Synthesis of (+)-(1R,2S,9S,9aR)-octahydro-1H-pyrrolo[1,2-a]azepine-1,2,9- triol: A potential glycosidase inhibitor

Article abstract of DOI:10.1016/j.tet.2004.03.050

The title compound was prepared as a potential glycosidase inhibitor. Key steps in the synthesis are vinyl epoxide aminolysis, ring-closing metathesis, cis-dihydroxylation and then ring closure.

Full text of DOI:10.1016/j.tet.2004.03.050

Tetrahedron 60 (2004) 4173–4176
Synthesis of (1)-(1R,2S,9S,9aR)-octahydro-1H-pyrrolo-
[1,2-a]azepine-1,2,9-triol: a potential glycosidase inhibitor
*
Karl B. Lindsay and Stephen G. Pyne
Department of Chemistry, University of Wollongong, New South Wales, 2522 Wollongong, Australia
Received 8 January 2004; revised 25 February 2004; accepted 18 March 2004
Abstract—The title compound was prepared as a potential glycosidase inhibitor. Key steps in the synthesis are vinyl epoxide aminolysis,
ring-closing metathesis, cis-dihydroxylation and then ring closure.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Polyhydroxylated pyrrolizidine [e.g., (þ)-alexine (1)] and
indolizidine [e.g., (2)-swainsonine (2)] alkaloids are potent
glycosidase inhibitors,1,2 making these compounds good
lead compounds for the development of new drugs for the
treatment of viral infections, cancer and diabetes.3,4
Consequently a substantial volume of research has been
conducted, aimed at the synthesis of these alkaloids and
their analogues.1,2,4,5 While compounds with the 5,5- and
5,6-heterocyclic ring system found in these natural products
have been extensively studied, we were surprised to
discover that analogues with the corresponding 5,7-hetero-
cyclic ring system (i.e. 1H-pyrrolo[1,2-a]azepines) remain
relatively unexplored. Recently we reported an asymmetric
total synthesis of (2)-swainsonine (2) and two of its
diastereomers, 1,2-diepi-swainsonine and 1,2,8a-triepi-
swainsonine.6 The non-chiral pool route used in that
synthesis was very flexible, and we envisaged that it could
be readily applied to polyhydroxylated systems of other ring
size combinations, such as the 5,7-heterocyclic ring system
of (þ)-11, reported here (Scheme 1).
The starting vinyl epoxide (2)-(2S,3R)-3 was prepared from
the corresponding Sharpless epoxy alcohol (92% ee) via
Swern oxidation followed by a Wittig-olefination reac-
tion.6–9
A solution of the vinyl epoxide (2)-3 and allylamine
(3 equiv.) in acetonitrile was heated at 120 8C in a closed
teflon vessel in a microwave reactor (Milestone, ETHOS
SEL), using LiOTf (1 equiv.) as a catalyst.8 This gave only
amino alcohol (2)-46,8 via an SN2 ring opening, with no
evidence of any other regio/stereoisomers. After protection
of (2)-4 as its N-Boc derivative, ring-closing metathesis
using 5 mol% benzylidene-bis-(tricyclohexylphosphine)-
dichlororuthenium (Grubbs’ catalyst) in refluxing CH2Cl2
at high dilution (,4 mM)6,8 for 20 h, gave the 2,5-di-
hydropyrrole (2)-5 in excellent yield (85% overall for the 2
steps). Compound (2)-5 was treated with 5 mol%
K2OsO4·2H2O and NMO (2.1 equiv.), to effect cis-dihy-
droxylation of the double bond, giving triol (2)-6 also in
excellent yield (96%). Only one diastereomeric product was
isolated, which was expected to arise from delivery of
the two hydroxyl groups to the least hindered face of the
3,4-double bond in (2)-5.6 Triol (2)-6 was then reacted
with NaH and benzyl bromide, together with a catalytic
amount of nBu4NI.10 This gave the desired tri-O-benzyl
derivative (2)-7 in 55% yield. The low yield was due
primarily to the formation of an unwanted oxazolidinone
(þ)-8, which was isolated in 21% yield. No attempt was
made to optimise the conditions of this reaction to lower the
amount of (þ)-8 being formed, but it is likely that a higher
concentration of nBuNI and/or benzyl bromide would
improve the ratio of compounds (2)-7 and (þ)-8 in the
reaction. Compound (2)-7 was then reacted with trifluoro-
acetic acid to accomplish N-deprotection. By using anisole
as a cation trap, the p-methoxybenzyl (PMB) protecting
Keywords: 2,5-Dihydropyrroles; Vinyl epoxide; Aminolysis; Ring-closing
metathesis; Dihydroxylation; Polyhydroxylated alkaloids; Azepine.
*
Corresponding author. Tel.: þ612-4221-3511; fax: þ612-4221-4287;
e-mail address: pyne@uow.edu.au
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.050

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K. B. Lindsay, S. G. Pyne / Tetrahedron 60 (2004) 4173–4176
3. Conclusions
In summary, the synthesis of a potential glycosidase
inhibitor, based on a novel 1H-pyrrolo[1,2-a]azepine
structure has been achieved. We believe the method is
flexible enough to allow the synthesis of many analogues,
including those with different stereochemistries and/or
larger ring systems simply by varying the vinyl epoxide
stereochemistry, and/or epoxide side-chain length. Further-
more, this method could potentially be extended to the
synthesis of the key 1H-pyrrolo[1,2-a]azepine core of the
stemona alkaloids.8
4. Experimental
4.1. General
4.1.1. (3S,4S)-8-[(4-Methoxyphenyl)methoxy]-3-(2-pro-
penylamino)-1-octen-4-ol (4). The vinyl epoxide 36–9
(500 mg, 1.90 mmol) was dissolved in CH3CN (3 mL)
then allylamine (328 mg, 5.718 mmol) and LiOTf (297 mg,
1.90 mmol) were added. The mixture was placed in a teflon
tube with a 100 bar pressure cap, then heated in a micro-
wave reactor at 120 8C for 1 h. After cooling all volatiles
were removed in vacuo to give an oil. Pure product was
obtained by column chromatography on flash silica gel
(increasing polarity from 5 to 15% MeOH in DCM as
eluant), which gave the title compound (591 mg,
1.85 mmol, 97%) as a pale yellow oil.
[a]2D9¼27 (c 1.3, CHCl3). MS (CIþ) m/z 320 (100%)
(Mþ1), HRMS (CIþ) found 320.2238, Calcd for
C19H30NO3 320.2226 (Mþ1). dH (300 MHz, CDCl3):
1.20–1.70 (6H, m, H5, H6 and H7), 2.43 (2H, br.s, NH
and OH), 2.77 (1H, t, J¼8.7 Hz, H3), 3.07 (1H, ddt,0J¼13.8.
6.3, 1.2 Hz, H10a), 3.20–3.50 (5H, m, H4, H8, H1 b), 3.80
(3H, s, OCH3), 4.42 (2H, s, OCH2Ar), 5.05–5.30 (4H, m,
H1 and H30), 5.49 (1H, ddd, J¼16.8, 10.2, 8.4 Hz, H2), 5.87
(1H, m, H20), 6.87 (2H, dt, J¼9.0, 2.7 Hz, 2£ArCH), 7.25
(2H, dt, J¼9.0, 2.7 Hz, 2£ArCH). dC (75 MHz, CDCl3):
22.3 (t, C6), 29.7, 33.4 (t, C5 and C7), 49.2 (t, C10), 55.2 (q,
OCH3), 66.4 (d, C3), 70.0 (t, C8), 72.5 (t, OCH2Ar), 72.6 (d,
C4), 113.7 (d, 2£ArCH), 116.2, 118.5 (t, C1 and C30), 1290.2
(d, 2£ArCH), 130.6 (s, ArC), 136.4, 136.8 (d, C2 and C2 ),
159.0 (s, ArC).
Scheme 1. Reagents and conditions: (a) allylamine (3 equiv.), LiOTf
(1 equiv.), CH3CN, 120 8C, microwave, 1 h; (b) (Boc)2O (2 equiv.), Et3N
(2 equiv.), Et2O, rt, 18 h; (c) Cl2(Cy3P)2Ru¼CHPh (5 mol%), CH2Cl2
reflux, 20 h; (d) K2OsO4.2H2O (5 mol%), NMO (2.2 equiv.), acetone,
water, rt, 20 h; (e) NaH (6 equiv.), BnBr (5.5 equiv.), nBu4NI (0.3 equiv.),
THF, rt, 3 d; (f) TFA (10 equiv.), anisole (10 equiv.), CH2Cl2, rt, 2 h;
(g) PPh3 (2.5 equiv.), CBr4 (2.5 equiv.), NEt3 (40 equiv.) CH2Cl2 4 8C,
20 h; (h) PdCl2 (0.9 equiv.), H2 (1 atm), MeOH, rt, 1 h; ion-exchange.
4.1.2. N-Boc derivative of 4 (1,1-dimethylethyl N-[(1S,
2S)-1-ethenyl-2-hydroxy-6-[(4-methoxyphenyl)methoxy]-
hexyl]-N-(2-propenyl)-carbamate. The amine 4 (110 mg,
0.344 mmol) was dissolved in Et2O (10 mL), then triethyl-
amine (75 mg, 0.776 mmol) and di-tert-butyldicarbonate
(161 mg, 0.776 mmol) were added. The mixture was stirred
at rt for under N2 18 h then all volatiles were removed in
vacuo to give an oil. Pure product was obtained by column
chromatography (increasing polarity from 25% to 50%
EtOAc in petroleum spirit (pet. sp.) as eluant), which gave
the title compound (135 mg, 0.322 mmol, 94%) as a clear
oil. [a]2D9¼215 (c 1.0, CHCl3). MS (CIþ) m/z 420 (30%)
(Mþ1), HRMS (CIþ) found 420.2745, Calcd for
C24H38NO5 420.2750 (Mþ1). dH (300 MHz, CDCl3):
1.10–1.65 (7H, m, H3, H4, H5 and OH), 1.42 (9H, s,
(CH3)3C), 3.41 (2H, br. t, J¼6.0 Hz, H6), 3.77 (3H, s,
group was also removed, resulting in the formation of amino
alcohol (þ)-9 in high yield (96%).6 Formation of the
7-membered azepine ring, was achieved by treating (þ)-9
with carbon tetrabromide and triphenylphosphine in the
presence of triethylamine at 4 8C for 20 h. This gave a
moderate yield (51%) of the protected bicyclic compound
(þ)-10, but it should be noted that this reaction was only
performed once, and higher yields may be achieved with
further optimisation (e.g., longer reaction time). Finally,
O-benzyl removal by catalytic hydrogenolysis, using PdCl2
under an atmosphere of H2 (1 atm), gave (þ)-11.HCl in
excellent yield, which was purified by ion-exchange
chromatography to give the free amine (þ)-11 as a white
solid (mp 100–104 8C, [a]2D5¼þ60.3 (c 0.46, MeOH)) in
98% yield.

K. B. Lindsay, S. G. Pyne / Tetrahedron 60 (2004) 4173–4176
4175
OCH3), 3.60–3.84 (3H, m, H2 and H100), 3.94 (1H, br. t,
J¼7.5 Hz, H1), 4.40 (2H, s, OCH2Ar), 5.02–5.22 (4H, m,
H20 and H300), 5.72–5.96 (2H, m, H10 and H200), 6.84 (2H, d,
J¼8.7 Hz, 2£ArCH), 7.23 (2H, d, J¼8.7 Hz, 2£ArCH). dC
(75 MHz, CDCl3): 22.4 (t, C4), 28.3 (q, (CH3)3C), 29.7,
34.2 (t, C3 and C5), 50.0 (br. t, C100), 55.1 (q, OCH3), 65.6
(d, C1), 69.9 (t, C6), 71.9 (br. d, C2), 72.4 (t, OCH2Ar), 80.2
(s, (CH3)3C), 113.5 (d, 2£ArCH), 116.6, 117.8 (t, C20 and
C3000), 129.000(d, 2£ArCH), 130.5 (s, ArCH), 134.2, 134.9 (d,
C1 and C2 ), 158.0 (s, ArCH), 171.0 (br. s, CO).
4.1.5. 1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-5-[(4-meth-
oxyphenyl)methoxyoxy)]-1-(phenylmethoxy)pentyl]-3,4-
bis(phenylmethoxy)-1-pyrrolidinecarboxylate (7) and
(1S,6S,7R,7aR)-tetrahydro-1-[4-[(4-methoxyphenyl)-
methoxy]butyl]-6,7-bis(phenylmethoxy)-1H,3H-pyrrolo-
[1,2-c]oxazol-3-one (8). The triol 6 (440 mg, 1.034 mmol)
was dissolved in THF (60 mL) then NaH (302 mg,
6.024 mmol, 50% dispersion in wax), benzylbromide
(0.64 mL, 5.50 mmol) and nBu4NI (112 mg, 0.30 mmol)
were added. The mixture was stirred at rt under N2 for 3 d
then poured into water (50 mL) and extracted with DCM
(3£40 mL). The combined organic portions were dried
(MgSO4), filtered and evaporated in vacuo to give an oil.
Pure products were obtained by column chromatography
(increasing polarity from 20 to 100% EtOAc in pet. sp. as
eluant), which gave the title compound (396 mg,
0.569 mmol, 55%), and the oxazolidinone (116 mg,
0.218 mmol, 21%) as clear oils.
4.1.3. 1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1S)-1-
hydroxy-5-[(4-methoxyphenyl)methoxy]pentyl]-1H-pyr-
role-1-carboxylate (5). The N-Boc derivative of 4 (500 mg,
1.193 mmol) was dissolved in dry DCM (300 mL) then
benzylidene-bis-(tricyclohexlphosphine)dichlororuthenium
(Grubbs’ cat.) (50 mg, 0.061 mmol) was added. The mixture
was heated at reflux under N2 for 20 h, then cooled, before
all solvent was removed in vacuo to give an oil. Pure
product was obtained by column chromatography (increas-
ing polarity from 25 to 50% EtOAc in pet. sp. as eluant),
which gave the title compound (426 mg, 1.088 mmol,
91.2%) as a clear oil. [a]2D9¼279 (c 0.9, CHCl3). MS
(CIþ) m/z 392 (37%) (Mþ1), HRMS (CIþ) found
392.2409, Calcd for C22H34NO5 392.2437 (Mþ1). dH
(300 MHz, CDCl3): 1.48 (9H, s, (CH3)3C), 1.20–1.73
(6H, m, H20, H30 and H40), 3.44 (2H, t, J¼6.3 Hz, H50),
3.56–3.66 (1H, m, H2), 3.79 (3H, s, OCH3), 3.99 (1H, br. d,
J¼15.7 Hz, H5a), 4.18 (1H, br. d,0J¼15.6 Hz, H5b), 4.41
(2H, s, OCH2Ar), 4.54 (1H, m, H1 ), 4.96 (1H, br. s, OH),
5.60–5.90 (2H, m, H3 and H4), 6.86 (2H, dt, J¼8.4, 3.0 Hz,
2£ArCH), 7.24 (2H, dt, J¼8.4, 3.0 Hz, 2£ArCH). dC
(75 MHz, CDCl3): 21.7 (t, C30), 28.4 (q, (CH3)3C), 29.7,
33.3 (C20 and C40), 53.9 (t, C5), 55.2 (q, OCH3), 70.0 (t,
C50), 70.0 (d, C2), 72.4 (t, OCH2Ar), 75.4 (d, C10), 80.4 (s,
(CH3)3C), 113.5 (d, 2£ArCH), 126.4, 126.7 (d, C3 and C4),
129.0 (d, 2£ArCH), 130.5 (s, ArC), 156.6 (CO), 158.8 (s,
ArC).
Compound 7. [a]3D0¼229 (c 3.96, CHCl3). MS (ESþ) m/z
696.4 (100%) (Mþ1), HRMS (ESþ) found 696.3895, Calcd
for C43H54NO7 696.3900 (Mþ1). dH (300 MHz, CDCl3):
1.45 (9H, s, (CH3)3C), 1.20–1.70 (6H, m, H20, H30 and H40),
3.28–3.43 (3H, m, H5a and H50), 3.52 (1H, br. d, J¼6.3 Hz,
H5b), 3.78 (3H, s, OCH3), 3.75–3.87 (1H, m, H10), 3.87–
4.06 (2H, m, H3 and H4), 4.17–4.74 (7H, m, H2 and
3£OCH2Ph), 4.40 (2H, s, OCH2Ar), 6.86 (2H, d, J¼9.0 Hz
2£ArCH), 7.21–7.36 (17H, m, 2£ArCH and 3£OCH2Ph).
dC (75 MHz, CDCl3): two rotamers were evident in equal
intensity 22.9/23.2 (t, C30), 28.4 (q, (CH3)3C), 29.6 (t, C40),
30.0/30.4 (t, C20), 48.8/49.5 (t, C5), 55.2 (q, OCH3), 62.5/
63.6 (d, C2), 69.9 (t, C50), 71.2, 71.3/71.8, 72.4, 72.3/72.6 (t,
OCH2Ar and 3£OCH2Ph), 75.3/76.3, 76.5/77.8, 78.4/78.6
(d, C3, C4 and C10), 79.7/80.0 (s, (CH3)3C), 113.7 (d,
ArCH), 127.6, 127.7, 127.7, 128.0, 128.0, 128.2, 128.2,
128.3, 128.3 (d, 3£OCH2Ph), 129.1 (d, 2£ArCH), 130.6 (s,
ArCH), 137.6, 138.0, 138.4 (s, 3£OCH2Ph), 159.0 (s,
2£ArCH), 164.0 (s, CO).
4.1.4. 1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-1-hydroxy-
pentyl-5-[(4-methoxyphenyl)methoxy]]-3,4-dihydroxy-
1-pyrrolidinecarboxylate (6). The 2,5-dihydropyrrole 5
(426 mg, 1.088 mmol) was dissolved in acetone (6 mL),
then water (4 mL), N-methyl-morpholine-N-oxide (269 mg,
2.32 mmol) and K2OsO4.2H2O (20 mg, 0.0544 mmol) were
added. The mixture was stirred at rt for 20 h, then all
volatiles were removed in vacuo to give a brown oil. Pure
product was obtained by column chromatography (increas-
ing polarity from 2.5 to 10% MeOH in DCM as eluant),
which gave the title compound (442 mg, 1.039 mmol,
95.5%) as a clear oil. [a]2D7¼228 (c 1.0, CHCl3). MS
(CIþ) m/z 426 (100%) (Mþ1), HRMS (CIþ) found
426.2482, Calcd for C22H36NO7 426.2492 (Mþ1). dH
(300 MHz, CDCl3): 1.40 (9H, s, (CH3)3C), 1.30–1.70
(8H, m, H20, H300, H400 and 2£OH), 3.30–4.30 (9H, m, H2,
H3, H4, H5, H1 , H5 and OH), 3.78 (3H, s, OCH3), 4.40
(2H, s, OCH2Ar), 6.84 (2H, d, J¼8.4 Hz, 2£ArCH), 7.23
(2H, d, J¼8.4 Hz, 2£ArCH). dC (75 MHz, CDCl3): 22.0 (br.
t, C30), 28.1 (q, (CH3)3C), 29.2, 32.7 (t, C20 and C40), 51.3
(br. t, C5), 54.9 (q, OCH3), 67.0 (br. d, C2), 69.5 (br. d, C4),
69.7 (t, C50), 72.2 (t, OCH2ArCH), 72.9 (br. d, C3), 76.4 (d,
C10), 80.3 (s, (CH3)3C), 113.5 (d, 2£ArCH), 129.0 (d,
2£ArCH), 130.1 (s, ArC), 156.8 (br. s, CO), 158.8 (s, ArC).
Compound 8. [a]3D0¼þ28 (c 1.03, CHCl3). MS (ESþ) m/z
532.3 (47%) (Mþ1), HRMS (ESþ) found 532.2698, Calcd
for C32H37NO6 532.2699 (Mþ1). dH (300 MHz, CDCl3):
1.40–1.86 (6H, m, H10, H20 and H30), 3.037 (1H, dd, J¼12.9,
1.5 Hz, H5a), 3.42 (2H, t, J¼6.3 Hz, H4 ), 3.53 (1H, dd, 9.0,
4.8 Hz, H7), 3.70–3.80 (2H, m, H5b and H7a), 3.77 (3H, s,
OCH3), 4.09 (1H, td, J¼5.1, 1.5 Hz, H6), 4.22 (1H, ddd,
J¼7.2, 5.4, 3.6 Hz, H1), 4.39 (1H, d, J¼12.0 Hz, OCH2Ph),
4.41 (2H, s, OCH2Ar), 4.59 (2H, AB system, J¼12.0 Hz,
OCH2Ph), 4.65 (1H, d, J¼12.0 Hz, OCH2Ph), 6.86 (2H, dt,
J¼8.4, 3.0 Hz, 2£ArCH), 7.22–7.38 (12H, m, 02£ArCH and
2£OCH2Ph). dC (75 MHz, CDCl3): 21.1 (t, C2 ), 29.2 (C30),
35.0 (t, C10), 50.8 (t, C5), 55.1 (q, OCH3), 65.0 (d, C7a),
69.4 (t, C40), 71.9, 72.2, 72.4 (t, OCH2Ar and 2£OCH2Ph),
75.8, 79.0 (C6 and C7), 81.5 (d, C1), 113.6 (d, 2£ArCH),
127.7, 127.9, 127.9, 128.1, 128.4, 128.5 (d, 2£OCH2Ph),
129.1 (d, 2£ArCH), 130.4 (s, ArC), 137.0, 137.2 (s,
2£OCH2Ph), 159.0 (s, ArC), 160.9 (s, C3).
4.1.6. (10S,2R,3R,4S)-10,3,4-tris(Phenylmethoxy)-2-pyrrol-
idinepentanol (9). The carbamate 7 (396 mg, 0.569 mmol)
was dissolved in DCM (5 mL), then TFA (5 mL) and
anisole (0.60 mL, 5.44 mmol) were added. The mixture was
stirred at rt for 2 h, then all volatiles were removed in vacuo.

4176
K. B. Lindsay, S. G. Pyne / Tetrahedron 60 (2004) 4173–4176
The residue was dissolved in CHCl3 then poured into sat.
Na2CO3 solution (5 mL), and extracted with CHCl3
(3£25 mL). The combined organics were dried (MgSO4),
filtered and evaporated in vacuo to give an oil. Pure product
was obtained by column chromatography (increasing
polarity from 5 to 15% MeOH in DCM as eluant), which
gave the title compound (260 mg, 0.547 mmol, 96%) as a
clear oil. [a]2D6¼þ81 (c 2.60, CHCl3). MS (ESþ) m/z 476.7
(100%) (Mþ1), HRMS (ESþ) found 476.2808, Calcd for
C30H38NO4 476.2801 (Mþ1).
dH (300 MHz, CDCl3): 1.26–1.90 (6H, m, H20, H30 and
H40), 2.96–3.15 (4H, m, H5, NH and OH), 3.31 (1H, dd,
J¼7.5, 2.4 Hz, H2), 30.50 (1H, td, J¼7.2, 2.4 Hz, H50), 3.58
(2H, t, J¼6.3 Hz, H1 ), 3.70 (1H, dd, J¼7.5, 5.1 Hz, H3),
3.90 (1H, q, J¼4.5 Hz, H4), 4.23 (1H, d, J¼11.1 Hz
OCH2Ph), 4.32 (1H, d, J¼11.7 Hz, OCH2Ph), 4.50 (1H, d,
J¼12.0 Hz, OCH2Ph), 4.55 (1H, d, J¼11.4 Hz, OCH2Ph),
4.60 (1H, d, J¼12.0 Hz, OCH2Ph), 4.62 (1H, d, J¼12.0 Hz,
OCH2Ph), 7.15–7.40 (15H, m, 3£OCH2Ph). dC (75 MHz,
CDCl3): 21.4 (t, C30), 30.6, 32.5 (t, C20 and C40), 49.3 (t, C5),
61.6 (t, C10), 63.0 (d, C2), 71.2, 71.9, 72.0 (t, 3£OCH2Ph),
76.4, 77.5, 79.6 (C3, C4 and C50), 127.5, 127.6, 127.6,
127.7, 127.9, 128.0, 128.2, 128.2, 128.2 (d, 3£OCH2Ph),
137.9, 138.0, 138.3 (s, 3£OCH2Ph).
then PdCl2 (40 mg, 0.226 mmol) was added and the flask
flushed with H2 (g). The mixture was stirred at rt under an
atmosphere of H2 for 1 h, then the flask was flushed with N2,
before the mixture was filtered through celite. The solids
were washed with MeOH (2£10 mL), and the combined
filtrates were evaporated in vacuo. The residue was
dissolved in water (2 mL) and applied to Dowex-1 basic
ion exchange resin (OH– form). Elution with water
(50 mL), followed by evaporation of the eluant in vacuo
gave the title compound (46 mg, 0.246 mmol, 97.9%) as
a white solid. mp. 100–104 8C. [a]2D5¼þ60.3 (c 0.46,
MeOH). MS (CIþ) m/z 188 (100%) (Mþ1), HRMS (ESþ)
found 188.1301, Calcd for C9H18NO3 188.1287 (Mþ1). dH
(300 MHz, D2O): 1.22–1.38 (1H, m, H7a), 1.42–4.62 (4H,
m, H6, H7b and H8a), 1.76–1.88 (1H, m, H8b), 2.34 (1H,
dt, J¼12.0, 6.3 Hz, H5a), 2.46 (1H, dd, J¼10.2, 6.6 Hz,
H3a), 2.63–2.70 (1H, m, H9a), 2.84 (1H, dt, J¼11.7,
5.7 Hz, H5b), 3.00 (1H, dd, J¼10.5, 5.4 Hz, H3b), 3.86–
3.97 (3H, m, H1, H2 and H9). dC (75 MHz, D2O ref
CH3CN): 21.4 (t, C7), 29.4, 36.1 (t, C6 and C8), 56.5, 59.7
(t, C3 and C5), 69.6 (d, C9a), 70.8 (d, C9), 73.6, 74.9 (d, C1
and C2).
Acknowledgements
4.1.7. (1R,2S,9S,9aR)-Octahydro-1,2,9-tris(phenylmeth-
oxy)-1H-pyrrolo[1,2-a]azepine (10). The amino alcohol 9
(240 mg, 0.505 mmol) was dissolved in DCM (20 mL) then
the solution was cooled to 0 8C. Carbontetrabromide (419 mg,
1.263 mmol), and triphenylphosphine (331 mg, 1.263 mmol)
were added, then the mixture was stirred under N2 for 5 min.
Triethylamine (2.8 mL, 20.09 mmol) was added, then the
mixture was stirred at 0 8C for 2 h, before being left to stand
at 4 8C for 18 h. The mixture was poured into water
(50 mL), then extracted with DCM (3£40 mL). The
combined organic portions were dried (MgSO4), filtered
and evaporated in vacuo to give a black semi solid. Pure
product was obtained by column chromatography (increas-
ing polarity from 1 to 5% MeOH in DCM as eluant), which
gave the title compound (118 mg, 0.258 mmol, 51%) as a
clear oil. [a]2D7¼þ64 (c 1.15, CHCl3). MS (ESþ) m/z 458.5
(100%) (Mþ1), HRMS (ESþ) found 458.2694, Calcd for
C30H36NO3 458.2695 (Mþ1). dH (300 MHz, CDCl3): 1.30–
1.46 (1H, m, H7a), 1.56–1.94 (5H, m, H6, H7b, H8), 2.51
(1H, ddd, J¼11.7, 8.4, 4.8 Hz, H5a), 2.84 (1H, dd, J¼9.3,
7.5 Hz, H3a), 2.90 (1H, dd, J¼3.9, 2.4 Hz, H9a), 3.03 (1H,
dt, J¼11.7, 5.7 Hz, H5b), 3.22 (1H, dd, J¼9.3, 5.1 Hz,
H3b), 3.56 (1H, td, J¼5.1, 2.4 Hz, H9), 3.85 (1H, t, J¼
4.5 Hz, H1), 4.02 (1H, dt, J¼7.5, 5.1 Hz, H2), 4.22 (1H, d,
J¼12.0 Hz OCH2Ph), 4.35 (1H, d, J¼12.0 Hz OCH2Ph),
4.53 (1H, d, J¼12.3 Hz OCH2Ph), 4.56 (1H, d, J¼12.0 Hz
OCH2Ph), 4.58 (1H, d, J¼12.3 Hz OCH2Ph), 4.59 (1H, d,
J¼12.0 Hz OCH2Ph), 7.17–7.42 (15H, m, 3£OCH2Ph). dC
(75 MHz, CDCl3): 21.7 (t, C7), 30.0, 31.9 (t, C6 and C8),
56.5, 57.9 (t, C3 and C5), 70.5, 71.6, 72.3 (t, 3£OCH2Ph),
72.3 (d, C9a), 75.9, 76.8 (d, C1 and C2), 80.4 (d, C9), 127.5,
127.5, 127.7, 127.9, 128.2, 128.2, 128.2, 128.3, 128.3 (d,
3£OCH2Ph), 138.5, 138.5, 138.5 (s, 3£OCH2Ph).
We thank the University of Wollongong for a PhD
scholarship to K.B.L., and the Australian Research Council
for financial support.
References and notes
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