Stereoselective syntheses of aza, amino and imino sugar derivatives by hydroboration of 3,6-dihydro-2H-1,2-oxazines as key reaction

Article abstract of DOI:10.1002/ejoc.201100230

Starting from enantiopure 3,6-dihydro-2H-1,2-oxazinessyn-1 we introduced an additional hydroxy group in a stereoselective fashion by a standard hydroboration/oxidation protocol. Under "regular" conditions substrate control was sufficient to achieve a very

Full text of DOI:10.1002/ejoc.201100230

FULL PAPER
DOI: 10.1002/ejoc.201100230
Stereoselective Syntheses of Aza, Amino and Imino Sugar Derivatives by
Hydroboration of 3,6-Dihydro-2H-1,2-oxazines as Key Reaction
Vjekoslav Dekaris,[a] Robert Pulz,[a] Ahmed Al-Harrasi,[a,b] Dieter Lentz,[a][‡] and
Hans-Ulrich Reissig*[a]
Keywords: 1,2-Oxazines / Alkoxyboranes / Hydroboration / Amino alcohols / Imino sugars / Pyrrolidines
Starting from enantiopure 3,6-dihydro-2H-1,2-oxazines
in a series of transformations leading to several amino polyol
syn-1 we introduced an additional hydroxy group in a stereo- derivatives. Complete deprotection of both diastereomers
selective fashion by a standard hydroboration/oxidation pro-
tocol. Under “regular“ conditions substrate control was suf-
ficient to achieve a very high degree of stereoselectivity.
However, a diastereomeric product was isolated when a par-
tially “degraded” borane reagent was used. We could syn-
thesise this new diastereomer on purpose by addition of
alcohols to the “fresh“ hydroboration reagent. The level of
stereoinduction increased with the steric bulk of the added
alcohol: MeOH Ͻ nBuOH Ͻ iPrOH Ͻ tBuOH. After a two-
step oxidation/reduction sequence, another 5-hydroxy-1,2-
oxazine epimer was accessible. The obtained 5-hydroxy-1,2-
oxazine diastereomers 2 were used as versatile intermediates
without cleavage of the N–O bond led to the novel poly-
hydroxylated tetrahydro-2H-1,2-oxazines 3 and epi-3. By
change of the deprotection conditions the open-chain amino
polyol 4 with D-iditol configuration became accessible. In an
alternative sequence 5-hydroxy-1,2-oxazines were utilised to
synthesise imino sugars (polyhydroxylated pyrrolidines). Sa-
marium diiodide induced cleavage of the 1,2-oxazine N–O
bond furnished 1,4-amino alcohols, which were cyclised to
give the corresponding pyrrolidine derivatives after acti-
vation by mesyl chloride. This sequence either led to a 3-
methoxy-substituted trihydroxylated pyrrolidine derivative
or to the related fully deprotected compound.
boration. Since its discovery by Brown[9] a great variety of
borane reagents were developed for this purpose addressing
the needs for substrate-specific optimisation, regioselectiv-
ity issues or asymmetric syntheses,[10] 9-BBN[11] or
Ipc2BH[12] being some of the most notable among these.
Introduction
Since our first synthesis of 3,6-dihydro-2H-1,2-oxazines
utilising lithiated alkoxyallenes and carbohydrate-derived
nitrones in a stepwise [3+3] cyclisation process[1] we are ex-
ploring the synthetic potential of this versatile class of com-
pounds and still discover interesting and useful transforma-
tions. These 1,2-oxazines exhibit three characteristic reac-
tive sites (Scheme 1): first, the N–O bond, which is suscepti-
ble to reductive ring opening processes leading to acyclic
1,3- and 1,4-amino alcohols as precursors for azetidine[2]
or pyrrolidine derivatives;[3] second, the O-substituted side
chain at C-3 proved to be essential in (Lewis) acid mediated
interactions with the enol ether moiety furnishing a variety
of heterocyclic skeletons, e.g. furans,[4] pyrans,[5] oxepanes;[6]
finally, the double bond can also be exploited by reaction
with external reagents for cyclopropanation[7] or bromina-
tion.[8] The stereochemical outcome of these processes is
strongly influenced by the configuration of the existing
stereogenic centre at C-3. An additional method to func-
tionalise the double bond of 1,2-oxazines is the hydro-
Scheme 1. Reactive sites of 3,6-dihydro-2H-1,2-oxazines.
After the hydroboration, the newly generated or-
ganoboron species often exhibits a higher degree of stability
compared to other organometallic compounds and gives
entry to numerous functionalisation options at the nega-
tively polarised carbon atom.[13] In particular, oxidative
workup in the presence of hydrogen peroxide proved to be
a reliable method to introduce a hydroxy group. Alkoxybo-
ranes are regarded as weaker hydroborating agents mainly
because of the diminished hydride character of the hydro-
gen atom. Even though there are examples for effective hy-
droborations with this class of compounds the substrate
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] University of Nizwa, College of Arts and Sciences, Department
of Biological Sciences and Chemistry,
Nizwa, Sultanate of Oman
[‡] Responsible for X-ray crystal structure determination
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Aza, Amino and Imino Sugar Derivatives
scope is rather limited compared to the typically used rea-
gents, and more forcing conditions or catalytic activation
are needed.[14] In this report we will supplement our earlier
studies towards the hydroboration of 1,2-oxazines.[2,15] We
demonstrate that the presence of alkoxyboranes can play a
crucial role for the stereoselectivity of hydroboration reac-
tions, although they are presumably not the active hydro-
borating species. Furthermore, we will present new short
and efficient routes to polyhydroxylated 1,2-oxazines as well
as to their analogous open-chain amino sugar derivatives.
We complete the overview of accessible amino polyols by
presenting the syntheses of pyrrolidine derivatives. All ap-
proaches to these target compounds depend on the stereo-
selective hydroboration of 1,2-oxazines.
Scheme 2. Hydroboration of 1,2-oxazines syn-1. (a) BH3·THF,
THF, –30 °C to r.t.; r.t., 3 h; NaOH, H2O2, –10 °C to r.t.; r.t., over-
night.
of diastereomers 2a and 2c with a ratio of ca. 1:1
(Scheme 3). It was possible to isolate pure 2c by HPLC sep-
aration and to prove the relative configuration of this unex-
pected product by X-ray crystal structure analysis (Fig-
ure 1).[17] Now the hydroboration reagent is less selective
and attacks syn-1a also from the side that bears the C-3
side chain. The X-ray crystal structure also shows a chair-
like conformation of the 1,2-oxazine skeleton, with the sub-
stituents at C-3, C-4 and C-5 in axial positions, whereas the
bulky N-benzyl group prefers the equatorial position.
Results and Discussion
Hydroboration Experiments
Our approach towards the syntheses of amino polyols
utilises 3,6-dihydro-2H-1,2-oxazines as enantiopure precur-
sors, which are readily accessible through stereoselective
[3+3] cyclisation of in situ generated lithiated alkoxyallenes
and chiral-pool-derived nitrones.[1] Precursors syn-1a and
syn-1b were chosen to start off the respective synthetic
routes allowing for the preparation of either fully depro-
tected amino polyols or their derivatives bearing one meth-
oxy group. In order to install an oxygen substituent at C-5
of the 1,2-oxazine core hydroboration of the incorporated
enol ether double bond followed by oxidative workup in
the presence of hydrogen peroxide was an obvious choice.
Treatment of 1,2-oxazines syn-1a and syn-1b with 4 equiv.
of borane–THF complex and subsequent oxidation and hy-
drolysis of the respective organoboranes gave entry to 5-
hydroxylated compound 2a in 80% yield and to 2b in 96%
yield (Scheme 2). As expected for a substrate with an elec-
tron-rich double bond[16] excellent regio- and stereoselecti-
vity were observed in both cases, forming the trans-4-alk-
oxy-5-hydroxy-1,2-oxazine derivatives. Substrate-induced
stereoselectivity was controlled by the configuration of the
stereogenic centre C-3, which led exclusively to 1,2-oxazine
diastereomers 2 (Scheme 2). The relative configuration was
confirmed by NOESY-NMR analyses.[15] As expected, the
borane reagent attacks the C-4/C-5 double bond opposite
to the (moderately) bulky 3-(1,3-dioxolan-2-yl) substituent.
We also performed hydroboration experiments with the anti
diastereomers of 1a and 1b, but here we observed that these
reactions are considerably less efficient, providing the ex-
pected diastereomers of 2 in low yields.[2,15] One side-reac-
tion diminishing the yield of the desired hydroboration
product was the N–O bond cleavage by the borane reagent.
These examples demonstrate again that the reactivity of 1,2-
oxazines strongly depends on their relative configuration.
By chance we discovered that it was possible to influence
Scheme 3. Hydroboration of 1,2-oxazine syn-1a with partially “de-
graded” borane–THF complex. (a) “BH3·THF“, THF, –30 °C to
r.t.; r.t., 3 h; NaOH, H2O2, –10 °C to r.t.; r.t., overnight.
Figure 1. X-ray crystal structure of 1,2-oxazine 2c.
Surprisingly, for the formation of diastereomer 2c the ad-
the stereochemical outcome of the hydroboration process. dition of the borane reagent must have occurred to the steri-
When the used borane–THF complex was stored for a cally more hindered face of the double bond, a fact which
longer period and thus apparently being “degraded” to we never observed before in hydroborations of this class
some extend, this reagent led to the formation of a mixture of 1,2-oxazines. In order to understand the origin of this
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unexpected selectivity the assumed degradation of the
borane–THF complex was further investigated. Although
its degradation process is very complex and not entirely
clear, it is known that at temperatures between 5 and 50 °C
an initial reduction of the coordinating tetrahydrofuran oc-
curs to provide a monoalkoxyborane.[18] At this point two
possible subsequent pathways of the monoalkoxyborane in-
clude: (a) reduction of two solvent molecules with forma-
tion of a trialkoxyborane via a dialkoxyborane,[18] (b) reac-
tion with a second monoalkoxyborane to regenerate borane
itself and to form a dialkoxyborane and subsequently a tri-
alkoxy species (Scheme 4).[19] Monoalkoxyboranes are un-
stable compounds and readily undergo further transforma-
tions; therefore, the newly formed species should mainly be
dialkoxy- or trialkoxyboranes.
Scheme 5. Hydroboration in the presence of alcohols. (a) ROH/
BH3·THF (2:3), THF, 0 °C, 15–60 min. (b) Addition of 1,2-oxazine
dissolved in THF at 0 °C, 1.5 h, r.t., 7 h; NaOH, H2O2, –10 °C to
r.t.; r.t., overnight. R = Me, nBu, iPr, tBu.
Table 1. Product ratios after hydroboration in the presence of
alcohols.
Entry
Alcohol
2a/2c[a]
1
2
3
4
MeOH
nBuOH
iPrOH
tBuOH
only traces of 2c[b]
2.7:1
2.2:1[b,c]
1.3:1[d]
[a] Ratios determined by integration of the signals of the methoxy
group by 1H NMR spectroscopy. [b] No purification performed. [c]
90% conversion. [d] 50% conversion.
borane itself, and that our hydroboration attempts with pri-
mary or secondary boranes such as thexylborane, disiamyl-
borane, 9-BBN and catecholborane[14g] completely failed,
we assume that in situ formed dialkoxyboranes are the key
for shifting the ratio of diastereomers, but are not the reduc-
ing agents. Currently, we can only speculate on the exact
mechanism. A coordination of the present dialkoxyborane
to one of the 1,2-oxazine heteroatoms probably changes the
reactive conformation of the substrate, and as a conse-
quence the remaining borane–THF complex then adds in
an unselective fashion by attacking the double bond from
both sides.
Scheme 4. Possible degradation processes of the borane–THF com-
plex. (a) Degradation mode at 5–50 °C. (b) Decomposition of
monoalkoxyboranes after in situ preparation with 1:1 mixtures of
borane–THF complex and various alcohols.
To test our hypothesis that alkoxyboranes are responsible
for the unexpected stereochemical outcome during the hy-
droboration of 3,6-dihydro-2H-1,2-oxazine syn-1a a series
of control experiments was performed. Newly purchased
“intact” borane–THF complex was treated with different
alcohols to intentionally form alkoxyboranes before the
substrate was added. Indeed, formation of the second dia-
stereomer 2c was now observed. The results indicate that
an increase of the steric bulk of the alcohol shifts the ratio
of 2a/2c towards the latter diastereomer, but the conversion
of starting material was also decreased (Scheme 5, Table 1).
The biggest impact was achieved by using tert-butyl
Subsequent Reactions
The 5-hydroxy-1,2-oxazines 2a and 2b proved to be ideal
alcohol, which resulted in a nearly 1.3:1 ratio for dia- intermediates en route to a variety of polyhydroxylated
stereomeric 1,2-oxazines 2a/2c. NMR spectra of the crude compounds. Short-time hydrogenolysis (20 min) of 2b cata-
products before the oxidation step indicate that two dia- lysed by palladium on charcoal led to the N-debenzylated
stereomers are already formed during the hydroboration 1,2-oxazine. Complete deprotection was achieved by cleav-
and exclude the possibility that the oxidation conditions be- age of the ketal in the presence of acidic ion exchange resin
ing somehow involved in the stereochemical outcome. Al- DOWEX 50 to furnish tetrahydroxylated 1,2-oxazine 3 in
though we never obtained a 1:1 ratio as observed in the 78% overall yield (Scheme 6). In order to synthesise its C-
initial experiment with “degraded” borane–THF complex, 5 epimer, the hydroxy group in 2b was first oxidised with
our experiments clearly demonstrate that formation of alk- Dess–Martin periodinane[20] to the corresponding ketone,
oxyboranes is very likely the reason for the reduced stereo- which was achieved without epimerisation at C-4. Subse-
selectivity.
quent stereoselective reduction by L-Selectride provided
Wojtkowski[19] had shown that 1:1 mixtures of alcohols epi-2b in an overall yield of 70% (Scheme 6). By applying
and borane led to equilibria of dialkoxy- and trialkoxybor- the same deprotection sequence as for 2b it was possible to
ane species with values for the equilibrium constant Kc = prepare epi-3 in a yield of 72% over both steps. Compounds
2.9–7 in favour of the trialkoxy species for sterically less of type 3 and epi-3, which we propose to name aza sugars
demanding alcohols and Kc = 0.13–0.17 in favour of the since one carbon atom of the pyran ring of carbohydrates
dialkoxyborane species for tert-butyl alcohol. Given the is replaced by a nitrogen atom, are very rare in literature.[21]
facts, that monoalkoxyboranes are fairly unstable, that alk- Their potentially very interesting biological activity de-
oxyboranes are significantly weaker reducing agents than serves more attention.[22]
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Aza, Amino and Imino Sugar Derivatives
Scheme 8. Synthesis of pyrrolidine hydrochloride 9. (a) NaH, BnBr,
DMF, r.t., overnight. (b) SmI2, THF, r.t., 3.5 h. (c) MsCl, Et3N,
CH2Cl2, r.t., 15 h. (d) pTsOH, MeOH, r.t., 2 d. (e) H2, Pd/C,
MeOH/HCl, r.t., 22 h.
Scheme 6. Syntheses of polyhydroxylated 1,2-oxazines. (a) H2, Pd/
C, MeOH, r.t., 20 min. (b) DOWEX 50, EtOH, 50 °C, 3 d. (c)
Dess–Martin periodinane, CH2Cl2, r.t., 6 h. (d) L-Selectride, THF,
–78 °C, 3 h.
For the synthesis of fully deprotected pyrrolidine deriva-
tive 13 we started from 1,2-oxazine derivative 2b bearing
the smoothly removable 2-(trimethylsilyl)ethoxy group
(Scheme 9). Here, we first cleaved the N–O bond by treat-
ment with samarium diiodide, which led to amino diol 10
in excellent yield. This intermediate was converted into the
dimesylate by using an excess of mesyl chloride. The pres-
ence of triethylamine rapidly induced the SN2 displacement
of the primary mesylate, thus leading to the desired pyrrol-
idine derivative 11 in 60% yield. The corresponding azetid-
ine derivative involving the secondary mesylate was also
formed, hence explaining the moderate yield for the pyrrol-
idine. Compound 11 was converted into the free alcohol 12
by treatment with LDA[24] in a yield of 90%. Finally, step-
wise deprotection by Lewis acid induced desilylation and
hydrogenolysis led to pyrrolidinium salt 13 with 90% yield
over both steps. Overall, this synthesis established a very
efficient approach to compound 13,[25] which is known as
moderate inhibitor of α-l-fucosidase.[26] The enantiomer of
13, which is a potent inhibitor of α-d-galactosidase and a
By a different deprotection sequence acyclic amino po-
lyol 4 was accessible (Scheme 7). First desilylation of 1,2-
oxazine 2b was performed by using BF3·OEt2 followed by
ketal cleavage under aqueous acidic conditions at elevated
temperature. Finally, reductive removal of the benzyl group
and cleavage of the N–O bond provided 4-amino-4-deoxy-
d-iditol 4 in a total yield of 80%. It should be emphasised
here that the enantiomers of the precursor 1,2-oxazines syn-
1a and syn-1b are also easily available.[4b,5d] As a conse-
quence, the smooth preparation of enantiomers of all com-
pounds mentioned in this report are possible.
Scheme 7. Conversion of 1,2-oxazine 2b into amino polyol 4. (a)
BF3·Et2O, CH2Cl2, r.t., 6 h. (b) aq. AcOH (60%), THF, 50 °C,
overnight. (c) H2, Pd/C, MeOH, r.t., 6 h.
The 1,2-oxazines 2a and 2b could also be successfully
employed for the preparation of two differently substituted
polyhydroxylated pyrrolidine derivatives (imino sugars).
Our strategy is shown in Scheme 8 illustrating the synthesis
of 5-methoxy-substituted pyrrolidinium salt 9. To avoid
side-product formation in the cyclisation step 1,2-oxazine
2a was first O-benzylated in 90% yield to afford 1,2-oxazine
derivative 5. Then the N–O bond of this intermediate was
quantitatively cleaved with samarium diiodide,[15,23] and the
resulting amino alcohol 6 underwent cyclisation by treat-
ment with mesyl chloride to furnish pyrrolidine 7 in 82%
yield for both steps. Deprotection of the side-chain diol to
give compound 8 was achieved with p-toluenesulfonic acid
followed by hydrogenation in HCl-saturated methanol,
which provided the desired pyrrolidine derivative as hydro-
chloride 9 in a yield of over 90% for the final two steps.
Scheme 9. Synthesis of pyrrolidine hydrochloride 13. (a) SmI2,
THF, r.t., 3 h. (b) MsCl, Et3N, THF, r.t., 1 d. (c) LDA, THF,
–78 °C to r.t., 7 h. (d) BF3·Et2O, CH2Cl2, r.t., 6 h. (e) H2, Pd/C,
MeOH/HCl, r.t., 1 d.
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V. Dekaris, R. Pulz, A. Al-Harrasi, D. Lentz, H.-U. Reissig
FULL PAPER
weak inhibitor of α-d-arabinosidase,[26] should also be ac-
cessible by our route due to the simple availability of the
enantiomer ent-syn-1b.[4b,5d] The high synthetic value of our
route to similar glycosidase inhibitors is evident.[27]
was separated, and the aqueous layer was extracted with Et2O. The
combined extracts were dried with MgSO4, and the solvent was
removed in vacuo. The crude product was purified by column
chromatography (silica gel; hexane/EtOAc, 1:1) to yield 2a as
colourless oil (0.914 g, 80%). [α]2D0 = +9.8 (CHCl3, c = 0.99). 1H
NMR (500 MHz, CDCl3): δ = 1.38, 1.41 (2 s, 3 H each, Me), 2.40
(br. s, 1 H, OH), 3.30 (dd, J = 3.3, 7.8 Hz, 1 H, 3-H), 3.37 (mc, 1
H, 4-H), 3.41 (s, 3 H, OMe), 3.63 (dd, J = 6.0, 11.4 Hz, 1 H, 6-
HA), 3.67–3.72 (m, 2 H, 5-H, 5Ј-HA), 3.85, 4.42 (2 d, J = 15.1 Hz,
1 H each, CH2Ph), 4.08–4.14 (m, 2 H, 5Ј-HB, 6-HB), 4.47 (br. dt,
J = 5.8, 7.8 Hz, 1 H, 4Ј-H), 7.21–7.39 (m, 5 H, Ph) ppm. 13C NMR
(126 MHz, CDCl3): δ = 26.2, 26.7 (2 q, Me), 58.0 (q, OMe), 60.3
(t, CH2Ph), 64.9 (d, C-3), 65.1 (d, C-5), 66.7 (t, C-5Ј), 71.1 (t, C-
6), 74.0 (d, C-4Ј), 81.6 (d, C-4), 108.4 (s, C-2Ј), 126.7, 128.0, 128.4,
Conclusions
3,6-Dihydro-2H-1,2-oxazines proved to be versatile pre-
cursors for the syntheses of aza, amino and imino sugars,
which mimic natural carbohydrates. An additional hydroxy
group was readily installed by hydroboration in a highly
stereoselective process when “fresh“ borane–THF complex
was used and the standard oxidative workup was employed.
The unexpected finding of a second diastereomeric 5-hy-
droxy-1,2-oxazine revealed an interesting and new opportu-
nity to alter the stereochemical outcome of the hydrobor-
ation of 1,2-oxazines. Further investigations are necessary
138.8 (3 d, s, Ph) ppm. IR (neat): ν = 3460 (OH), 2980–2930 (CH)
˜
cm–1. MS (EI): m/z (%) = 323 (7) [M+], 308 (4) [M+ – Me], 222
(100) [M+ – C5H9O2], 101 (3) [C5H9O2+], 91 (78) [Bn+]. C17H25NO5
(323.4): calcd. C 63.14, H 7.79, N 4.33; found C 61.65, H 7.53, N
4.02.
(3S,4S,5S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-5-hy-
to prove that dialkoxyboranes play indeed an integral role droxy-4-methoxy-3,4,5,6-tetrahydro-2H-1,2-oxazine (2c)
in influencing the hydroboration mechanism, but our obser-
Procedure for Using Intact BH3·THF Complex in the Presence of
vations may have general significance. Starting from 5-hy-
droxy-substituted 1,2-oxazines and by careful control of the
subsequent steps we could prepare unusual aza sugar deriv-
atives, amino polyols and polyhydroxylated pyrrolidine de-
rivatives.[28] All these compounds are of interest due to their
known or expected biological activity. Again it should be
emphasised that both enantiomers of the compounds pre-
sented in this report are easily available by the methods de-
veloped.
nBuOH: To a solution of BH3·THF (1 m in THF; 492 μL,
0.492 mmol) in THF (1 mL) nBuOH (30.1 μL, 0.329 mmol) was
added at 0 °C, and the mixture was stirred for 15 min. Then 1a
(50 mg, 0.164 mmol) dissolved in THF (1 mL) was added dropwise.
The solution was warmed to room temp. and stirred for 3 h, then
NaOH solution (2 m; 740 μL) and H2O2 (30%; 250 μL) were added.
Stirring was continued at room temp. overnight. After addition of
Na2S2O3 solution (satd.), the layers were separated, and the aque-
ous layer was extracted with Et2O. The combined extracts were
dried with MgSO4, and the solvent was removed in vacuo. The
crude product was purified by column chromatography (silica gel;
hexane/EtOAc gradient 4:1, 2:1, 1:1) to yield a mixture of 2a/2c
(2.7:1) as a colourless oil (34 mg, 65%).
Experimental Section
Procedure for Using Partially Degraded BH3·THF Complex: By a
procedure similar to that for 2a, 1a (2.70 g, 8.85 mmol) was treated
with BH3·THF (1 m in THF; 35.4 mL, 35.4 mmol), NaOH solution
(2 m; 53 mL) and H2O2 (30 %; 18 mL). Chromatography of the
crude product (silica gel, hexane/EtOAc, 2:1) and subsequent puri-
fication by HPLC yielded pure 2c (531 mg, 19%) as colourless crys-
tals and a mixture of 2a/2c (ca. 2:1) (907 mg) as a colourless oil.
M.p. 61–63 °C. [α]2D0 = +13.0 (CHCl3, c = 0.72). 1H NMR
(500 MHz, CDCl3): δ = 1.39, 1.43 (2 s, 3 H each, Me), 2.87 (br. s,
1 H, OH), 3.01 (dd, J = 3.7, 6.4 Hz, 1 H, 3-H), 3.17 (t, J = 3.7 Hz,
1 H, 4-H), 3.46 (s, 3 H, OMe), 3.62 (dd, J = 3.6, 11.8 Hz, 1 H, 6-
HA), 3.69 (mc, 1 H, 5-H), 3.77 (br. t, J ≈ 8.1 Hz, 1 H, 5Ј-HA), 3.96,
4.40 (2 d, J = 13.8 Hz, 1 H each, NCH2), 4.07 (dd, J = 6.4, 8.1 Hz,
1 H, 5Ј-HB), 4.19 (dd, J = 2.8, 11.8 Hz, 1 H, 6-HB), 4.51 (td, J =
6.4, 8.1 Hz, 1 H, 4Ј-H), 7.20–7.50 (m, 5 H, Ph) ppm. 13C NMR
(126 MHz, CDCl3): δ = 26.0, 26.4 (2 q, Me), 58.1 (q, OMe), 59.3
(t, NCH2), 65.0 (d, C-3), 66.6 (d, C-5), 67.3 (t, C-5Ј), 69.6 (t, C-6),
74.2 (d, C-4Ј), 79.2 (d, C-4), 109.0 (s, C-2Ј), 126.8, 128.0, 128.5,
General: If not differently stated all reactions were carried out un-
der Ar. The solvents used were purified by distillation using com-
mon drying agents and procedures and were transferred under Ar.
Flash chromatography: Merck silica gel 60 (230–400 mesh). NMR:
Spectra were recorded with AC 500 (Bruker), ECP 500 and
ECX 400 (Jeol) spectrometers in the solvents indicated; chemical
shifts (δ) are given in ppm relative to residual solvent peaks; cou-
pling constants (J) are given in Hz. IR: Nicolet-FT-IR spectrome-
ter 5 SXC: wavenumbers are given in cm–1. MS, HRMS: MAT 711
(EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV), CH5DF (FAB,
3 kV) (all Finnigan), Ionspec QFT-7 (ESI-FT ICRMS) (Varian)
und Agilent 6210 (ESI-TOF, 4 μL/min, 1.0 bar, 4 kV). Melting
points: Thermovar (Reichert) melting point apparatus (not cor-
rected). Elemental analyses: Elemental Analyzer (Perkin–Elmer),
Vario EL elemental analysis system. All commercially available
compounds (Acros, Lancaster, Fluka, Aldrich, TCI Europe) were
used as received unless stated otherwise. Dess–Martin periodinane
was prepared according to a previously described procedure.[20]
138.3 (3 d, s, Ph) ppm. IR (KBr): ν = 3435 (OH), 2985–2830 (CH)
˜
cm–1. MS (EI): m/z (%) = 323 (6) [M+], 308 (5) [M+ – CH3], 222
(85) [M+ – C5H9O2], 91 (100) [C7H7+], 43 (47). C17H25NO5 (323.2):
calcd. C 63.14, H 7.79, N 4.33; found C 63.03, H 7.72, N 4.19.
(3S,4R,5R,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-5-
hydroxy-4-methoxy-3,4,5,6-tetrahydro-2H-1,2-oxazine (2a): To a
solution of syn-1a (1.08 g, 3.54 mmol) in THF (70 mL) BH3·THF
(1 m in THF; 14.1 mL, 14.1 mmol) was added at –30 °C. The solu-
tion was warmed to room temp. and stirred for 3 h, then cooled to
(3S,4R,5R,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-5-
hydroxy-4-[(2ЈЈ-trimethylsilyl)ethoxy]-3,4,5,6-tetrahydro-2H-1,2-ox-
–10 °C, and NaOH solution (2 m; 21.2 mL) and H2O2 (30 %; azine (2b): A stirred solution of 1,2-oxazine 1b (500 mg, 1.28 mmol)
7.1 mL) were added. Stirring was continued at room temp. over-
night. After addition of Na2S2O3 solution (satd.), the organic layer
in dry THF (25 mL) was cooled to –30 °C. To this solution was
added dropwise a solution of the BH3·THF complex (1 m in THF;
3214
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3210–3219

Aza, Amino and Imino Sugar Derivatives
5.1 mL, 5.10 mmol). The mixture was stirred at –30 °C for 0.5 h
and then warmed up slowly to room temp. After 3 h at room temp.,
the mixture was cooled to –10 °C and then treated successively with
NaOH (2 m; 7.68 mL) and H2O2 (30%; 2.56 mL) and stirred at
this temperature for 0.5 h, then warmed to room temp. and stirred
overnight. NH4Cl solution (satd.; 10 mL) was added, and the mix-
ture was extracted with CH2Cl2, dried with Na2SO4 and concen-
trated. The crude product was subjected to column chromatog-
raphy (silica gel; hexane/EtOAc, 2:1). The pure product 2b was ob-
(121 mg, 0.114 mmol) in MeOH (8 mL) was saturated with hydro-
gen for 1 h. Then a solution of 1,2-oxazine 2b (260 mg,
0.635 mmol) in MeOH (2 mL) was added, and the mixture was
stirred under hydrogen at normal pressure and room temp. for
20 min. After filtration through a pad of Celite, the solvent was
removed in vacuo. The crude product was purified by chromatog-
raphy (silica gel; hexane/EtOAc 2:1, then 1:1, then 1:2). The respec-
tive debenzylated 1,2-oxazine (170 mg, 84 %) was isolated as a
colourless oil. [α]2D0 = –34.1 (c = 0.75, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.04 (s, 9 H, SiMe3), 0.82–0.95 (m, 2 H, CH2Si), 1.30,
tained as colourless crystals (503 mg, 96%). M.p. 82–85 °C. [α]2D0
=
–14.2 (CHCl3, c = 0.23). 1H NMR (500 MHz, CDCl3): δ = 0.03 (s, 1.35 (2 s, 3 H each, Me), 2.67 (br. s, 1 H, OH), 3.27 (dd, J = 3.3,
9 H, SiMe3), 0.87, 1.04 (2 mc, 1 H each, CH2Si), 1.38, 1.39 (2 s, 3 9.1 Hz, 1 H, 3-H), 3.32 (br. s, 1 H, 4-H), 3.47–3.53 (m, 1 H, OCH2),
H each, Me), 2.32 (br. s, 1 H, OH), 3.28 (dd, J = 3.4, 7.7 Hz,
3.54–3.61 (m, 1 H, OCH2), 3.62–3.68 (m, 2 H, 6-HA, 5Ј-HA), 3.71
1 H, 3-H), 3.47 (br. s, 1 H, 4-H), 3.57 (mc, 1 H, 6-HA), 3.62 (mc, 2 (dt, J = 3.3, 5.7 Hz, 1 H, 5-H), 4.03–4.10 (m, 2 H, 6-HB, 5Ј-HB),
H, OCH2), 3.68 (mc, 1 H, 5Ј-HA), 3.70 (mc, 1 H, 5-H), 3.85, 4.39 4.24 (br. q, J ≈ 7.5 Hz, 1 H, 4Ј-H), 5.89 (br. s, 1 H, NH) ppm. 13C
(2 d, J = 15.1 Hz, 1 H each, NCH2Ph), 4.10 (dd, J = 2.5, 10.8 Hz,
NMR (126 MHz, CDCl3): δ = –1.34 (q, SiMe3), 18.8 (t, CH2Si),
1 H, 6-HB), 4.13 (dd, J = 5.6, 8.3 Hz, 1 H, 5Ј-HB), 4.50 (br. s, 1 H, 25.7, 26.9 (2 q, Me), 61.0 (d, C-3), 65.7 (d, C-5), 67.1 (t, C-5Ј), 68.2
4Ј-H), 7.21–7.38 (m, 5 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): (t, OCH2), 71.7 (t, C-6), 73.1 (d, C-4Ј), 76.9 (d, C-4), 109.0 (s, C-
δ = –2.0 (q, SiMe3), 18.7 (t, CH2Si), 26.4, 26.8 (2 q, Me), 60.2 (t,
NCH2Ph), 64.8 (d, C-3), 66.4 (d, C-5), 67.7 (t, OCH2), 71.1 (t, C-
2Ј) ppm. IR (neat): ν = 3435, 3295 (OH, NH), 2985–2895 (CH)
˜
cm–1. HRMS (ESI-TOF): calcd. for C14H29NO5Si [M + Na]+
6), 73.8 (d, C-4Ј), 81.4 (d, C-4), 108.2 (s, C-2Ј), 126.8, 128.1, 128.4, 342.1707; found 342.1704. C14H29NO5Si (319.5): calcd. C 52.63, H
138.9 (3 d, s, Ph) ppm. IR (KBr): ν = 3430 (OH), 3080–3030
9.15, N 4.38; found C 52.37, H 9.03, N 4.43. To a solution of
this N-debenzylated 1,2-oxazine (160 mg, 0.501 mmol) acidic ion
exchange resin DOWEX 50 (640 mg; washed several times with
EtOH before usage) was added. The suspension was heated to
50 °C and stirred for 3 d. After filtration and evaporation of the
solvent, crude 1,2-oxazine 3 was isolated as an amorphous colour-
less solid. It was purified by recrystallisation with MeOH and H2O.
Pure tetrahydroxylated 1,2-oxazine 3 (84 mg, 93%) was isolated as
colourless crystals. M.p. 183–185 °C. [α]2D0 = +19.5 (H2O, c = 0.21).
1H NMR (500 MHz, D2O): δ = 3.42 (br. dd, J ≈ 1.5, 7.8 Hz, 1 H,
3-H), 3.62 (dd, J = 4.0, 6.9 Hz, 1 H, 2Ј-HA), 3.71 (mc, 1 H, 5-H),
3.69–3.82 (m, 4 H, 4-H, 6-HA, 1Ј-H, 2Ј-HB), 4.13 (br. dd, J ≈ 1.5,
12.8 Hz, 1 H, 6-HB) ppm. 13C NMR (126 MHz, D2O): δ = 58.0 (d,
C-3), 62.4 (t, C-2Ј), 65.6 (d, C-4), 67.1 (d, C-5), 70.0 (d, C-1Ј), 70.1
˜
(=CH), 2990–2890 (CH) cm–1. MS (EI): m/z (%) = 409 (5) [M+],
394 (1) [M+ – Me], 308 (100) [M+ – C2H5OSiMe3], 91 (47) [Bn+],
73 (16) [Me3Si+]. C21H35NO5Si (409.6): calcd. C 61.58, H 8.61, N
3.42; found C 61.18, H 8.58, N 3.34.
(3S,4R,5S,4ЈS)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-5-
hydroxy-4-[(2ЈЈ-trimethylsilyl)ethoxy]-3,4,5,6-tetrahydro-2H-1,2-ox-
azine (epi-2b): To a solution of 2b (520 mg, 1.28 mmol) in CH2Cl2
(2.5 mL) Dess–Martin periodinane (1.71 g, 4.03 mmol) was added.
The mixture was stirred at room temp. for 6 h. Afterwards Na2S2O3
solution (satd.; 2.5 mL) was added, and the mixture was stirred for
additional 30 min. Then it was diluted with Et2O (10 mL), washed
with H2O, and the organic layer was dried with Na2SO4. After
filtration and removal of the solvents in vacuo, the respective 1,2-
oxazinone (570 mg, quant.) was isolated as a pale yellow oil. No
purification was performed. To a solution of this 1,2-oxazinone
(122 mg, 0.299 mmol) in THF (3 mL) L-Selectride (1 m in THF;
450 μL, 0.450 mmol) was added dropwise at –78 °C. The mixture
was stirred at this temperature for 3 h and afterwards quenched
with H2O (3 mL). It was warmed to room temp. and extracted with
Et2O. After drying with Na2SO4, the solvents were removed in
vacuo. The crude product was purified by column chromatography
(silica gel; hexane/EtOAc gradient 8:1, 6:1, 4:1). 1,2-Oxazine epi-2b
was obtained as a colourless oil (86 mg, 70%). [α]2D0 = –45.3
(t, C-6) ppm. IR (KBr): ν = 3450, 3365, 3295, 3235, 3200 (OH,
˜
NH), 2960–2615 (CH) cm–1. HRMS (ESI-TOF): calcd. for
C6H13NO5Na [M + Na+] 202.0686; found 202.0690. C6H13NO5
(179.2): calcd. C 40.22, H 7.31, N 7.82; found C 40.32, H 7.24, N
7.79.
(3S,4R,5S,1ЈS)-4,5-Dihydroxy-3-(1Ј,2Ј-dihydroxyethyl)-3,4,5,6-tetra-
hydro-2H-1,2-oxazine (epi-3): By a procedure similar to that of 3,
first 1,2-oxazine epi-2b (325 mg, 0.794 mmol) was treated with hy-
drogen and Pd/C (151 mg, 0.142 mmol) in MeOH (5 mL) at room
temp. for 20 min. Purification of the crude product by chromatog-
raphy (silica gel; hexane/EtOAc 2:1, then 1:1, then 1:2) yielded the
respective debenzylated 1,2-oxazine (229 mg, 90%). [α]2D0 = –47.2 (c
= 0.35, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.00 (s, 9 H,
SiMe3), 0.95 (mc, 2 H, CH2Si), 1.34, 1.37 (2 s, 3 H each, Me), 2.32
(br. s, 1 H, OH), 3.01 (dd, J = 2.9, 6.0 Hz, 1 H, 3-H), 3.59–3.67
(m, 3 H, 4-H, OCH2), 3.77 (t, J = 6.0 Hz, 1 H, 5Ј-HA), 3.81 (mc, 1
H, 5-H), 3.86–3.90 (m, 1 H, 6-H), 4.07 (dd, J = 4.4, 6.0 Hz, 1 H,
5Ј-HB), 4.67 (mc, 1 H, 4Ј-H) ppm; NH signal could not be assigned
unambiguously. 13C NMR (126 MHz, CDCl3): δ = –1.27 (q,
SiMe3), 19.0 (t, CH2Si), 25.7, 27.0 (2 q, Me), 62.5 (d, C-3), 66.3 (d,
C-5), 67.5 (t, C-5Ј), 68.6 (d, C-4), 71.9 (t, C-6), 73.6 (d, C-4Ј), 75.4
1
(CHCl3, c = 0.40). H NMR (500 MHz, CDCl3): δ = 0.01 (s, 9 H,
SiMe3), 0.94 (mc, 2 H, CH2Si), 1.39, 1.40 (2 s, 3 H each, Me), 2.32
(br. s, 1 H, OH), 3.22 (dd, J = 5.3, 8.4 Hz, 1 H, 3-H), 3.58–3.63
(m, 2 H, OCH2), 3.72 (t, J = 8.8 Hz, 1 H, 5Ј-HA), 3.78 (dd, J =
3.5, 5.4 Hz, 1 H, 4-H), 3.82 (mc, 1 H, 5-H), 3.87–3.96 (m, 2 H, 6-
H), 3.98, 4.32 (2 d, J = 14.9 Hz, 1 H each, NCH2), 4.09 (d, J =
5.4, 8.8 Hz, 1 H, 5Ј-HB), 4.99 (mc, 1 H, 4Ј-H), 7.20–7.24, 7.27–7.31,
7.34–7.38 (3 m, 5 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ =
1.27 (q, SiMe3), 18.7 (t, CH2Si), 26.5, 27.1 (2 q, Me), 60.5 (t,
NCH2), 64.9 (d, C-3), 66.2 (d, C-5), 67.4 (t, OCH2), 68.0 (t, C-5Ј),
72.7 (t, C-6), 73.7 (d, C-4Ј), 77.8 (d, C-4), 107.7 (s, C-2Ј), 126.9,
128.2, 128.5, 139.4 (3 d, s, Ph) ppm. IR (neat): ν = 3475 (OH),
˜
(t, OCH ), 108.7 (s, C-2Ј) ppm. IR (neat): ν = 3450, 3295 (OH,
˜
2
3085–3030 (=CH), 2985–2900 (CH) cm–1. HRMS (ESI-TOF):
calcd. for C21H35NO5SiNa [M + Na+] 432.2177; found 432.2180.
C21H35NO5Si (409.6): calcd. C 61.58, H 8.61, N 3.42; found C
61.84, H 6.26, N 3.70.
NH), 2985–2895 (CH) cm–1. HRMS (ESI-TOF): calcd. for
C14H29NO5Si [M + Na]+ 342.1707; found 342.1700. This N-deben-
zylated 1,2-oxazine (184 mg, 0.576 mmol) was then treated with
DOWEX 50 (732 mg) in EtOH (5 mL) at 50 °C for 3 d. Crude epi-
(3S,4R,5R,1ЈS)-4,5-Dihydroxy-3-(1Ј,2Ј-dihydroxyethyl)-3,4,5,6-tetra- 3 was isolated as a pale yellow oil and purified by precipitation
hydro-2H-1,2-oxazine (3): A stirred solution of Pd on charcoal from CH3CN and MeOH. epi-3 (83 mg, 80%) was isolated as an
Eur. J. Org. Chem. 2011, 3210–3219
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3215

V. Dekaris, R. Pulz, A. Al-Harrasi, D. Lentz, H.-U. Reissig
FULL PAPER
amorphous colourless solid. M.p. 132–134 °C. [α]2D0 = +36.4 (H2O,
c = 0.47). 1H NMR (500 MHz, D2O): δ = 3.16 (dd, J = 1.5, 7.9 Hz,
1 H, 3-H), 3.65 (dd, J = 6.5, 12.6 Hz, 1 H, 6-HA), 3.68–3.78 (m, 3
H, 1Ј-H, 2Ј-H), 3.80–3.86 (m, 2 H, 5-H, 6-HB), 3.99 (mc, 1 H, 4-
H) ppm. 13C NMR (101 MHz, D2O): δ = 61.5 (d, C-3), 62.2 (t, C-
2Ј), 65.7 (d, C-4), 66.3 (t, C-6), 68.1 (d, C-5), 69.7 (d, C-1Ј) ppm.
(m, 5 H, 1-H, 2-H, 6-H), 3.88 (mc, 1 H, 5-H), 3.94 (mc, 1 H, 3-H)
ppm. 13C NMR (CD3OD, 126 MHz): δ = 57.1 (d, C-4), 63.8 (t, C-
1), 64.7 (t, C-6), 78.3 (d, C-2, C-3), 81.1 (d, C-5) ppm. IR (neat):
ν = 3435–3355 (OH), 2955–2845 (CH), 1250 (CO) cm–1. MS (EI):
˜
m/z (%) = 182 (8) [M+ + H], 164 (2) [M+ + H – H2O], 132 (12)
[C5H10NO3+]. HRMS (EI): calcd. for C6H15NO5 [M+ – 49]
IR (KBr): ν = 3475, 3430, 3350, 3205, 3165 (OH, NH), 2925–2875 132.0661; found 132.0662.
˜
(CH) cm–1. HRMS (ESI-TOF): calcd. for C6H14NO5 [M + H+]:
180.0867; found 180.0865. C6H13NO5 (179.2): calcd. C 40.22, H
7.31, N 7.82; found C 39.90, H 6.64, N 7.70.
(3S,4R,5R,4ЈS)-2-Benzyl-5-benzyloxy-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-diox-
olan-4Ј-yl)-4-methoxy-3,4,5,6-tetrahydro-1,2-oxazine (5): A solution
of 2a (0.300 g, 0.928 mmol) in DMF (8 mL) was added to NaH
(60% in mineral oil; 0.056 g, 1.39 mmol) at 0 °C. Benzyl bromide
(0.198 g, 1.16 mmol) was added and the solution was stirred at
room temp. overnight. H2O (10 mL) was added, the aqueous layer
was extracted with Et2O (3 ϫ 10 mL), and the combined extracts
were dried with MgSO4. After filtration, the solvent was removed
in vacuo. The crude product was purified by column chromatog-
raphy (silica gel; hexane/EtOAc, 6:1) giving rise to compound 5 as
colourless oil (0.346 g, 90%). [α]2D0 = +8.0 (CHCl3, c = 1.7). 1H
NMR (500 MHz, CDCl3): δ = 1.37, 1.40 (2 s, 3 H each, Me), 3.31
(dd, J = 3.6, 8.1 Hz, 1 H, 3-H), 3.33 (s, 3 H, OMe), 3.40 (mc, 1 H,
4-H), 3.45 (dt, J = 3.5, 5.4 Hz, 1 H, 5-H), 3.67 (dd, J = 8.3, 9.2 Hz,
1 H, 5Ј-HA), 3.75 (dd, J = 5.4, 11.9 Hz, 1 H, 6-HA), 3.98 (dd, J =
3.5, 11.9 Hz, 1 H, 6-HB), 4.09 (dd, J = 5.5, 8.3 Hz, 1 H, 5Ј-HB),
4.39–4.44 (m, 1 H, 4Ј-H), 3.84, 4.41 (2 d, J = 14.9 Hz, 1 H each,
(2R,3R,4S,5S)-4-Aminohexane-1,2,3,5,6-pentaol (4): To a solution
of hydroborated 1,2-oxazine 2b (300 mg, 0.730 mmol) in CH2Cl2
(3 mL) at 0 °C was added BF3·Et2O (264 μL, 2.20 mmol), and the
resulting solution was stirred at 0 °C for 5 min, then at room temp.
for 6 h, and then quenched with H2O (ca. 3 mL). The two layers
were separated, and the aqueous layer was extracted several times
with EtOAc. The organic layer was dried with MgSO4 and concen-
trated under vacuum. Column chromatography (silica gel; hexane/
EtOAc, 1:5) gave rise to the respective desilylated 1,2-oxazine
(221 mg, 98%) as colourless crystals. M.p. 74–76 °C. [α]2D2 = +66.3
1
(c = 0.24, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.41, 1.83 (2
s, 3 H each, Me), 2.54, 2.97 (2 br. s, 1 H each, OH), 3.28 (dd, J =
1.9, 7.6 Hz, 1 H, 3-H), 3.56 (mc, 1 H, 5-H), 3.63 (mc, 1 H, 4-H),
3.68 (dd, J = 2.0, 12.6 Hz, 1 H, 6-HB), 3.78 (mc, 1 H, 5Ј-HB), 3.80
(d, J = 15.1 Hz, 1 H, NCH2Ph), 4.12 (dd, J = 1.6, 12.6 Hz, 1 H,
6-HA), 4.22 (mc, 1 H, 5Ј-HA), 4.26 (mc, 1 H, 4Ј-H), 4.42 (d, J =
15.1 Hz, 1 H, NCH2Ph), 7.22–7.37 (m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 26.4, 26.8 (2 q, Me), 59.8 (t, NCH2Ph),
63.3 (d, C-3), 66.3 (d, C-4), 66.4 (t, C-5Ј), 68.0 (d, C-5), 71.7 (t, C-
6), 74.9 (d, C-4Ј), 109.2 (s, C-2Ј), 126.8, 128.1, 128.4, 138.8 (3 d, s,
NCH2Ph), AB system (δA = 4.63 ppm, δB = 4.59 ppm, JAB
=
12.1 Hz, 2 H, OCH2Ph), 7.19–7.40 (m, 10 H, Ph) ppm. 13C NMR
(126 MHz, CDCl3): δ = 26.2, 26.7 (2 q, Me), 58.0 (q, OMe), 60.2
(t, NCH2Ph), 65.5 (d, C-3), 66.7 (t, C-5Ј), 68.8 (t, C-6), 71.8 (t,
OCH2Ph), 68.7, 74.2, 80.1 (3 d, C-4, C-5, C-4Ј), 108.3 (s, C-2Ј),
126.5, 127.6, 127.7, 127.9, 128.3, 128.3, 138.2, 139.0 (6 d, 2 s, Ph)
ppm. IR (neat): ν = 2985–2830 (CH) cm–1. MS (EI): m/z (%) = 413
˜
Ph) ppm. IR (KBr): ν = 3535–3430 (OH), 2990–2890 (CH) cm–1.
˜
(4) [M+], 398 (2) [M+ – Me], 312 (100) [M+ – C5H9O2], 178 (12),
91 (36) [Bn+]. C24H31NO5 (413.5): calcd. C 69.71, H 7.56, N 3.39;
found C 69.44, H 7.47, N 3.22.
MS (EI): m/z (%) = 309 (5) [M+], 294 (4) [M+ – CH3], 208 (100)
[M+ – C2H5OSiMe3], 91 (47) (CH2Ph+]. HRMS (EI): calcd. for
C16H23NO5 [M+] 309.15762; found 309.15933. C16H23NO5 (309.4):
calcd. C 62.12, H 7.22, N 4.50; found C 62.46, H 7.22, N 4.27.
This desilylated 1,2-oxazine (290 mg, 0.940 mmol) was dissolved in
a mixture of AcOH/H2O (60:40; 18 mL) and THF (9 mL). After
stirring at 50 °C overnight, the solvent was co-evaporated with tol-
uene. The crude product was purified by column chromatography
(silica gel; CH2Cl2/MeOH, 4:1) to give the respective tetrahy-
droxylated 1,2-oxazine 207 mg (82%) as colourless crystals. M.p.
43–45 °C. [α]2D2 = +39.3 (c = 0.40, MeOH). 1H NMR (500 MHz,
CD3OD): δ = 3.28 (dd, J = 2.7, 6.5 Hz, 1 H, 3-H), 3.57–3.61 (m, 2
H, 5-H, 6-HB), 3.75 (dd, J = 6.3, 11.4 Hz, 1 H, 1-HB), 3.80 (d, J =
14.4 Hz, 1 H, NCH2Ph), 3.82 (dd, J = 3.7, 11.4 Hz, 1 H, 1-HA),
3.88 (dd, J = 2.7, 4.3 Hz, 1 H, 4-H), 3.97 (ddd, J = 3.7, 6.3, 6.5 Hz,
1 H, 2-H), 4.07 (dd, J = 3.7, 13.1 Hz, 1 H, 6-HA), 4.32 (d, J =
14.4 Hz, 1 H, NCH2Ph), 7.15–7.39 (m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CD3OD): δ = 60.2 (t, NCH2Ph), 65.0 (t, C-2Ј), 67.1 (d,
C-3), 69.3 (d, C-5), 70.0 (d, C-4), 70.2 (t, C-6), 71.9 (d, C-1Ј), 127.7,
(4S,1ЈS,2ЈR,3ЈR)-4-(1Ј-Benzylamino-3Ј-benzyloxy-4Ј-hydroxy-2Ј-
methoxybut-1Ј-yl)-2,2-dimethyl-1,3-dioxolane (6): 1,2-Diiodoethane
(2.48 g, 8.80 mmol) and samarium (1.65 g, 11.0 mmol) were trans-
ferred into a dry flask under argon. THF (50 mL) was added, and
the solution was stirred. After the solution had turned blue, the
mixture was stirred at room temp. for 2 h. 1,2-Oxazine 5 (0.910 g,
2.20 mmol) was added, and the reaction mixture was stirred at
room temp. for 3.5 h, then quenched with NaHCO3 (satd.; 20 mL)
solution. The filtrate was decanted from the residue, and the sol-
vent was removed to yield amino alcohol 6 (495 mg, 98%) as pale
yellow oil. [α]2D0 = –7.8 (CHCl3, c = 1.2). 1H NMR (500 MHz,
CDCl3): δ = 1.36, 1.42 (2 s, 3 H each, Me), 3.08 (dd, J = 2.2,
7.5 Hz, 1 H, 1Ј-H), 3.35 (s, 3 H, OMe), 3.41 (dd, J = 2.2, 6.6 Hz,
1 H, 2Ј-H), 3.64 (td, J = 4.0, 6.6 Hz, 1 H, 3Ј-H), 3.72 (d, J = 4.0 Hz,
2 H, 4Ј-H), 3.77 (dd, J = 7.5, 8.3 Hz, 1 H, 5-HA), 4.02 (dd, J = 6.3,
8.3 Hz, 1 H, 5-HB), 3.98, 4.03 (2 d, J = 12.6 Hz, 1 H each,
NCH2Ph), 4.11 (br. s, 2 H, NH, OH), 4.40 (dt, J = 6.3, 7.5 Hz, 1
H, 4-H), 4.59, 4.69 (2 d, J = 11.8 Hz, 1 H each, OCH2Ph), 7.23–
7.35 (m, 10 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 25.3,
26.5 (2 q, Me), 51.6 (t, NCH2Ph), 58.0 (d, C-1Ј), 59.2 (q, OMe),
59.6 (t, C-4Ј), 67.1 (t, C-5), 71.9 (t, OCH2Ph), 76.1 (d, C-4), 77.9
(d, C-3Ј), 81.4 (d, C-2Ј), 108.9 (s, C-2), 127.3, 127.5, 127.7, 128.2,
128.9, 129.6, 140.2 (3 d, s, Ph) ppm. IR (KBr): ν = 3430–3365 (O–
˜
H), 3060–3030 (=CH), 2980–2880 (C–H) cm–1. MS (EI): m/z (%)
= 270 (14) [M+ + H], 208 (30) [M+ – C2H5O2], 91 (62) [CH2Ph+].
C13H19NO5 (269.3): C 57.98, H 7.11, N 5.20; C 57.60, H 7.03, N
5.18. A stirred suspension of Pd on charcoal (150 mg, 0.140 mmol)
in MeOH (25 mL) was saturated with hydrogen for 1 h. Then a
solution of the tetrahydroxylated 1,2-oxazine (100 mg, 0.371 mmol)
in MeOH (10 mL) was added, and the mixture was stirred under
hydrogen at normal pressure at room temp. for 6 h. Filtration
through a pad of Celite and removal of the solvent in vacuo yielded
the amino alcohol 4 (76 mg, quant.) as a colourless oil. The product
128.4, 128.4, 138.2, 138.8 (6 d, 2 s, Ph) ppm. IR (neat): ν = 3340
˜
(NH, OH), 3030–2935 (CH) cm–1. MS (EI): m/z (%) = 415 (Ͻ 1)
[M+], 400 (3) [M+ – Me], 314 (5) [M+ C5H9O2], 220 (50), 91 (100)
[Bn+]. C24H33NO5 (415.5): calcd. C 69.37, H 8.00, N 3.37; found
C 69.07, H 7.95, N 3.08.
1
could not be purified. [α]2D2 = –66.8 (MeOH, c = 0.33). H NMR
(2S,3R,4R,4ЈS)-1-Benzyl-4-benzyloxy-2-(2Ј,2Ј-dimethyl-1Ј,3Ј-diox-
(500 MHz, CD3OD): δ = 3.47 (t, J = 4.9 Hz, 1 H, 4-H), 3.60–3.74 olan-4Ј-yl)-3-methoxypyrrolidine (7): The crude amino alcohol 6
3216
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3210–3219

Aza, Amino and Imino Sugar Derivatives
(0.913 g, 2.20 mmol) was dissolved CH2Cl2 (40 mL), and mesyl (500 MHz, CD3OD): δ = 3.14 (d, J = 12.2 Hz, 1 H, 5-HA), 3.42 (s,
chloride (0.378 g, 3.30 mmol) and triethylamine (1.34 g, 13.2 mmol)
were added. After stirring at room temp. for 15 h, H2O (20 mL)
was added. The two layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 ϫ 30 mL), the combined extracts
were dried with MgSO4, and the solvents were removed in vacuo.
The crude product 7 was purified by column chromatography (alu-
minum oxide; hexane/EtOAc, 7:1). Compound 7 was obtained as
a colourless oil (0.720 g, 82%). [α]2D0 = +91.7 (CHCl3, c = 0.96). 1H
NMR (500 MHz, CDCl3): δ = 1.35, 1.43 (2 s, 3 H each, Me), 2.25
(dd, J = 6.1, 10.2 Hz, 1 H, 5-HA), 2.92 (dd, J = 6.3, 8.0 Hz, 1 H,
2-H), 3.30 (s, 3 H, OMe), 3.31 (dd, J = 6.1, 10.2 Hz, 1 H, 5-HB),
3.42, 4.49 (2 d, J = 13.3 Hz, 1 H each, NCH2Ph), 3.63 (dd, J =
2.4, 6.3 Hz, 1 H, 3-H), 3.64 (t, J = 8.0 Hz, 1 H, 5Ј-HA), 3.92 (dt, J
= 2.4, 6.1 Hz, 1 H, 4-H), 4.19 (dd, J = 6.4, 8.0 Hz, 1 H, 5Ј-HB),
4.36 (dt, J = 6.4, 8.0 Hz, 1 H, 4Ј-H), AB system (δA = 4.44 ppm,
δB = 4.43 ppm, JAB = 11.6 Hz, 2 H, OCH2Ph), 7.21–7.38 (m, 10
H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 25.5, 26.7 (2 q,
Me), 57.1 (q, OMe), 57.5 (t, C-5), 59.2 (t, NCH2Ph), 67.5 (t, C-5Ј),
68.7 (d, C-2), 71.4 (t, OCH2Ph), 80.8 (d, C-4), 86.5 (d, C-3), 108.7
(s, C-2Ј), 126.7, 127.5, 127.7, 128.0, 128.4, 129.1, 137.8, 139.1 (6 d,
3 H, OMe), 3.46 (dd, J = 3.7, 12.2 Hz, 1 H, 5-HB), 3.59 (dd, J =
4.1, 11.6 Hz, 1 H, 2Ј-HA), 3.68 (dd, J = 3.5, 11.6 Hz, 1 H, 2Ј-HB),
3.80–3.84 (m, 2 H, 2-H, 3-H), 4.01 (td, J ≈ 4.0, 8.3 Hz, 1 H, 1Ј-H),
4.52 (d, J = 3.7 Hz, 1 H, 4-H) ppm. 13C NMR (126 MHz,
CD3OD): δ = 52.0 (t, C-5), 58.5 (q, OMe), 64.4 (d, C-2), 64.7 (t,
C-2Ј), 69.0 (d, C-1Ј), 72.0 (d, C-4), 84.9 (d, C-3) ppm. MS (EI):
m/z (%) = 212 (Ͻ 1) [M+ – H], 177 (1) [M+ – HCl], 160 (1) [M+
–
HCl – OH], 146 (7) [M+ – HCl – CH2OH], 116 (100) [M+ – HCl –
C2H5O2], 36 (63) [HCl].
(4S,1ЈR,2ЈR,3ЈR)-4-{1Ј-Benzylamino-3Ј,4Ј-dihydroxy-2Ј-[2-(trimeth-
ylsilyl)ethoxy]but-1Ј-yl}-2,2-dimethyl-1,3-dioxolane (10): By a pro-
cedure similar to that for 5, compound 2b (500 mg, 1.22 mmol) was
treated with samarium diiodide generated from samarium (656 mg,
4.39 mmol) and 1,2-diiodoethane (1.14 g, 4.03 mmol) for 3 h yield-
ing amino alcohol 10 (495 mg, 98%) as a pale yellow oil. This prod-
1
uct was not further purified and used directly for the next step. H
NMR (500 MHz, CDCl3): δ = 0.00 (s, 9 H, SiMe3), 0.54 (mc, 2 H,
CH2Si), 1.32, 1.38 (2 s, 3 H each, Me), 2.90 (dd, J = 2.5, 7.4 Hz, 1
H, 1Ј-H), 3.32 (dd, J = 2.5, 5.2 Hz, 1 H, 2Ј-H), 3.43–3.60 (m, 4 H,
5-HA, 4Ј-HA, OCH2), 3.76 (d, J = 13.7 Hz, 1 H, NCH2Ph), 3.77
(mc, 1 H, 3Ј-H), 3.86 (mc, 1 H, 4Ј-HB), 3.92 (d, J = 13.7 Hz, 1 H,
NCH2Ph), 4.03 (dd, J = 6.3, 8.4 Hz, 1 H, 5-HB), 4.34 (dt, J = 6.3,
7.4 Hz, 1 H, 4-H), 7.21–7.38 (m, 5 H, Ph) ppm; signal of OH not
detected. 13C NMR (126 MHz, CDCl3): δ = –1.5 (q, SiMe3), 18.8
(t, CH2Si), 25.4, 26.7 (2 q, Me), 51.6 (t, C-4Ј), 59.0 (d, C-1Ј), 63.0
(t, CH2Ph), 67.1 (t, C-5), 68.4 (t, OCH2), 71.0 (d, C-3Ј), 77.8 (d,
C-4), 79.3 (d, C-2Ј), 108.8 (s, C-2), 127.9, 129.2, 129.3, 139.0 (3 d,
2 s, Ph) ppm. IR (neat): ν = 3030–2820 (CH) cm–1. MS (EI): m/z
˜
(%) = 397 (Ͻ 1) [M+], 382 (3) [M+ – Me], 296 (100) [M+ – C5H9O2],
91 (39) [Bn+]. C24H31NO4 (397.5): calcd. C 72.52, H 7.86, N 3.52;
found C 72.29, H 7.66, N 3.46.
(2S,3R,4R,4ЈS)-1-Benzyl-4-benzyloxy-2-(1Ј,2Ј-dihydroxyethyl)-3-
methoxypyrrolidine (8): To a stirred solution of 7 (0.530 g,
1.33 mmol) in MeOH (10 mL) a solution of p-toluenesulfonic acid
(0.380 g, 2.00 mmol) in MeOH (5 mL) was added. The solution
was stirred at room temp. for 2 d, and then aqueous NaHCO3 solu-
tion (satd.) was added. The aqueous layer was extracted with
CH2Cl2 (3 ϫ 10 mL), and the combined extracts were dried with
MgSO4. After evaporation of the solvent in vacuo, the crude prod-
uct was purified by column chromatography (silica gel; CH2Cl2/
MeOH, 9:1) giving rise to pure pyrrolidine 8 (0.470 g, 99%) as a
colourless oil. [α]2D0 = +15.8 (CHCl3, c = 0.48). 1H NMR (500 MHz,
CDCl3): δ = 2.47 (dd, J = 6.3, 10.6 Hz, 1 H, 5-HA), 3.19 (dd, J =
5.8, 10.7 Hz, 1 H, 5-HB), 3.28 (dd, J = 4.6, 7.9 Hz, 1 H, 2-H), 3.43
(s, 3 H, OMe), 3.66 (dd, J = 5.8, 11.0 Hz, 1 H, 2Ј-HA), 3.74 (dd, J
= 4.6, 11.0 Hz, 1 H, 2Ј-HB), 3.87 (td, J = 4.6, 5.8 Hz, 1 H, 1Ј-H),
3.97 (dd, J = 5.4, 7.9 Hz, 1 H, 3-H), 3.63, 4.03 (2 d, J = 12.9 Hz,
1 H each, NCH2Ph), 4.06 (br. q, J ≈ 5.8 Hz, 1 H, 4-H), AB system
(δA = 4.51 ppm, δB = 4.53 ppm, JAB = 11.7 Hz, 2 H, OCH2Ph),
7.25–7.35 (m, 10 H, Ph) ppm; the OH signals have not been ob-
served. 13C NMR (126 MHz, CDCl3): δ = 54.8 (t, C-5), 58.5 (q,
OMe), 61.6 (t, NCH2Ph), 65.1 (d, C-2), 65.3 (t, C-2Ј), 68.7 (d, C-
1Ј), 71.9 (t, OCH2Ph), 82.0 (d, C-4), 85.8 (d, C-3), 127.3, 127.4,
127.7, 128.0, 128.4, 128.8, 137.9, 138.2 (6 d, 2 s, Ph) ppm. IR (neat):
s, Ph) ppm. IR (neat): ν = 3340 (OH), 3090–3030 (=CH), 2980–
˜
2890 (CH) cm–1. MS (EI): m/z (%) = 412 (4) [M+], 101 (18)
[C2H5OSiMe3+], 91 (86) [CH2Ph+], 73 (100) [SiMe3+].
(2S,3R,4R,4ЈS)-1-Benzyl-2-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4-yl)-3-[2-
(trimethylsilyl)ethoxy]-4-methylsulfonyloxypyrrolidine (11): By a
procedure similar to that for 6, crude 10 (500 mg, 1.21 mmol) was
treated with mesyl chloride (261 mg, 2.38 mmol) and triethylamine
(370 mg, 3.66 mmol) in CH2Cl2 (30 mL) for 1 d. Purification was
performed by column chromatography (silica gel; hexane/EtOAc,
3:1) to yield mesylate 11 (340 mg, 60%) as colourless crystals. M.p.
55–57 °C. [α]2D2 = +67.5 (CHCl3, c = 0.35). 1H NMR (500 MHz,
CDCl3): δ = 0.00 (s, 9 H, SiMe3), 0.89 (mc, 2 H, CH2Si), 1.37, 1.42
(2 s, 3 H each, Me), 2.43 (dd, J = 5.2, 11.1 Hz, 1 H, 5-HA), 2.91
(s, 3 H, Ms), 2.97 (dd, J = 6.4, 7.8 Hz, 1 H, 2-H), 3.36–3.45 (m, 2
H, OCH2, 5-HB), 3.54 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.63 (t, J ≈
8.0 Hz, 1 H, 5Ј-HA), 3.70 (mc, 1 H, OCH2), 3.91 (dd, J = 2.6,
6.4 Hz, 1 H, 3-H), 4.16 (dd, J = 6.4, 8.0 Hz, 1 H, 5Ј-HB), 4.34 (dt,
J = 6.4, 7.8 Hz, 1 H, 4Ј-H), 4.39 (d, J = 13.5 Hz, 1 H, NCH2Ph),
4.93 (ddd, J = 2.6, 5.2, 6.3 Hz, 1 H, 4-H), 7.22–7.39 (m, 5 H, Ph)
ppm. 13C NMR (126 MHz, CDCl3): δ = –1.2 (q, SiMe3), 18.2 (t,
CH2Si), 26.2, 27.0 (2 q, Me), 38.3 (q, Ms), 56.1 (t, C-5), 59.0 (t,
NCH2Ph), 72.3 (d, C-2), 72.4 (t, C-5Ј), 72.6 (t, OCH2), 77.5 (d, C-
4Ј), 81.2 (d, C-4), 83.3 (d, C-3), 108.0 (s, C-2Ј), 126.9, 128.2, 129.0,
ν = 3415 (OH), 2930–2830 (CH) cm–1. MS (EI): m/z (%) = 357
˜
(Ͻ 1) [M+], 326 (6) [M+ – OMe], 296 (100) [M+ – C2H5O2], 91 (85)
[Bn+]. HRMS (EI): calcd. for C20H24NO3 [M+ – OMe] 326.1756;
found 326.1783.
138.7 (3 d, s, Ph) ppm. IR (KBr): ν = 3025–2950 (=CH), 2895–
˜
(2S,3R,4R,4ЈS)-2-(1Ј,2Ј-Dihydroxyethyl)-3-methoxy-4-hydroxypyr-
rolidine Hydrochloride (9): A stirred suspension of Pd/C (10 %,
0.101 g, 0.095 mmol) in MeOH (10 mL) was saturated with hydro-
gen for 1 h. Then HCl/MeOH (satd., 0.6 mL) and a solution of
pyrrolidine 8 (0.170 g, 0.476 mmol) in MeOH (5 mL) were added,
and the mixture was stirred under hydrogen at normal pressure at
room temp. for 22 h. Filtration through a pad of Celite and removal
of the solvent in vacuo yielded spectroscopically pure hydrochloride
9 (0.130 g, 100% = 0.102 g) as a pale yellow oil. Since the mass of
the product isolated is higher than 100%, it probably contains more
than 1 equiv. of HCl. [α]2D0 = +18.4 (MeOH, c = 1.79). 1H NMR
2805 (CH), 1030 (SO2) cm–1. MS (EI): m/z (%) = 471 (Ͻ 1) [M+],
456 (2) [M+ – CH3], 370 (100) [M+ – C2H5OSiMe3], 101 (5)
[C2H5OSiMe3+], 91 (75) [C7H7+], 73 (32) [Me3Si+]. HRMS (EI):
calcd. for C22H37NO6SSi [M+] 471.2111; found 471.2144.
(2S,3R,4R,4ЈS)-1-Benzyl-2-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4-yl)-4-
hydroxy-3-[2-(trimethylsilyl)ethoxy]pyrrolidine (12): nBuLi (2.0 m in
hexanes, 0.210 mL, 0.410 mmol) was added to diisopropylamine
(0.060 mL, 0.410 mmol) in THF (1 mL) at –78 °C. At this tempera-
ture mesylated pyrrolidine derivative 11 (120 mg, 0.257 mmol) was
added to the previously generated LDA solution. The reaction mix-
Eur. J. Org. Chem. 2011, 3210–3219
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3217

V. Dekaris, R. Pulz, A. Al-Harrasi, D. Lentz, H.-U. Reissig
FULL PAPER
ture was stirred at –78 °C and then at room temp. for 7 h and then
quenched with NH4Cl solution (satd.) followed by addition of
EtOAc. The two layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried,
filtered and concentrated to yield pyrrolidine derivative 12 (91 mg,
Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie and the Bayer Schering Pharma
AG for financial support. We are grateful to Holger Erdbrink and
Luise Schefzig for experimental help and Dr. Reinhold Zimmer for
his assistance during the preparation of the manuscript. We also
thank Amélie Castiglia, Jeanne Heller and Prof. Volker Jäger (Uni-
versität Stuttgart) for the testing of compounds 3 and epi-3 as gly-
cosidase inhibitors.
1
90%) as colourless oil. [α]2D2 = +61.6 (CHCl3, c = 0.35). H NMR
(500 MHz, CDCl3): δ = 0.00 (s, 9 H, SiMe3), 0.90 (mc, 2 H, CH2Si),
1.37, 1.42 (2 s, 3 H each, Me), 2.19 (dd, J = 6.0, 10.2 Hz, 1 H, 5-
HA), 2.98 (dd, J = 7.1, 8.0 Hz, 1 H, 2-H), 3.24 (dd, J = 6.2, 10.2 Hz,
1 H, 5-HB), 3.39 (ddd, J = 5.5, 9.4, 10.7 Hz, 1 H, OCH2), 3.54 (d,
J = 13.5 Hz, 1 H, NCH2Ph), 3.58 (mc, 1 H, OCH2), 3.60 (dd, J =
3.4, 6.6 Hz, 1 H, 5Ј-HA), 3.63 (d, J = 8.0 Hz, 1 H, 3-H), 4.17 (mc,
2 H, 4-H, 5Ј-HB), 4.35 (mc, 1 H, 4Ј-H), 4.36 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 7.22–7.39 (m, 5 H, Ph) ppm. 13C NMR (126 MHz,
CDCl3): δ = –1.4 (q, SiMe3), 18.6 (t, CH2Si), 25.4, 26.8 (2 q, Me),
59.2 (t, C-5), 59.3 (t, NCH2Ph), 67.3 (t, OCH2), 67.7 (t, C-5Ј), 68.0
(d, C-2), 74.8 (d, C-4), 78.2 (d, C-4Ј), 86.2 (d, C-3), 108.6 (s, C-2Ј),
[1] a) W. Schade, H.-U. Reissig, Synlett 1999, 632–634; b) M.
Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-Harrasi, L.
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126.7, 128.0, 129.1, 138.7 (3 d, s, Ph) ppm. IR (neat): ν = 3435
˜
(OH), 3085–3025 (=CH), 2895–2805 (CH), 1250 (CO) cm–1. MS
(EI): m/z (%) = 393 (1) [M+], 378 (2) [M+ – CH3], 350 (1) [M+
–
SiMe3], 292 (82) [M+ – C2H5O2], 91 (100) [C7H7+], 73 (49) [Me3Si+].
HRMS (EI): calcd. for C21H35NO4Si [M+]: 393.2336; found
393.2353.
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3498–3500; b) B. Bressel, B. Egart, A. Al-Harrasi, R. Pulz, H.-
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(2S,3R,4R,2ЈS)-2-(1,2-Dihydroxyethyl)pyrrolidine-3,4-diol Hydro-
chloride (13): To a solution of pyrrolidine derivative 12 (70 mg,
0.180 mmol) in CH2Cl2 (1 mL) at 0 °C was added BF3·Et2O (63 μL,
0.590 mmol), and the resulting solution was stirred at 0 °C for
5 min, then at room temp. for 6 h, and then quenched with H2O
(ca. 1 mL). The two layers were separated, and the aqueous layer
was extracted several times with EtOAc. The organic layer was
dried with MgSO4 and concentrated under vacuum to yield the
respective O-deprotected compound (41 mg, 90%) as colourless oil.
[α]2D2 = +10.0 (c = 0.90, MeOH). H NMR (500 MHz, CD3OD): δ
1
= 3.22 (dd, J = 1.6, 12.5 Hz, 1 H, 5-HB), 3.48 (dd, J = 3.0, 12.5 Hz,
1 H, 5-HA), 3.69 (dd, J = 3.8, 11.7 Hz, 1 H, 1Ј-HB), 3.79 (dd, J =
3.2, 11.7 Hz, 1 H, 1Ј-HA), 3.95 (dd, J = 3.8, 10.1 Hz, 1 H, 2-H),
4.21 (d, J = 12.6 Hz, 1 H, NCH2Ph), 4.24 (dd, J = 1.6, 3.0 Hz, 1
H, 4-H), 4.30 (mc, 2 H, 3-H, 2Ј-H), 4.99 (d, J = 12.6 Hz, 1 H,
NCH2Ph), 7.46–7.54 (m, 5 H, Ph) ppm. 13C NMR (125 MHz,
CD3OD): δ = 57.6 (t, C-5), 64.7 (t, C-1Ј), 65.0 (t, NCH2Ph), 70.2
(d, C-2Ј), 74.5 (d, C-2), 75.1 (d, C-3), 76.6 (d, C-4), 130.3, 131.0,
131.9, 139.4 (3 d, s, Ph) ppm. IR (neat): ν = 3475, 3445 (O–H),
˜
3090–3030 (=C–H), 2960–2855 (C–H) cm–1. MS (FAB): m/z (%) =
254 (64) [M+ + H], 236 (6) [M+ – OH], 91 (100) [C7H7+]. C13H19NO
(253.3): C 61.64, H 7.56, N 5.53; C 60.97, H 7.31, N 5.43. A stirred
solution of Pd on charcoal (12 mg, 0.060 mmol) in MeOH (2 mL)
was saturated with hydrogen for 1 h. Then a solution of the O-
deprotected compound (21 mg, 0.083 mmol) in MeOH (2 mL) was
added followed by addition of a methanolic HCl solution (1 mL),
and the mixture was stirred under hydrogen at normal pressure at
room temp. for 1 d. Filtration through a pad of Celite and removal
of the solvent in vacuo yielded hydrochloride 13 in (17 mg, quant.)
as pale yellow crystals. M.p. 153–155 °C. [α]2D0 = +3.7 (MeOH, c =
0.40) {ref.[25] 157–158 °C; [α]2D2 = +1.95 (H2O, c = 3)}. 1H NMR
(500 MHz, CD3OD): δ = 3.11 (d, J = 12.5 Hz, 1 H, 5-HA), 3.52 (d,
J = 12.5 Hz, 1 H, 5-HB), 3.62 (d, J = 11.3 Hz, 1 H, 1Ј-HA), 3.70
(d, J = 11.3 Hz, 1 H, 1Ј-HB), 3.75 (d, J = 7.6 Hz, 1 H, 2-H), 4.03
(mc, 1 H, 2Ј-H), 4.13 (mc, 1 H, 3-H), 4.29 (mc, 1 H, 4-H) ppm. 13C
NMR (126 MHz, CD3OD): δ = 52.2 (t, C-5), 64.7 (d, C-2), 65.1 (t,
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˜
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= 163 (21) [M+ – HCl], 36 (100) [HCl+]. MS (FAB): m/z = 164
(100) [M+ – Cl].
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Received: February 21, 2011
Published Online: May 3, 2011
Eur. J. Org. Chem. 2011, 3210–3219
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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