Stereocontrolled synthesis of glycosidase inhibitors (+)-hyacinthacines A1 and A2

Article abstract of DOI:10.1016/j.tetasy.2014.12.002

(+)-Hyacinthacines A₁ and A₂ have been prepared from an easily available, advanced intermediate. The non-chiral pool approach features a dichloroketene-enol ether [2+2] cycloaddition and a dihydroxylation or epoxidation as key stereoselective transformations.

Full text of DOI:10.1016/j.tetasy.2014.12.002

Tetrahedron: Asymmetry 26 (2015) 85–94
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereocontrolled synthesis of glycosidase inhibitors
(+)-hyacinthacines A1 and A2
⇑
Amaël Veyron, Paidi Venkatram Reddy, Peter Koos, Alexandre Bayle, Andrew E. Greene, Philippe Delair
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, F-38041 Grenoble, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 November 2014
Accepted 2 December 2014
(+)-Hyacinthacines A1 and A2 have been prepared from an easily available, advanced intermediate. The
non-chiral pool approach features a dichloroketene–enol ether [2+2] cycloaddition and a dihydroxylation
or epoxidation as key stereoselective transformations.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
by the presence of a hydroxymethyl substituent at C-3 on a pyrro-
lizidine ring system (Fig. 1). Since the initial isolation of three hya-
Glycosidases, a large group of hydrolytic enzymes, catalyze the
cleavage of glycosidic bonds in oligosaccharides and glycoconju-
gates.1 The hydrolysis mechanism has been shown to involve a
charged, oxocarbenium-like transition state.2 These ubiquitous
enzymes are of primary importance because they are involved in
a large array of central biological phenomena, such as digestion,
lysosomal catabolism, and cell–cell and cell–virus recognition.
Since inhibitors of the enzymes can be viewed as potential drugs
against various diseases, such as diabetes, cancer, viral and para-
sitic infections, and lysosomal disorders,3 it is not surprising that
their study has been of considerable interest for quite some time.4
Iminosugars5 are among the most prominent of the various
inhibitors discovered to date. These carbohydrate-like compounds,
characterized by a nitrogen atom in the place of the endocyclic
oxygen, are believed to exert their potent glycosidase inhibition
through the synergic effects of their structural resemblance to car-
bohydrates and the presence of the nitrogen, which is protonated
at physiological pH and thus mimics the charged nature of the
transition state of the natural substrate of the enzyme. Despite
their high inhibitory activity, relatively few iminosugars at present
enjoy widespread clinical use,6 mainly due to poor selectivity
toward the targeted enzyme. Even GlysetÒ, which has been used
since 1996 for the treatment of type II diabetes, often provokes
severe gastrointestinal complications. For this reason, current
investigations in iminosugar glycosidase inhibition are largely
aimed at finding new candidates that might present more specific
profiles.7
cinthacines by Asano et al. in 1999,9 more than 20 structures have
been identified, which are now subdivided into three groups, A, B,
and C, on the basis of the number of hydroxyl and hydroxymethyl
substituents on ring B of the pyrrolizidine.10 These alkaloids are
powerful glycosidase inhibitors with selective profiles, thus mak-
ing them good drug candidates and/or possible tools for glycobiol-
ogy.11 In addition to this biological potential, the compact and
highly functionalized structures of the hyacinthacines make them
interesting synthetic targets. Herein we describe in detail our
asymmetric12 synthesis of (+)-hyacinthacines A1 and A2.13j
OH
OH
H
H
N
7
1
7a
2
3
B
6
A
OH
OH
N
5
8
OH
OH
(+)-hyacinthacine A1
1
(+)-hyacinthacineA2 2
OH
H
OH
H
OH
OH
N
N
Me
OH
OH
OH
(+)-hyacinthacine A3
3
(-)-α-5-C-(3-hydroxybutyl)-
hyacinthacine A1
4
In this context, we sought an effective synthetic route to hya-
cinthacines, polyhydroxylated alkaloids8 that are characterized
Figure 1. Examples of A-group hyacinthacines.
⇑
Corresponding author.
E-mail address: Philippe.Delair@ujf-grenoble.fr (P. Delair).
http://dx.doi.org/10.1016/j.tetasy.2014.12.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

86
A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
The formation of the bicyclic system was addressed next. To
2. Results and discussion
this end, the pyrrolidine derivatives were transformed into alco-
hols 10 by hydroboration with disiamylborane (Scheme 3).22 In
order to generate the second ring of the pyrrolizidine, a cyclization
was then realized by mesylation of the hydroxyl group, followed
by selective cleavage of the Boc group in the presence of the
acid-sensitive benzylic ether. This cleavage, initially problematic,
could be successfully accomplished with TBSOTf in the presence
of 2,6-lutidine, followed by brief treatment with TBAF, and trig-
gered spontaneous cyclization to give the corresponding pyrrolizi-
dines 11. The removal of the chiral auxiliary in 11 was easily
carried out by treatment with trifluoroacetic acid, which afforded
pure pyrrolizidinol 12 after separation of the epimers by silica
gel chromatography.
2.1. Synthesis of hyacinthacine A1
Hyacinthacine A1 was isolated in low yield (5 mg/kg) from the
bulbs of Muscari armeniacum (hyacinthaceae) and found to exhibit
selective inhibitory activity toward rat intestinal lactase (IC50 value
of 4.4 l
M).14 To the best of our knowledge, the previous syntheses
of this alkaloid have either used chiral pool material or enzymatic
techniques,15,16 or produced racemic17 material. In our envisioned
nonchiral pool/nonenzymatic synthesis of (+)-hyacinthacine A1,
the natural product would be derived from the protected pyrrolizi-
dine I by the appropriate introduction of the hydroxyl groups
(Scheme 1). This pyrrolizidine was expected to be accessible from
lactam 5 by stereoselective reductive alkylation with a hydroxy-
methyl group equivalent, followed by hydration and cyclization.
This lactam had earlier been efficiently prepared13i,18 in our labora-
tory starting from (S)-(À)-StericolÒ 6, an easily prepared and com-
mercially available chiral auxiliary.19
Ar
Ar
HO
O
O
H
N
d
b, c
a
BocN
9
mixture of
isomers
mixture of
isomers
SiMe2Ph
10 (81%)
SiMe2Ph
Ar
11 (99%, 3 steps)
OH
O
H
N
H
elimination
dihydroxylation
H
OH
OH
SePh
H
N
H
N
N
conversion to
hydroxyl
function
g
e, f
I
N
X
OH
1
(+)-hyacinthacine A1
Ar = 2,4,6-triisopropylphenyl
X = protected hydroxyl or
SiMe2Ph
15 (60%)
SiMe2Ph
SiMe2Ph
14 (71%, 2 steps)
equivalent
hydration,
cyclization
12 (68%)
Scheme 3. Reagents and conditions: (a) Sia2BH, THF; H2O2; (b) CH3SO2Cl, pyridine;
(c) TBSOTf, 2,6-lutidine, CH2Cl2; TBAF, THF; (d) TFA, CH2Cl2; SiO2; (e) CH3SO2Cl,
Et3N, CH2Cl2; (f) (PhSe)2, NaBH4, EtOH; (g) m-CPBA, CH2Cl2, À25 °C. Ar = 2,4,6-
triisopropylphenyl.
Ar
O
HO
Ref 13i
HN
O
reductive
alkylation
5
(S)-(-)-stericol 6
At this juncture, it seemed that the introduction of the missing
C-2 hydroxyl group might be feasible from 12 by dehydration, fol-
lowed by syn-dihydroxylation, with the expectation that stereo-
control would be governed by the bulky silylmethyl substituent.
However, direct as well as indirect dehydration proved to be more
difficult to achieve than expected: treatment of 12 with Martin sul-
furane23 or Burgess inner salt24 furnished mainly unidentified deg-
radation products and little olefin, whereas the chloride, formed in
modest yield with SOCl2, could not be cleanly converted into the
olefin. While an attempted tosylation resulted in a Grob-type frag-
mentation reaction25 (cleavage of the C-3AN bond, Scheme 4),
mesylation did proceed as expected, but elimination efforts led
either to degradation once again or (with a strong base) to the
starting alcohol, presumably through the formation of a sulfene.26
Scheme 1. Retrosynthesis of (+)-hyacinthacine A1.
Lactam 5 was transformed in 71% overall yield into the
hemiaminal derivative, through successive treatment with Boc
anhydride, Super HydrideÒ, and p-toluenesulfonic acid in methanol
(Scheme 2). Despite considerable effort, the reaction of 8 with
hydroxymethylcuprate derivatives20 under different reaction
conditions provided at best only low yields of the desired adduct.
Fortunately, the cuprate derived from dimethylphenylsilylmethyl-
magnesium chloride gave a synthetically useful 85:15 mixture of
the corresponding alkylated pyrrolidines 9 in excellent yield
(major isomer depicted throughout). The stereochemical outcome
of this transformation was determined by careful analysis of the
spectroscopic data. The fact that the major isomer displayed an
NOE correlation between one hydrogen of the CH2Si substituent
and the methine hydrogen on C-3 of the pyrrolidine ring and that
the minor isomer showed an NOE correlation between the C-3 and
C-5 hydrogens was particularly revealing. This result is concordant
with the previously reported21 preferential attack of nucleophiles
on the less hindered face of transient acyl-iminium ions.
OH
H
a
12
N
Ts
13
(84%)
Ar
Ar
O
O
3
Scheme 4. Reagents and conditions: (a) TsCl, Et3N, pyridine, DMAP, 20 °C.
2
c
a
5
BocN
BocN
5
85:15
Fortunately, however, the displacement of the mesylate with
the phenylselenide anion was efficient and furnished pyrrolizidine
14 in 71% yield from pyrrolizidinol 12.27 Careful, low temperature
oxidation of this seleno ether with 1.1 equiv of m-CPBA
circumvented a problem of fragmentation28 and provided the
X
Y
SiMe2Ph
(96%)
7
8
X,Y = O (85%)
b
X,Y = H, OMe (84%)
9
Scheme 2. Reagents and conditions: (a) Boc2O, DMAP, Et3N; (b) LiEt3BH; p-TsOH,
MeOH; (c) PhMe2CH2MgCl, CuBrÁMe2S, BF3ÁEt2O, Et2OÁMe2S.

A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
87
corresponding selenoxide, which after elimination gave the desired
olefin 15 (60%).29
proved uneventful. First, the latent primary hydroxyl group in 16
was unmasked through Tamao–Fleming oxidation,35 and the
resulting lactam 22 was then reduced with the borane–dimethyl
sulfide complex to give in 65% overall yield hyacinthacine A1
With olefin 15 in hand, OsO4-catalyzed dihydroxylation was
next examined. With trimethylamine oxide as the stoichiometric
oxidant in t-BuOH/H2O, however, only a ca. 1:1 mixture of syn-
stereoisomers was obtained in mediocre yield, with the desired
isomer surprisingly present as the over-oxidized pyrrolizidinone
16 (Scheme 5).30 The stereochemistry depicted in 16 was based
on the observation of an NOE correlation between the C-1 (or C-
2) and C-8 hydrogens, whereas the assignment in 17 was made
on the basis of NOE correlations observed between the C-1, C-2,
and C-3 hydrogens, but not with those on C-8, in the derived
diacetate.
{[a]
21 = +43.9 (c 0.29, H2O)], which provided spectroscopic data
D
in excellent agreement with those of the naturally derived product
{[a]
D = +38.2 (c 0.23, H2O)}.14
OH
H
OH
H
N
a
c
OH
21
OH
N
O
OH
(+)-hyacinthacine A1 1 (78%)
R
16
R = SiMe2Ph (99%)
b
R = OH (83%)
22
OH
OH
H
N
H
N
1
2
3
Scheme 7. Reagents and conditions: (a) OsO4, Me3NO, acetone; (b) HBF4ÁOMe2,
CH2Cl2; KF, m-CPBA, DMF. (c) BH3ÁSMe2, THF.
a
OH
15
+
OH
O
8
SiMe2Ph
SiMe2Ph
2.2. Synthesis of hyacinthacine A2
16
(ca. 25%)
17
(ca. 25%)
It was hoped that the excellent degree of stereoselectivity
exhibited in the above dihydroxylation of pyrrolizidinone 21 might
also be observed in the epoxidation of the same substrate. It
seemed likely that the epoxide, if obtained, could be converted
by hydrolysis into the trans-vicinal diol required for the prepara-
tion of hyacinthacine A2.
Scheme 5. Reagents and conditions: (a) OsO4 (cat.), Me3NO, t-BuOH/H2O.
The lactam corresponding to pyrrolizidine 15 was therefore
prepared next in anticipation that the dihydroxylation would
now proceed not only in improved yield because of the lower reac-
tivity of the lactam nitrogen lone pair, but also with improved ste-
reoselectivity since the lactam carbonyl serves to flatten the
bicyclic system, thus most likely leading to dominant stereochem-
ical control by the bulky silyl group. The required pyrrolizidinone
21 was obtained by modification of the previous pathway, as
shown in Scheme 6. The mixture of alcohols 10 was first trans-
formed into the corresponding epimeric esters by oxidation31,32
and esterification. After selective removal of the Boc group, the epi-
mers were heated in refluxing toluene. This operation triggered the
cyclization of only the desired epimer, and pure pyrrolizidinone 19
was thus easily isolated in 63% yield (2 steps). Steric interactions
that would be encountered in cyclization of the minor isomer of
pyrrolidine 18 most likely underlie this fortuitous occurrence.
The cleavage of the chiral auxiliary in 19 with trifluoroacetic acid
led to pyrrolizidinol 20 in 87% yield, which was best dehydrated
by pyrolysis of the corresponding xanthate (72%).33,34
Hyacinthacine A2 has been isolated in low yield (1.2 mg/kg)
from the bulbs of Muscari armeniacum (hyacinthaceae) and found
to be a selective inhibitor of amyloglucosidase from Aspergillus
niger (IC50 value of 1.9 l
M).14,36 This alkaloid has been a frequent
synthetic target, mainly through chiral-pool approaches;37,38 to
the best of our knowledge, our work represents the first non-chiral
pool/non-enzymatic approach to hyacinthacine A2.
After some experimentation, it was found that treatment of
pyrrolizidinone 21 with in situ generated trifluoromethylmethyl
dioxirane39 gave the corresponding epoxide 23 as the sole observa-
ble stereoisomer in nearly quantitative yield (Scheme 8). The
observation of NOE correlations between the C-1, C-2, C-7a, and
C-8 hydrogens offered strong confirmation that the expected ste-
reochemistry of the epoxide ring had indeed been produced.
OH
H
N
H
O
1
7a
b
a
2
3
OH
21
N
O
8
O
Ar
SiMe2Ph
MeO2C
SiMe2Ph
O
OR
H
N
H
N
23 (98%)
24 (68%)
f, g
a, b
c, d
BocN
10
OH
H
OH
H
N
c
d
O
mixture of
isomers
O
SiMe2Ph
21 (72%)
SiMe2Ph
e
OH
SiMe2Ph
OH
N
18 (83%)
19
20
R = (S)-1-(2,4,6-triiso-
O
propylphenyl)ethyl (63%)
OH
25 (94%)
OH
(+)-hyacinthacine A2 2 (97%)
R = H (87%)
Scheme 6. Reagents and conditions: (a) Dess–Martin periodinane; (b) NaClO2;
CH2N2; (c) TMSOTf, 2,6-lutidine, CH2Cl2; (d) toluene, reflux; (e) TFA, CH2Cl2; (f) KH;
CS2; MeI; (g) xylene, 180 °C. Ar = 2,4,6-triisopropylphenyl.
Scheme 8. Reagents and conditions: (a) CF3COCH3, Oxone,ÒEDTA, Na2CO3, CH3CN;
(b) TFA, THF–H2O, 70 °C; (c) HBF4ÁOMe2, CH2Cl2; KF, m-CPBA, DMF; (d) BH3ÁSMe2,
THF.
It was felt that epoxide opening would most likely occur in the
desired sense in epoxide 23 in view of the silylmethyl group at C-3,
which could be expected to exert greater shielding at C-2 than at
C-1. Exposure of epoxide 23 to hydrolysis40 furnished essentially
a unique diol 24, which was isolated in 68% yield by silica gel
Dihydroxylation of pyrrolizidinone 21 proceeded with high ste-
reoselectivity under conditions similar to those above: the desired
diol 16 was formed exclusively in almost quantitative yield
(Scheme 7). The completion of the synthesis of hyacinthacine A1

88
A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
chromatography. NOE data for 24 were in agreement with the
assigned stereochemistry: correlations were observed between
the C-2, C-7a, and C-8 hydrogens and, additionally, a correlation
was noted between the C-1 and C-3 hydrogens.
J = 7.9, 5.1, 5.1 Hz, 1H), 4.98–5.15 (m, 3H), 5.90 (dddd, J = 17.5,
10.2, 7.5, 7.5 Hz, 1H), 6.95 (s, 1H), 7.05 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) d 23.1 (CH3), 23.8 (CH3), 24.2 (CH3) 25.0 (CH3),
27.9 (CH3), 29.1 (CH), 33.2 (CH2), 33.9 (CH), 38.8 (CH2), 59.9 (CH),
69.3 (CH), 71.5 (CH), 82.9 (C), 118.5 (CH2), 120.6 (CH), 123.4
(CH), 131.8 (C), 134.2 (CH), 145.9 (C), 147.8 (C), 148.7 (C), 149.5
(C) 170.9 (C); MS (ESI) m/z 966 (2MNa+), 494 (MNa+); anal. calcd
for C29H45NO4: C, 73.85; H, 9.62; N, 2.97. Found: C, 73.67; H,
9.65; N, 3.06.
Completion of the synthesis could be readily achieved from
pyrrolizidinone 24 by Tamao–Fleming oxidation and lactam reduc-
tion, as described above for pyrrolizidinone 16, to give in 91% yield
over the two steps hyacinthacine A2, which provided NMR data in
full agreement with those of the naturally derived product. Fur-
thermore, the magnitude and sign of the specific rotation
{[a]
23 = +12.0 (c 0.45, H2O)} accorded extremely well with all but
D
4.1.2. (2R,3R,5S)- and (2R,3R,5R)-tert-Butyl 2-allyl-5-methoxy-3-
[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]-pyrrolidine-1-carboxy-
late 8
one of the many (>10) reported15d values for the synthetically
derived natural product; the naturally derived substance has been
reported14 to have [
a]D = +20.1 (c 0.44, H2O).
To a stirred solution of 4.20 g (8.90 mmol) of lactam 7 in 45 mL
of dry THF at À78 °C was added 19.6 mL (19.6 mmol) of LiEt3BH
(1.0 M solution in THF). After being stirred for 1 h, the solution
was treated with saturated aqueous NaHCO3 solution and allowed
to warm to 0 °C over 1 h, whereupon 4 mL of 30% hydrogen perox-
ide was added. After 1 h, the reaction mixture was diluted with
ether, and the separated aqueous layer was extracted with ether.
The combined organic layers were dried over Na2SO4, filtered,
and concentrated to give 4.56 g of the corresponding hemiaminal
derivative ((2R,3R)-tert-butyl 2-allyl-5-hydroxy-3-((S)-1-(2,4,6-tri-
isopropylphenyl)ethoxy)-pyrrolidine-1-carboxylate) as a yellow
oil, which was used without purification: 1H NMR (300 MHz,
CDCl3) d 1.15–1.37 (m, 18H), 1.43 (br s, 9H), 1.53 (d, J = 6.8 Hz,
3H), 1.83–2.08 (m, 1H), 2.15–2.40 (m, 1H), 2.42–2.62 (m, 2H),
2.85 (sept, J = 6.9 Hz, 1H), 3.02–3.30 (m, 1H), 3.72 (br s, 1H),
3.75–4.02 (m, 3H), 4.90–5.15 (m, 3H), 5.32 (m, 1H), 5.74–5.95
(m, 1H), 6.94 (br s, 1H), 7.04 (br s, 1H). A solution of the above
crude hemiaminal derivative and 0.190 g (1.00 mmol) of p-tolu-
enesulfonic acid monohydrate in 15 mL of methanol was stirred
at 20 °C for 3 h. The reaction mixture was quenched with saturated
aqueous NaHCO3 and methanol was evaporated at 20 °C under
reduced pressure. The aqueous layer was extracted with ether to
yield the crude product, which was purified on deactivated (2.5%
v/v of Et3N) silica gel with 3% ethyl acetate in pentane to give
3.63 g (84%) of 8 as a colorless oil. Minor stereoisomer (in mixture):
1H NMR (500 MHz, DMSO, 85 °C) d 1.16–1.26 (m, 18H), 1.42 (s, 9H),
1.51 (d, J = 6.8 Hz, 3H), 1.79–1.90 (m, 1H), 2.14–2.24 (m, 2H), 2.45–
2.54 (m, 1H), 2.86 (sept, J = 6.8 Hz, 1H), 3.20 (s, 3H), 3.05–3.94 (m,
2H), 3.78–3.87 (m, 1H), 4.11 (ddd, J = 11.2, 6.8, 6.8 Hz, 1H), 4.85–
4.97 (m, 3H), 5.13 (q, J = 6.8 Hz, 1H), 5.71–5.86 (m, 1H), 7.02 (s,
2H). Major stereoisomer (in mixture): IR (film) 2960, 2929, 2869,
3. Conclusion
In conclusion, we have reported an effective approach to A-
group hyacinthacines. The success of the approach, which features
clean introduction of the different stereogenic centers, is due to the
high diastereoselectivity of the dichloroketene–chiral enol ether
cycloaddition, as well as that of the dihydroxylation and epoxida-
tion reactions.41 The overall flexibility inherent in this approach
would seem to augur well for the preparation of other A-group
hyacinthacines.
4. Experimental
4.1. General
All reactions were carried out under argon, unless otherwise
stated. THF and Et2O were distilled from Na-benzophenone, CH2Cl2
and iPr2NH from CaH2, and DMF from CaSO4. All other commercial
materials were used as received without purification. NMR spectra
were recorded on a Bruker Avance 300, Bruker Avance 400, or Var-
ian U+ 500 spectrometer and the coupling constants have been cal-
culated, where possible, by using the method described by Hoye
et al.42 Melting points are uncorrected. IR spectra were recorded
on neat samples or KBr pellets with a Nicolet 397 FT-spectrometer.
The mass spectra were recorded on a Nermag R10 mass spectrom-
eter in ESI mode. High-resolution mass spectra (HRMS) were per-
formed on a Bruker Q-TOF maXis mass spectrometer by the
‘Fédération de Recherche’ ICOA/CBM (FR2708) platform. In general,
extraction of the reaction mixture with the specific organic solvent
was followed by appropriate aqueous washing, drying over
Na2SO4, filtration, and evaporation of the solvent under reduced
pressure.
1703, 1389, 1366, 1168 cmÀ1 1H NMR (500 MHz, DMSO, 85 °C) d
;
1.16–1.26 (m, 18H), 1.40 (s, 9H), 1.47 (d, J = 6.8 Hz, 3H), 1.79–
1.90 (m, 1H), 2.14–2.24 (m, 1H), 2.27–2.35 (m, 1H), 2.58 (ddd,
J = 13.7, 7.3, 7.3 Hz, 1H), 2.85 (sept, J = 6.8 Hz, 1H), 3.05–3.94 (m,
2H), 3.28 (s, 3H), 3.90 (ddd, J = 7.3, 7.3, 7.3 Hz, 1H), 3.96 (ddd,
J = 9.3, 7.3, 4.9 Hz, 1H), 4.85–4.97 (m, 2H), 5.05 (q, J = 6.8 Hz, 1H),
5.05–5.09 (m, 1H), 5.71–5.86 (m, 1H), 7.00 (s, 2H); MS (ESI) m/z
998 (2MNa+), 588, 510 (MNa+), 231; HRMS calcd for C30H49NO4Na
510.3554, found 510.3548 (MNa+).
4.1.1. (2R,3R)-tert-Butyl 2-allyl-5-oxo-3-[(S)-1-(2,4,6-triisopro-
pylphenyl)ethoxy]-pyrrolidine-1-carboxylate 7
A
solution of 3.12 g (8.40 mmol) of lactam 5,13i 1.20 mL
(8.61 mmol) of triethylamine, 3.66 g (16.77 mmol) of Boc anhy-
dride, and 1.03 g (8.43 mmol) of DMAP in 17 mL of dichlorometh-
ane was stirred at 20 °C for 3 h. The reaction mixture was
concentrated under reduced pressure and the residue was dis-
solved in ether, which was washed with 10% aqueous HCl, dried
over Na2SO4, filtered, and evaporated. The crude product was puri-
fied by silica gel chromatography with ethyl acetate in pentane
(1:9) to afford 3.38 g (85%) of lactam 7 as a colorless solid: mp
4.1.3. (2R,3R,5S)- and (2R,3R,5R)-tert-Butyl 2-allyl-5-{[dimethyl
(phenyl)silyl]methyl}-3-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]
pyrrolidine-1-carboxylate 9
To a stirred solution of 5.23 g (25.4 mmol) of CuBrÁSMe2 com-
146.9–147.4 °C (pentane); [
a]
D
21 = À98.4 (c 0.6, CHCl3); IR (KBr)
plex in dimethyl sulfide–ether (3:7, 70 mL) at À40 °C was added
2960, 2928, 2868, 1756, 1726, 1368, 1303, 1204, 1157, 1102,
over 20 min 31.8 mL (ca. 25.4 mmol) of
a
solution of
1058 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.05–1.35 (m, 18H), 1.49
;
[dimethyl(phenyl)silyl]methylmagnesium chloride in THF (pre-
pared from 5.10 g (210 mmol) of magnesium turnings, 1.00 mL
(11.7 mmol) of dibromoethane, and 12.0 mL (66.5 mmol) of (chlo-
romethyl)dimethyl(phenyl)silane in 70 mL of refluxing THF; ca.
0.8 M). After being stirred for 45 min, the reaction mixture was
(s, 9H), 1.56 (d, J = 6.8 Hz, 3H), 2.35–2.50 (m, 1H), 2.55–2.80 (m,
1H), 2.61 (A of ABX, J = 16.7, 10.1 Hz, 1H), 2.70 (B of ABX, J = 16.7,
7.9 Hz, 1H), 2.85 (sept, J = 6.9 Hz, 1H), 3.02–3.20 (m, 1H), 3.77–
3.95 (m, 1H), 4.09 (ddd, J = 10.1, 7.9, 7.9 Hz, 1H), 4.24 (ddd,

A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
89
cooled to À78 °C and treated dropwise with 3.22 mL (26.1 mmol)
of BF3ÁOEt2. The resultant mixture was stirred for 45 min and a
solution of 3.10 g (6.36 mmol) of 8 in 10 mL of ether was then
added dropwise. After 15 min, the temperature was allowed to rise
to 0 °C over 1 h and the mixture was stirred for 20 min. The reac-
tion mixture was then treated with 40 mL of a solution of 28%
aqueous ammonia saturated with NH4Cl, warmed to 20 °C, and
extracted with ether. The resulting crude product was purified by
silica gel chromatography with 3% ethyl acetate in pentane to
afford 3.69 g (96%) of adduct 9 as a mixture of diastereomers
(85:15): IR (film) 2959, 2927, 2868, 1693, 1458, 1387, 1364,
1249, 1177 cmÀ1. Minor stereoisomer: 1H NMR (500 MHz, DMSO,
85 °C) d 0.31 (s, 3H), 0.32 (s, 3H), 0.95 (dd, J = 13.7, 11.6 Hz, 1H),
1.15 (d, J = 6.9 Hz, 6H), 1.20 (d, J = 6.9 Hz, 12H), 1.36 (s, 9H), 1.43
(d, J = 6.9 Hz, 3H), 1.43–1.50 (m, 1H), 1.75 (dd, J = 13.7, 2.6 Hz,
1H), 2.05 (ddd, J = 14.8, 7.4, 7.4 Hz, 1H), 2.21 (ddd, J = 12.1, 6.9,
6.9 Hz, 1H), 2.26–2.33 (m, 1H), 2.84 (sept, J = 6.9 Hz, 1H), 3.10–
3.90 (m, 2H), 3.64–3.73 (m, 1H), 3.74–3.89 (m, 2H), 4.84–4.93
(m, 2H), 4.98 (q, J = 6.9 Hz, 1H), 5.76 (dddd, J = 17.4, 10.0, 7.4,
7.4 Hz, 1H), 6.98 (s, 2H), 7.35–7.41 (m, 3H), 7.50–7.58 (m, 2H).
Major stereoisomer: 1H NMR (500 MHz, DMSO, 85 °C) d 0.31 (s,
6H), 0.80 (dd, J = 14.3, 11.6 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H), 1.19–
1.24 (m, 12H), 1.39 (s, 9H), 1.44 (d, J = 6.7 Hz, 3H), 1.53 (br d,
1H), 1.77–1.83 (m, 1H), 1.88–1.99 (m, 1H), 2.12–2.18 (m, 1H),
2.44 (ddd, J = 14.3, 6.9, 6.9 Hz, 1H), 2.85 (sept, J = 6.9 Hz, 1H),
3.05–3.75 (m, 2H), 3.76–3.83 (m, 1H), 3.83–3.90 (m, 1H), 4.10
(ddd, J = 10.6, 6.9, 6.9 Hz, 1H), 4.86–4.93 (m, 2H), 5.02 (q,
J = 6.7 Hz, 1H), 5.72–5.83 (m, 1H), 7.00 (s, 2H), 7.35–7.41 (m, 3H),
7.50–7.58 (m, 2H); 13C NMR (75.5 MHz, CDCl3, mixture of rota-
mers) d À2.3 (CH3), 23.1 (CH3), 23.9 (CH3), 24.4 (CH3), 24.9 (CH3),
25.2 (CH3), 28.2 (CH3), 28.6 (CH3), 29.2 (CH), 32.4 (CH2), 34.0
(CH), 35.5 (CH2), 36.5 (CH2), 52.4 (CH), 52.8 (CH), 58.7 (CH), 58.9
(CH), 71.4 (CH), 74.0 (CH), 75.0 (CH), 79.0 (C), 116.4 (CH2), 120.3
(CH), 123.3 (CH), 127.8 (CH), 129.0 (CH), 133.1 (C), 133.6 (CH),
136.6 (CH), 139.1 (C), 145.3 (C), 147.3 (C), 148.9 (C), 153.6 (C);
MS (ESI) m/z 1234 (2MNa+), 628 (MNa+); Anal. calcd for C38H59NO3-
Si: C, 75.32; H, 9.82; N, 2.32. Found: C, 75.51; H, 10.14; N, 2.58.
(CH), 127.1 (CH), 128.3 (CH), 132.7 (CH), 132.9 (C), 138.1 (C),
146.4 (C), 152.6 (C); MS (ESI) m/z 1270 (2MNa+), 646 (MNa+); anal.
calcd for C38H61NO4SiÁ1/4H2O: C, 72.62; H, 9.86; N, 2.23. Found: C,
72.73; H, 9.97; N, 1.92.
4.1.5. (1R,3R,7aR)- and (1R,3S,7aR)-3-{[Dimethyl(phenyl)silyl]
methyl}-1-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]-hexahydro-
1H-pyrrolizine 11
To a solution of 2.70 g (4.33 mmol) of alcohol 10 in 12 mL of pyr-
idine at 0 °C was added 0.600 mL (7.75 mmol) of methanesulfonyl
chloride. The reaction mixture was stirred at 0 °C for 10 min and
then at 20 °C for 1 h. The reaction mixture was then concentrated
under reduced pressure and the residue was dissolved in
ether, which was washed twice with water, dried over Na2SO4,
filtered, and concentrated to yield 3.13 g of crude (2R,3R,5R)-
and (2R,3R,5S)-tert-butyl 5-{[dimethyl(phenyl)silyl]methyl}-2-
[3-(methylsulfonyloxy)propyl]-3-[(S)-1-(2,4,6-triisopropylphenyl)
ethoxy]pyrrolidine-1-carboxylate as a yellow oil. This material was
used in the following step without purification: IR (film) 2960,
2929, 2869, 1690, 1460, 1391, 1363, 1250, 1176 cmÀ1 1H NMR
;
(300 MHz, CDCl3) d 0.33 (s, 6H), 0.60–0.77 (m, 1H), 1.10–1.30 (m,
19H), 1.35–1.50 (m, 13H), 1.65–2.00 (m, 5H), 2.84 (sept,
J = 6.9 Hz, 1H), 2.92 (s, 3H), 3.00–3.20 (m, 1H), 3.60–4.30 (m, 6H),
4.85–5.05 (m, 1H), 6.92 (s, 1H), 7.03 (s, 1H), 7.30–7.42 (m, 3H),
7.42–7.60 (m, 2H); MS (ESI) m/z 1425 (2MNa+), 1207, 1055, 724
(MNa+), 506; anal. calcd for C39H63NO6SSi: C, 66.73; H, 9.05; N,
2.00. Found: C, 66.80; H, 9.45; N, 1.91.
A solution of the above mesylate and 2.00 mL (17.2 mmol) of
2,6-lutidine was treated with 3.00 mL (13.1 mmol) of tert-butyldi-
methylsilyl trifluoromethanesulfonate (TBSOTf) and stirred for 1 h.
The reaction mixture was then quenched with 35 mL of saturated
aqueous NH4Cl and extracted with ether. The resultant crude
N-tert-butyldimethylsilyloxycarbonyl derivative (4.36 g), was
dissolved in 9.0 mL of THF and treated with 4.6 mL (4.6 mmol) of
a 1.0 M solution of TBAF in THF. After 1 h, the reaction mixture
was quenched with 30 mL of saturated aqueous NH4Cl and
extracted with ether. The resulting crude compound was purified
by silica gel chromatography (triethylamine-deactivated) with
0–10% methanol saturated with ammonia in dichloromethane to
afford 2.18 g (99%) of protected pyrrolizidines 11 as an orange
oil. Major diastereomer (in mixture): IR (film) 2959, 2926, 2868,
4.1.4. (2R,3R,5S)- and (2R,3R,5R)-tert-Butyl 5-{[dimethyl(phenyl)
silyl]methyl}-2-(3-hydroxypropyl)-3-[(S)-1-(2,4,6-triisopropyl-
phenyl)ethoxy]pyrrolidine-1-carboxylate 10
A stirred solution of 5.78 g (9.54 mmol) of the mixture of olefins
9 in 70 mL of THF at 0 °C was treated with freshly prepared disi-
amylborane (27.0 mL, 1.42 M in THF, 38.3 mmol). After 15 min,
the reaction mixture was allowed to warm to 20 °C and stirred
for 2 h, after which it was cooled to 0 °C and treated successively
with water, 3 M aqueous NaOH (45.0 mL), and 50% hydrogen per-
oxide (8.0 mL), and then stirred for an additional 2 h. The reaction
mixture was diluted with ether and the separated aqueous layer
was extracted with ether. The combined organic phases were then
processed as usual to leave the crude product, which was purified
by silica gel chromatography with 20% ethyl acetate in pentane to
afford 4.81 g (81%) of an isomeric mixture of alcohols 10. Major
stereoisomer (in mixture): IR (film) 3425, 2960, 2929, 2869,
1460, 1427, 1382, 1362, 1249, 1209, 1112, 1078 cmÀ1 1H NMR
;
(300 MHz, CDCl3) d 0.33 (s, 3H), 0.34 (s, 3H), 0.89 (dd, J = 14.3,
11.3 Hz, 1H), 1.07–1.30 (m, 18H), 1.29–1.36 (m, 2H), 1.40 (d,
J = 6.8 Hz, 3H), 1.42–1.55 (m, 1H), 1.63–1.90 (m, 2H), 1.94–2.06
(m, 2H), 2.46 (ddd, J = 9.9, 7.3, 7.3 Hz, 1H), 2.74–2.95 (m, 3H),
3.06 (sept, J = 6.8 Hz, 1H), 3.51 (ddd, J = 7.3, 7.3, 5.2 Hz, 1H),
3.58–3.66 (m, 1H), 3.92 (sept, J = 6.8 Hz, 1H), 4.89 (q, J = 6.8 Hz,
1H), 6.91 (s, 1H), 7.00 (s, 1H), 7.30–7.42 (m, 3H), 7.46–7.60 (m,
2H); 13C NMR (75.5 MHz, CDCl3) d À2.3 (CH3), À2.1 (CH3), 22.6
(CH2), 23.2 (CH3), 23.9 (CH3), 24.4 (CH3), 24.7 (CH2), 25.3 (CH3),
27.4 (CH2), 27.9 (CH), 29.0 (CH), 33.9 (CH), 41.1 (CH2), 52.9 (CH2),
61.3 (CH), 68.6 (CH), 69.8 (CH), 75.6 (CH), 120.5 (CH), 123.1 (CH),
127.8 (CH), 128.9 (CH), 132.8 (C), 133.6 (CH), 139.2 (C), 145.7 (C),
147.2 (C), 148.7 (C); MS (DCI, NH3+isobutane) m/z 506 (MH+),
274, 231; anal. calcd for C33H51NOSiÁ1/4H2O: C, 77.66; H, 10.17;
N, 2.74. Found: C, 77.57; H, 10.48; N, 2.39.
1690, 1668, 1456, 1392, 1250, 1175, 1143, 1097 cmÀ1 1H NMR
;
(300 MHz, DMSO, 85 °C) d 0.31 (s, 6H), 0.77 (dd, J = 13.9, 11.3 Hz,
1H), 1.16 (d, J = 6.7 Hz, 6H), 1.19–1.25 (m, 12H), 1.34–1.46 (m,
3H), 1.38 (s, 9H), 1.43 (d, J = 6.7 Hz, 3H), 1.52–1.62 (m, 1H), 1.60–
1.70 (m, 1H), 1.76–1.84 (m, 1H), 1.87–1.97 (m, 1H), 2.85 (sept,
J = 6.7 Hz, 1H), 3.24–3.31 (m, 2H), 3.40–3.64 (m, 2H), 3.68–3.74
(m, 1H), 3.83–3.92 (m, 1H), 4.04 (ddd, J = 10.9, 6.7, 6.7 Hz, 1H),
5.01 (q, J = 6.7 Hz, 1H), 7.00 (s, 2H), 7.33–7.42 (m, 3H), 7.50–7.60
(m, 2H); 13C NMR (75.5 MHz, DMSO, 85 °C) d À3.1 (CH3), À3.0
(CH3), 22.1 (CH3), 22.6 (CH2), 23.0 (CH3), 23.8 (CH3), 24.1 (CH3),
25.2 (CH2), 27.7 (CH3), 29.2 (CH2), 32.6 (CH), 35.3 (CH2), 51.2
(CH), 57.6 (CH), 60.9 (CH2), 70.9 (CH), 74.3 (CH), 77.8 (C), 120.7
4.1.6. (1R,3S,7aR)-3-{[Dimethyl(phenyl)silyl]methyl}-hexahydro-
1H-pyrrolizin-1-ol 12
To a solution of 2.18 g (4.31 mmol) of pyrrolizidines 11 in 46 mL
of dichloromethane at 0 °C was added 4.60 mL (60.1 mmol) of TFA.
After 15 min, the reaction mixture was allowed to warm to 20 °C,
stirred for 2 h, and then concentrated under reduced pressure. The
residue was dissolved in methanol saturated with ammonia and
concentrated under reduced pressure (repeated 3 times). The result-

90
A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
ing oil was dissolved in dichloromethane, which was washed with
10% aqueous NaOH, dried over Na2SO4, filtered, and concentrated
to afford the crude product. This material was purified by deacti-
vated silica gel chromatography with 5–20% methanol saturated
with ammonia in dichloromethane to afford 0.809 g (68%) of pyr-
15 min at this temperature and then refluxed for 16 h, after which
it was concentrated under reduced pressure to give the crude prod-
uct. This material was purified by florisil chromatography with 1–
10% methanol saturated with ammonia in dichloromethane to
afford 0.194 g (71% from 12) of phenylselenide 14 as an orange
oil: IR (film) 2955, 2922, 2851, 1732, 1437, 1427, 1250,
rolizidinol 12 as an orange oil: [
a
]
D
21 = À45.0 (c 0.91, CHCl3); IR (film)
3356, 2957, 2912, 1427, 1249, 1114, 832, 729, 700 cm–1
;
1H NMR
1113 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.27 (s, 6H), 0.97 (dd,
;
(300 MHz, CDCl3) d 0.29 (s, 3H), 0.30 (s, 3H), 0.94 (dd, J = 14.3,
10.9 Hz, 1H), 1.33 (dd, J = 14.3, 3.4 Hz, 1H), 1.50–1.68 (m, 2H),
1.70–1.95 (m, 4H), 2.49 (ddd, J = 9.9, 7.3, 7.3 Hz, 1H), 2.83–2.97 (m,
2H), 3.50–3.62 (m, 1H), 4.08 (app dd, J = 4.4, 4.1 Hz, 1H), 7.28–7.38
(m, 3H), 7.45–7.55 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.2
(CH3), À2.1 (CH3), 23.5 (CH2), 24.8 (CH2), 27.4 (CH2), 45.7 (CH2),
53.4 (CH2), 61.3 (CH), 68.9 (CH), 72.0 (CH), 127.8 (CH), 128.9 (CH),
133.5 (CH), 139.3 (C); MS (DCI, NH3 + isobutane) m/z 276 (MH+),
274; HRMS calcd for C16H26NOSi: 276.1778, found: 276.1775 (MH+).
J = 14.5, 10.5 Hz, 1H), 1.27 (dd, J = 14.5, 3.6 Hz, 1H), 1.34–1.48 (m,
1H), 1.54–1.85 (m, 4H), 2.20 (ddd, J = 12.3, 6.3, 5.0 Hz, 1H), 2.51
(ddd, J = 10.6, 6.1, 6.1 Hz, 1H), 2.67 (dddd, J = 10.5, 10.5, 5.0,
3.6 Hz, 1H), 2.88 (ddd, J = 10.6, 6.4, 6.4 Hz, 1H), 3.02 (ddd, J = 11.8,
8.8, 6.3 Hz, 1H), 3.53 (ddd, J = 8.8, 7.1, 5.1 Hz, 1H), 7.15–7.28 (m,
3H), 7.28–7.40 (m, 3H), 7.43–7.57 (m, 4H); 13C NMR (75.5 MHz,
CDCl3) d À2.31 (CH3), À2.28 (CH3), 22.4 (CH2), 25.3 (CH2), 31.0
(CH2), 43.5 (CH2), 45.0 (CH), 53.2 (CH2), 65.0 (CH), 71.3 (CH),
127.9 (CH), 128.1 (CH), 129.09 (CH), 129.15 (CH), 131.5 (C), 133.5
(CH), 135.5 (CH), 138.4 (C); MS (DCI, NH3 + isobutane) m/z 418
(MH+), 416 (MH+), 415, 414 (MH+), 413 (MH+), 412 (MH+), 260,
258; anal. calcd for C22H29NSeSiÁ1/3H2O: C, 62.83; H, 7.11; N,
3.33. Found: C, 62.69; H, 6.91; N, 3.48.
4.1.7. (RS)-1-[(RS)-1-Tosylpyrrolidin-2-yl]but-3-en-1-ol 13
To a solution of 0.020 g (0.073 mmol) of racemic pyrrolizidinol
12, 0.051 mL (0.363 mmol) of triethylamine, and 0.010 g
(0.082 mmol) of DMAP in 0.350 mL of pyridine at 0 °C was added
0.029 g (0.152 mmol) of p-toluenesulfonyl chloride. The reaction
mixture was allowed to warm to 20 °C and stirred over 1.5 h,
whereupon 0.090 mL of saturated aqueous NaHCO3 was added.
After 1 h, the reaction mixture was diluted with ethyl acetate
and water. The organic phase was washed with saturated aqueous
NaHCO3, dried over Na2SO4, filtered, and concentrated to give the
crude product, which was purified by silica gel chromatography
with 0–5% methanol saturated with ammonia in dichloromethane
to afford 0.018 g (84%) of pyrrolidine 13 as a red oil: IR (film) 3507,
4.1.9. (3RS,7aSR)-3-{[Dimethyl(phenyl)silyl]methyl}-5,6,7,7a-
tetrahydro-3H-pyrrolizine 15
To a solution of 0.194 g (0.47 mmol) of racemic phenylselenide
14 in 5.8 mL of dichloromethane at À25 °C was added dropwise a
solution of 0.118 g (0.51 mmol) of m-CPBA (75%) in 5.8 mL of
dichloromethane. The reaction mixture was stirred for 1.25 h,
quenched with aqueous NaOH (1 M), and extracted with dichloro-
methane. The organic phase was dried over Na2SO4, filtered, and
concentrated to afford the crude product. This material was puri-
fied by silica gel chromatography with 1–10% methanol saturated
with ammonia in dichloromethane to afford 0.073 g (60%) of
unsaturated pyrrolizidine 15 as an orange oil: IR (film) 3067,
3072, 2977, 1640, 1598 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.28–
;
1.43 (m, 1H), 1.50–1.85 (m, 4H), 2.06–2.24 (m, 1H), 2.30–2.45
(m, 1H), 2.37 (s, 3H), 2.85–3.10 (br s, 1H), 3.22–3.27 (m, 2H),
3.55–3.65 (m, 2H), 5.05–5.15 (m, 2H), 5.80–5.97 (m, 1H), 7.27 (d,
J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
d 21.5 (CH3), 24.5 (CH2), 28.2 (CH2), 37.9 (CH2), 49.8 (CH2), 64.2
(CH), 72.8 (CH), 117.6 (CH2), 127.7 (CH), 129.8 (CH), 134.4 (C),
134.6 (CH), 143.8 (C); MS (DCI, NH3 + isobutane) m/z 312, 296
(MH+, 100), 278, 224, 140; HRMS calcd for C15H22NO3S:
296.1315, found: 296.1319 (MH+).
2956, 2900, 2866, 1427 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.31
;
(s, 3H), 0.33 (s, 3H), 1.05 (dd, J = 14.4, 9.4 Hz, 1H), 1.24 (dd,
J = 14.4, 5.5 Hz, 1H), 1.30–1.48 (m, 1H), 1.55–1.77 (m, 2H), 1.82–
1.96 (m, 1H), 2.48 (ddd, J = 10.1, 6.7, 6.7 Hz, 1H), 3.01 (ddd,
J = 10.1, 5.7, 5.7 Hz, 1H), 3.53–3.64 (m, 1H), 4.14–4.27 (m, 1H),
5.40 (ddd, J = 5.8, 1.9, 1.9 Hz, 1H), 5.58 (ddd, J = 5.8, 1.8, 1.8 Hz,
1H), 7.30–7.40 (m, 3H), 7.45–7.57 (m, 2H); 13C NMR (75.5 MHz,
CDCl3) d À2.2 (CH3), À1.9 (CH3), 25.2 (CH2), 25.6 (CH2), 30.7
(CH2), 55.7 (CH), 70.6 (CH), 71.2 (CH), 127.7 (CH), 128.8 (CH),
130.2 (CH), 132.1 (CH), 133.6 (CH), 139.5 (C); HRMS calcd for C16-
H24NSi 258.1673, found 258.1675 (MH+).
4.1.8. (1RS,3RS,7aSR)-3-{[Dimethyl(phenyl)silyl]methyl}-1-(phe-
nylselenyl)-hexahydro-1H-pyrrolizine 14
To a solution of 0.201 g (0.73 mmol) of racemic pyrrolizidinol
12 in 16.5 mL of dichloromethane at 0 °C were added 0.350 mL
(2.51 mmol) of triethylamine and 0.115 mL (1.48 mmol) of meth-
anesulfonyl chloride. The reaction mixture was stirred for
45 min, quenched with saturated aqueous NaHCO3 (24 mL), and
extracted with dichloromethane to give 0.285 g of the correspond-
ing crude mesylate as an orange oil. This intermediate was used in
the following step without purification: IR (film) 2955, 2918, 2850,
4.1.10. (1RS,2SR,3SR,7aRS)-3-{[Dimethyl(phenyl)silyl]methyl}-
hexahydro-1H-pyrrolizine-1,2-diol 17
To a solution of 4 mg (0.016 mmol) of racemic unsaturated
pyrrolizidine 15 and 4 mg (0.053 mmol) of trimethylamine N-
t
oxide in 0.130 mL of BuOH/H2O (3:1) was added 0.032 mL of a
solution of osmium tetroxide (2.5% in t-BuOH, 0.2 equiv). The reac-
tion mixture was stirred at 35 °C for 6 h and then allowed to cool to
20 °C and treated with 20 mg (0.19 mmol) of sodium hydrogeno-
sulfite. After 30 min, the mixture was filtered over CeliteÒ to afford
the crude product, which was purified by silica gel chromatogra-
phy with 0–50% methanol saturated with ammonia in dichloro-
methane to afford 1 mg of pyrrolizidinone 16 (see below for
spectroscopic data) and 1 mg of pyrrolizidine 17: IR (film) 3373,
1427, 1357, 1252, 1198, 1176, 1113 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 0.32 (s, 6H), 1.01 (dd, J = 14.5, 10.6 Hz, 1H), 1.33 (dd,
J = 14.5, 3.6 Hz, 1H), 1.65–1.94 (m, 5H), 2.12 (ddd, J = 13.9, 5.0,
1.2 Hz, 1H), 2.47–2.60 (m, 1H), 2.85–3.02 (m, 2H), 2.91 (s, 3H),
3.75–3.90 (m, 1H), 4.98 (app dd, J = 4.2, 4.1 Hz, 1H), 7.31–7.39
(m, 3H), 7.46–7.55 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.3
(CH3), À2.2 (CH3), 22.7 (CH2), 25.8 (CH2), 26.9 (CH2), 38.5 (CH3),
42.9 (CH2), 53.0 (CH2), 61.9 (CH), 67.9 (CH), 82.7 (CH), 127.9
(CH), 129.1 (CH), 133.5 (CH), 138.6 (C); MS (DCI, NH3+isobutane)
m/z 354 (MH+), 258, 180; anal. calcd for C17H27NO3SSiÁH2O: C,
54.95; H, 7.87; N, 3.77. Found: C, 54.56; H, 7.82; N, 3.67.
3068, 2955, 2922 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.33 (s, 3H),
;
0.34 (s, 3H), 1.03 (dd, J = 14.7, 3.7 Hz, 1H), 1.31 (dd, J = 14.7,
11.5 Hz, 1H), 1.53–1.66 (m, 1H), 1.72 (quint, J = 6.5 Hz, 2H), 1.87–
2.06 (m, 1H), 2.41–2.53 (m, 1H), 2.69 (app dt, J = 11.5, 3.2, 3.2 Hz,
1H), 2.86 (ddd, J = = 10.7, 6.5, 6.5 Hz, 1H), 3.19–3.30 (m, 1H),
3.62–3.77 (m, 2H), 7.33–7.41 (m, 3H), 7.49–7.58 (m, 2H); 13C
NMR (125 MHz, CDCl3) d À2.7 (CH3), À2.2 (CH3), 17.6 (CH2), 25.6
(CH2), 30.9 (CH2), 52.8 (CH2), 64.8 (CH), 68.7 (CH), 76.0 (CH), 78.6
A solution of 0.258 g of the above crude mesylate and 0.455 g of
diphenyldiselenide (1.46 mmol) in 7.5 mL of absolute ethanol was
cooled to 0 °C and treated portionwise with 0.066 g (1.74 mmol)
of sodium borohydride. The reaction mixture was stirred for

A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
91
(CH), 128.1 (CH), 129.3 (CH), 133.4 (CH), 138.9 (C); HRMS calcd for
16H26NO2Si: 292.1727, found: 292.1732 (MH+).
(25.8 mmol) of 2,6-lutidine and 3.06 mL (16.9 mmol) of TMSOTf
and the resulting mixture was allowed to warm to 20 °C over
30 min. After being stirred for 2 h, the mixture was cooled to
0 °C, quenched with saturated aqueous NH4Cl, and extracted with
ether. The combined organic phases were washed with 10% aque-
ous NaOH and processed in the usual way to give 2.44 g of an epi-
meric mixture of amino esters, which was used without
purification. Major isomer (in mixture): 1H NMR (300 MHz, CDCl3)
d 0.33 (s, 6H), 0.93 (dd, J = 14.0, 8.5 Hz, 1H), 1.13–1.26 (m, 19H),
1.28–1.38 (m, 1H), 1.45 (d, J = 6.9 Hz, 3H) 1.53–1.95 (m, 2H),
1.96–2.06 (m, 1H), 2.23–2.46 (m, 2H), 2.84 (sept, J = 6.9 Hz, 1H),
2.95–3.20 (m, 2H), 3.44–3.52 (m, 1H), 3.63 (s, 3H), 3.76–3.95 (m,
2H), 4.92–4.99 (m, 1H), 6.92 (s, 1H), 7.01 (s, 1H), 7.33–7.39 (m,
3H), 7.50–7.55 (m, 2H).
C
4.1.11. (2R,3R,5R)- and (2R,3R,5S)-tert-Butyl 3-((S)-1-(2,4,6-
triisopropylphenyl)ethoxy)-2-(2-(methoxycarbonyl)ethyl)-5-
((dimethyl(phenyl)silyl)methyl)pyrrolidine-1-carboxylates 18
To a mixture of 3.19 g (5.11 mmol) of alcohols 10 and 1.29 g
(15.36 mmol) of NaHCO3 in 100 mL of dichloromethane at 0 °C
was slowly added 30 mL of Dess–Martin periodinane solution
(0.37 M in dichloromethane, 11.1 mmol). The mixture was stirred
at 0 °C for 1.5 h and then at 20 °C for 1.5 h, which was followed
by the addition of 2-propanol (15 mL). After being stirred for an
additional 15 min, the reaction mixture was concentrated under
reduced pressure to half of its volume and then diluted with pen-
tane and filtered through CeliteÒ. The filtrate was concentrated
under reduced pressure and the residue diluted with pentane, fil-
tered, and concentrated (repeated 4 times) to yield 3.25 g of an epi-
meric mixture of the corresponding aldehydes, which was used in
the next step without purification. Major stereoisomer (in mix-
ture): IR (film) 3048, 2928, 2869, 1692, 1607, 1454, 1426, 1390,
The above crude amino esters were refluxed in 10 mL of toluene
for 4 h, whereupon toluene was evaporated under reduced pres-
sure to give a mixture of the bicyclic lactam 19 and unreacted
amino ester, which were separated by silica gel chromatography
with ethyl acetate in pentane (3:7) to give 1.38 g (63% from 18)
of bicyclic lactam 19 as a white solid: mp 116.6–117.3 °C (pen-
1249, 1175 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 0.33 (s, 6H), 1.15–
tane); [
a]
21 = À82.9 (c 1.4, CHCl3); IR (film) 2959, 2928, 2869,
D
1.30 (m, 20H), 1.35–1.49 (m, 14H), 1.99–2.23 (m, 2H), 2.37–2.61
(m, 2H), 2.80–2.94 (sept, J = 6.7 Hz, 1H), 3.02–3.20 (m, 1H), 3.70–
3.96 (m, 3H), 3.98–4.10 (m, 1H), 4.90–5.02 (m, 1H), 6.93 (s, 1H),
7.02 (s, 1H), 7.34–7.39 (m, 3H), 7.47–7.56 (m, 2H), 9.65 (s, 1H);
MS (ESI) m/z 231, 622 (MH+).
1692, 1405, 1247, 1112 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 0.33
(s, 3H), 0.40 (s, 3H), 0.94 (A of ABX, J = 14.3, 10.2 Hz, 1H), 1.09–
1.30 (m, 18H), 1.37–1.51 (m, 4H), 1.55 (B of ABX, J = 14.3, 4.5 Hz,
1H), 1.75–1.86 (m, 1H), 2.17–2.28 (m, 1H), 2.30–2.42 (m, 2H),
2.48 (ddd, J = 18.8, 16.2, 9.4 Hz, 1H), 2.78 (sept, J = 6.8 Hz, 1H),
3.04 (sept, J = 7.5 Hz, 1H), 3.58 (t, J = 3.4 Hz, 1H), 3.73–3.90 (m,
2H), 4.00–4.10 (m, 1H), 4.97 (q, J = 6.4 Hz, 1H), 6.94 (s, 1H), 7.03
(s, 1H), 7.32–7.41 (m, 3H), 7.53–7.61 (m, 2H); 13C NMR
(75.5 MHz, CDCl3) d À2.5 (CH3), À2.3 (CH3), 18.4 (CH2), 23.1
(CH3), 23.4 (CH2), 23.8 (CH3), 24.2 (CH3), 24.8 (CH3), 24.9 (CH3),
25.3 (CH3), 27.8 (CH), 28.9 (CH), 33.8 (CH), 34.4 (CH2), 41.2 (CH2),
49.9 (CH), 64.5 (CH), 69.3 (CH), 74.4 (C), 120.5 (CH), 123.0 (CH),
127.7 (CH), 128.9 (CH), 132.1 (C), 133.5 (CH), 138.8 (C), 145.7 (C),
147.4 (C), 148.7 (C), 175.8 (C); MS (ESI) m/z 558 (MK+), 542
(MNa+), 442; HRMS calcd for C33H49O2NNaSi: 542.3425; found:
542.3429 (MNa+); anal. calcd for C33H49NO2Si: C, 76.25; H, 9.50;
N, 2.69. Found: C, 75.85; H, 9.43; N, 2.55.
To a solution of 3.08 g of the above aldehydes in 50 mL of tert-
butanol and 5.5 mL of 2-methyl-2-butene at 20 °C was added a
solution of 2.24 g (24.8 mmol) of sodium chlorite and 4.75 g
(39.6 mmol) of NaH2PO4 in 25 mL of water. The reaction mixture
was stirred at 20 °C for 30 min and then diluted with 100 mL of
brine and extracted with ethyl acetate to give 3.07 g of an isomeric
mixture of the corresponding acids. Major stereoisomer (in mix-
ture): IR (film) 3582, 2960, 2930, 2869, 1709, 1692, 1461, 1385,
1366, 1174 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.33 (s, 6H), 0.78–
;
1.00 (m, 1H), 1.15–1.30 (m, 19H), 1.41 (m, 14H), 1.56–1.97 (m,
2H), 2.03–2.20 (m, 1H), 2.35–2.49 (m, 1H), 2.86 (sept, J = 6.7 Hz,
1H), 3.02–3.20 (m, 1H), 3.69–4.11 (m, 4H), 4.89–5.00 (m, 1H),
6.92 (s, 1H), 7.01 (s, 1H), 7.30–7.39 (m, 3H), 7.43–7.55 (m, 2H).
A solution of 2.78 g of the above acid mixture in 50 mL of ether
at 20 °C was treated with excess ethereal diazomethane and stirred
for 30 min, whereupon the excess diazomethane was destroyed
with a small amount of acetic acid. The reaction mixture was then
concentrated under reduced pressure and the residue was purified
on silica gel with ethyl acetate in pentane (1:20) to yield 2.36 g
(83% from 10) of methyl esters 18. Major stereoisomer (in mix-
ture): IR (film) 2960, 2869, 1740, 1692, 1386, 1365, 1250,
4.1.13. (5S,7R,7aR)-5-((Dimethyl(phenyl)silyl)methyl)-7-
hydroxy-hexahydro-1H-pyrrolizin-3-one 20
To a stirred solution at 0 °C of 0.646 g (1.24 mmol) of bicyclic
lactam 19 in 9.0 mL of dichloromethane was added 0.95 mL
(14.6 mmol) of trifluoroacetic acid. The cooling bath was removed
and the reaction mixture was stirred for 45 min, which was then
treated at 0 °C with a solution of methanol saturated with ammo-
nia and concentrated under reduced pressure (repeated 3 times).
The resultant residue was dissolved in dichloromethane, washed
with water, and processed as the usual way to yield the crude
product. Purification of this material by silica gel chromatography
with methanol (saturated with NH3) in dichloromethane (2:98)
1173 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.33 (s, 6H), 0.56–0.77
;
(m, 1H), 1.10–1.33 (m, 19H), 1.34–1.57 (m, 12H), 1.64–1.99 (m,
3H), 1.99–2.16 (m, 1H), 2.24–2.53 (m, 2H), 2.85 (sept, J = 6.7 Hz,
1H), 3.00–3.25 (m, 1H), 3.63 (s, 3H), 3.67–4.08 (m, 4H), 4.85–5.05
(m, 1H), 6.92 (s, 1H), 7.03 (s, 1H), 7.29–7.41 (m, 3H), 7.41–7.58
(m, 2H); 13C NMR (75.5 MHz, CDCl3) d –2.4 (CH3), 23.2 (CH3),
23.9 (CH3), 24.4 (CH3), 24.9 (CH3), 28.2 (CH), 28.5 (CH3), 29.2
(CH), 31.3 (CH2), 33.9 (CH), 35.4 (CH2), 35.9 (CH2), 51.3 (CH), 52.0
(CH), 57.7 (CH), 71.3 (CH), 74.0 (CH), 74.9 (CH), 79.3 (C), 120.3
(CH), 123.3 (CH), 127.8 (CH), 129.0 (CH), 133.0 (C) 133.5 (CH),
138.9 (C), 145.4 (C), 147.4 (C), 148.8 (C), 153.8 (C), 174.3 (C); MS
(ESI) m/z 694 (MK+), 674 (MNa+), 652 (MH+); HRMS calcd for C39-
H62NO5Si: 652.4392, found: 652.4382 (MH+).
afforded 0.313 g (87%) of hydroxy lactam 20: [
a
]
D
21 = À73.4 (c 1.6,
CHCl3); IR (film) 3369, 2954, 2927, 1666, 1426, 1249, 1112 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 0.31 (s, 3H), 0.33 (s, 3H), 0.95 (A of
ABX, J = 14.4, 10.2 Hz, 1H), 1.48 (B of ABX, J = 14.4, 4.9 Hz, 1H),
1.65 (ddd, J = 8.7, 4.7, 4.2 Hz, 1H), 1.82–1.93 (m, 1H), 2.03–2.15
(m, 1H), 2.18 (dd, J = 14.0, 7.6 Hz, 1H), 2.31 (ddd, J = 16.8, 10.2,
3.6 Hz, 1H), 2.46–2.64 (m, 2H), 3.81 (ddd, J = 8.3, 5.9, 2.8 Hz, 1H),
3.93 (br s, 1H), 4.00–4.10 (m, 1H), 7.32–7.38 (m, 3H), 7.49–7.55
(m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.1 (CH3), À2.0 (CH3),
18.1 (CH2), 24.1 (CH2), 34.8 (CH2), 46.2 (CH2), 50.0 (CH), 65.6
(CH), 70.8 (CH), 128.0 (CH), 129.3 (CH), 133.8 (CH), 139.2 (C),
176.4 (C); MS (ESI) m/z 328 (MK+), 312 (MNa+), 212; HRMS (ESI)
calcd for C16H23O2NNaSi: 312.1390, found 312.1394 (MNa+); anal.
calcd for C16H23NO2Si: C, 66.39; H, 8.01; N, 4.84, found: C, 66.18; H,
8.29; N, 4.64.
4.1.12. (5S,7R,7aR)-5-((Dimethyl(phenyl)silyl)methyl)-7-((S)-1-
(2,4,6-triisopropylphenyl)ethoxy)-hexahydro-1H-pyrrolizin-3-
one 19
To a stirred solution at 0 °C of 2.76 g (4.23 mmol) of esters 18 in
30 mL of dichloromethane were added successively 3.00 mL

92
A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
4.1.14. (5S,7aR)-5-((Dimethyl(phenyl)silyl)methyl)-1,2,5,7a-
tetrahydropyrrolizin-3-one 21
m/z 344 (MK+), 328 (MNa+); HRMS (ESI) calcd for C16H23O3NNaSi:
328.1339; found: 328.1343 (MNa+).
A suspension of 0.414 g (3.10 mmol) of 30% KH in mineral oil
was washed with pentane under argon and then treated with a
solution of 0.307 g (1.06 mmol) of alcohol 20 in 5 mL of THF and
stirred for 1 h. The resulting mixture was cooled to 0 °C and
0.383 mL (6.37 mmol) of carbon disulfide was slowly added. After
being stirred for 2 h, the mixture was treated with 0.660 mL
(10.60 mmol) of iodomethane, allowed to warm to 20 °C, and stir-
red for 12 h. The excess KH was then destroyed at 0 °C by the drop-
wise addition of methanol. The reaction mixture was diluted with
ether, and then washed with water, dried over Na2SO4, filtered, and
evaporated under reduced pressure to give the crude product. This
material was filtered through a small pad of silica gel to afford
4.1.16. (5R,6R,7S,7aR)-6,7-Dihydroxy-5-(hydroxymethyl)hexahy-
dropyrrolizin-3-one 22
To a stirred solution at 20 °C of 0.0364 g (0.119 mmol) of diol 16
in 1.0 mL of dichloromethane was added dropwise 0.058 mL
(0.477 mmol) of HBF4ÁOMe2. After 5 h, methanol was added and
the reaction mixture was concentrated to dryness under reduced
pressure (repeated 3 times) to afford the crude fluoride, which
was used without purification: 1H NMR (300 MHz, CD3OD) d 0.28
(d, J = 7.6 Hz, 3H), 0.32 (d, J = 7.6 Hz, 3H), 1.15 (ddd, J = 14.4, 9.1,
5.3 Hz, 1H), 1.33 (ddd, J = 14.7, 6.0, 5.7 Hz, 1H), 2.01–2.12 (m,
1H), 2.20–2.33 (m, 1H), 2.36 (ddd, J = 16.6, 10.2, 2.8 Hz, 1H), 2.73
(ddd, J = 16.6, 9.4, 8.3 Hz, 1H), 3.60–3.68 (m, 1H), 3.85 (dd, J = 3.4,
3.0 Hz, 1H), 4.06 (dd, J = 7.2, 3.8 Hz, 1H), 4.17 (ddd, J = 7.9, 6.8,
2.8 Hz, 1H).
0.369 g of the xanthate: [
a]
21 = À23.7 (c 1.4, CHCl3); IR (film)
D
3067, 2953, 2923, 1692, 1405, 1250, 1112 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d 0.34 (s, 3H), 0.36 (s, 3H), 1.04 (A of ABX,
J = 14.3, 9.4 Hz, 1H), 1.48 (B of ABX, J = 14.3, 4.9 Hz 1H), 1.81–
2.05 (m, 3H), 2.28–2.46 (m, 2H), 2.50–2.62 (m, 1H), 2.52 (s, 3H),
4.01–4.16 (m, 2H), 5.87 (t, J = 3.7 Hz, 1H), 7.33–7.38 (m, 3H),
7.50–7.55 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.1 (CH3), 19.3
(CH2), 19.4 (CH3), 24.2 (CH2), 34.2 (CH2), 43.2 (CH2), 50.6 (CH),
64.0 (CH), 82.8 (CH), 128.1 (CH), 129.4 (CH), 133.8 (CH), 138.9
(C), 175.8 (C), 215.8 (C); MS (ESI) m/z 759 (2MH+), 402 (MNa+), 302.
The above xanthate was refluxed in 2.0 mL of diethylene glycol
diethyl ether under argon for 4 h. After being allowed to cool to
20 °C, the reaction mixture was diluted with pentane, which was
washed with water, dried over Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product. Purification of
this material by silica gel chromatography with acetone in pentane
To the above crude fluoride and 0.027 g (0.46 mmol) of KF in
1.0 mL of DMF at 20 °C was added 0.134 g (75%, 0.58 mmol) of
m-CPBA in one portion and the mixture was stirred for 12 h. The
solvent was then removed under reduced pressure and the residue
was dissolved in 10% methanol in ethyl acetate, which was filtered
through cotton and the filtrate then placed on a silica gel column.
Elution with acetic acid in ethyl acetate (1:9) and then methanol in
ethyl acetate (1:1) provided 0.0184 g (83%) of triol 22:
[a]
21 = À49.9 (c 0.7, MeOH); IR (film) 3363, 2924, 1659, 1650,
D
1419, 1380, 1289, 1120, 833 cmÀ1
;
1H NMR (300 MHz, CD3OD) d
1.98–2.15 (m, 1H), 2.21–2.42 (m, 2H), 2.58–2.74 (m, 1H), 3.49–
3.58 (m, 1H), 3.68 (dd, J = 11.3, 4.1 Hz, 1H), 3.88 (t, J = 3.2 Hz,
1H), 3.92 (dd, J = 11.3, 3.4 Hz, 1H), 4.02 (ddd, J = 9.8, 7.3, 3.2 Hz,
1H), 4.38 (dd, J = 7.9, 3.2 Hz, 1H); 13C NMR (75.5 MHz, CD3OD) d
20.1 (CH2), 34.6 (CH2), 62.6 (CH2), 62.7 (CH), 66.0 (CH), 72.7 (CH),
77.4 (CH), 180.0 (C); MS (DCI) m/z 188 (MH+); HRMS (ESI) calcd
for C8H13O4NNa: 210.0737, found: 210.0739 (MNa+).
(2:8) yielded 0.206 g (72% from 20) of olefin 21: [
a
]
21 = À177.2 (c
D
0.7, CHCl3); IR (film) 2959, 2928, 2869, 1692, 1405, 1247,
1112 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.34 (s, 3H), 0.38 (s, 3H),
;
1.05 (A of ABX, J = 14.5, 7.8 Hz, 1H), 1.19 (B of ABX, J = 14.6,
6.9 Hz, 1H), 1.62–1.76 (m, 1H), 2.20–2.34 (m, 2H), 2.57 (dddd,
J = 16.2, 12.8, 8.3, 8.3, Hz, 1H), 4.47–4.54 (m, 1H), 4.70–4.76 (m,
1H), 5.69–5.73 (m, 2H), 7.31–7.36 (m, 3H), 7.48–7.56 (m, 2H);
13C NMR (75.5 MHz, CDCl3) d À2.6 (CH3), À2.5 (CH3), 22.9 (CH2),
29.1 (CH2), 34.2 (CH2), 58.5 (CH), 66.0 (CH), 127.7 (CH), 128.87
(CH), 128.91 (CH), 133.6 (CH), 134.8 (CH), 138.9 (C), 177.1 (C);
MS (ESI) m/z 294 (MNa+); HRMS (ESI) calcd for C16H21ONNaSi:
294.1285, found 294.1288 (MNa+).
4.1.17. (+)-Hyacinthacine A1
1
To a solution of 0.0125 g (0.067 mmol) of triol 22 in 1.0 mL of
THF at 20 °C was added dropwise 0.031 mL (94%, 0.31 mmol) of
BH3ÁSMe2 and the resulting reaction mixture was refluxed for
5 h. Methanol was then added dropwise, after which the solvents
were evaporated under reduced pressure (methanol addition–
evaporation was repeated 3 times) to yield the crude amino–bor-
ane complex. This material was dissolved in methanol and stirred
at 20 °C with 0.010 g of 10% Pd/C overnight. The mixture was then
filtered through CeliteÒand the filtrate was concentrated under
reduced pressure to afford the crude product. This material was
purified by chromatography on silica gel with CHCl3–MeOH–NH3
(5:4:1) and then filtered over Dowex (OHÀ) resin to provide
4.1.15. (5S,6R,7S,7aR)-6,7-Dihydroxy-5-((dimethyl(phenyl)silyl)
methyl)-hexahydropyrrolizin-3-one 16
To a solution of 0.200 g (0.74 mmol) of olefin 21 in 5.0 mL of
acetone at 0 °C was added over 5 min 0.372 mL (0.04 mmol) of a
2.5% solution of OsO4 in tert-butyl alcohol, followed by 0.172 g
(1.47 mmol) of 4-methylmorpholine N-oxide in one portion. The
reaction mixture was stirred at 0 °C for 4 h, treated with a satu-
rated aqueous solution of NaHSO3, and then stirred at 20 °C for
an additional 20 min. The acetone was evaporated under reduced
pressure and the aqueous mixture was extracted with dichloro-
methane, which was processed in the usual manner to afford the
crude product. Purification of this material by silica gel chromatog-
raphy with acetone in pentane (3:7) gave 0.224 g (99%) of diol 16:
0.0090 g (78%) of (+)-hyacinthacine A1 1: [a]
21 = +43.9 (c 0.3,
D
H2O); 1H NMR (400 MHz, CD3OD) d 1.63–1.74 (m, 1H), 1.75–1.84
(m, 1H), 1.91–2.00 (m, 1H), 2.06–2.15 (m, 1H), 2.62–2.69 (m,
1H), 2.75–2.82 (m, 1H), 3.05–3.12 (m, 1H), 3.45–3.52 (m, 1H),
3.60 (dd, J = 11.0, 6.5 Hz, 1H), 3.82 (dd, J = 11.0, 3.4 Hz, 1H), 3.88–
3.92 (m, 2H); 13C NMR (75.5 MHz, CD3OD) d 25.9 (CH2), 28.8
(CH2), 57.5 (CH2), 65.4 (CH2), 67.7 (CH), 71.8 (CH), 73.7 (CH), 77.5
(CH); MS (ESI) m/z 174 (MH+). These spectral data were in perfect
agreement with those of the natural product.14
mp 93.2–93.9 °C (pentane); [
a]
21 = À58.7 (c 1.1, CHCl3); IR (film)
D
3385, 2955, 2922, 1659, 1426, 1113 cmÀ1
;
1H NMR (400 MHz,
CDCl3) d 0.35 (s, 3H), 0.40 (s, 3H), 1.10 (A of ABX, J = 14.5, 8.8 Hz,
1H), 1.35 (B of ABX, J = 14.5, 5.8 Hz, 1H), 1.84–1.93 (m, 1H), 2.11–
2.20 (m, 1H), 2.23–2.31 (m, 1H), 2.37–2.46 (m, 1H), 3.00 (br s,
2H), 3.66–3.71 (m, 1H), 3.75–3.79 (m, 1H), 3.82 (t, J = 3.8 Hz, 1H),
3.84–3.88 (m, 1H), 7.33–7.35 (m, 3H), 7.53–7.56 (m, 2H); 13C
NMR (100.6 MHz, CDCl3) d À2.7 (CH3), À2.5 (CH3), 18.1 (CH2),
21.1 (CH2), 33.0 (CH2), 57.1 (CH), 62.3 (CH), 71.4 (CH), 81.9 (CH),
127.8 (CH), 129.0 (CH), 133.6 (CH), 139.0 (C), 176.8 (C); MS (ESI)
4.1.18. (1aR,2S,6aR,6bS)-2-((Dimethyl(phenyl)silylmethyl)-
hexahydro-oxireno[2,3-a]pyrrolizin-4-one 23
To a stirred solution of 0.080 g (0.295 mmol) of olefin 21 and
0.923 mL (10.31 mmol) of 1,1,1-trifluoroacetone in a mixture of
4.0 mL of acetonitrile and 1.5 mL of a 10À4 M solution of EDTA in
water was added at 0 °C a premixed oxone (1.45 g, 4.71 mmol)
and Na2CO3 (0.50 g, 4.72 mmol) mixture in four portions over
30 min. After being stirred for an additional 1 h, the reaction mix-

A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
93
ture was diluted with water, extracted with dichloromethane, and
then treated in the usual way to give the crude epoxide, which was
purified by flash chromatography (10–15% of acetone in pentane)
allowed to cool to room temperature and quenched by the careful
addition of MeOH. The solvents were evaporated under reduced
pressure (addition of methanol and evaporation were repeated 3
times) to afford a crude amine-borane complex. A solution of the
complex in methanol was treated for 16 h at 20 °C with 0.010 g
of 10% Pd/C and then filtered through Celite.ÒThe filtrate was con-
centrated to give the crude product, which was purified by silica
gel chromatography with MeOH–CHCl3–NH4OH (4:5:1) and then
converted into the free amine through filtration over Dowex
(OHÀ) resin to afford 0.018 g (97%) of hyacinthacine A2:
to afford 0.083 g (98%) of epoxide 23: [
a]
23 = À95.6 (c 1.2, CHCl3);
D
IR (film) 1692, 1589, 1407, 1262, 1113 cmÀ1
;
1H NMR (400 MHz,
CDCl3) d 0.38 (s, 6H), 0.84–0.98 (m, 2H), 1.94–2.11 (m, 2H), 2.25–
2.44 (m, 2H), 3.32 (d, J = 2.8 Hz, 1H), 3.39 (d, J = 2.8 Hz, 1H), 3.67
(t, J = 7.2 Hz, 1H), 4.25 (dd, J = 6.2, 9.6 Hz, 1H), 7.32–7.37 (m, 3H),
7.49–7.55 (m, 2H); 13C NMR (75.5 MHz, CDCl3); d À3.2 (CH3),
À2.8 (CH3), 17.7 (CH2), 20.9 (CH2), 33.5 (CH2), 53.0 (CH), 55.2
(CH), 58.8 (CH), 60.6 (CH), 127.8 (CH), 129.0 (CH), 133.4 (CH),
138.7 (C), 177.9 (C); MS (ESI) m/z 210, 310 (MNa+), 575 (2MH+),
597 (2MNa+); HRMS (ESI) calcd for C16H21O2NNaSi: 310.1234,
found: 310.1232 (MNa+).
[a]
23 = +12.0 (c 0.45, H2O); 1H NMR (400 MHz, D2O) d 1.72–1.84
D
(m, 2H), 1.84–2.04 (m, 2H), 2.72 (ddd, J = 3.9, 6.5, 8.6 Hz, 1H),
2.77 (ddd, J = 5.8, 5.8, 11.1 Hz, 1H), 2.92 (ddd, J = 6.1, 7.3, 11.1 Hz,
1H), 3.16 (ddd, J = 4.5, 7.5, 7.5 Hz, 1H), 3.66 (dd, J = 6.5, 11.6 Hz,
1H), 3.72–3.84 (m, 3H); 13C NMR (100 MHz, D2O) d 27.3 (CH2),
32.6 (CH2), 57.6 (CH2), 66.0 (CH2), 68.7 (CH), 72.0 (CH), 80.1 (CH),
83.1 (CH); MS (ESI) m/z 174 (MH+); HRMS (ESI) calcd for
C8H16O3N: 174.1125, found: 174.1122 (MH+).
4.1.19. (5S,6R,7R,7aR)-6,7-Dihydroxy-5-((dimethyl(phenyl)silyl)-
methyl)-hexahydropyrrolizin-3-one 24
A solution of 0.030 g (0.110 mmol) of epoxide 23 in 0.240 mL of
20% TFA in aqueous THF (2:3) was heated at 70 °C for 22 h. The
reaction was quenched by the addition of a saturated aqueous
NaHCO3 solution and extracted with ether to give the crude diol,
which was purified by chromatography (0–8% of MeOH saturated
with NH3 in CHCl3) to afford 0.023 g (68%) of diol 24:
Acknowledgments
We thank the CNRS and the Université Joseph Fourier (UMR
5250, FR 2607) for financial support.
[
a]
D
23 = À52.1 (c 0.7, CHCl3); IR (film): 3390, 2922, 1655, 1648,
1458, 1425, 1113 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 0.35 (s, 3H),
References
0.38 (s, 3H), 1.12 (A of ABX, J = 8.4, 14.7 Hz, 1H), 1.42 (B of ABX,
J = 7.3, 14.7 Hz, 1H), 1.79 (dddd, J = 7.2, 10.0, 10.0, 12.8 Hz, 1H),
2.16–2.31 (m, 2H), 2.36–2.47 (m, 1H), 3.54 (dd, J = 4.4, 7.2 Hz,
1H), 3.65 (ddd, J = 7.2, 7.2, 7.2 Hz, 1H), 3.74 (dd, J = 4.4, 4.4 Hz,
1H), 3.82 (ddd, J = 4.4, 7.3, 8.4 Hz, 1H), 7.32–7.39 (m, 3H), 7.51–
7.58 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.8 (CH3), À2.7
(CH3), 20.5 (CH2), 24.8 (CH2), 33.2 (CH2), 58.2 (CH), 64.0 (CH),
82.5 (CH), 86.1 (CH), 127.8 (CH), 129.1 (CH), 133.5 (CH), 138.8
(C), 175.8 (C). MS (ESI) m/z 228, 328 (MNa+), 611 (2MH+), 633
(2MNa+); HRMS (ESI) calcd for C16H23O3NNaSi: 328.1339, found:
328.1337 (MNa+).
1. Rate enhancements of up to 1017 have been found: Wolfenden, R.; Lu, X.;
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4.1.20. (5R,6R,7R,7aR)-6,7-Dihydroxy-5-(hydroxymethyl)hexahy-
dropyrrolizin-3-one 25
To a stirred solution of 0.040 g (0.131 mmol) of diol 24 in 2.0 mL
of dichloromethane was added 0.063 mL (0.518 mmol) of HBF4Á
OMe2. After being stirred for 5 h, the reaction mixture was concen-
trated to dryness under reduced pressure to afford the crude fluo-
ride. To a solution of this material in 1.0 mL of DMF was added
0.030 g (0.516 mmol) of KF. After being stirred for 45 min, the reac-
tion mixture was treated with 0.111 g (0.643 mmol) of m-CPBA
and then stirred for an additional 18 h before being concentrated
under reduced pressure. The residue was dissolved in 10% MeOH
in AcOEt and the mixture filtered. The filtrate was then concen-
trated and the residue purified by silica gel chromatography (10%
AcOH in AcOEt, then 50% MeOH in AcOEt) to afford 0.023 g (94%)
of triol lactam 25: [
a
]
D
23 = À46.3 (c 1.2, MeOH); IR (film) 3363,
2924, 1659, 1650, 1419, 1380, 1289, 1120 cmÀ1
;
1H NMR
(400 MHz, CD3OD) d 1.91–2.02 (m, 1H), 2.35–2.44 (m, 2H), 2.66–
2.76 (m, 1H), 3.56–3.61 (m, 1H), 3.62 (dd, J = 6.6, 7.7 Hz, 1H),
3.68 (dd, J = 4.1, 11.5 Hz, 1H), 3.80 (ddd, J = 7.7, 7.7, 7.7 Hz, 1H),
3.86 (dd, J = 3.8, 11.5 Hz, 1H), 4.19 (dd, J = 6.6, 6.6 Hz, 1H); 13C
NMR (75.5 MHz, CD3OD) d 27.2 (CH2), 35.1 (CH2), 62.8 (CH2),
64.4 (CH), 66.7 (CH), 81.4 (CH), 83.5 (CH), 179.2 (C); MS (ESI) m/z
210 (MNa+), 397 (2MNa+); HRMS (ESI) calcd for C8H13O4NNa:
210.0737, found: 210.0735 (MNa+).
10. (a) Ritthiwigrom, T.; Au, C. W. G.; Pyne, S. G. Curr. Org. Synth. 2012, 9, 583; (b)
Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda,
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12. Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525.
13. Asymmetric dichloroketene–enol ether cycloaddition has been applied for the
preparation of a variety of alkaloids: pyrrolidines: (a) Kanazawa, A.; Gillet, S.;
Delair, P.; Greene, A. E. J. Org. Chem. 1998, 63, 4660; (b) Delair, P.; Brot, E.;
Kanazawa, A.; Greene, A. E. J. Org. Chem. 1999, 64, 1383; (c) Ceccon, J.; Poisson,
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P.; Rasmussen, M.; Greene, A. E. J. Org. Chem. 2000, 65, 6966; (e) Rasmussen,
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E.; Poisson, J-F. Org. Biomol. Chem. 2009, 7, 2029; Pyrrolizidines: (h) Roche, C.;
4.1.21. (+)-Hyacinthacine A2
2
To a solution of 0.020 g (0.107 mmol) of triol lactam 25 in
1.0 mL of dry THF at 20 °C was added 0.050 mL (0.527 mmol) of
BH3ÁSMe2. The reaction mixture was refluxed for 5 h and was then

94
A. Veyron et al. / Tetrahedron: Asymmetry 26 (2015) 85–94
Delair, P.; Greene, A. E. Org. Lett. 2003, 5, 1741; (i) Roche, C.; Kadlecíková, K.;
0.010 mL (0.73 mmol) of diisopropylamine was added. The reaction was stirred
for an additional 30 min and then quenched with aqueous NaOH (1 M), and
extracted with dichloromethane. The crude material was purified by silica gel
chromatography with 0–5% methanol saturated with ammonia in
dichloromethane to afford 5 mg (40%) of the N-hydroxy pyrrolidine. IR (KBr)
Veyron, A.; Delair, P.; Philouze, C.; Greene, A. E.; Flot, D.; Burghammer, M. J. Org.
Chem. 2005, 70, 8352; (j) Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A.
E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (k) Reddy, P. V.; Smith, J.;
Kamath, A.; Jamet, H.; Veyron, A.; Koos, P.; Philouze, C.; Greene, A. E.; Delair, P.
J. Org. Chem. 2013, 78, 4840; (l) Smith, J.; Kamath, A.; Greene, A. E.; Delair, P.
Synlett 2014, 209.
3300, 3068, 3046, 2955, 2925, 2854, 1710, 1633 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 0.35 (s, 6H), 1.52–1.65 (m, 1H), 1.70–1.86 (m, 2H), 1.91–2.06 (m, 1H),
2.73–2.36 (m, 1H), 3.20–3.35 (m, 2H), 5.73 (dd, J = 15.3, 7.5 Hz, 1H), 5.95 (d,
J = 18.3 Hz, 1H), 6.27 (dd, J = 15.3, 10.1 Hz, 1H), 6.58 (dd, J = 18.3, 10.1 Hz, 1H),
7.31–7.41 (m, 3H), 7.46–7.57 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d À2.6 (CH3),
19.8 (CH2), 28.0 (CH2), 57.3 (CH2), 70.3 (CH), 127.8 (CH), 129.0 (CH), 131.4 (CH),
133.8 (CH), 135.2 (CH), 138.6 (C), 145.2 (CH) MS (ESI) m/z 274 (MH+); HRMS
calcd for C16H24NOSi: 274.1622, found: 274.1616 (MH+).
14. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson,
A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1.
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2587; (b) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73,
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minor component filtered out over the remainder of the synthesis.
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20. Tested cuprates were obtained from ROCH2Li, R = Bn, p-MeOC6H4CH2, tert-Bu,
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7219. The presence of dimethyl sulfide as a co-solvent has a significant effect
on the stereochemical outcome of this reaction: ether alone furnished only a
3:1 ratio of the isomers.
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N-oxide. 2-((1E,3E)-4(Dimethyl(phenyl)silyl)buta-1,3-dienyl)pyrrolidin-1-ol:
A
solution of 17 mg (0.098 mmol) of m-CPBA in 0.057 mL of dichloromethane
was added dropwise to a solution of 19 mg (0.046 mmol) of phenylselenide 14
in 0.57 mL of dichloromethane at À25 °C. After being stirred for 30 min,
42. (a) Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. J. Org. Chem. 1994, 59, 4096; (b) Hoye,
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