CH2Cl2 (2 ꢀ 50 mL), and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 40-60 °C
petroleum ether/EtOAc, 1:1) gave 11 as a colorless oil (124 mg,
30%, >99:1 dr): IR νmax (film) 3385 (O-H), 3079, 2985, 2971
(C-H); NMR δH (400 MHz, CDCl3) 2.68 (1H, dd, J = 13.4, 7.3
Hz, C(7)HA), 3.09-3.19 (3H, m, C(7)HB, C(2)H2), 3.64 (2H, A2
system, NCH2Ph), 3.70-4.00 (3H, m, C(3)H, 2 ꢀ OH), 4.36 (1H,
ddd, J = 7.3, 3.7, 1.4 Hz, C(4)H), 5.60-5.69 (1H, m, C(6)H),
5.73-5.80 (1H, m, C(5)H), 7.23-7.36 (5H, m, Ph); δC (100 MHz,
CDCl3) 55.4 (C(7)), 60.1 (C(2)), 62.1 (NCH2Ph), 71.4 (C(3)), 73.1
(C(4)), 127.4, 128.5, 128.8, 129.0 (o,m,p-Ph, C(6)), 132.1 (C(5)),
138.2 (i-Ph); MS m/z (ESIþ) 220 ([M þ H]þ, 100); HRMS (ESIþ)
C13H18NO2þ [M þ H] þ requires 220.1332, found 220.1332.
(-)-(2S,3R,4R,5S)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-
4,5-dihydroxypiperidine 12. Cl3CCO2H (1.05 g, 6.40 mmol)
was added to a stirred solution of (þ)-(2S,3R,4R,5R)-7 (110
mg, 0.32 mmol) in CH2Cl2 (1.1 mL), and the resultant solution was
stirred for 16 h at rt. The reaction mixture was diluted with CH2Cl2
(10 mL) and then washed with 2 M aq NaOH (2 ꢀ 50 mL). The
combined aqueous layers were extracted with CHCl3/iPrOH (v/v
3:1, 2 ꢀ 20 mL). The combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (gradient elution, 10f100% EtOAc in 30-40 °C petroleum
ether) gave (-)-(2S,3R,4R,5S)-12 as a colorless oil (59 mg, 51%,
99:1 dr, >99% ee):33 [R]25D -26.7 (c 1.0 in CHCl3); IR νmax (film)
3387 (O-H) 3030, 2915 (C-H); NMR δH (400 MHz, CDCl3) 1.98
(1H, app t, J = 10.5 Hz, C(6)HA), 2.45 (1H, app d, J = 8.8 Hz,
C(2)H) 2.78 (1H, br s, OH), 2.97-3.05 (2H, m, C(6)HB, OH), 3.16
(1H, d, J = 12.9 Hz, NCHAHBPh), 3.42-3.66 (3H, m, C(3)H,
C(4)H, C(5)H), 4.00 (1H, dd, J = 12.6, 3.3 Hz, CHAHBCl), 4.09
(1H, dd, J = 12.6, 1.8 Hz, CHAHBCl), 4.14 (1H, d, J = 12.9 Hz,
NCHAHBPh), 4.82 (1H, d, J =11.4 Hz, OCHAHBPh), 4.90 (1H, d,
J= 11.4 Hz, OCHAHBPh), 7.25-7.43 (10H, m, Ph);NMRδC (100
MHz, CDCl3) 41.8 (CH2Cl), 54.7 (C(6)), 56.0 (NCH2Ph), 64.6
(C(2)), 69.7 (C(5)), 75.3 (OCH2Ph), 78.7 (C(4)), 79.3 (C(3)),
127.4, 128.0, 128.1, 128.4, 128.7, 129.2 (o,m,p-Ph), 137.7, 138.2
(i-Ph); MS m/z (ESIþ) 386 ([M þ Na]þ, 37Cl, 34), 384 ([M þ Na]þ,
35Cl, 100), 364 ([MþH]þ, 37Cl, 24), 362 ([M þ H]þ, 35Cl, 64);
Step 2. K2CO3 (143 mg, 1.04 mmol) was added to a stirred
solution of (2R,3R,4R,5S)-13 (20 mg, 0.05 mmol) in MeOH
(1 mL), and the resultant suspension was stirred for 16 h at rt
before being concentrated in vacuo. The residue was dissolved in
H2O (2 mL) and extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ
2 mL). The combined organic extracts were dried and concen-
trated in vacuo to give (2R,3R,4R,5S)-14 as a colorless oil
(18 mg) that was used without purification.
Step 3. Pd(OH)2/C (18 mg) was added to a stirred solution of
(2R,3R,4R,5S)-14 (18 mg, 0.05 mmol) in degassed MeOH
(0.5 mL), and the resultant suspension was stirred for 72 h under
an atmosphere of H2 (1 atm). Concentrated aq HCl (10 μL) was
then added, and the resultant suspension was stirred for a further
5 min before being filtered through Celite (eluent MeOH). The
filtrate was concentrated in vacuo, and the residue was purified via
flash column chromatography (eluent CHCl3/MeOH, 4:1) to give
(þ)-(2R,3R,4R,5S)-2 HCl as a white semisolid (5 mg, 30% from
3
(-)-(2S,3R,4R,5S)-12, 99:1 dr, >99% ee):2 [R]25D þ31.0 (c 0.45 in
H2O) [lit.3a for natural sample [R]22 þ38.0 (c 1.0 in H2O); lit.9m
D
[R]23D þ36.9 (c 1.1 in H2O)]; NMR δH (500 MHz, D2O) 3.17 (1H,
dd, J = 13.6, 2.8 Hz, CHAHBOH), 3.27-3.35 (2H, m, C(4)H,
CHAHBOH),3.77(1H,dd, J= 12.6, 6.9 Hz, C(6)HA),3.91(1H,dd,
J= 12.6, 3.2 Hz, C(6)HB),3.94-3.99 (2H, m, C(3)H,C(5)H),4.08-
4.11 (1H, br m, C(2)H); NMR δC (125 MHz, D2O) 43.9 (CH2OH),
55.8 (C(4)), 58.2 (C(6)), 63.6 (C(5)), 66.2 (C(2)), 68.5 (C(3)).
(-)-(2S,3S,4S,5R)-2-Hydroxymethyl-3,4,5-trihydroxypiperi-
dine Hydrochloride [(-)-1-Deoxynojirimycin Hydrochloride]
(2 HCl). Step 1. AgOAc (21 mg, 0.12 mmol) was added to a
3
stirred solution of (þ)-(2R,3S,4S,5R)-12 (30 mg, 0.08 mmol) in
DMF (1 mL), and the resultant suspension was stirred for 24 h at
65 °C. The reaction mixture was then allowed to cool to rt before
the addition of H2O (4 mL). The mixture was extracted with
Et2O (3 ꢀ 2 mL), and the combined organic extracts were
washed with H2O (3 ꢀ 6 mL) before being dried and concen-
trated in vacuo to give (2S,3S,4S,5R)-13 as a colorless oil
(20 mg) that was used without purification.
Step 2. K2CO3 (143 mg, 1.04 mmol) was added to a stirred
solution of (2S,3S,4S,5R)-13 (20 mg, 0.05 mmol) in MeOH
(1 mL), and the resultant suspension was stirred for 16 h at rt
before being concentrated in vacuo. The residue was dissolved
in H2O (2 mL) and extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ
2 mL). The combined organic extracts were dried and concen-
trated in vacuo to give (2S,3S,4S,5R)-14 as a colorless oil
(18 mg) that was used without purification.
Step 3. Pd(OH)2/C (18 mg) was added to a stirred solution of
(2S,3S,4S,5R)-14 (18 mg, 0.05 mmol) in degassed MeOH
(0.5 mL), and the resultant suspension was stirred for 72 h under
an atmosphere of H2 (1 atm). Concentrated aq HCl (10 μL) was
then added, and the resultant suspension was stirred for a
further 5 min before being filtered through Celite (eluent
MeOH). The filtrate was concentrated in vacuo, and the residue
was purified via flash column chromatography (eluent CHCl3/
þ
HRMS (ESIþ) C20H2535ClNO3 ([M þ H]þ) requires 362.1517,
found 362.1516.
(þ)-(2R,3S,4S,5R)-N(1)-Benzyl-2-chloromethyl-3-benzyloxy-
4,5-dihydroxypiperidine 12. Cl3CCO2H (1.19 g, 7.27 mmol)
was added to a stirred solution of (-)-(2R,3S,4S,5S)-7 (125
mg, 0.36 mmol) in CH2Cl2 (1.3 mL), and the resultant solution was
stirred for 16 h at rt. The reaction mixture was diluted with CH2Cl2
(10 mL) and then washed with 2 M aq NaOH (2 ꢀ 50 mL). The
combined aqueous layers were extracted with CHCl3/iPrOH (3:1,
2 ꢀ 20 mL). The combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (gradient elution, 10f100% EtOAc in 30-40 °C petroleum
MeOH, 4:1) to give (-)-(2S,3S,4S,5R)-2 HCl as a white semi-
3
solid (6 mg, 36% from (þ)-(2R,3S,4S,5R)-12, 99:1 dr, >99%
ee):2 [R]25 -34.0 (c 0.45 in H2O) [lit.9i [R]25 -46.0 (c 1.3 in
D
D
H2O); lit.9m [R]24D -38.7 (c 1.0 in H2O)].
8142 J. Org. Chem. Vol. 75, No. 23, 2010

Bagal et al.
JOCArticle
Dimethyl (Z,Z)-Hexa-2,4-dienedioate 16. MeI (9.59 mL,
155 mmol) and K2CO3 (38.9g, 281 mmol) wereadded sequentially
to a stirred solution of 15 (10.0 g, 70.4 mmol) in DMF (200 mL),
and the resultant mixture was stirred for 24 h at rt. H2O (800 mL)
was then added, and the aqueous layer was extracted with Et2O
(3 ꢀ 200 mL). The combined organic extracts were then washed
with H2O (3 ꢀ 500 mL) before being dried and concentrated in
vacuo to give 16 as a white solid (11.4 g, 91%):8,34 mp 74-75 °C
(lit.34 mp 72-73 °C); NMR δH (400 MHz, CDCl3) 3.76 (6H, s,
CO2CH3), 5.95-6.04 (2H, m, C(2)H, C(5)H), 7.86-7.95 (2H, m,
C(3)H, C(4)H).
(Z,Z)-1,6-Dibromohexa-2,4-diene 18. Step 1. DIBAL-H
(1.0 M in cyclohexane, 195 mL, 195 mmol) was added to a stirred
solution of 16 (8.29 g, 48.7 mmol) in CH2Cl2 (290 mL) at 0 °C, and
the resultant solution was stirred for 16 h at rt. The reaction
mixture was cooled to 0 °C, and MeOH was added dropwise until
effervescence ceased. The resultant mixture was diluted with
MeOH (500 mL), which produced a paste-like suspension. The
suspension was filtered through Celite (eluent MeOH). The
insoluble aluminum-containing solids were collected from the
column and ground using a pestle and mortar, MeOH (100 mL)
was added, and the mixture was filtered though Celite (eluent
MeOH). The combined filtrates were dried and concentrated in
vacuo to give 17 as a yellow oil (5.55 g) that was used without
purification.
3.44-3.52 (1H, m, C(5)HA), 3.61-3.69 (1H, m, C(5)HB), 4.04
(1H, q, J = 6.6 Hz, C(10)H), 4.25-4.32 (1H, m, C(2)H), 5.08
(1H, app d J = 10.1 Hz, CHdCHAHB), 5.18 (1H, app d, J =
17.3 Hz, (CHdCHAHB), 5.66 (1H, dq, J = 6.4, 2.0 Hz, C(4)H),
5.77 (1H, dq, J = 6.4, 2.0 Hz, C(3)H), 5.93 (1H, ddd, J = 17.3,
10.1, 7.8 Hz, CHdCH2), 7.42-7.52 (2H, m, Ar), 7.56 (1H, dd,
J = 8.3, 2.0 Hz, Ar), 7.76 (1H, s, Ar), 7.82-7,87 (3H, m, Ar);
NMR δC (100 MHz, CDCl3) 23.6 (C(10)Me), 58.2 (C(5)), 62.4
(C(10)), 70.9 (C(2)), 114.6 (CHdCH2), 125.4, 125.8, 126.1, 127.2,
127.6, 127.8, 128.0 (C(3), Ar), 131.2 (C(4)), 132.7, 133.4 (Ar),
141.4 (CHdCH2), 142.6 (Ar); MS m/z (ESIþ) 250 ([M þ H]þ,
100); HRMS (ESIþ) C18H20Nþ ([M þ H]þ) requires 250.1590,
found 250.1587. Further elution gave 20 as a white solid (450
mg, 62%): mp 59-61 °C; [R]25D þ48.1 (c 1.0 in CHCl3); IR νmax
(film) 3053, 3010, 2971, 2933 (C-H), 1601 (CdC); NMR δH (400
MHz, CDCl3) 1.54 (3H, d, J = 6.6 Hz, C(10)Me), 3.55 (2H, dd,
J = 16.7, 3.5 Hz, C(2)HA, C(7)HA), 3.76 (2H, dd, J = 16.7, 3.5
Hz, C(2)HB, C(7)HB), 4.14 (1H, q, J = 6.6 Hz, C(10)H), 5.75 (2H,
app dt, J = 12.6, 3.5 Hz, C(3)H, C(6)H), 6.02-6.12 (2H, m,
C(4)H, C(5)H), 7.48-7.56 (2H, m, Ar), 7.67-7.73 (1H, m, Ar),
7.81-7.95 (4H, m, Ar); NMR δC (100 MHz, CDCl3) 21.3
(C(10)Me), 53.6 (C(2), C(7)), 58.3 (C(10)), 125.5, 125.7, 125.8,
126.2, 126.6, 127.6, 127.9, 128.0 (C(4), C(5), Ar), 132.9 (C(3),
C(6)), 132.8, 133.4, 147.8 (Ar); MS m/z (ESIþ) 250 ([M þ H]þ,
100); HRMS (ESIþ) C18H20Nþ ([M þ H]þ) requires 250.1590,
found 250.1588.
Step 2. A solution of PBr3 (3.02 mL, 32.1 mmol) in Et2O
(260 mL) was added to a stirred solution of 17 (5.55 g) in Et2O
(170 mL) at 0 °C. After 7 h, the reaction mixture was concen-
trated in vacuo. The residue was recrystallized from hexane to
give 18 as a light red/brown solid (9.71 g, 83%):8,34 mp 84-86 °C
(lit.34 mp 91-93 °C); NMR δH (400 MHz, CDCl3) 4.12 (4H, d,
J 8.2, C(1)H2, C(6)H2), 5.87-5.99 (2H, m, C(2)H, C(5)H),
6.41-6.50 (2H, m, C(3)H, C(4)H).
X-ray Crystal Structure Determination for 20. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealized
positions. The structure was refined using CRYSTALS.35
X-ray crystal structure data for 20 [C18H19N]: M = 249.36,
(R)-N(1)-r-Methylbenzyl-2,7-dihydro-1H-azepine
19.
(R)-R-Methylbenzylamine (3.26 g, 26.9 mmol, 99% ee)18 and
K2CO3 (7.44 g, 53.8 mmol) were added sequentially to a stirred
solution of 18 (3.23 g, 13.5 mmol) in THF (160 mL) at rt. After
24 h, the reaction mixture was concentrated in vacuo. The residue
was dissolved in CH2Cl2 (50 mL) and filtered through Celite
(eluent CH2Cl2), and the filtrate was concentrated in vacuo.
Purification via flash column chromatography (gradient elution,
0f10% EtOAc in 30-40 °C petroleum ether) gave 19 as a pale
yellow oil (1.92 g, 71%, 99% ee): [R]25D þ45.0 (c 1.0 in CHCl3); IR
orthorhombic, space group P212121, a = 5.60290(10) A, b =
˚
3
˚
˚
˚
8.2626(2) A, c = 30.1557(8) A, V = 1396.04(6) A , Z = 4, μ =
0.068 mm-1, colorless plate, crystal dimensions = 0.11 ꢀ 0.17 ꢀ
0.19 mm3. A total of 1816 unique reflections were measured for 5 < θ
< 27, and 1815 reflections were used in the refinement. The final
parameters were wR2 = 0.089 and R1 = 0.047 [I > -3.0σ(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 788731. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
νmax (film) 3059, 3013, 2972, 2934 (C-H); NMR δH (400 MHz,
CDCl3) 1.37 (3H, d, J = 6.6 Hz, C(R)Me), 3.38-3.46 (2H, m,
C(2)HA, C(7)HA), 3.58-3.67 (2H, m, C(2)HB, C(7)HB), 3.87 (1H,
q, J = 6.6 Hz, C(R)H), 5.61 (2H, ddd, J = 12.6, 3.8, 3.6 Hz,
C(3)H, C(6)H), 5.91-5.98 (2H, m, C(4)H, C(5)H), 7.22-7.38
(5H, m, Ph); NMR δC (100 MHz, CDCl3) 21.3 (C(R)Me), 53.5
(C(2), C(7)), 58.2 (C(R)), 126.5 (C(4), C(5)), 126.9, 127.6, 128.2 (o,
m,p-Ph), 132.6 (C(3), C(6)), 145.1 (i-Ph); MS m/z (ESIþ) 200 ([M
þ H]þ,100); HRMS (ESIþ) C14H18Nþ ([M þ H]þ) requires
200.1434, found 200.1433.
(R)-N(1)-10-(100-Naphthyl)ethyl-2,7-dihydro-1H-azepine 21.
(R)-1-(10-Naphthyl)ethylamine (8.03 mL, 50.0 mmol, 98% ee)18
and K2CO3 (13.8 g, 100 mmol) were added sequentially to a stirred
solution of 18 (6.00 g, 25.0 mmol) in THF (300 mL) at rt. After 24 h,
the reaction mixture was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (150 mL) and filtered through Celite (eluent
CH2Cl2), and the filtrate was concentrated in vacuo. Purification via
flash column chromatography (gradient elution, 0f5% EtOAc in
30-40 °C petroleum ether) gave 25 as a green oil (312 mg, 5%, 98%
ee): [R]25D þ96.6 (c 1.0 in CHCl3); IR νmax (film) 3010, 2971 (C-H);
NMR δH (400 MHz, CDCl3) 1.55 (3H, d, J = 6.8 Hz, C(10)Me),
3.39-3.47 (1H, m, C(5)HA), 3.62-3.75 (1H, m, C(5)HB) 4.35-4.42
(1H,m,C(2)H), 4.65 (1H, q, J=6.8Hz,C(10)H),4.99-5.03 (1H, m,
CHdCHAHB), 5.08-5.15 (1H, m, CHdCHAHB), 5.59-5.63 (1H,
m, C(4)H), 5.74-5.79 (1H, m, C(3)H), 5.89-6.00 (1H, m,
CHdCH2), 7.45-7.55 (3H, m, Ar), 7.67-7.79 (2H, m, Ar),
7.85-7.91 (1H, m, Ar), 8.45 (1H, d, J 7.4, Ar); NMR δC (100
MHz, CDCl3) 23.0 (C(10)Me), 59.3 (C(5)), 59.8 (C(10)), 71.3 (C(2)),
(R)-N(1)-10-(200-Naphthyl)ethyl-2,7-dihydro-1H-azepine 20.
(R)-1-(20-Naphthyl)ethylamine (1.00 g, 5.83 mmol)18 and
K2CO3 (1.61 g, 11.7 mmol) were added sequentially to a stirred
solution of 18 (700 mg, 2.92 mmol) in THF (35 mL) at rt. After
24 h, the reaction mixture was concentrated in vacuo. The
residue was dissolved in CH2Cl2 (25 mL) and filtered through
Celite (eluent CH2Cl2), and the filtrate was concentrated in
vacuo. Purification via flash column chromatography (gradient
elution, 0f5% EtOAc in 30-40 °C petroleum ether) gave 24 as
a colorless oil (70 mg, 10%): [R]25 þ152 (c 1.0 in CHCl3); IR
D
νmax (film) 3056, 2974, 2931, 2873, 2789 (C-H) 1724 (CdC);
NMR δH (400 MHz, CDCl3) 1.51 (3H, d, J 6.6, C(10)Me),
(35) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.;
Watkin, D. J. CRYSTALS; Chemical Crystallography Laboratory, University
of Oxford: Oxford, U.K., 2010; Issue 14.
(34) Walsh, J. G.; Furlong, P. J.; Byrne, L. A.; Gilheany, D. G. Tetra-
hedron 1999, 55, 11519.
J. Org. Chem. Vol. 75, No. 23, 2010 8143

Bagal et al.
JOCArticle
114.1 (CHdCH2), 123.8, 124.8, 125.2, 125.5, 125.6, 127.0, 127.1,
128.8 (C(3),CHdCH2,Ar), 131.2, 134.0, 141.3, 141.9 (C(4),Ar);MS
m/z (ESIþ) 250 ([M þ H]þ, 100); HRMS (ESIþ) C18H20Nþ ([M þ
H]þ) requires 250.1590, found 250.1594. Further elution gave 21 as a
white solid (4.67 g, 75%, 98% ee): mp 55-57 °C; [R]25D þ76.4 (c 1.0
in CHCl3); IR νmax (film) 3008, 2974, 2934, 2874, 2791 (C-H);
NMR δH (400 MHz, CDCl3) 1.72 (3H, d, J = 6.8 Hz, C(10)Me),
3.54 (2H, dd, J = 16.7, 3.5 Hz, C(2)HA, C(7)HA), 3.74 (2H, dd, J =
16.7, 3.5 Hz, C(2)HB, C(7)HB), 4.72 (1H, m, C(10)H), 5.70 (2H, dt,
J = 8.8, 3.5 Hz, C(3)H, C(6)H), 5.97-6.06 (2H, m, C(4)H, C(5)H),
7.42-7.55 (3H, m, Ar), 7.66-7.73 (1H, m, Ar), 7.74-7.81 (1H, m,
Ar), 7.84-7.94 (1H, m, Ar), 8.51 (1H, d, J = 4.3 Hz, Ar); NMR δC
(100 MHz, CDCl3) 21.0 (C(10)Me), 53.6 (C(2), C(7)), 55.2 (C(10)),
124.2, 125.2, 125.4, 125.6, 126.5, 127.2, 128.7 (Ar, C(4), C(5)), 131.7
(C(3), C(6)), 133.2, 134.0, 141.4 (Ar); MS m/z (ESIþ) 250 ([M þ
H]þ, 100); HRMS (ESIþ) C18H20Nþ ([M þ H]þ) requires 250.1590,
found 250.1593. Anla. Calcd for C, 86.7; H, 7.7; N, 5.6. Found: C,
86.8; H, 7.6; N, 5.5.
was washed with 2 M aq NaOH (2 ꢀ 50 mL). The combined
aqueous washings were extracted with CH2Cl2 (2 ꢀ 50 mL), and
the combined organic extracts were dried and concentrated in
vacuo. The residue was then passed through a Biotage SCX-2
scavenger column, eluting first with CH2Cl2/MeOH (v/v 1:1) and
then 2 M NH3 in MeOH. The ammonia-containing eluent was
concentrated in vacuo to give a 65:35 mixture of 27:31. Purification
via flash column chromatography (eluent 40-60 °C petroleum
ether/EtOAc, 2:1) gave a 65:35 mixture of 27:31 as a yellow oil (122
mg, 35%): IR νmax (film) 3381 (O-H), 3084, 3061, 3027, 2981,
2971 (C-H); NMR δC (100 MHz, CDCl3) 17.8, 18.1 (2 ꢀ C(R)-
Me), 53.4, 54.1 (2 ꢀ C(7)), 56.3, 56.6 (2 ꢀ C(2)), 62.8, 63.0 (2 ꢀ
C(R)), 71.9, 72.1 (2 ꢀ C(3)), 72.8, 73.0 (2 ꢀ C(4)), 127.3, 127.5,
128.5, 129.8, 130.0, 130.8 (2 ꢀ C(5), 2 ꢀ C(6), 2 ꢀ o-,m-,p-Ph,),
142.8, 143.1 (2 ꢀ i-Ph); MS m/z (ESIþ) 234 ([M þ H]þ, 100);
HRMS (ESIþ) C14H19NNaO2 ([M þ Na]þ) requires 256.1308,
þ
found 256.1304. Data for 27: NMR δH (400 MHz, CDCl3) 1.40
(3H, d, J = 6.6 Hz, C(10)Me), 2.69 (1H, dd, J = 13.8, 6.7 Hz,
C(2)HA), 3.08 (1H, m, C(2)HB), 3.19-3.24 (2H, m, C(7)H2),
3.73-3.88 (2H, m, C(3)H, C(10)H), 4.34-4.39 (1H, m, C(4)H),
5.61-5.71 (1H, m, C(6)H), 5.74-5.85 (1H, m, C(5)H), 7.24-7.40
(5H, m, Ph). Data for 31: δH (400 MHz, CDCl3) (selected peaks)
2.63 (1H, dd, J = 13.6, 7.1 Hz, C(2)HA), 3.11-3.17 (1H, m,
C(2)HB), 3.25-3.28 (1H, m, C(7)HA), 4.26-4.34 (1H, m, C(7)HB).
(3S,4S,rR)- and (R,R,R)-N(1)-10-(100-Naphthyl)ethyl-3,4-dihy-
droxy-2,3,4,7-tetrahydro-1H-azepine (3S,4S,rR)-29 and (R,R,R)-33.
Cl3CCO2H (1.64 g, 10.0 mmol) was added to a stirred solution
of 21 (500 mg, 2.01 mmol, 98% ee) in CH2Cl2 (5.0 mL), and the
resultant solution was stirred for 5 min at rt. m-CPBA (75%, 923 mg,
4.02 mmol) was then added, and the resultant solution was stirred for
21 h before the addition of solid Na2SO3 (∼500 mg) until
starch-iodide paper indicated that no oxidant remained. The mix-
ture was diluted with CH2Cl2 (100 mL), and the organic layer was
washed with 2 M aq NaOH (2 ꢀ 100 mL). The combined aqueous
washings were extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ 100 mL),
and the combined organic extracts were dried and concentrated in
vacuo. The residue was then passed through a Biotage SCX-2
scavenger column, eluting first with CH2Cl2/MeOH (v/v 1:1), then
2 M NH3 in MeOH. The ammonia-containing eluent was concen-
trated in vacuo to give an 80:20 mixture of 29:33 (50% conversion
from 21). Purification via flash column chromatography (eluent
40-60 °C petroleum ether/EtOAc, 2:1) gave 29 as a yellow oil
(51 mg, 9%, >99:1 dr, 98% ee): [R]25D þ27.4 (c 1.0 in CHCl3); IR
X-ray Crystal Structure Determination for 21. Data were collected
using an Enraf-Nonius κ-CCD diffractometer with graphite-mono-
chromated Mo KR radiation using standard procedures at 150 K.
The structure was solved by direct methods (SIR92); all non-hydro-
gen atoms were refined with anisotropic thermal parameters. Hydro-
gen atoms were added at idealized positions. The structure was
refined using CRYSTALS.35
X-ray crystal structure data for 21 [C18H19N]: M = 249.36,
˚
orthorhombic, space group P212121, a=7.1891(2) A, b=7.2120(2)
3
-1
˚
˚
˚
A, c = 27.0900(9) A, V = 1404.56(7) A , Z = 4, μ = 0.068 mm
,
colorless plate, crystal dimensions =0.12 ꢀ 0.14 ꢀ 0.19 mm3. A total
of 1860 unique reflections were measured for 5 < θ < 27 and 1860
reflections were used in the refinement. The final parameters were
wR2 = 0.118 and R1 = 0.084 [I > -3.0σ(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 788732. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
(RS)-N(1)-10-(200-Tolyl)ethyl-2,7-dihydro-1H-azepine 22. (RS)-
1-(20-Tolyl)ethylamine (600 mg, 4.44 mmol)18 and K2CO3 (1.23 g,
8.87 mmol) were added sequentially to a stirred solution of 18
(532 mg, 2.22 mmol) in THF (30 mL) at rt. After 24 h, the reaction
mixture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (30 mL) and filtered through Celite (eluent CH2Cl2), and
the filtrate was concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 0f10% EtOAc in
30-40 °C petroleum ether) gave a 93:7 mixture of 22:26 as a pale
yellow oil (405 mg, 86%): IR νmax (film) 2970 (C-H), 1605
(CdC); MS m/z (ESIþ) 214 ([M þ H]þ, 100); HRMS (ESIþ)
C15H20Nþ ([M þ Hþ]) requires 214.1590, found 214.1589. Data
for 22: NMR δH (400 MHz, CDCl3) 1.31 (3H, d, J = 6.6 Hz,
C(10)Me), 2.33 (3H, s, ArMe), 3.48 (2H, dd, J = 17.2, 3.1 Hz,
C(2)HA, C(7)HA), 3.64 (2H, dd, J = 17.2, 3.1 Hz, C(2)HB,
C(7)HB), 4.19 (3H, q, J = 6.6 Hz, C(10)H), 5.68 (2H, app dt,
J 12.4, 3.1, C(3)H, C(6)H), 5.90-6.00 (2H, m, C(4)H, C(5)H),
7.08-7.15 (2H, m, Ar), 7.20 (1H, app t, J = 7.1 Hz, Ar), 7.56 (1H,
d, J= 7.6 Hz, Ar);NMRδC (100 MHz, CDCl3) 19.5 (ArMe), 20.8
(C(10)Me), 53.4 (C(10), C(2), C(7)), 126.2 (C(4), C(5)), 126.1,
126.2, 126.5, 126.9, 130.3, 133.1 (C(3), C(6), Ar), 135.6, 143.6 (Ar).
(3S,4S,rR)- and (R,R,R)-N(1)-r-Methylbenzyl-3,4-dihydroxy-
2,3,4,7-tetrahydro-1H-azepine (3S,4S,rR)-27 and (R,R,R)-31.
Cl3CCO2H (1.23 g, 7.5 mmol) was added to a stirred solution
of 19 (300 mg, 1.5 mmol, >99% ee) in CH2Cl2 (3.0 mL), and
the resultant solution was stirred for 5 min at rt. m-CPBA (75%,
693 mg, 3.01 mmol) was then added, and the resultant solution was
stirred for 21 h before the addition of solid Na2SO3 (∼500 mg)
until starch-iodide paper indicated that no oxidant remained. The
mixture was diluted with CH2Cl2 (50 mL), and the organic layer
νmax (film) 3385 (O-H), 3048, 2972 (C-H), 1658 (CdC); NMR δH
(400 MHz, CDCl3) 1.52 (3H, d, J 6.6, C(10)Me), 2.77 (1H, dd, J =
13.9, 6.0 Hz, C(2)HA), 3.20 (1H, dd, J = 13.9, 5.0 Hz, C(2)HB),
3.32-3.35 (2H, m, C(7)H2), 3.63 (1H, app q, J = 6.0 Hz, C(3)H),
4.31-4.36 (1H, m, C(4)H), 4.59 (1H, q, J = 6.6 Hz, C(10)H),
5.61-5.71 (2H, m, C(5)H, C(6)H), 7.43-7.56 (4H, m, Ar),
7.77-7.78 (1H, m, Ar), 7.85-7.89 (1H, m, Ar), 8.32 (1H, d, J =
8.5 Hz, Ar); NMR δC (100 MHz, CDCl3) 15.0 (C(10)Me), 53.1
(C(7)), 56.8 (C(2)), 59.4 (C(10)), 72.6, 72.7 (C(3), C(4)), 123.9, 124.4,
125.1, 125.6, 126.1, 128.1, 128.9 (Ar), 128.7, 130.5 (C(5), C(6)), 131.7,
134.1, 139.0 (Ar); MS m/z (ESIþ) 306 ([M þ Na]þ, 100), 284 ([M þ
H]þ, 85); HRMS (ESIþ) C18H22NO2þ ([MþH]þ) requires 284.1645,
found 284.1648. Further elution gave a 70:30 mixture of 29:33 as a
yellow oil (116 mg, 29%). Further elution gave a 24:76 mixture of
29:33 as a yellow oil (15 mg, 3%). Data for 33: NMR δH (400 MHz,
CDCl3) 1.52 (3H, d, J = 6.6 Hz, C(10)Me), 2.80 (1H, dd, J = 13.9,
5.7 Hz, C(2)HA), 3.11 (1H, dd, J= 13.9, 4.7 Hz, C(2)HB), 3.38-3.42
(2H, m, C(7)H2), 3.63-3.68 (1H, m, C(3)H), 4.26-4.32 (1H, m,
C(4)H), 4.61 (1H, q, J=6.6Hz, C(10)H), 5.58-5.75 (2H, m, C(5)H,
C(6)H), 7.40-7.60 (4H, m, Ar), 7.79 (1H, d, J = 7.9 Hz, Ar), 7.87
(1H, d, J = 7.9 Hz, Ar), 8.26 (1H, d, J = 8.2 Hz, Ar); NMR δC (100
MHz, CDCl3) (selected peaks) 14.6 (C(10)Me), 53.1 (C(10)), 54.5
(C(2)), 54.7 (C(7)), 72.9 (C(4)), 73.2 (C(3)).
(3S,4R,5S,6S,10R)-N(1)-10-(100-Naphthyl)ethyl-3-hydroxy-4-ben-
zyloxy-5,6-epoxyazepane 35. From 21. HBF4 Et2O (1.93 mL,
3
8144 J. Org. Chem. Vol. 75, No. 23, 2010

Bagal et al.
JOCArticle
14.0 mmol) was added to a stirred solution of 21 (500 mg, 2.01
mmol, 98% ee) in BnOH (10 mL), and the resultant solution was
stirred for 5 min at rt. m-CPBA (73%, 1.90 g, 8.02 mmol) was then
added, and the resultant solution was stirred for 24 h before the
addition of solid Na2SO3 (∼1 g) until starch-iodide paper indi-
cated that no oxidant remained. The mixture was diluted with
CH2Cl2 (25 mL), and the organic layer was washed with 2 M aq
NaOH (2 ꢀ 200 mL). The combined aqueous washings were
extracted with CH2Cl2 (3 ꢀ 100 mL), and the combined organic
extracts were dried and concentrated in vacuo. The residue was then
passed through a Biotage SCX-2 scavenger column, eluting first
with CH2Cl2/MeOH (v/v 1:1) and then 2 M NH3 in MeOH. The
ammonia-containing eluent was concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30-40 °C petroleum
ether/EtOAc, 10:1) gave 35 as a colorless oil (190 mg, 25%, >99:1
(C(4)), 52.7 (C(5)), 53.2 (C(10)), 57.0 (C(2)), 71.7 (OCH2Ph), 74.1
(C(3)), 125.0, 125.5, 125.6, 127.8, 128.0, 128.3, 128.5 (o-,m-,p-Ph,
Ar), 132.2, 133.9, 138.2, 134.4 (i-Ph, Ar); MS m/z (ESIþ) 432 ([M þ
Na]þ, 37Cl, 28), 430 ([M þ Na]þ, 35Cl, 90), 410 ([M þ H]þ, 37Cþl,
35), 408 ([M þ H]þ, 35Cl, 100); HRMS (ESIþ) C25H2635ClNNaO2
([M þ Na]þ) requires 430.1544, found 430.1543.
X-ray Crystal Structure Determination for 36. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealized
positions. The structure was refined using CRYSTALS.35
X-ray crystal structure data for 36 [C25H26.5ClNO2]:M= 816.89,
˚
˚
triclinic, space group P1, a = 9.7315(3) A, b = 10.5112(3) A, c =
11.3814(4) A, R = 64.3905(14)°, β = 87.8962(14)°, γ =
dr, 98% ee): [R]25 þ21.0 (c 1.0 in CHCl3); IR νmax (film) 3443
˚
D
3
-1
˚
(O-H), 2972 (C-H); NMR δH (400 MHz, CDCl3) 1.52 (3H, d,
J = 6.8 Hz, C(10)Me), 2.66 (1H, dd, J = 13.4, 6.8 Hz, C(2)HA),
2.77 (1H, d, J = 3.0 Hz, OH), 2.85 (1H, dd, J = 8.6, 4.3 Hz,
C(7)HA), 3.10-3.15 (2H, m, C(5)H, C(7)HB), 3.16-3.20 (2H, m,
C(2)HB, C(6)H), 3.76-3.89 (1H, m, C(3)H), 3.95 (1H, dd, J = 7.8,
1.8 Hz, C(4)H), 4.57 (1H, d, J = 11.6 Hz, OCHAHBPh), 4.69 (1H,
q, J = 6.8 Hz, C(10)H), 4.81 (1H, d, J = 11.6 Hz, OCHAHBPh),
7.30-7.41 (5H, m, Ph), 7.43-7.57 (4H, m, Ar), 7.80 (1H, d, J = 7.8
Hz, Ar), 7.88 (1H, d, J = 7.8 Hz, Ar), 8.38 (1H, d, J = 8.3 Hz, Ar);
NMR δC (100 MHz, CDCl3) 14.2 (C(10)Me), 49.0 (C(6)), 54.2
(C(7)), 54.5 (C(5)), 55.8 (C(2)), 59.5 (C(10)), 69.4 (C(3)), 71.8
(OCH2Ph), 79.7 (C(4)), 124.2, 124.7, 125.0, 125.5, 125.9, 127.9,
128.0, 128.7 (o-,m-,p-Ph, Ar), 132.1, 134.1, 138.0, 139.1 (i-Ph, Ar);
MS m/z (ESIþ) 412 ([M þ Na]þ, 96), 390 ([M þ H]þ, 100); HRMS
(ESIþ) C25H28NO3þ ([Mþ H]þ) requires 390.2064, found 390.2064.
85.5140(15)°, V = 1046.61(6) A , Z = 2, μ = 0.204 mm ,
colorless plate, crystal dimensions = 0.11 ꢀ 0.13 ꢀ 0.22 mm3. A
total of 8261 unique reflections were measured for 5 < θ < 27
and 6624 reflections were used in the refinement. The final
parameters were wR2 = 0.084 and R1 = 0.095 [I > 3.0σ(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 788733. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
(3S,4S,10R)- and (R,R,R)-N(1)-10-(100-Naphthyl)ethyl-3-hy-
droxy-4-benzyloxy-2,3,4,7-tetrahydro-1H-azepine (3S,4S,10R)-
38 and (R,R,R)-39. HBF4 Et2O (3.58 mL, 26.1 mmol) was
3
added to a stirred solution of 21 (968 mg, 5.20 mmol, 98% ee)
in BnOH (18.5 mL), and the resultant solution was stirred for
5 min at rt. m-CPBA (75%, 4.81 g, 20.9 mmol) was then added,
and the resultant solution was stirred for 24 h before the
addition of solid Na2SO3 (∼1 g) until starch-iodide paper
indicated that no oxidant remained. The mixture was diluted
with CH2Cl2 (50 mL), and the organic layer was washed with 2
M aq NaOH (2 ꢀ 100 mL). The combined aqueous washings
were extracted with CHCl3/iPrOH (v/v 3:1, 2 ꢀ 100 mL), and the
combined organic extracts were dried and concentrated in
vacuo. The residue was then passed through a Biotage SCX-2
scavenger column, eluting first with CH2Cl2/MeOH (v/v 1:1)
and then 2 M NH3 in MeOH. The ammonia-containing eluent
was concentrated in vacuo to give an 80:20 mixture of 38:39
(∼50% conversion from 21). Purification via flash column
chromatography (gradient elution, 5f50% EtOAc in 30-40 °C
petroleum ether) gave an 80:20 mixture of 38:39 as a colorless oil
(211 mg, 32%): IR νmax (film) 3453 (O-H), 3030, 2971, 2878
(C-H), 1598 (CdC); MS m/z (ESIþ) 374 ([M þ H]þ, 100);
From 38. HBF4 Et2O (0.09 mL, 0.63 mmol) was added to a
3
stirred solution of an 80:20 mixture of 38:39 (47 mg, 0.13 mmol)
in BnOH (1.0 mL), and the resultant solution was stirred for
5 min at rt. m-CPBA (75%, 115 mg, 0.50 mmol) was then added,
and the resultant solution was stirred for 24 h before the
addition of solid Na2SO3 (∼500 mg) until starch-iodide paper
indicated that no oxidant remained. The mixture was diluted
with CH2Cl2 (10 mL), and the organic layer was washed with 2
M aq NaOH (2 ꢀ 50 mL). The combined aqueous washings were
extracted with CH2Cl2 (3 ꢀ 50 mL), and the combined organic
extracts were dried and concentrated in vacuo. The residue was
then passed through a Biotage SCX-2 scavenger column, eluting
first with CH2Cl2/MeOH (v/v 1:1) and then 2 M NH3 in MeOH.
The ammonia-containing eluent was concentrated in vacuo.
Purification via flash column chromatography (gradient elu-
tion, 10f100% EtOAc in 30-40 °C petroleum ether) gave an
80:20 mixture of 35:40 as a colorless oil (30 mg, 60%, 80:20 dr).
(2S,3R,4S,5S,10R)-N(1)-10-(100-Naphthyl)ethyl-2-chloromethyl-
3-benzyloxy-4,5-epoxypiperidine 36. Et3N (0.04 mL, 0.31 mmol)
and MsCl (0.02 mL, 0.23 mmol) in CH2Cl2 (3 mL) were added
sequentially to a stirred solution of 35 (60 mg, 0.15 mmol) in
CH2Cl2 (6 mL) at 0 °C, and the resultant solution was stirred for
1.5 h at 0 °C before being concentrated in vacuo. Purification via
flash column chromatography (eluent 30-40 °C petroleum
ether/EtOAc, 20:1) gave 36 as a white solid (40 mg, 66%,
þ
HRMS (ESIþ) C25H28NO2 ([M þ H]þ) requires 374.2115,
found 374.2117. Data for 38: NMR δH (400 MHz, CDCl3) 1.53
(3H, d, J = 6.8 Hz, C(10)Me), 2.90-3.25 (5H, m, C(2)H2, C(7)-
H2, OH), 3.87 (1H, ddd, J = 7.8, 4.3, 4.0 Hz, C(3)H), 4.36-4.42
(1H, m, C(4)H), 4.45 (1H, d, J = 11.6 Hz, OCHAHBPh), 4.64-
4.70 (2H, m, C(10)H, OCHAHBPh), 5.51-5.65 (2H, m, C(5)H,
C(6)H), 7.29-7.40 (5H, m, Ph), 7.41-7.53 (4H, m, Ar), 7.79 (1H,
d, J =7.8 Hz, Ar), 7.84-7.90 (1H, m, Ar), 8.40-8.48(1H, m, Ar);
NMR δC (100 MHz, CDCl3) 13.7 (C(10)Me), 50.3 (C(2)), 57.9
(C(7)), 59.9 (C(10)), 71.6 (C(3), OCH2Ph), 80.1 (C(4)), 124.4,
124.9, 125.5, 125.8, 127.8, 127.9, 128.5, 128.6, 129.1, 130.1 (C(5),
C(6), Ar, o-,m-,p-Ph), 132.1, 134.1, 138.3, 139.0 (Ar, i-Ph). Data
for 39: NMR δH (400 MHz, CDCl3) (selected peaks) 3.69-3.78
(1H, m, C(3)H), 4.19 (1H, dd, J = 7.3, 2.1 Hz, C(4)H), 5.64-5.74
(2H, m, C(5)H, C(6)H); NMR δC (100 MHz, CDCl3) (selected
peaks) 15.4 (C(10)Me), 54.9 (C(7)), 70.3 (C(3)), 80.3 (C(4)).
(2S,3R,4S,5R,10R)-N(1)-10-(100-Naphthyl)ethyl-2-chloromethyl-
3-benzyloxy-4,5-dihydroxypiperidine 43. Cl3CCO2H (241 mg, 1.47
mmol) was added to a stirred solution of 36 (30 mg,
>99:1 dr, 98% ee): mp 101-103 °C; [R]25 þ76.6 (c 1.0 in
D
CHCl3); IR νmax (KBr) 3039, 3050, 3033, 2979, 2943, 2885, 2521,
2749 (C-H); NMR δH (400 MHz, CDCl3) 1.48 (3H, d, J = 6.6
Hz, C(10)Me), 2.50 (1H, dd, J = 14.2, 4.0 Hz, C(6)HA), 2.95 (1H,
app d, J = 14.2 Hz, C(6)HB), 3.07-3.15 (1H, m, C(2)H), 3.15
(1H, app t, J = 4.2 Hz, C(5)H), 3.35-3.41 (1H, m, C(4)H), 4.00
(1H, dd, J = 12.1, 4.0 Hz, CHAHBCl), 4.13-4.23 (2H, m,
C(3)H, CHAHBCl), 4.76 (1H, d, J = 11.6 Hz, OCHAHBPh),
4.83 (1H, d, J = 11.6 Hz, OCHAHBPh), 5.03 (1H, q, J = 6.6 Hz,
C(10)H), 7.30-7.55 (9H, m, Ph, Ar), 7.79 (1H, d, J = 8.1 Hz, Ar),
7.84-7.89 (1H, m, Ar), 8.79-8.85 (1H, m, Ar); NMR δC (100
MHz, CDCl3) 12.5 (C(10)Me), 42.2 (C(6)), 42.6 (CH2Cl), 51.3
J. Org. Chem. Vol. 75, No. 23, 2010 8145

Bagal et al.
JOCArticle
0.07 mmol) in CH2Cl2 (0.3 mL), and the resultant solution was
stirred for 16 h at rt. The reaction mixture was diluted with CH2Cl2
(5 mL) and then washed with 2 M aq NaOH (2 ꢀ 10 mL). The
combined aqueous layers were extracted with CHCl3/iPrOH (v/v
3:1, 3 ꢀ 5 mL). The combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatog-
raphy (gradient elution, 10f100% EtOAc in 30-40 °C petroleum
ether) gave 43 as a colorless oil (20 mg, 67%, >99:1 dr, 98% ee):
[R]25D -12.8 (c 1.0 in CHCl3); IR νmax (film) 3443 (O-H), 3089,
3051, 3034, 2924, 2973 (C-H); NMR δH (400 MHz, CDCl3) 1.52
(3H, d, J = 6.8 Hz, C(10)Me), 2.17 (1H, br s, OH), 2.23 (1H, dd,
J = 12.2, 4.3 Hz, C(6)HA), 2.42 (1H, br, s, OH), 2.79 (1H, app d,
J = 12.2 Hz, C(6)HB), 3.21 (1H, app d, J = 7.8 Hz, C(2)H),
3.50-3.60 (1H, m, C(5)H), 3.92-4.00 (1H, m, C(4)H), 4.11-4.19
(2H, m, C(3)H, CHAHBCl), 4.22-4.29 (1H, m, CHAHBCl),
4.62-4.72 (2H, m, OCH2Ph), 5.04 (1H, q, J = 6.8 Hz, C(10)H),
7.31-7.58 (9H, m, Ar, Ph), 7.80 (1H, d, J = 7.6 Hz, Ar), 7.86
(1H, d, J = 8.1 Hz, Ar), 8.91 (1H, d, J = 8.3 Hz, Ar);NMR δC (100
MHz, CDCl3) 12.0 (C(10)Me), 41.8 (CH2Cl), 45.3 (C(6)), 53.5
(C(10)), 58.9 (C(2)), 67.1 (C(5)), 72.3 (C(4)), 75.3 (OCH2Ph),
77.3 (C(3)), 124.7, 124.9, 125.3, 125.7, 126.1, 128.1, 128.2, 128.5,
128.7, 128.8 (o,m,p-Ph, Ar), 131.8, 134.2, 137.6, 137.7 (i-Ph, Ar);
MS m/z(ESIþ) 450 ([M þ Na]þ, 37Cl, 6), 448([Mþ Na]þ, 35Cl, 18),
428 ([M þ H]þ, 37Cl, 29), 426 ([M þ H]þ, 35Cl, 100); HRMS
(ESIþ) C25H2835ClNNaO3þ ([M þ Na]þ) requires 448.1650, found
448.1654.
(2R,3R,4S,5R,10R)-N(1)-10-(100-Naphthyl)ethyl-2-acetoxymethyl-
3-benzyloxy-4,5-dihydroxypiperidine 45 and (3R,4S,5S,6R,10R)-
N(1)-10-(100-Naphthyl)ethyl-3-acetoxy-4-benzyloxy-5,6-dihydroxy-
azepane 46. AgOAc (89 mg, 0.54 mmol) was added to a stirred
solution of 43 (65 mg, 0.15 mmol) in DMF (1 mL), and the
resultant suspension was stirred for 24 h at 65 °C. The reaction
mixture was then allowed to cool to rt before the addition of H2O
(8 mL). The mixture was extracted with Et2O (3 ꢀ 10 mL), and the
combined organic extracts were washed with H2O (3 ꢀ 30 mL)
before being dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 10f100% EtOAc in
30-40 °C petroleum ether) gave 46 as a colorless oil (5 mg, 7%,
>99:1 dr, 98% ee): [R]25D þ44.8 (c 1.0 in CHCl3); IR νmax (film)
3444 (O-H), 3088, 3050, 3034, 3006, 2917, 2887 (C-H), 1734
(CdO); NMR δH (400 MHz, CDCl3) 1.48 (3H, d, J 6.6, C(10)Me),
2.15 (3H, s, COMe), 2.21 (1H, br s, OH), 2.69 (1H, m, C(7)HA),
2.80 (1H, dd, J = 14.0, 2.7 Hz, C(7)HB), 3.17-3.22 (1H, m,
C(2)HA), 3.27 (1H, dd, J = 14.8, 4.1 Hz, C(2)HB), 3.41-3.46 (1H,
m, C(6)H), 3.87(1H, appd, J=6.3Hz, C(4)H), 3.93-3.97 (1H, m,
C(5)H), 4.49 (1H, d, J = 14.5 Hz, OCHAHBPh), 4.55-4.64 (2H,
m, C(10)H, OCHACHBPh), 5.11-5.15 (1H, m, C(3)H), 7.25-7.50
(9H, m, Ar, Ph), 7.80 (1H, d, J = 7.6 Hz, Ar), 7.88 (1H, d, J = 7.9
Hz, Ar), 8.47 (1H, d, J = 8.5 Hz, Ar); NMR δC (100 MHz, CDCl3)
11.5 (C(10)Me), 21.4 (COMe), 52.3 (C(7)), 59.0 (C(2)), 60.6 (C(10)),
70.5 (C(6)), 72.5 (OCH2Ph), 74.1 (C(5)), 74.4 (C(3)), 79.6 (C(4)),
124.5, 124.7, 125.1, 125.7, 126.0, 127.7, 127.9, 128.4, 128.6, 129.0,
131.4, 134.2, 138.1, 138.3 (Ar, Ph), 170.3 (COMe); MS m/z (ESIþ)
472 ([M þþNa]þ, 41), 450 ([M þ H]þ, 100); HRMS (ESIþ)
C27H32NO5 ([M þ H]þ) requires 450.2275, found 450.2273.
Further elution gave 45 as a white solid (40 mg, 60%, >99:1 dr,
98% ee): mp 129-131 °C; [R]25D þ48.3 (c 1.0 in CHCl3); IR νmax
(film) 3484 (O-H), 3088, 3050, 3035, 2924, 2881, 2850 (C-H),
1741 (CdO); NMR δH (400 MHz, CDCl3) 3.01(3H, d, J=6.6Hz,
C(10)Me), 1.60 (1H, br s, OH), 2.19 (3H, s, COMe), 2.27 (1H, dd,
J = 12.3, 4.1 Hz, C(6)HA), 2.45 (1H, br s, OH), 2.81 (1H, dd, J =
12.3, 1.3 Hz, C(6)HB), 3.06-3.15 (1H, m, C(2)H), 3.53-3.61 (1H,
m, C(5)H), 3.90 (1H, dd, J = 9.1, 3.4 Hz, C(3)H), 4.01-4.07 (1H,
m, C(4)H), 4.51 (1H, d, J = 11.3 Hz, OCHAHBPh), 4.56 (1H, dd,
J = 12.3, 2.5 Hz, CHAHBOAc), 4.62 (1H, d, J = 11.3 Hz,
OCHAHBPh), 4.72 (1H, d, J = 12.3, 2.2 hz, CHAHBOAc), 4.92
(1H, q, J = 6.6 hz, C(10)H), 7.32-7.50 (9H, m, Ar, Ph), 7.76-7.82
(1H, m, Ar), 7.84-7.89 (1H, m, Ar), 8.67-8.74 (1H, m, Ar); NMR
δC (100 MHz, CDCl3) 11.4 (C(10)Me), 21.1 (COMe), 45.1 (C(6)),
52.4 (C(10)), 57.4 (C(2)), 59.8 (CH2OAc) 67.0 (C(5)) 67.5 (C(4)),
71.4 (OCH2Ph), 73.7(C(3)), 124.0, 125.0, 125.3, 125.5, 125.9, 128.0,
128.2, 128.4, 128.5, 128.7, 129.1, 131.9, 134.3, 137.2 (Ar, Ph), 170.7
(COMe); MS m/z (ESIþ) 472 ([M þ Na]þ, 100), 450 ([M þ H]þ,
þ
98); HRMS (ESIþ) C27H32NO5 ([M þ H]þ) requires 450.2275,
found 450.2273.
X-ray Crystal Structure Determination for 45. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealized
positions. The structure was refined using CRYSTALS.35
X-ray crystal structure data for 45 [C27H31NO5]: M = 449.55,
˚
˚
monoclinic, space group P21, a = 9.3063(2) A, b = 9.0446(2) A,
3
˚
˚
c = 14.3162(3) A, β = 103.4925(10)°, V = 1171.76(4) A , Z = 2,
μ = 0.087 mm-1, colorless plate, crystal dimensions = 0.08 ꢀ
0.13 ꢀ 0.17 mm3. A total of 2818 unique reflections were measured
for 5 < θ < 27 and 2818 reflections were used in the refinement.
The final parameters were wR2 = 0.100 and R1 = 0.048 [I >
-3.0σ(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 788734. Copies of the
data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
(þ)-(2R,3R,4S,5R)-2-Hydroxymethyl-3,4,5-trihydroxypiperi-
dine Hydrochloride [(þ)-1-Deoxyaltronojirimycin Hydrochloride]
3 HCl. Step1. K2CO3 (154 mg, 1.10 mmol) was addedtoa stirred
3
solution of 45 (25 mg, 0.06 mmol) in MeOH (1 mL) and the
resultant suspension was stirred for 16 h at rt before being con-
centrated in vacuo. The residue was dissolved in H2O (5 mL)
and extracted with CHCl3/iPrOH (v/v 3:1, 3 ꢀ 10 mL). The
combined organic extracts were dried and concentrated in vacuo
to give 47 as a colorless oil (17 mg) that was used without
purification.
Step 2. Pd(OH)2/C (17 mg) was added to a stirred solution of
47 (17 mg, 0.05 mmol) in degassed MeOH (0.5 mL) and the
resultant suspension was stirred for 72 h under an atmosphere of
H2 (1 atm). Concentrated aq HCl (10 μL) was then added, and
the resultant suspension was stirred for a further 5 min before
being filtered through Celite (eluent MeOH). The filtrate was
concentrated in vacuo, and the residue was purified via flash
column chromatography (eluent CHCl3/MeOH, 4:1) to give
(þ)-(2R,3R,4S,5R)-3 HCl as a white semisolid (8 mg, 71% from
3
45, >99:1 dr, 98% ee):3 [R]25 þ31.1 (c 0.5 in MeOH) [lit.9i
D
[R]23 þ31.0 (c 2.0 in MeOH); lit.10f [R]25 þ33.2 (c 0.5 in
D
D
MeOH)]; NMR δH (500 MHz, D2O) 3.17 (1H, dd, J 13.6, 2.8,
CHAHBOH), 3.27-3.35 (2H, m, C(4)H, CHAHBOH), 3.77 (1H,
dd, J 12.6, 6.9, C(6)HA), 3.91 (1H, dd, J 12.6, 3.2, C(6)HB),
3.94-3.99 (2H, m, C(3)H, C(5)H), 4.08-4.11 (1H, m, C(2)H);
NMR δC (125 MHz, D2O) 43.9 (CH2OH), 55.8 (C(4)), 58.2
(C(6)), 63.6 (C(5)), 66.2 (C(2)), 68.5 (C(3)).
Acknowledgment. We thank Pfizer for a CASE student-
ship (P.M.S.), Laure Hitzel for assistance with preparative
Chiral HPLC, and the Oxford Chemical Crystallography
Service for the use of their X-ray diffractometers.
1
Supporting Information Available: Copies of H and 13C
NMR spectra and CIF (for structures CCDC 788731-788734).
This material is available free of charge via the Internet at http://
pubs.acs.org.
8146 J. Org. Chem. Vol. 75, No. 23, 2010