Intramolecular amidomercurations under allylic control: A stereoselective synthesis of (+)-pseudohygroline and (+)-3-hydroxypyrrolizidine

Article abstract of DOI:10.1016/S0957-4166(01)00064-7

The diastereoselectivity of intramolecular amidomercurations can be reversed by altering the remote allylic substituent of ω-alkenylcarbamates. This methodology has been applied to the synthesis of (+)-pseudohygroline and (+)-3-hydroxypyrrolizidine.

Full text of DOI:10.1016/S0957-4166(01)00064-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 597–604
Intramolecular amidomercurations under allylic control:
a stereoselective synthesis of (+)-pseudohygroline and
(+)-3-hydroxypyrrolizidine
Gina Enierga,a Maria Espiritu,a Patrick Perlmutter,a,* Ngoc Pham,a Mark Rose,a Stefan Sjo¨berg,b
Neeranat Thienthonga and Katie Wonga
aDepartment of Chemistry, Monash University, PO Box 23, Victoria 3800, Australia
bDepartment of Organic Chemistry, Uppsala University, Uppsala, Sweden
Received 3 January 2001; accepted 5 February 2001
Abstract—The diastereoselectivity of intramolecular amidomercurations can be reversed by altering the remote allylic substituent
of v-alkenylcarbamates. This methodology has been applied to the synthesis of (+)-pseudohygroline and (+)-3-hydroxy-
pyrrolizidine. © 2001 Published by Elsevier Science Ltd.
1. Introduction
stereoselective tetrahydrofuran synthesis using the
intramolecular oxymercuration of (Z)-alkenes such as
5, we reasoned that it should be possible to develop a
general enantioselective synthetic strategy to com-
pounds of the type 1 and 2 by using allylic control in an
intramolecular amidomercuration reaction,2,8–10 where
an alkylamine residue (X=NR¦) is present in the pre-
cursor 5 instead of an alcohol.
We recently reported a stereoselective synthesis of (+)-
pseudohygroline 11 using an intramolecular amidomer-
curation step under allylic control as a key reaction.2
Herein, we report full details of this work. In addition,
we describe the remarkable reversal of diastereoselec-
tion in intramolecular amidomercuration when employ-
ing a different allylic protecting group. This chemistry
was applied to an enantioselective synthesis of (+)-3-
hydroxypyrrolizidine 2.3,4
In this synthetic approach the alkene starting material
has an allylic ether function remote from the locus
of ring closure; oxymercuration of 5 affords the het-
The pyrrolidine and pyrrolizidine nuclei are found in
many alkaloids, including those possessing potent phar-
macological activity.5–7 From our earlier work on
erocycle
4
by electrophilic ring closure, which
may then be further elaborated to provide the desired
target 3.
* Corresponding author. E-mail: patrick.perlmutter@sci.monash.edu.au
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00064-7

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2. Results and discussion
ing group of 12 was then reduced with lithium alu-
minium hydride17,18 to furnish the N-methyl analogue
13 in a 50% yield. Finally, removal of the silyl protect-
ing group19 resulted in a 50% yield and completed the
synthesis to give enantiomerically pure (+)-pseudo-
hygroline 1.2,20,21
2.1. Synthesis of (+)-pseudohygroline 1
The synthesis of 1 is outlined in Scheme 1.8
Wittig olefination of the silyl ether of (S)-lactaldehyde
611 with the known ylide 712 gave (Z)-alkene 8 in 80%
yield. Reduction of the nitrile function of 8 with lithium
aluminium hydride13 then gave primary amine 9 in 83%
yield. We next attempted to ring close the free amine 9
to pyrrolidine 14; however, we only observed formation
of a precipitate. None of the conditions we examined,
including elevated reaction temperature, prolonged
reaction times and solvent variations, proved successful.
2.2. Synthesis of (+)-3-hydroxpyrrolizidine
The synthesis of (+)-3-hydroxypyrrolizidine 2 involved
a similar sequence to that for 1, leading to 18 as an
important target intermediate. Wittig olefination11 of
D
-glyceraldehyde acetonide 15 with the ylide derived
from 712 gave a new alkene, 16, in 70% yield. Carba-
mate 18 was then prepared by reduction and protection
in 62% yield from 16 (Scheme 2).
Ring closure of 18, using the same conditions as those
used for the closure of 10, provided pyrrolidine 19 with
>10:1 diastereoselectivity and in an excellent yield
(82%). Reductive demercuration2,9,10 of 19 afforded 20
in 73% yield and was followed by removal of the
acetonide protecting group with aqueous acetic acid22
to give 21 in 73% yield. Selective mesylation23 at the
primary alcohol generated the activated precursor for
the second ring closure, 22, in 72% yield. Catalytic
hydrogenation of 22 removed the benzyloxycarbonyl
protecting group, and the resultant free amine sponta-
neously displaced mesylate to yield 224 in 91% yield.
The pyrrolizidine 2 (obtained as its mesylate salt)
As it is well known that carbamates undergo
intramolecular amidomercurations,14–16 we converted 9
into its corresponding benzyl carbamate 10. Pleasingly,
10 underwent smooth ring closure to the organomercu-
rial 11 in a good yield (62%); additionally, the
diastereoselectivity was ꢀ12:1 in favour of the desired
(2R)-isomer, as confirmed by X-ray crystallography.
Reductive demercuration,9,10 under radical conditions,
then afforded 12 in 55% yield. The carbamate protect-
Scheme 1. (i) NaN(TMS)2, 80%; (ii) LiAlH4, Et2O, 83%; (iii) BnOCOCl, Et3N, 43%; (iv) (a) Hg(OAc)2, CH2Cl2, rt; (b) aq. NaCl
62%; (v) Bu3SnH, AIBN, toluene, 55%; (vi) LiAlH4, Et2O, 50%; (vii) NH4F, MeOH 50%.
Scheme 2. (i) NaN(TMS)2, 70%; (ii) LiAlH4, Et2O, 94%; (iii) BnOCOCl, Et3N, 66%.

G. Enierga et al. / Tetrahedron: Asymmetry 12 (2001) 597–604
599
Scheme 3. (i) (a) Hg(OAc)2, CH2Cl2, rt; (b) aq. NaCl 82%; (ii) Bu3SnH, AIBN, toluene, 73%; (iii) aq. AcOH, rt, 77%; (iv) MsCl
(1 equiv.), CH2Cl2, Et3N, 72%; (v) Pd–C, H2, 91%; (vi) (PhCO)2O, pyridine, 70%.
proved to be quite difficult to purify. Consequently, it
was converted into the benzoate 23 in 70% yield, which
was readily purified by column chromatography
(Scheme 3).
3. Conclusion
We have demonstrated that a similar sequence of reac-
tions involving the intramolecular amidomercuration
reaction of an allylic ether leads to useful, enantiomeri-
cally pure intermediates for pyrrolidine and pyrrolizi-
dine synthesis. In addition, we have shown that the
nature of the O-protecting group of the allylic ether can
dramatically influence the diastereoselectivity of intra-
molecular amidomercuration reactions.
X-Ray crystal structure analysis revealed that the rela-
tive stereochemistry of 19 is as shown in Fig. 1. Clearly,
ring closure proceeded with the opposite sense of
diastereoselection to that for 10. This is the most
remarkable ‘reversal’ of diastereoselection in all our
studies so far on intramolecular oxy-8–10 and amido-2
mercurations and obviously reflects the influence of an
allylic dioxolane moiety on this process.
4. Experimental
4.1. (4Z,6S)-6-[(tert-Butyldiphenylsilyl)oxy]-4-
heptenenitrile 8
2.3. Diastereoselectivity in intramolecular
amidomercurations
Sodium bis(trimethylsilyl)amide (1 M in THF, 4.5 mL,
4.5 mmol) was added to a stirred suspension of phos-
Previously we have argued that, where the remote
allylic substituent is a bulky silyl ether, the diastere-
ocontrol is determined by the approach of the metal ion
(possibly +HgOAc or an incipient form) to the less
hindered face of the most stable conformation of the
alkene.8–10 This conformation (I, Fig. 2) contains the
smallest allylic substituent (H-6) in plane and is closest
to the allylic methylene protons (H-3a and H-3b). Nat-
urally, this assumes that the most stable conformation
is also the major reacting conformation. This simple
model, as shown in Fig. 2, accounts for the observed
diastereoselection associated with all the intramolecular
oxymercurations we have so far studied, as well as the
closure of carbamate 10. However, in the case of 18, the
dioxolane clearly reacts via a different conformation to
those of the related allylic TBS ethers. Given the stereo-
chemical outcome of this particular closure, it appears
reasonable to propose that this case involves the
approach of the metal ion to a conformation resem-
bling II (Fig. 2). In conformation II the dioxolane
oxygen attached to C-(6) occupies the most hindered
position. This renders the Si-face more sterically hin-
dered when compared to the Re-face.
Figure 1. X-Ray crystal structure of 19.

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G. Enierga et al. / Tetrahedron: Asymmetry 12 (2001) 597–604
Figure 2.
phonium salt 7 (1.60 g, 3.9 mmol) in THF (35 mL)
under nitrogen at 0°C. The bright orange mixture was
stirred for 30 min. A solution of the aldehyde 611 (600
mg, 1.92 mmol) in THF (10 mL) was added. The
reaction mixture was then stirred for a further 4 h at
0°C, poured into ether (110 mL) and the mixture
washed with satd NaCl (2×35 mL), dried (Na2SO4) and
concentrated. The crude product was purified by pre-
column and preparative TLC (ethyl acetate–hexane 1:8,
Rf=0.3). Nitrile 8 was obtained as a colourless liquid
solid washed with ether. The carbamate was extracted
with ether. The ether solution was then washed with
saturated aqueous NaCl, dried (Na2SO4) and evapo-
rated in vacuo. Purification using radial chromatogra-
phy (ethyl acetate–hexane 1:2, Rf=0.47) gave the
carbamate 10 as an oil (112 mg, 43%). [a]D +3.8 (c 1.8,
CHCl3). IR nmax (cm−1): 3342 (NH), 1731 (CO). 1H
NMR (200 MHz, CDCl3): d 1.03 (s, 9H, t-Bu), 1.16 (d,
3H, J=6.0 Hz, 3×H-7), 1.35 (m, 2H, 2×H-2), 1.59–1.68
(m, 2H, 2×H-3), 2.97 (dd, 2H, J=12.0, 6.0 Hz, 2×H-1),
4.49–4.56 (m, 2H, H-6 and NH), 5.07–5.28 (m, 3H,
CH2Ph and H-4), 5.53 (t, 1H, J=8.6 Hz, H-5), 7.28–
7.41 (m, 4H, Ph), 7.63–7.68 (m, 9H, Ph). 13C NMR (50
MHz, CDCl3): d 19.1 (C-2), 24.4 (C-3), 24.6 (C-7), 26.9
(t-Bu), 29.5 (Si-C), 40.6 (C-1), 65.8 (C-6), 66.5
(CH2Ph), 127.0, 127.4, 127.5, 128.1, 128.5, 129.4, 129.5,
134.2, 134.4, 135.4, 135.8, 135.9, 136.6 (C-4, C-5 and
Ph), 156.2 (CO). Anal. calcd for C31H39NO3Si: C,
74.21; H, 7.83; N, 2.79. Found: C, 74.28; H, 7.80; N,
2.60%.
1
(0.563 g, 80%). IR nmax (cm−1): 2963 (CN). H NMR
(200 MHz, CDCl3): d 1.04 (s, 9H, t-Bu), 1.22 (d, 3H,
J=6.2 Hz, 3×H-7), 1.8–2.0 (m, 4H, 2×H-2 and 2×H-3),
4.5 (m, 1H, H-6), 5.13 (m, 1H, H-4), 5.63 (m, 1H, H-5),
7.38–7.48 (m, 6H, Ph), 7.63–7.74 (m, 4H, Ph). Anal.
calcd for C23H29NOSi: C, 75.98; H, 8.04; N, 3.85.
Found: C, 76.03; H, 8.11; N, 3.79%.
4.2. (4Z,6S)-6-[(tert-Butyldiphenylsilyl)oxy]-4-
heptenamine 9
To a stirred suspension of LiAlH4 (0.212 g, 5.64 mmol)
in anhydrous ether (4.8 mL) was added a solution of
the nitrile 8 (1.365 g, 3.75 mmol) in ether (12 mL) at
room temperature. The reaction mixture was heated
under reflux for 2.5 h and then left to cool to rt.
Sodium sulfate decahydrate was added in portions until
effervescence ceased. The mixture was filtered and the
solid was washed with ether. The combined organic
solvents were evaporated to give the amine 9 as an oil
4.4. N-(Benzyloxycarbonyl)-(2R)-2-[(1S,2S)-1-chloro-
mercurio-2-((tert-butyldiphenylsilyl)oxy)prop-1-yl]-
pyrrolidine 11
A solution of carbamate 10 (51 mg, 0.10 mmol) in
chloroform (1 mL) was added to Hg(OAc)2 (36 mg, 0.1
mL) dissolved in chloroform (1 mL). The mixture was
left to stir for 2 days at rt. Saturated aqueous sodium
chloride was added and the reaction was stirred for a
further 15 min. The reaction mixture was diluted with
CH2Cl2 and washed with brine. The organic layer was
then dried (Na2SO4) and evaporated in vacuo. Purifica-
tion by preparative TLC (diethyl ether–hexane 1:2,
Rf=0.40) gave the cyclised product 11 as an oil (43 mg,
62%). [a]D +2.8 (c 1.8, CHCl3). IR nmax (cm−1): 3070
1
(1.152 g, 83%). IR nmax (cm−1): 3356 (NH2). H NMR
(200 MHz, CDCl3): d 1.0 (s, 9H, t-Bu), 1.16 (d, 3H,
J=6.2 Hz, 3×H-7), 1.2–1.39 (m, 2H, 2×H-2), 1.63 (m,
2H, 2×H-3), 2.47 (m, 2H, 2×H-1), 4.56 (m, 1H, H-6),
5.16 (m, 1H, H-4), 5.50 (m, 1H, H-5), 7.25–7.44 (m, 6H,
Ph), 7.65–7.69 (m, 4H, Ph). EIMS m/z 368 (M+). Anal.
calcd for C23H33NOSi: C, 75.15; H, 9.05; N, 3.81.
Found: C, 71.23; H, 9.01; N, 3.35%.
1
(NH), 1668 (CO). H NMR (200 MHz, CDCl3): d 1.11
(s, 9H, t-Bu), 1.15 (d, 3H, J=6.0 Hz, 3×H-3%), 1.23–
1.33 (m, 2H, 2×H-4), 1.54 (m, 2H, 2×H-3), 2.26 (d, 1H,
J=11.0 Hz, H-1%), 3.25–3.45 (m, 2H, 2×H-5), 4.16–4.18
(m, 2H, H-2 and H-2%), 5.12 and 5.26 (AB quartet, 2H,
J=12.3 Hz, CH2Ph), 7.31–7.43 (m, 11H, Ph), 7.65–7.74
(m, 4H, Ph). 13C NMR (75 MHz, CDCl3): d 19.2 (C-4),
23.5 (C-3), 27.2 (t-Bu), 31.1 (Si-C), 46.7 (C-5), 59.9
(C-1%), 67.4 (CH2Ph), 68.4 (C-2), 70.6 (C-2%), 127.6,
127.9, 128.2, 128.5, 128.6, 129.8, 130.0, 133.4, 134.2,
136.1, 136.2, 136.6 (Ph), 155.5 (CO).
4.3. N-(Benzyloxycarbonyl)-(4Z,6S)-6-[(tert-
butyldiphenylsilyl)oxy]-4-heptenamine 10
Benzyl chloroformate (0.30 mL, 2.05 mmol) was added
dropwise to a solution of amine 9 (503 mg, 1.37 mmol)
and triethylamine (0.60 mL, 4.31 mmol) in THF under
a nitrogen atmosphere. The reaction mixture was
stirred overnight at rt. The mixture was filtered and the

G. Enierga et al. / Tetrahedron: Asymmetry 12 (2001) 597–604
601
4.7. (+)-Pseudohygroline 1
4.5. N-(Benzyloxycarbonyl)-(2R)-2-[(2S)-2-((tert-
butyldiphenylsilyl)oxy)prop-1-yl]pyrrolidine 12
The silyl ether 13 (33 mg, 0.1 mmol) was dissolved in
methanol (1 mL) and ammonium fluoride (38 mg, 1
mmol) was added. The reaction was stirred at rt
overnight, after which the solvent was evaporated, the
residue taken up in dichloromethane, stirred for 1 h
and filtered. Evaporation of the dichloromethane gave
the crude alkaloid 1. Purification by chromatography
on alumina (methanol–ethyl acetate 1:9, Rf=0.25) gave
pseudohygroline 1 (7 mg, 50%) as a colourless oil. [a]D
+70.7 (c 2.0, CH3CH2OH); lit.1 [a]D +84.4° (c 3.4,
CH3CH2OH). IR nmax (cm−1): 3500–3250 (OH). 1H
NMR (300 MHz, CDCl3): d 1.16 (d, 3H, J=6.1 Hz,
3×H-3%), 1.45 (m, 3H, 2×H-4 and H-1%a), 1.80 (m, 2H,
2×H-3), 2.02 (dq, 1H, J=12.4, 8.0 Hz, H-1%b), 2.35–
2.42 (s, 3H, CH3N and m, 1H, H-5a), 2.72 (m, 1H,
H-5b), 3.05 (dt, 1H, J=10.6, 6.7 Hz, H-2), 3.95 (m, 1H,
H-2%). 13C NMR (50 MHz, CDCl3): d 22.8 (C-4), 24.3
(C-3%), 30.5 (C-3), 42.8 (C-1%), 43.1 (CH3N), 55.4 (C-5),
65.9 (C-2), 67.5 (C-2%). HRMS calcd for (M+H)
C8H18NO: 144.1388. Found: 144.1360.
The chloromercurial 11 (431 mg, 0.6 mmol) was dis-
solved in toluene (1 mL) under N2. A solution of AIBN
(8 mg) in toluene (1.4 mL) was added, followed by
tributylstannane (0.43 mL). After addition of the stan-
nane, mercury was seen to precipitate. The reaction
mixture was stirred at rt for 1 h, then heated to 60°C
and stirred at this temperature for 1 h. Carbon tetra-
chloride (0.3 mL) was added and the reaction was
cooled to rt with stirring and then stirred for a further
1 h. The supernatant reaction mixture was decanted
from the precipitated mercury, taken up in CH2Cl2–
pentane (1:3) (50 mL) and washed with 5% aqueous KF
solution (2×30 mL). After drying (Na2SO4) and filtra-
tion through silica (ethyl acetate–hexane 1:5), the mix-
ture was evaporated in vacuo to afford the crude
product as a gum. Further purification by column
chromatography (ethyl acetate–hexane 1:3, Rf=0.2,
hexane–ether 4:1) gave the carbamate 12 as a colourless
gum (164 mg, 55%). [a]D +10.9 (c 2.3, CHCl3). IR nmax
(cm−1): 1701 (CO). 1H NMR (300 MHz, DMSO at
90°C): d 1.01 (s, 9H, t-Bu), 1.10 (d, 3H, J=5.6 Hz,
3×H-3%), 1.46 (m, 1H, H-1%), 1.55 (m, 2H, 2×H-4), 1.70
(m, 2H, 2×H-3), 1.94 (m, 1H, H-1%), 3.15 (m, 1H,
H-5a), 3.30 (m, 1H, H-5b), 3.95 (m, 2H, H-2 and H-2%),
5.01 (s, 2H, CH2Ph), 7.22–7.40 (m, 10H, Ph), 7.60 (m,
5H, Ph). 13C NMR (75 MHz, DMSO at 90°C): d 18.7
(C-4), 22.7 (Si-C), 23.5 (C-3%), 26.9 (t-Bu), 30.1 (C-3),
43.9 (C-1%), 45.8 (C-5), 54.3 (C-2), 65.7 (CH2Ph), 67.5
(C-2%), 127.4, 127.5, 127.6, 128.2, 129.5, 129.6, 133.9,
134.4, 135.3, 137.2 (Ph), 153.9 (CO). Anal. calcd for
C31H39NO3Si: C, 74.24; H, 7.78; N, 2.79. Found: C,
74.37; H, 7.62; N, 2.91%.
4.8. (4Z)-5-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-
pentenenitrile 1625
Sodium bis(trimethylsilyl)amide (1.0 M in THF, 3.9
mL, 3.9 mmol) was added dropwise to a stirred solu-
tion of the phosphonium salt 7 (1.53 g, 3.72 mmol) in
THF (3.9 mL). The resultant bright yellow mixture was
stirred at 0°C under a nitrogen atmosphere for 30 min.
A solution of the aldehyde 15 (0.315 g, 2.4 mmol) in
dry THF (5 mL) was added dropwise. The mixture was
stirred for a further 4 h at 0°C and poured into a
separating funnel containing diethyl ether (60 mL). The
organic layer was washed with saturated aqueous
sodium chloride (2×20 mL), dried (Na2SO4) and con-
centrated in vacuo. Flash chromatography (ethyl ace-
tate–hexane 1:3) of the resulting crude oil gave the
nitrile 16 (Rf=0.3) as a light yellow oil (0.32 g, 70%).
IR nmax (cm−1): 2246 (CN). 1H NMR (300 MHz,
CDCl3): d 1.38 (s, 3H, CH3), 1.48 (s, 3H, CH3), 2.21 (m,
4H, 2×H-3 and 2×H-2), 3.60 (t, 1H, J=8 Hz, H-5%),
4.12–4.17 (m, 1H, H-5%), 4.81–4.86 (m, 1H, H-4%), 5.62
(m, 2H, H-4 and H-5). 13C NMR (75 MHz, CDCl3): d
17.6 (C-2), 23.4 (C-3), 25.9 (CH3), 26.8 (CH3), 69.4
(C-5%), 71.5 (C-4%), 109.4 (CMe2), 118.8 (C-1), 129.7
(C-4), 130.8 (C-5).
4.6. N-(Methyl)-(2R)-2-[(2S)-2-((tert-butyldiphenyl-
silyl)oxy)prop-1-yl]pyrrolidine 13
A solution of 12 (344 mg, 0.7 mmol) in ether (7 mL)
was treated with LiAlH4 (63 mg, 1.7 mmol). After 6 h
the reaction was quenched by addition of
Na2SO4·10H2O (617 mg, 1.9 mmol). Water (2 mL) was
added to the reaction solution, the ether layer separated
and the aqueous layer extracted further with ether (2×5
mL). The combined organic extracts were dried
(Na2SO4), filtered and evaporated. Following chro-
matography on silica (methanol–ether 1:9, Rf=0.3), the
silyl ether 13 was obtained as a colourless oil (132 mg,
4.9. (4Z)-5-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-
pentenamine 17
1
50%). [a]D +31.7 (c 1.4, CHCl3). H NMR (300 MHz,
CDCl3): d 1.02 (s, 9H, t-Bu), 1.15 (d, 3H, J=6.1 Hz,
3×H-7), 1.25 (m, 2H, 2×H-2), 1.60 (m, 3H, 2×H-3 and
H-5a), 1.90–2.20 (m, 3H, 2×H-1 and H-5b), 2.24 (s, 3H,
CH3N), 3.00 (t, 1H, J=9.0 Hz, H-4), 3.85 (m, 1H,
A solution of nitrile 16 (1 g, 5.52 mmol) in dry ether (5
mL) was added slowly to a stirred suspension of lithium
aluminium hydride (0.9 g, 23.7 mmol) in dry ether (75
mL). The reaction mixture was heated under reflux for
2 h under nitrogen and was then allowed to cool to rt.
Sodium sulfate decahydrate was slowly added in small
portions until excess LiAlH4 was destroyed. The reac-
tion mixture was then filtered through Celite, washed
with ether and the filtrate concentrated in vacuo to give
the amine 17 as a light yellow oil (0.96 g, 94%). [a]D
H-6), 7.30–7.50 (m, 6H, Ph), 7.65–7.72 (m, 4H, Ph). 13
C
NMR (50 MHz, CDCl3): d 19.4 (C-2), 22.0 (Si-C), 24.8
(C-7), 27.2 (t-Bu), 31.2 (C-3), 40.4 (CH3N), 44.3 (C-5),
57.1 (C-1), 63.0 (C-4), 68.4 (C-6), 127.4, 127.5, 127.6,
129.5, 129.6, 134.2, 134.9, 135.9, 136.0, 136.1 (ArH).
HRMS calcd for (M+H) C24H36NOSi: 382.2566.
Found: 382.2566.
1
+3.5 (c 1.0, CH2Cl2). IR nmax (cm−1): 3357 (NH2). H

602
G. Enierga et al. / Tetrahedron: Asymmetry 12 (2001) 597–604
NMR (300 MHz, CDCl3): d 1.37 (s, 3H, CH3), 1.40 (s,
3H, CH3), 1.52–1.60 (m, 2H, 2×H-2), 2.12–2.38 (m, 2H,
2×H-3), 2.49–2.68 (bs, 2H, NH2), 2.75 (t, 2H, J=7.3
Hz, 2×H-1), 3.54 (t, 1H, J=8.3 Hz, H-5%), 4.08 (m, 1H,
H-5%), 4.84–4.92 (m, 1H, H-4%), 5.44 (m, 1H, H-4),
5.62–5.70 (m, 1H, H-5). 13C NMR (75 MHz, CDCl3): d
24.9 (C-3), 25.8 (CH3), 26.6 (CH3), 33.2 (C-2), 41.3
(C-1), 69.1 (C-5%), 71.5 (C-4%), 108.6 (CMe2), 128.2
(C-4), 131.7 (C-5).
(CH2Ph), 76.5 (C-4%), 109.2 (CMe2), 127.2, 127.3, 128.6,
136.1 (Ph), 156.2 (CO). HRMS calcd for (M+Na+)
C18H24ClHgNNaO4: 578.0997. Found: 578.0998. Anal.
calcd for C18H24ClHgNO4: C, 38.99; H, 4.36; N, 2.53.
Found: C, 39.06; H, 4.23; N, 2.57%.
4.12. N-Benzyloxycarbonyl-(5R)-[((4S)-2,2-dimethyl-
1,3-dioxolan-4-yl)methyl]pyrrolidine 20
Tributylstannane (0.63 g, 2.16 mmol) was added drop-
wise to a stirred solution of 19 (0.3 g, 0.54 mmol) and
AIBN (0.03 g, 0.18 mmol) in toluene (3 mL) under a
nitrogen atmosphere. Metallic mercury immediately
began to precipitate. The reaction was stirred at rt for
1 h and then at 70°C for 2 h. The mixture was allowed
to cool to rt. Carbon tetrachloride (2 mL) was added
and the mixture stirred for an additional 1 h. The
solution was decanted from the precipitated mercury,
diluted with ether (100 mL) and washed with a 5%
aqueous potassium fluoride solution (2×45 mL). The
organic layer was dried (MgSO4), filtered and concen-
trated in vacuo. Purification of the residue by column
chromatography (ethyl acetate–dichloromethane 1:4,
Rf=0.5) gave 20 as a yellow oil (0.13 g, 73%). [a]D
4.10. N-Benzyloxycarbonyl-(4Z)-5-[(4S)-2,2-dimethyl-
1,3-dioxolan-4-yl]-4-pentenamine 18
Benzyl chloroformate (2.4 mL, 1.62 mmol) was added
dropwise to an ice-cooled solution of the amine 17 (252
mg, 1.35 mmol) and triethylamine (3 mL, 2.16 mmol) in
THF (5 mL) under nitrogen. The reaction mixture was
stirred overnight at rt, filtered and the solid washed
with ether. The filtrate was washed with saturated
aqueous sodium chloride, separated and dried
(Na2SO4). The solvent was removed under reduced
pressure and the crude product was purified by flash
chromatography (ethyl acetate–hexane 1:3, Rf=0.7).
Carbamate 18 was obtained as a yellow oil (0.29 g,
66%). [a]D −10.0 (c 1.0, CH2Cl2). IR nmax (cm−1): 3364
1
+35.1 (c 1.0, CH2Cl2). IR nmax (cm−1): 1699 (CO). H
1
(NH), 1706 (CO). H NMR (300 MHz, CDCl3): d 1.37
NMR (300 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.37 (s,
3H, CH3), 1.53–1.68 (bm, 2H, 2×H-3), 1.81–1.93 (bm,
4H, 2×H-4 and 2×H), 3.38 (m, 2H, 2×H-2), 3.52 (m,
1H, H-5%a), 3.86 (m, 1H, H-5%b), 4.04 (m, 1H, H-5),
4.16 (m, 1H, H-4%), 5.10 (m, 2H, CH2Ph), 7.32 (m, 5H,
Ph). 13C NMR (75 MHz, CDCl3): d 24.1 (C-3), 26.1
(CH3), 27.3 (CH3), 31.1 (C-4), 38.7 (CH2), 46.4 (C-2),
54.4 (C-5), 66.8 (CH2Ph), 67.3 (C-5%), 68.5 (C-4%), 108.2
(CMe2), 127.6, 127.7, 128.3, 137.8 (Ph), 154.9 (CO).
HRMS calcd for (M+Na+) C18H25NaO4: 342.1681.
Found: 342.1681. Anal. calcd for C18H25NO4: C, 67.69;
H, 7.89; N, 4.39. Found: C, 67.39; H, 7.76; N, 4.46%.
(s, 3H, CH3), 1.41 (s, 3H, CH3), 1.65 (m, 2H, 2×H-2),
2.25 (m, 2H, 2×H-3), 3.21 (m, 2H, 2×H-1), 3.53 (t, 1H,
J=7.8 Hz, H-5%), 4.10 (m, 1H, H-5%), 4.81 (m, 1H,
H-4%), 5.10 (bs, 3H, CH2Ph and NH), 5.41–5.50 (m, 1H,
H-4), 5.56–5.66 (m, 1H, H-5), 7.30–7.39 (m, 5H, Ph).
13C NMR (75 MHz, CDCl3): d 24.9 (C-3), 25.9 (CH3),
26.7 (CH3), 27.4 (C-2), 39.9 (C-1), 66.4 (CH2Ph), 69.4
(C-5%), 71.6 (C-4%), 109.1 (CMe2), 127.7, 127.9, 128.3
(Ph), 134.2 (C-4), 136.5 (C-5), 156.2 (CO). HRMS calcd
for (M+Na+) C18H25NNaO4: 342.1681. Found:
342.1911.
4.11. N-Benzyloxycarbonyl-(5R)-5-[(S)-chloromercu-
rio((4S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl]pyrrolidine 19
4.13. N-Benzyloxycarbonyl-(5R)-5-[(2S)-2,3-dihydroxy-
prop-1-yl]pyrrolidine 21
A solution of mercuric acetate (1.99 g, 6.26 mmol) in
dry dichloromethane (34 mL) was added slowly to a
stirred solution of carbamate 18 (1 g, 3.13 mmol). The
mixture was allowed to stir for 24 h at rt, aqueous
saturated NaCl was added and the mixture was stirred
for an additional 15 min. The organic phase was dried
(Na2SO4), filtered and concentrated in vacuo. Purifica-
tion by column chromatography (ethyl acetate–
dichloromethane 1:4, Rf=0.75) of the crude residue
afforded pyrrolidine 19 as a white solid (1.4 g, 82%).
[a]D +59.6 (c 1.0, CH2Cl2). IR nmax (cm−1): 1664 (CO).
1H NMR (300 MHz, CDCl3): d 1.26 (s, 3H, CH3), 1.39
(s, 3H, CH3), 1.78–1.98 (m, 4H, 2×H-3 and 2×H-4),
2.62 (dd, 1H, J=11.6, 5.8 Hz, CHHgCl), 3.31 (m, 2H,
2×H-2), 3.58 (t, 1H, J=7.6 Hz, H-5%a), 3.84–3.94 (m,
1H, H-5), 4.08 (bt, J=5.9 Hz, 1H, H-5%b), 4.36 (m, 1H,
H-4%), 5.05 and 5.08 (ABq, 2H, J=11.4 Hz, CH2Ph),
7.30–7.39 (m, 5H, Ph). 13C NMR (75 MHz, CDCl3): d
23.9 (C-3), 25.7 (CH3), 27.4 (CH3), 32.1 (C-4), 46.5
(C-2), 59.8 (C-HgCl), 60.1 (C-5), 67.5 (C-5%), 70.9
A 50% aqueous acetic acid solution (1 mL) was added
to 20 (50 mg, 0.16 mmol) and the resulting solution was
stirred at rt for 24 h. The solvent was removed under
reduced pressure without heating. Toluene (0.5 mL)
was added and the solvent was concentrated in vacuo.
Purification of the crude mixture by flash chromatogra-
phy (ethyl acetate, Rf=0.5) afforded the diol 21 as a
yellow oil (45 mg, 77%). [a]D −2.4 (c 1.0, CH2Cl2). IR
nmax (cm−1): 3404 (OH), 1676 (CO). 1H NMR (300
MHz, CDCl3): d 1.44 (m, 2H, H-1%), 1.63 (m, 2H,
2×H-4), 1.94 (m, 3H, 2×H-3 and OH), 3.43 (bt, J=6.6
Hz, 2H, 2×H-2), 3.46–3.61 (bm, 2H, 2×H-3%), 3.68 (m,
1H, H-5), 4.26 (m, 1H, H-2%), 5.15 (s, 2H, CH2Ph), 7.36
(m, 5H, Ph). 13C NMR (75 MHz, CDCl3): d 23.6 (C-1%),
31.3 (C-3), 39.3 (C-4), 46.5 (C-2), 54.5 (C-5), 66.5
(CH2Ph), 67.4 (C-3%), 68.7 (C-2%), 127.9, 128.2, 128.6,
136.6 (Ph), 157.1 (CO). HRMS calcd for (M+Na+)
C15H21NaO4: 302.1368. Found: 302.1365. Anal. calcd
for C15H21NO4: C, 64.5; H, 7.58; N, 5.01. Found: C,
64.34; H, 7.48; N, 4.86%.

G. Enierga et al. / Tetrahedron: Asymmetry 12 (2001) 597–604
603
1
4.14. N-Benzyloxycarbonyl-(5R)-5-[(2S)-2-hydroxy-3-
(c 1.0, CH2Cl2). IR nmax (cm−1): 1716 (CO). H NMR
(75 MHz, CDCl3): d 1.6–2.5 (m, 5H, 2×H-6, 2×H-7 and
H-4a), 2.44 (ddd, 1H, J=14.3, 8.2, 6.2 Hz, H-4b), 2.87
(m, 1H, H-8a), 3.05 (m, 1H, H-2a), 3.20 (ddd, 1H,
J=10.5, 6.7, 4.4 Hz, H-8b), 3.40 (dd, 1H, J=12.6, 5.0
Hz, H-2b), 3.67 (m, 1H, H-5), 5.49 (m, 1H, H-3), 7.40
(m, 2H, Ph), 7.55 (m, 1H, Ph), 8.00 (m, 2H, Ph). 13C
NMR (300 MHz, CDCl3): d 26.1 (C-7), 32.9 (C-6), 38.1
(C-4), 55. (C-8), 59.6 (C-2), 63.8 (C-5), 77.6 (C-3),
128.5, 129.5, 130.3, 133.0 (Ph), 166.1 (CO). HRMS
calcd for (M+H+) C14H18NO2: 232.1337. Found:
232.1332.
methanesulfonyloxyprop-1-yl]pyrrolidine 22
Methanesulfonyl chloride (0.33 mL, 4.2 mmol) in
dichloromethane (10 mL) was added dropwise to a
stirred ice-cooled solution of the diol 21 (1.18 g, 4.2
mmol) and triethylamine (0.59 mL, 4.2 mmol) in
dichloromethane (25 mL). The resulting mixture was
stirred for 2 h at 0°C, after which the solvent was
removed in vacuo. The residue was then diluted with
dichloromethane (70 mL) and washed with ice-
cold water (2×50 mL). The organic layer was
dried (MgSO4), filtered and concentrated in vacuo to
give
a
yellow oil. Flash chromatography (1:15
dichloromethane–ethyl acetate) gave the mono-mesyl-
ated product 22 as an oil (1.08 g, 72%). [a]D +4.1 (c 1.0,
CH2Cl2). IR nmax (cm−1): 3402 (OH), 1638 (CO), 1417,
Acknowledgements
1
1355, 1174 (SO3CH3). H NMR (300 MHz, CDCl3): d
Financial support from the Australian Research Coun-
cil is gratefully acknowledged. The authors would like
to thank Dr. Gary D. Fallon for determining the X-ray
crystal structure of compound 19.
1.51 (m, 2H, 2×H-1%), 1.68 (bs, 1H, OH), 1.94 (bm, 4H,
2×H-3 and 2×H-4), 3.10 (s, 3H, CH3SO2), 3.34 (bt,
J=6.5 Hz, 2H, 2×H-2), 3.88 (m, 1H, H-5), 4.21 (m, 2H,
2×H-3%), 4.31 (m, 1H, H-2%), 5.15 (bs, 2H, C6 H2Ph), 7.36
(m, 5H, Ph). 13C NMR (300 MHz, CDCl3): d 23.5
(C-3), 31.9 (C-4), 37.7 (CH3SO3), 39.2 (C-1%), 46.5 (C-
2), 54.1 (C-5), 66.1 (C-2%), 67.4 (C-3%), 73.3 (CH2Ph),
128.8, 128.1, 128.5 (Ph). HRMS calcd for (M+Na+)
C16H23NNaO6S: 380.1144. Found: 380.1149.
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