Asymmetric approach to hyacinthacines B1 and B2

Article abstract of DOI:10.1021/jo400386f

Naturally occurring hyacinthacines B₁ and B₂ have been prepared from a common, easily available, advanced intermediate. The approach features several highly stereoselective transformations: inter alia, a dichloroketene-enol ether [2 + 2] cycloaddition, a Bruylants alkylation, and an amino-nitrile alkylation-reduction.

Full text of DOI:10.1021/jo400386f

Subscriber access provided by UNIV LAVAL
Article
Asymmetric Approach to Hyacinthacines B1 and B2
Paidi Venkatram Reddy, Julien Smith, Anushree Kamath, Helene Jamet, Amaël
Veyron, Peter Koos, Christian Philouze, Andrew Elliot Greene, and Philippe Delair
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400386f • Publication Date (Web): 04 Apr 2013
Downloaded from http://pubs.acs.org on April 28, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
Asymmetric Approach to Hyacinthacines B1 and B2
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Paidi Venkatram Reddy,† Julien Smith,† Anushree Kamath,† Hélène Jamet,‡ Amaël Veyron,† Peter
Koos,† Christian Philouze,# Andrew E. Greene,† and Philippe Delair*†
Univ. Grenoble Alpes, Département de Chimie Moléculaire, ICMG FR-2607, F-38041 Grenoble
CNRS, UMR-5250, Département de Chimie Moléculaire, F-38041 Grenoble
† DCM – SERCO, ‡ DCM – Theoretical Chemistry, # DCM – MUST
Philippe.Delair@ujf-grenoble.fr
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
(S)-(-)-Stericol
Ar
OH
Ar = 2,4,6-triisopropylphenyl
Ph
OH
OH
O
66% overall yield
unique stereoisomer
44% overall yield
unique stereoisomer
O
H
N
H
N
H
N
OH
OH
NC
OH
Hyacinthacine B1
SiMe2Ph
OH
Hyacinthacine B2
HO
HO
6.7:1
ABSTRACT: Naturally occurring hyacinthacines B1 and B2 have been prepared from a common,
easily available, advanced intermediate. The approach features several highly stereoselective
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
transformations: inter alia, a dichloroketene–enol ether [2+2] cycloaddition, a Bruylants alkylation,
4
5
and an amino-nitrile alkylation–reduction.
6
7
8
9
INTRODUCTION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Glycosidase inhibition has received considerable attention over the past several years, mainly
because glycosidases, which catalyze the hydrolysis of oligosaccharides and glycoconjugates, are
involved in an array of diverse biological processes.i Inhibitors of these enzymes can thus be viewed
as potential drugs against various human diseases.ii With relatively few compounds presently in
clinical use, however, research aimed at finding new inhibitors continues unabated.iii
The iminosugarsiv are currently among the most studied glycosidase inhibitors and the
hyacinthacines, which are polyhydroxylated pyrrolizidines, figure prominently within this group
(Figure 1).v Since the isolation of the first of the hyacinthacine alkaloids by Asano and coworkers in
1999,vi more than 20 have been identified. These iminosugars are characterized by the presence of an
hydroxymethyl substituent at C-3 and are divided into 3 groups, A, B, and C, depending on the
number of hydroxyl and hydroxylmethyl substituents on ring B of the pyrrolizidine system.vii
Figure 1. Examples of Hyacinthacines
OH
OH
H
H
N
7
1
7a
2
3
6
B
OH
OH
A
N
5
OH
OH
hyacinthacine B1 (2)
HO
hyacinthacine A1 (1)
HO
OH
H
OH
H
N
OH HO
OH
N
H3C
OH
hyacinthacine B2 (3)
OH
HO
hyacinthacine C1 (4)
The hyacinthacines have been shown to possess strong, selective biological activities, which,
2
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
coupled with their compact, highly functionalized structures, make them worthwhile synthetic
targets. Not surprisingly, synthetic efforts toward the hyacinthacines have so far focused primarily
on the preparation of the simpler group A members, in both racemic form and natural form (using
chiral pool or enzymatic techniques).viii,ix A few years ago, we reported the first non-chiral pool/non-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
enzymatic approach to natural hyacinthacine A1,x which relied on a strategy based on asymmetric
xii,xiii,xiv
dichloroketene–chiral enol ether cycloaddition, xi previously applied
for the preparation of a
variety of other alkaloids.xv We now describe in detailxvi the extension of this work to access the
more structurally complexe hyacinthacines B1 and B2. These alkaloids, isolated in low yield (22
mg/kg and 5 mg/kg, respectively) by Asano and coworkers from bulbs of Scilla campanulata, have
been shown to be selective inhibitors of ß-glucosidase and ß-galactosidase.vi Their structures are
characterized by the presence of five stereocenters and two synthetically challenging
hydroxymethyls at C-3 and C-5. To the best of our knowledge, only one other approach to these
alkaloids, which employed L-pyroglutamic acid for chirality, has been reported.ixa
RESULTS AND DISCUSSION
Synthesis of Hyacinthacine B1
It was envisaged that hyacinthacine B1 would be obtained from the disilyl derivative III through an
uncommon double Tamao-Fleming oxidation to generate in a single step the requisite hydroxymethyl
groups. The C-5 dimethylphenylsilylmethyl substituent might be introduced stereoselectively
through a Bruylants reactionxvii of the amino-nitrile obtained through reductive cyanation of
pyrrolizidinone II. Significantly, pyrrolizidinone II seemed to offer as well several means to access
hyacinthacine B2 (see below). The unprotected pyrrolizidinone II (P=H) had earlier been prepared
from enol ether I (R*OH = Stericol®).x
Scheme 1. Retrosynthesis of (+)-Hyacinthacine B1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
OH
OP
H
N
H
N
OH
OP
6
7
OH
HO
SiMe2Ph
PhMe2Si
8
hyacinthacine B1 (2)
III
9
OP
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OP
SiMe2Ph
N
O
OR*
II
I
The synthesis started from the commercially available chiral auxiliary (S)-(–)-Stericol® 5,xviii
which was transformed in a highly stereoselective manner into pyrrolizidinone 7 via lactam 6xivb,xix
(Scheme 2).x The key diastereoselective steps in this preparation included: a [2+2] cycloaddition of
dichloroketene to the Stericol-derived dienol ether, a Bruylants-like addition of a silylmethyl
substituent, and an endo-selective dihydroxylation.
Scheme 2. Preparationx of Pyrrolizidinone 7
Ar
OH
O
H
N
OH
HN
Ar
OH
O
O
SiMe2Ph
(S)-(-)-Stericol 5
6
7
Ar = 2,4,6-triisopropylphenyl
The protection of the cis hydroxyls in 7 was expected to be crucially important in the approach not
only because of introduction–removal considerations, but also the attendant steric hindrance that
could play a significant role in the subsequent C-5 alkylation. Thus, different groups were examined.
Protection with triethylsilyl groups and a methylidene group proceeded smoothly to give lactams 8
and 10 in 94% and 88% yields, respectively (Scheme 3).
Scheme 3.a Diol Protection and Amino-Nitrile Formation
4
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OTES
OTES
SiMe2Ph
OTES
H
N
H
b
a
7
OTES
N
O
NC
SiMe2Ph
1.6:1
H
8
9
O
O
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
b
O
O
7
N
O
NC
SiMe2Ph
SiMe2Ph
1.5:1
10
11
Ph
Ph
O
O
O
H
H
d
b
O
7
N
N
O
NC
SiMe2Ph
SiMe2Ph
6.7:1
12
13
a
Reagents and conditions: (a) TESCl, imidazole, CH2Cl2, 20 °C, 94%. (b) DIBAL-H/n-BuLi ate
complex, THF, 20 °C, then TMSCN, 0 °C, 89% for 9 from 8, 93% for 11 from 10, 97% for 13 from
7 (2 steps). (c) P2O5, CH2(OMe)2, CH2Cl2, 20 °C, 88%. (d) PhCH(OMe)2, p-TSA, CH2Cl2, 20 °C.
Benzylidene protection of 7 was particularly interesting in that a single, crystalline acetal was
formed in excellent yield; structural determination by X-ray diffraction analysisxx revealed that the
phenyl group of the acetal was endo in the tricyclic structure (Figure 2). This endo stereoselectivity,
while at first surprising, is in fact often encountered with cyclic diolsxxi and is believed to result from
kinetic acetal formation, with minimization of allylic strainxxii (A1,3) in the cyclization of the
intermediate oxonium ion.xxiii
Figure 2. Solid State Structure of Benzylidene 12
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The transformation of the lactams to the corresponding amino-nitrilesxxiv by reductive cyanation,
studied initially with the bis-TES derivative 8, turned out to be more challenging than expected:
reductive cyanation with the often used DIBAL-H/KCN systemxxv led invariably to significant
amounts of over-reduced material, while the use of Schwartz’s reagent with TMSCNxxvi led
primarily to recovered starting material. Fortunately, however, the DIBAL-H/n-BuLi ate complexxxvii
smoothly produced the desired hemiaminal, which, following treatment in situ with TMSCN, gave in
89% yield an inconsequential 1.6:1 mixture of the epimeric amino-nitriles 9 (Scheme 3), with the
silylmethyl group governing the observed selectivity.xxviii
This procedure applied to the
methylidene-protected derivative 10 provided in 89% yield the expected amino-nitrile derivatives 11
as a 1.5:1 mixture (see below for stereochemical assignment), less pronounced than had been
expected. When lactam 12 was subjected to the reductive cyanation conditions, however, the amino-
nitriles 13 were obtained in 97% overall yield from 7 (2 steps) as a 6.7:1 mixture.xxix This facial
discrimination proved to be a harbinger of the stereoselectivity of the upcoming alkylation.
With a highly efficient formation of the amino-nitriles in hand, the Bruylants reactionxvii was next
examined. The mixture of amino-nitriles 9 reacted with dimethylphenylsilylmethylmagnesium
6
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
chloride in ether–THF at room temperature to afford a 5:1 epimeric mixture of the corresponding
4
5
alkylated pyrrolizidines 14 (Scheme 4). A sample of the major isomer, separated with difficulty by
6
7
1
silica gel chromatography, provided H NMR data in agreement with the depicted structure.
8
9
Particularly diagnostic was the strong NOE (10%) between the C-3 and C-5 hydrogens. The TES
groups were next removed from 14 by treatment with TBAF and the resultant mixture could now be
easily separated by chromatography to give diol 15a and its C-5 epimer 15b in 68% and 12% overall
yields, respectively, from 9. For additional proof of the stereochemical assignments from the
Bruylants reaction, the pure diol 15b was silylated to give back the minor C-5 epimer of 14, which
displayed no NOE between the C-3 and C-5 hydrogens, but one between those at C-5 and C-7a.
Better yet, when the mixture of amino-nitriles 13 was treated similarly with the same Grignard
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
reagent, a unique stereoisomer (16) was formed (by H NMR: single signal for the benzylidene
acetal hydrogen at 5.70 ppm). Acetal cleavage with aqueous acid then furnished diol 15a in 88%
overall yield from 13 (2 steps).
Scheme 4.a Bruylants Reaction and Diol Deprotection
OTES
OTES
OH
OH
H
N
H
N
H
N
a
b
+
9
OH
OH
5:1
SiMe2Ph
SiMe2Ph
PhMe2Si
SiMe2Ph
PhMe2Si
PhMe2Si
14
15a
15b
68% (from 9)
12% (from 9)
Ph
O
H
N
a
c
O
13
15a
88% (from 13)
>15:1
PhMe2Si
SiMe2Ph
16
a
Reagents and conditions: (a) Me2PhSiCH2MgCl, Et2O–THF, 20 °C. (b) TBAF, THF, 20 °C. (c)
TFA (20%), THF–H2O, 55 °C.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
6
7
8
Silyl oxidation can be performed through several different procedures,xxx but few have been
successfully used with a potentially oxidizable amino group in the substrate.xxxi With a model
substrate, the basic oxidation conditions developed by Smitrovich and Woerpelxxxia proved
insufficiently reactive, whereas treatment with tetrafluoroboric acid, followed by basic work-up and
hydrogen peroxide oxidation, produced the corresponding protodesilylated amine oxide as the major
product. However, by eliminating the basic treatment following the first step so as to keep the
nitrogen protonated and thus limit its oxidation, it was found that the desired alcohol was cleanly
formed, without significant amounts of the N-oxide. To our delight, on application of these
conditions, the disilyl derivative 15a underwent clean double oxidation to afford hyacinthacine B1 in
75% yield, without discernible N-oxide formation (Scheme 5). This result is noteworthy since
double Tamao-Fleming oxidations are relatively few in the literaturexxxii and, moreover, attendant
nitrogen oxidation is often difficult to suppress.xxxiii Synthetically derived (+)-hyacinthacine B1 ([α]D
+40) was spectroscopically and chromatographically indistinguishable from an authentic sample of
the natural product ([α]D +41.3). vi,xxxiv
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Double Tamao-Fleming Oxidation of 15a to give (+)-Hyacinthacine B1
OH
H
1. HBF4.OMe2
15a
OH
N
2. H2O2, KF, DMF
75%
OH
(+)-Hyacinthacine B1
HO
2
Synthesis of Hyacinthacine B2
In order to evaluate the possibility of accessing hyacinthacine B2 through a similar strategy, the
minor diol 15b was subjected to the above oxidation conditions. Surprisingly, this isomer did not
8
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
5
undergo transformation into the expected polyhydroxylated pyrrolizidine, but suffered an oxidation-
fragmentation to generate pyrrolidine 17 in 69% yield after treatment with basic Dowex (Scheme 6).
Scheme 6. Oxidation-Fragmentation of 15b
6
7
8
9
OH
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. HBF4.OMe2
15b
OH
OH
HN
2. H2O2, KF, DMF
69%
17
This dichotomous behavior of the isomeric disilanes 15a and 15b most likely results from
conformational biases. Calculationsxxxv,xxxvi indicate that in 15a the silane in question enjoys a degree
of conformational freedom (a preferred conformation places the silane toward the nitrogen, dihedral
angle of –61.4°, Figure 3A), where as in 15b it is essentially blocked opposite the nitrogen (dihedral
angle of –176.3°, Figure 3B) and favorably disposed to participate in a Grob-type fragmentation.xxxvii
A different approach, which did not involve a double Tamao-Fleming oxidation, was obviously
required for reaching hyacinthacine B2.
Figure 3. Calculated conformations for 15a and 15b
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
5
6
7
8
9
A potential alternative emerged with the observation that the mixture of amino-nitriles 11
(unassigned stereochemistry, scheme 3), in solution at –30 °C, underwent over several days a 1.5:1
to 9:1 modification of the epimeric composition. It was subsequently found that on heating a DMF
solution of the epimers, the 9:1 ratio could be attained in only 45 min.xxxviii While these isomers
could be separated by silica gel chromatography, their stereo attribution could not be made with
absolute confidence. For this reason, CN → CH2OH transformation (methanolysis, reduction),
Tamao-Fleming oxidation, and diol deprotection in the major isomer were carried out; unfortunately,
hyacinthacine B1 and not B2 was produced. The cyano and silylmethyl group were thus, in fact, cis
in the major isomer of 11 (scheme 3) and yet another strategy for the synthesis of hyacinthacine B2
was required.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The complete diastereselectivity induced above with the benzylidene protecting group suggested
that an approach based on hydride reductionxxxix of an alkylated amino-nitrilexl might constitute a
viable strategy for preparing hyacinthacine B2.xli This approach would be particularly attractive in
that both hyacinthacines would result from a common, late intermediate. After considerable
experimentation, it was found that treatment of amino-nitriles 13 with LDA at low temperature,
followed by addition of an excess of benzyl chloromethyl ether, gave the corresponding amino-nitrile
18 in high diastereomeric purity by NMR (Scheme 7). For a successful alkylation, it was necessary
to operate with rigorous exclusion of oxygen to avoid reversion of the substrate to lactam 12.xlii
Although the crude product was not stable to purification, it could be smoothly reduced with sodium
borohydride in methanol at 0 °C to afford after purification uniquely the desired stereoisomer 19 in
49% yield (55% brsm, 2 steps). Thus, once again, the benzylidene protection allowed total, and in
this case opposite, stereocontrol in the introduction of a latent C-5 hydroxymethyl group.
Scheme 7.a Alkylation of 13 and Reduction
10
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Ph
b
Ph
O
O
H
H
N
a
O
O
13
N
(mixture of
epimers)
CN
SiMe2Ph
SiMe2Ph
OBn
OBn
8
18
19
9
10
11
12
13
a Reagents and conditions: (a) LDA, THF, –60 °C; benzyl chloromethyl ether, –60 °C; (b) NaBH4,
MeOH, 0 °C, 49% (55% brsm, 2 steps).
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To our temporary dismay, attempted Tamao-Fleming oxidation of silane 19 under the conditions
that had previously been used successfully for hyacinthacine B1 led mainly to degradation.
Fortunately, however, the conditions developed by Smitrovich and Woerpelxxxia were found to be
productive and furnished the expected primary alcohol 20 in essentially quantitative yield (Scheme
8). The completion of the synthesis was realized by double deprotection through acidic
hydrogenolysis, followed by deprotonation with basic Dowex resin, to provide (+)-hyacinthacine B2
1
in 89% yield from silane 19 (2 steps). Synthetically derived (+)-hyacinthacine B2 provided H and
13C NMR data in excellent accord with those described for the naturally derived material.vi,xliii
Scheme 8.a Completion of the Synthesis of (+)-Hyacinthacine B2
Ph
OH
O
H
N
H
a
b
O
OH
19
N
OH
(+)-Hyacinthacine B2 (3)
OH
BnO
HO
20
a
Reagents and conditions: (a) KH, t-BuOOH, TBAF, DMF, 0 °C. (b) H2, Pd-C, 6N HCl, EtOH,
20 °C; Dowex (OH— form), H2O, 89% (2 steps).
Conclusion
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
7
8
9
Hyancinthacines B1 and B2 have been prepared efficiently from a common, advanced intermediate,
which is obtained in enantiopure form through asymmetric cycloaddition methodology. These
syntheses are characterized by excellent levels of stereocontrol of the 5 stereogenic centers and high
overall yields from the starting chiral auxiliary (6.5% and 4.4%, respectively). Critical to the success
of this work is the synthetic versatility of the amino-nitrile moiety, which provides highly selective
access to these diastereomeric hyacinthacines. Synthetic studies toward other C-5 substituted
hyacinthacines are currently in progress in our laboratory.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General experimental details
All experiments were carried out under argon atmosphere unless otherwise stated. THF and Et2O
were distilled over Na-benzophenone. CH2Cl2 was distilled over CaH2 and DMF over CaSO4. All
other products were directly used as received from commercial sources without purification. NMR
spectra were recorded on a Bruker Avance 300, Bruker Avance 400 or Varian U+ 500 spectrometer
in chloroform-d, unless otherwise stated. All coupling constants have been calculated, when possible,
xliv
by using the method described by Hoye et al.
Melting points are uncorrected. IR spectra were
recorded as neat samples or in CH2Cl2 solution on a Nicolet 397 FT-spectrometer. The mass spectra
were recorded on a Nermag R10 mass spectrometer in ESI mode. High-resolution mass spectrometry
data were obtained via electrospray ionization with an orbitrap detector.
(5S,6R,7S,7aR)-5-((Dimethyl(phenyl)silyl)methyl)-6,7-bis(triethylsilyloxy)-hexahydro-1H-
pyrrolizin-3-one (8). To a stirred solution of dihydroxy lactam 7 (0.200 g, 0.655 mmol) and
imidazole (0.267 g, 3.92 mmol) in anhydrous dichloromethane (10 mL) at 0 °C was added 0.329 mL
12
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(0.295 g, 1.96 mmol) of triethylsilyl chloride. The mixture was allowed to warm to 20 °C over 30
min and then stirred for 16 h, whereupon water was added. The mixture was extracted with
dichloromethane, the combined organic layers were washed with water, dried over anhydrous
Na2SO4, and filtered, and the filtrate was evaporated to give the crude product. Purification of this
material by flash chromatography on silica gel with ethyl acetate in pentane (1:10) afforded 0.330 g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
(94%) of lactam 8: [〈]D –23 (c 3.2, CHCl3); IR (film) 2955, 2904, 2873, 1693, 1583, 1458, 1382,
1
1242, 1181, 1116, 1014 cm-1; H NMR (400 MHz, CDCl3)  0.34 (s, 3 H), 0.38 (s, 3 H), 0.51-0.63
(m, 12 H), 0.87-0.97 (m, 19 H), 1.17 (dd, J = 14.7, 5.2 Hz, 1 H), 1.71-1.80 (m, 1 H), 2.04-2.16 (m, 1
H), 2.17-2.26 (m, 1 H), 2.30-2.41 (m, 1 H), 3.59 (ddd, J = 7.0, 5.0, 5.0 Hz, 1 H), 3.75 (dd, J = 4.5,
3.5 Hz, 1 H), 3.81-3.87 (m, 1 H), 4.00 (dd, J = 5.0, 3.5 Hz, 1 H), 7.32-7.36 (m, 3 H), 7.50-7.55 (m, 2
13
H); C NMR (75.5 MHz, CDCl3)  –2.8 (CH3), 2.7 (CH3), 4.9 (CH2), 6.7 (CH3), 6.8 (CH3), 19.8
(CH2), 20.3 (CH2), 32.4 (CH2), 58.4 (CH), 61.3 (CH), 73.6 (CH), 82.2 (CH), 127.6 (CH), 128.7
(CH), 133.5 (CH), 139.5 (C), 178.4 (C); MS (ESI) m/z 556 (MNa+), 456 (M-Ph)+; HRMS (ESI)
calcd for C28H51NO3Si3Na: 556.3069. Found: 556.3065 (MNa+).
(3R,5S,6R,7S,7aR)
and
(3S,5S,6R,7S,7aR)-5-((Dimethyl(phenyl)silyl)methyl)-6,7-
stirred solution of
bis(triethylsilyloxy)-hexahydro-1H-pyrrolizine-3-carbonitriles (9).
A
compound 8 (0.122 g, 0.228 mmol) in anhydrous THF (3.0 mL) was treated at 0 °C with a freshly
prepared solution of DIBALH-BuLi ate complex (2.5 mL, prepared from 2.8 mL of 1.0 M DIBAL-H
in hexanes and 1.1 mL of 2.5 M n-BuLi in hexanes in 1.2 mL of anhydrous THF). The reaction
mixture was allowed to warm to 20 °C over 30 min and stirred for 16 h, whereupon it was cooled to
–60 °C and treated with 0.243 mL (0.193 g, 1.94 mmol) of TMSCN. After being allowed to warm to
0 °C over 1 h, the mixture was diluted with water and then ethyl acetate and filtered through a small
pad of celite. The filtrate was concentrated under reduced pressure to give the crude nitriles, which
were purified by flash chromatography with ethyl acetate in pentane (1:10) to give 0.111 g (89%) of
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
the amino-nitriles 9 as a 1.6:1 diastereomeric mixture. A comparable sample was separated for
4
5
1
characterization purposes. Major isomer (in mixture with small amount of minor isomer): H NMR
6
7
8
9
(400 MHz, CDCl3)  0.31 (s, 3 H), 0.33 (s, 3 H), 0.60-0.69 (m, 12 H), 0.93-1.03 (m, 18 H), 1.08 (dd,
J = 15.5, 5.0 Hz, 1 H), 1.25 (dd, J = 15.2, 5.0 Hz, 1 H), 1.57-1.65 (m, 1 H), 1.80-1.89 (m, 1 H), 1.99-
2.12 (m, 2 H), 3.10-3.14 (m, 1 H), 3.27-3.32 (m, 1 H), 3.36-3.42 (m, 1 H), 3.70-3.77 (m, 2 H), 7.30-
7.34 (m, 3 H), 7.51-7.55 (m, 2 H); 13C NMR (75.5 MHz, CDCl3)  –1.7 (CH3), 5.1 (CH2), 6.9
(CH3), 19.6 (CH2), 22.9 (CH2), 33.2 (CH2), 52.8 (CH), 60.0 (CH), 65.2 (CH), 65.3 (CH), 72.9 (CH),
82.5 (CH), 118.2 (CN), 127.6 (CH), 128.7 (CH), 133.6 (CH), 140.0 (C). Minor isomer: [〈]D24 +50 (c
0.5, CHCl3); IR (film) 2960, 2910, 2876, 2234 (w), 1957, 1453, 1246, 1148, 1007 cm-1;1H NMR
(400 MHz, CDCl3)  0.38 (s, 3 H), 0.42 (s, 3 H), 0.48-0.62 (m, 12 H), 0.86-0.99 (m, 20 H), 1.65-
1.74 (m, 1 H), 1.88-1.98 (m, 1 H), 2.11-2.22 (m, 2 H), 2.94 (ddd, J = 7.0, 7.0, 3.3 Hz, 1 H), 3.53
(ddd, J = 8.0, 6.4, 4.5 Hz, 1 H), 3.62 (dd, J = 3.3, 3.3 Hz, 1 H), 3.82 (dd, J = 6.8, 6.8 Hz, 1 H), 4.11
(dd, J = 6.4, 3.3 Hz, 1 H), 7.33-7.37 (m, 3 H), 7.52-7.57 (m, 2 H); 13C NMR (75.5 MHz, CDCl3)  –
2.6 (CH3), –1.6 (CH3), 4.8 (CH2), 4.9 (CH2), 6.8 (CH3), 21.8 (CH2), 25.6 (CH2), 31.8 (CH2), 56.8
(CH), 65.3 (CH), 67.4 (CH), 73.9 (CH), 80.9 (CH), 121.4 (CN), 127.8 (CH), 128.9 (CH), 133.6
(CH), 139.2 (C); MS (ESI) m/z 545 (MH+); HRMS (ESI) calcd for C29H53N2O2Si3: 545.3409. Found:
545.3413 (MH+); Anal. calcd for C29H52N2O2Si3: C, 63.91; H, 9.62; N, 5.14. Found: C, 63.81; H,
9.54; N, 4.78.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3aR,4S,8aR,8bS)-4-((Dimethyl(phenyl)silyl)methyl)-hexahydro-[1,3]dioxolo[4,5-a]pyrrolizin-
6-one (10). To a stirred solution of diol 7 (14.3 mg, 0.047 mmol) in DCM (0.22 mL) at 20 °C was
added dimethoxymethane (0.22 mL) and phosphoric anhydride (31.0 mg, 0.218 mmol). After being
stirred for 16 h, the reaction mixture was quenched with a cold saturated solution of sodium
bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure. Purification of the resultant crude
14
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
material by flash chromatography on silica gel with ether in dichloromethane (3-10%) provided 13.1
4
5
mg (88%) of protected diol 10: [〈]D24 –59 (c 1.0, CHCl3); IR (film) 3068, 2954, 1690, 1407 cm-1; 1H
6
7
8
9
NMR (500 MHz, CDCl3)  0.36 (s, 3 H), 0.40 (s, 3 H), 0.95 (A of ABX, J = 14.8, 10.3 Hz, 1H),
1.02 (B of ABX, J = 14.8, 6.6 Hz, 1H), 1.82 (dddd, J = 6.2, 8.9, 9.1, 13.2 Hz, 1 H), 2.11 (dddd, J =
4.2, 6.7, 10.8, 13.2 Hz, 1 H), 2.26-2.39 (m, 2 H), 3.68 (ddd, J = 4.1, 4.1, 8.9, 1 H), 4.23 (ddd, J = 0.0,
6.6, 10.3 Hz, 1 H), 4.31-4.36 (m, 2 H), 4.69 (s, 1 H), 4.92 (s, 1 H), 7.33-7.37 (m, 3 H), 7.48-7.53 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2 H); C NMR (125 MHz, CDCl3)  -3.6 (CH3), -2.8 (CH3), 17.1 (CH2), 19.2 (CH2), 32.8 (CH2),
56.3 (CH), 61.6 (CH), 80.0 (CH), 89.6 (CH), 96.1 (CH2), 127.7 (CH), 129.0 (CH), 133.4 (CH), 138.7
(C), 175.6 (C); MS (ESI) m/z 240 (MH+ - C6H6), 318 (MH+), 340 (MNa+), 635 (2MH+); HRMS
(ESI) calcd for C17H24NO3Si: 318.1525. Found: 318.1522 (MH+).
(3aR,4S,6R,8aR,8bS) and (3aR,4S,6S,8aR,8bS)-4-((Dimethyl(phenyl)silyl)methyl)-hexahydro-
4H-[1,3]dioxolo[4,5-a]pyrrolizine-6-carbonitriles (11). A stirred solution of compound 10 (0.037
g, 0.117 mmol) in anhydrous THF (3.0 mL) was treated at 0 °C with a freshly prepared solution of
DIBALH-BuLi ate complex (0.38 mL), as described for compound 9 to give 0.045g of crude oil
(1.6:1 diastereomeric mixture) which was heated in DMF at 145°C for 45 min. The 9:1
diastereomeric mixture obtained after removal of solvent was purified by flash chromatography on
silica gel with ethyl acetate 5 to 15% in pentane to give 0.033 g (86%) of the major isomer of amino-
24
nitriles 11 and 0.0026 g (7%) of the minor isomer. Major isomer: [〈]D +14 (c 0.25, CHCl3); IR
1
(film) 3063, 2953, 2922, 2225, 1096 cm-1, H NMR (400 MHz, CDCl3)  0.35 (s, 6 H), 0.84 (A of
ABX, J = 14.8, 9.9 Hz, 1 H), 0.86 (B of ABX, J = 14.8, 6.6 Hz, 1 H), 1.85-2.08 (m, 3 H), 2.12-2.25
(m, 1 H), 3.40-3.50 (m, 2 H), 3.93 (dd, J = 5.8, 7.9 Hz, 1 H), 4.22 (dd, J = 0.0, 5.6 Hz, 1 H), 4.33
13
(dd, J = 5.6, 5.6 Hz, 1H), 4.55 (s, 1 H), 4.98 (s, 1 H), 7.25-7.31 (m, 3 H), 7.44-7.52 (m, 2 H); C
NMR (75.5 MHz, CDCl3)  -3.0 (CH3), -2.6 (CH3), 21.4 (CH2), 23.9 (CH2), 31.9 (CH2), 54.2 (CH),
63.7 (CH), 65.7 (CH), 82.7 (CH), 90.4 (CH), 96.1 (CH2), 121.2 (C), 127.8 (CH), 128.9 (CH), 133.6
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
(CH), 139.1 (C); MS (ESI) m/z 251 (MH+ - C6H6), 302 (MH+ - HCN), 329 (MH+); HRMS (ESI)
4
5
24
calcd for C18H25N2O2Si: 3291685, Found: 329.1683 (MH+). Minor isomer: [〈]D –12 (c 0.32,
6
7
8
9
CHCl3); IR (film) 3073, 2953, 2926, 2238, 1090 cm-1, 1H NMR (400 MHz, CDCl3)  0.33 (s, 3 H),
0.34 (s, 3 H), 1.07 (d, J = 7.8 Hz, 2 H), 1.79-1.89 (m, 1 H), 2.00-2.12 (m, 1 H), 2,18-2,31 (m, 2 H),
3.51 (ddd, J = 2.4, 7.8, 7.8 Hz, 1 H), 3.57-3.67 (m, 2 H), 4.28 (dd, J = 5.0, 5.0 Hz, 1H), 4.44 (dd, J =
2.4, 5.0 Hz, 1 H), 4.83 (s, 1 H), 5.32 (s, 1 H), 7.32-7.37 (m, 3 H), 7.48-7.53 (m, 2 H); 13C NMR (75.5
MHz, CDCl3)  -2.4 (CH3), -2.3 (CH3), 22.3 (CH2), 23.5 (CH2), 33.6 (CH2), 52.4 (CH), 61.9 (CH),
65.7 (CH), 81.6 (CH), 91.8 (CH), 96.4 (CH2), 119.6 (C), 127.8 (CH), 128.9 (CH), 133.4 (CH), 139.1
(C); MS (ESI) m/z 251 (MH+ - C6H6), 302 (MH+ - HCN), 329 (MH+), HRMS (ESI) calcd for
C18H25N2O2Si: 329.1685, Found: 329.1682 (MH+).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2S,3aR,4S,8aR,8bS)-4-((Dimethyl(phenyl)silyl)methyl)-2-phenylhexahydro-[1,3]dioxolo[4,5-
a]pyrrolizin-6-one (12). To a stirred solution of diol 7 (0.105 g, 0.34 mmol) in DCM (3.4 mL) at 20
°C was added PhCH(OMe)2 (0.072 mL, 0.48 mmol) and p-TSA.H2O (6.4 mg, 0.03 mmol). After
being stirred for 16 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure to give 136 mg of crude 12, which was
used without further purification. An analytical sample was obtained by purification of comparable
crude material by flash chromatography on silica gel with ethyl acetate in pentane (1:10), which
afforded 12 as a white solid: mp 134-135 °C; [α]23D –72 (c 2.1, CHCl3); IR (film) 3076, 2946, 1688,
1
1465 cm-1; H NMR (400 MHz, CDCl3) δ 0.41 (s, 3 H), 0.46 (s, 3 H) , 0.98 (B of ABX, J = 14.7,
10.7 Hz, 1 H) , 1.06 (A of ABX, J = 14.7, 6.5 Hz, 1 H) , 1.85 – 1.72 (m, 1 H) , 2.10 (dddd, J = 13.2,
8.0, 8.0, 3.4 Hz, 1 H) , 2.41 – 2.26 (m, 2 H) , 3.72 (ddd, J = 8.9, 3.4, 3.4 Hz, 1 H) , 4.47 (dd, J = 10.7,
13
6.5 Hz, 1 H) , 4.56 – 4.50 (m, 2 H) , 5.61 (s, 1 H) , 7.45 – 7.31 (m, 8 H), 7.63 – 7.49 (m, 2 H); C
NMR (100 MHz, CDCl3) δ -3.6 (CH3), -2.8 (CH3), 16.7 (CH2), 18.8 (CH2), 32.7 (CH2), 57.0 (CH),
16
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
61.6 (CH), 81.1 (CH), 90.1 (CH), 105.4 (CH), 127.0 (CH), 127.7 (CH), 128.5 (CH), 129.0 (CH),
129.8 (CH), 133.4 (CH), 135.4 (C), 138.8 (C),176.4 (C); MS (ESI) m/z 316 (M-Ph)+, 416 (MNa+),
809 (2M+Na)+; HRMS (ESI) calcd for C23H27NO3NaSi: 416.1652. Found: 416.1646 (MNa+).
(2S,3aR,4S,6R,8aR,8bS) and (2S,3aR,4S,6S,8aR,8bS)-4-((Dimethyl(phenyl)silyl)methyl)-2-
phenylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine-6-carbonitriles (13). A stirred solution of the
above crude lactam 12 in anhydrous THF (3.0 mL) was treated at 0 °C with 1.6 mL of a freshly
prepared solution of DIBALH-BuLi ate complex (prepared from 5.5 mL of 1.0 M DIBAL-H in
hexanes and 2.0 mL of 2.5 M n-BuLi in hexanes in 2.5 mL of anhydrous THF at 0 °C). The reaction
was allowed to warm to 20 °C and was monitored by TLC. After 1.5 h, the reaction mixture was
cooled to 0 °C and TMSCN (0.236 mL, 0.187 g, 1.89 mmol) was added. After an additional 20 min,
EtOAc and water were added and the resulting mixture was stirred for another 20 min. The mixture
was then directly filtered through a plug of Celite and the latter was washed with EtOAc. The filtrate
was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography on silica gel with ethyl acetate in
pentane (2:8) to afford 0.135 g (97% overall from 7) of a 6.7:1 mixture of amino-nitriles 13 as a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
colorless oil. Pure, analytical samples of each epimers could be secured by a second chromatography
1
on silica gel. Major isomer: [α]21 +57 (c 2.2, CHCl3); IR (film) 3063, 2919, 2237 cm-1; H NMR
D
(400 MHz, CDCl3) δ 0.44 (s, 6 H), 0.99 (d, J = 8.2 Hz, 2 H), 2.08 – 1.92 (m, 2 H), 2.32 –2.13 (m, 2
H), 3.63 – 3.56 (m, 1 H), 3.65 (t, J = 8.2 Hz, 1 H), 4.08 (dd, J = 8.1, 6.3 Hz, 1 H), 4.53 (dd, J = 6.0,
0.8 Hz, 1 H), 4.61 (dd, J = 6.0, 4.9 Hz, 1 H), 7.38 – 7.34 (m, 3 H), 5.68 (s, 1 H), 7.60 – 7.54 (m, 2
13
H), 7.39 (s, 5 H); C NMR (100 MHz, CDCl3) δ -2.9 (CH3), -2.6 (CH3), 21.4 (CH2) , 23.4 (CH2) ,
31.8 (CH2), 54.0 (CH), 63.9 (CH), 65.7 (CH), 83.7 (CH), 91.2 (CH), 104.8 (CH), 121.2 (C), 126.0
(CH), 127.7 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 133.6 (CH), 135.9 (C), 139.2 (C); MS (ESI)
m/z 405 (MH+), 378 (M-CN)+, 327 (M-Ph)+; HRMS (ESI) calcd for C24H29N2O2Si: 405.19928.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
Found: 405.20002 (MH+). Minor isomer: [α]21 +15 (c 0.7, CHCl3); IR (film) 2923, 2236, 1459,
D
4
5
1
1426, 1407, 1248, 1112 cm-1; H NMR (400 MHz, toluene-d8) δ 0.31 (s, 6 H), 0.90 (B of ABX, J =
6
7
8
9
14.7, 7.4 Hz, 1 H), 0.97 (A of ABX, J = 14.7, 7.8 Hz, 1 H), 1.28 (dddd, J = 12.8, 6.7, 6.7, 5.6 Hz, 1
H), 1.46 (dddd, J = 12.1, 7.9, 6.7,6.7 Hz, 1 H), 1.86 (dddd, J = 12.1, 6.7, 5.6, 5.6 Hz, 1 H), 2.01
(dddd, J = 12.8, 7.9, 6.7, 6.7 Hz , 1 H), 3.16 (ddd, J = 6.7, 6.7, 5.3 Hz, 1 H), 3.28 (dd, J = 6.7, 5.6
Hz, 1 H), 3.85 (ddd, J = 7.8, 7.4, 3.1 Hz, 1 H), 4.02 (dd, J = 5.6, 5.3 Hz, 1 H), 4.16 (dd, J = 5.6, 3.1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 1 H), 7.25 – 7.17 (m, 6 H), 5.60 (s, 1 H), 7.73 – 7.69 (m, 2 H), 7.46 – 7.40 (m, 2 H); C NMR
(100 MHz, toluene-d8) δ -2.5 (CH3), -2.2 (CH3), 22.4 (CH2), 24.8 (CH2), 33.3 (CH2), 52.2 (CH), 63.4
(CH), 65.8 (CH), 82.1 (CH), 91.2 (CH), 106.6 (CH), 118.5 (C), 127.5 (CH), 128.0 (CH), 128.4 (CH),
129.1 (CH), 129.3 (CH), 133.8 (CH), 136.8 (C), 139.7 (C); MS (ESI) m/z 427 (MNa+), 405 (MH+),
378 (M-CN)+, 327 (M-Ph)+.
(1S,2R,3S,5R,7aR)-3,5-Bis((dimethyl(phenyl)silyl)methyl)-1,2-bis(triethylsilyloxy)-
hexahydro-1H-pyrrolizine (14). To the diastereomeric mixture of amino-nitriles 9 (0.201 g, 0.369
mmol) in anhydrous ether (7.0 mL) was added at 0 °C dimethylphenylsilylmethylmagnesium
chloride (3.7 mL, 0.8 M in THF, 3.0 mmol). The reaction mixture was allowed to warm to 20 °C
over 45 min and stirred for 48 h, after which it was cooled to 0 °C and treated with a saturated
aqueous solution of NH4Cl. The mixture was extracted with ethyl acetate and the combined organic
layers were washed with water, dried over anhydrous Na2SO4,, and filtered. Concentration of the
filtrate under reduced pressure gave the crude product 14 (5:1 diastereomeric mixture), which was
used directly below. A comparable sample was subjected to silica gel chromatography for
characterization purposes. Mixture of isomers: IR (film) 3068, 3048, 2953, 2876, 1426, 1249, 1112
cm-1; MS (ESI) m/z 668 (MH+); HRMS (ESI) calcd for C37H66NO2Si4: 668.4165. Found: 668.4166
(MH+). Major isomer: 1H NMR (400 MHz, CDCl3)  0.21 (s, 6 H), 0.29 (s, 3 H), 0.34 (s, 3 H), 0.42-
18
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
0.50 (m, 6 H), 0.52-0.59 (m, 6 H), 0.73 (dd, J = 13.7, 12.7 Hz, 1 H), 0.83-0.89 (m, 9 H), 0.90-0.95
(m, 9 H), 0.98-1.12 (m, 3 H), 1.14-1.27 (m, 1 H), 1.41-1.50 (m, 1 H), 1.66-1.75 (m, 1 H), 2.00-2.11
(m, 1 H), 2.82-2.88 (m, 1 H), 3.15-3.25 (m, 1 H), 3.50 (ddd, J = 15.3, 7.2, 7.2 Hz, 1 H), 3.66 (dd, J =
3.3, 3.3 Hz, 1 H), 4.12 (dd, J = 7.2, 3.3 Hz, 1 H), 7.29-7.35 (m, 6 H), 7.42-7.47 (m, 2 H), 7.48-7.53
(m, 2 H); 13C NMR (75.5 MHz, CDCl3)  –2.2 (CH3), –2.1 (CH3), –1.4 (CH3), 4.9 (CH2), 5.0 (CH2),
6.8 (CH3), 6.9 (CH3), 23.3 (CH2), 23.6 (CH2), 26.4 (CH2), 34.5 (CH2), 65.0 (CH), 65.2 (CH), 65.8
(CH), 74.5 (CH), 80.8 (CH), 127.6 (CH), 127.7 (CH), 128.6 (CH), 128.8 (CH), 133.5 (CH), 133.7
(CH), 139.5 (C), 139.8 (C); Minor isomer (from re-silylation of 15b): 1H NMR (400 MHz, CDCl3) 
0.21 (s, 3 H), 0.23 (s, 3 H), 0.28 (s, 3 H), 0.32 (s, 3 H), 0.49-0.67 (m, 12 H), 0.77 (dd, J = 14.3, 11.8
Hz, 1 H), 0.88-0.99 (m, 18 H), 1.00-1.12 (m, 3 H), 1.27-1.37 (m, 2 H), 1.45-1.54 (m, 1 H), 1.89-1.98
(m, 1 H), 2.95-3.03 (m, 1 H), 3.18 (ddd, J = 7.5, 4.1, 4.1 Hz, 1 H), 3.35 (ddd, J = 8.5, 5.3, 5.3 Hz, 1
H), 3.63 (dd, J = 4.1, 4.1 Hz, 1 H), 3.99 (dd, J = 5.3, 4.1 Hz, 1 H), 7.28-7.37 (m, 6 H), 7.43-7.47 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2 H), 7.48-7.53 (m, 2 H); C NMR (75.5 MHz, CDCl3)  –2.3 (CH3), –2.1 (CH3), –1.4 (CH3), 4.9
(CH2), 5.2 (CH2), 6.9 (CH3), 7.0 (CH3), 16.7 (CH2), 24.1 (CH2), 24.7 (CH2), 32.1 (CH2), 58.6 (CH),
59.0 (CH), 66.2 (CH), 73.3 (CH), 80.3 (CH), 127.6 (CH), 128.0 (CH), 128.6 (CH), 128.7 (CH),
133.0 (CH), 133.5 (CH), 133.7 (CH), 139.5 (C), 139.9 (C).
(1S,2R,3S,5R,7aR) and (1S,2R,3S,5S,7aR)-3,5-Bis((dimethyl(phenyl)silyl)methyl)-hexahydro-
1H-pyrrolizine-1,2-diols (15a,b). A solution of the above crude diastereomeric mixture 14 in THF
at 20 °C was treated with TBAF (1.1 mL, 1.0 M in THF) and then stirred for 4 h, after which water
was added and the mixture was extracted with chloroform. The combined organic layers were
washed with water, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to give the crude diols, which were purified by flash silica gel chromatography with
methanol–aqueous NH4OH–chloroform (0.4:0.4:10) to afford 0.111 g (68% from 9) of the major
24
isomer 15a and 0.019 g (12% from 9) of the minor isomer 15b. Minor isomer: [〈]D –9 (c 1.1,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
7
8
CHCl3); IR (film) 3378, 3072, 3048, 2953, 2910, 1113 cm-1; 1H NMR (400 MHz, CDCl3)  0.24 (s,
3 H), 0.26 (s, 3 H), 0.32 (s, 3 H), 0.34 (s, 3 H), 0.73 (dd, J = 14.0, 13.0 Hz, 1 H), 1.00-1.19 (m, 3 H),
1.32-1.52 (m, 2 H), 1.64-1.71 (m, 1 H), 1.73-1.87 (m, 1 H), 2.10-2.70 (br s, 2 H), 3.06-3.26 (m, 2 H),
3.38-3.49 (m, 1 H), 3.71 (dd, J = 6.6, 4.5 Hz 1 H), 3.85 (dd, J = 4.5, 4.5 Hz, 1 H), 7.29-7.38 (m, 6
H), 7.42-7.49 (m, 2 H), 7.50-7.57 (m, 2 H); 13C NMR (75.5 MHz, CDCl3)  –2.2 (CH3), –1.6 (CH3),
17.3 (CH2), 22.2 (CH2), 23.1 (CH2), 32.8 (CH2), 57.2 (CH), 57.8 (CH), 65.6 (CH), 71.3 (CH), 80.6
(CH), 127.79 (CH), 127.88 (CH), 128.9 (CH), 133.4 (CH), 133.6 (CH), 139.7 (C). Major isomer:
[〈]D24 +24 (c 0.9, CHCl3); IR (film) 3388, 3068, 3048, 2952, 2908, 1426, 1248, 1113 cm-1; 1H NMR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3)  0.28 (s, 6 H), 0.33 (s, 3 H), 0.38 (s, 3 H), 0.89 (dd, J = 14.2, 11.5 Hz, 1 H),
1.14 (dd, J = 14.7, 11.0, Hz, 1 H), 1.20-1.40 (m, 3 H), 1.61-1.71 (m, 1 H), 1.79-1.98 (m, 2 H), 2.21
(br s, 2 H), 2.71 (ddd, J = 11.0, 8.1, 3.0 Hz, 1 H), 2.84-2.91 (m, 1 H), 3.55 (ddd, J = 7.5, 7.5, 4.2 Hz,
1 H), 3.68-3.73 (m, 1 H), 3.76 (dd, J = 4.2, 4.2 Hz, 1 H), 7.32-7.39 (m, 6 H), 7.47-7.52 (m, 2 H),
7.53-7.58 (m, 2 H); 13C NMR (75.5 MHz, CDCl3)  –2.4 (CH3), –2.0 (CH3), –1.2 (CH3), 23.1
(CH2), 23.6 (CH2), 24.0 (CH2), 34.8 (CH2), 64.6 (CH), 64.8 (CH), 65.5 (CH), 72.5 (CH), 80.9 (CH),
127.7 (CH), 128.0 (CH), 128.8 (CH), 129.0 (CH), 133.5 (CH), 139.4 (C), 139.7 (C); MS (ESI) m/z
440 (MH+); HRMS (ESI) calcd for C25H38NO2Si2: 440.2436. Found: 440.2435 (MH+).
(1S,2R,3S,5R,7aR)-3,5-Bis((dimethyl(phenyl)silyl)methyl)-hexahydro-1H-pyrrolizine-1,2-diol
(15a from 13). To the diastereomeric mixture of amino-nitriles 13 (10.0 mg, 0.025 mmol) in
anhydrous ether (0.5 mL) at 0 °C was added a solution of dimethylphenylsilylmethylmagnesium
chloride (0.247 mL, 0.8 M in THF, 0.20 mmol). The reaction mixture was allowed to warm to 20 °C
over 45 min and stirred for 48 h, after which it was cooled to 0 °C and treated with a saturated
aqueous solution of NH4Cl. The mixture was extracted with ethyl acetate and the combined organic
layers were washed with water, dried over anhydrous Na2SO4, and filtered. Concentration of the
filtrate under reduced pressure gave the crude product 16, which was used directly below. A
20
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
comparable sample was subjected to silica gel chromatography for characterization purposes: IR
4
5
1
(film): 3068, 3020, 2951, 2920, 1664, 1589, 1561, 1426, 1248, 1113, 1087 cm-1; H NMR (CDCl3,
6
7
8
9
400 MHz) δ 0.10 (s, 3 H), 0.15 (s, 3 H), 0.34 (s, 3 H), 0.36 (s, 3 H), 0.64 (dd, J = 11.6, 14.2 Hz, 1 H),
0.94 -1.08 (m, 3 H), 1.19 - 1.32 (m, 1 H), 1.78 - 1.89 (m, 2 H), 2.02- 2.13 (m, 1 H), 3.23 - 3.33 (m, 1
H), 3.37 (dd, J = 6.5, 9.0 Hz, 1 H), 3.66 (ddd, J = 4.1, 4.1, 8.6 Hz, 1 H), 4.49 (dd, J = 0.6, 6.1 Hz, 1
H), 4.59 (dd, J = 5.3, 11.1 Hz, 1 H), 5.67 (s, 1 H), 7.28- 7.41 (m, 13 H), 7.50-7.55 (m, 2 H); 13C
NMR (75.5 MHz, CDCl3) δ -2.4, (CH3), -2.3 (CH3), -2.2 (CH3), -2.1 (CH3), 22.3 (CH2), 22.5 (CH2),
23.6 (CH3), 34.6 (CH2), 60.9 (CH), 61.7 (CH), 64.7 (CH), 84.8 (CH), 91.1 (CH), 105.4 (CH), 126.7
(CH), 127.6 (CH), 127.7 (CH), 128.2 (CH), 128.7 (CH), 129.1 (CH), 133.4 (CH), 133.6 (CH), 136.4
(C), 139.0 (C), 139.6 (C); MS (ESI) m/z 528 (MH+); HRMS (ESI) calcd for C32H42O2NSi2:
528.27486. Found: 528.27407 (MH+). The above crude mixture was dissolved in 0.600 mL of
TFA/H2O/THF (1:2:3) and heated at 60 °C for 3 h. After being allowed to cool to 20 °C, the reaction
mixture was quenched by the addition of 1N NaOH and extracted with AcOEt. The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure to give the crude product, which was purified by flash
chromatography on silica gel with methanol–aqueous NH4OH–chloroform (0-5%) to afford 9.6 mg
(88%) of pure diol 15a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,2R,3R,5R,7aR)-3,5-Bis(hydroxymethyl)-hexahydro-1H-pyrrolizine-1,2-diol
(Hyacinthacine B1 (2)). A solution of diol 15a (66 mg, 0.150 mmol) in dichloromethane (2.0 mL) at
20 °C was treated with 0.182 mL (0.200 g, 1.50 mmol) of tetrafluoroboric acid dimethyl ether
complex and stirred for 5 h, whereupon the solution was evaporated under reduced pressure. A
solution of the resulting crude material in dimethylformamide (1.5 mL) was treated with 86 mg (1.48
mmol) of potassium fluoride and, after 30 min, cooled to 0 °C and treated with 0.288 mL (0.101 g,
35% in water, 2.96 mmol) of aqueous hydrogen peroxide. The reaction mixture was allowed to warm
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
5
6
7
8
9
to 20 °C over 1 h and then heated at 40 °C for 2 h. Solid NaHSO3 (0.308 g) was added to the reaction
mixture at 0 °C (until the starch-iodide test was negative) and the mixture was then filtered through
a small pad of sand, which was washed with dimethylformamide. The filtrate was concentrated
under reduced pressure at 20 °C to afford the crude product, which was purified by flash silica gel
chromatography with methanol–aqueous NH4OH–chloroform (1:1:5) and then passed throught a
Dowex (OH-) ion exchange column with water to afford 23 mg (75%) of pure hyacinthacine B1 (2):
[〈]D24 +40 (c 0.4, H2O); IR (film) 3352, 2928, 2880 cm-1; 1H NMR (400 MHz, CD3OD)  1.52-1.61
(m, 1 H), 1.73-1.82 (m, 1 H), 2.00-2.10 (m, 1 H), 2.10-2.20 (m, 1H), 2.91 (ddd, J = 9.0, 6.1, 3.1 Hz,
1 H), 3.03-3.10 (m, 1 H), 3.42 (dd, J = 11.0, 6.4 Hz, 1 H), 3.44 (dd, J = 11.0, 5.4 Hz, 1H), 3.54-3.58
(m, 1 H), 3.60 (dd, J = 10.9, 6.1 Hz, 1H), 3.78 (dd, J = 10.9, 3.1 Hz, 1 H), 3.83 (dd, J = 3.8, 3.8 Hz, 1
H), 3.92 (dd, J = 8.8, 4.1 Hz, 1 H); 1H NMR (400 MHz, D2O)  1.46-1.55 (m, 1 H), 1.73-1.82 (m, 1
H), 1.91-2.08 (m, 2 H), 2.85-2.92 (m, 1 H), 2.97-3.05 (m, 1 H), 3.42 (dd, J = 11.5, 6.0 Hz, 1 H),
3.49-3.54 (m, 1 H), 3.55 (dd, J = 11.0, 6.5 Hz,1 H), 3.60 (dd, J = 11.5, 6.5 Hz, 1 H), 3.73 (dd, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
11.5, 4.0 Hz, 1 H), 3.90-3.95 (m, 2 H); C NMR (100.6 MHz, CD3OD)  25.0 (CH2), 31.2 (CH2),
13
65.6 (CH2), 67.4 (CH2), 69.3 (CH), 71.4 (CH), 72.4 (CH), 74.6 (CH), 77.6 (CH); C NMR (100. 6
MHz, D2O)  25.3 (CH2), 32.3 (CH2), 66.1 (CH2), 67.5 (CH2), 69.4 (CH), 71.9 (CH), 72.1 (CH),
74.9 (CH), 78.2 (CH); MS (ESI) m/z 204 (MH+); HRMS (ESI) calcd for C9H18NO4: 204.1230.
Found: 204.1230 (MH+).
(2R,3S,4R,5R)-2-(But-3-enyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol (17). A solution of diol
15b (16.0 mg, 0.036 mmol) in dichloromethane (1.0 mL) was stirred with 0.044 mL (48 mg, 0.36
mmol) of terafluoroboric acid dimethyl ether complex for 5 h at 20 °C. The solvent was then
evaporated and the resulting crude product was dissolved in DMF (0.5 mL) was treated with 21 mg
(0.36 mmol) of potassium fluoride. After being stirred for 30 min, the reaction mixture was cooled
to 0 °C and 0.070 mL (24 mg, 35% in water, 0.72 mmol) of hydrogen peroxide solution was added.
22
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
After being allowed to warm to 20 °C over 1 h, the reaction mixture was heated at 40 °C for 2 h. The
excess peroxide was destroyed by addition of solid NaHSO3 (75 mg) at 0 °C and the resulting
reaction mixture was filtered through small pad of sand, which was then washed with DMF. The
solvents were evaporated under reduced pressure at 20 °C to afford the crude product, which was
purified by flash chromatography on silica gel with methanol–aqueous NH4OH–chloroform (1:1:5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
This resulting salt, after passage over Dowex (OH-) with water, gave 4.7 mg (69%) of pure 17. H
NMR (400 MHz, D2O) δ 1.53-1.64 (m, 1 H), 1.65-1.76 (m, 1 H), 2.14 (q, J = 7.6, 14.4 Hz, 2 H),
3.09-3.20 (m, 2 H), 3.63 (dd, J = 6.4, 12.0 Hz, 1 H), 3.73 (dd, J = 4.2, 11.3 Hz, 1 H), 4.01 (dd, J =
4.2, 4.2 Hz, 2 H), 4.04 (dd, J = 4.2, 6.2 Hz, 1 H), 5.07 (m, 2H), 5.92 (dddd, J = 6.6, 6.6, 10.1, 10.1
Hz, 1 H); 13C NMR (75.5 MHz, D2O) δ 28.1 (CH2), 30.4 (CH2), 58.8 (CH), 61.5 (CH), 62.9 (CH2),
73.0 (CH), 74.5 (CH), 114.9 (CH2), 139.1 (CH); MS (ESI) m/z 188 (MH+); HRMS (ESI) calcd for
C9H18O3N1: 188.1281. Found: 188.1278 (MH+).
(2S,3aR,4S,6S,8aR,8bS)-6-(Benzyloxymethyl)-4-((dimethyl(phenyl)silyl)methyl)-2-
i
phenylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine (19). To a stirred solution of Pr2NH (0.770
mL, 0.556 g, 5.49 mmol) in freshly distilled THF (2.2 mL) at –35 °C under Ar was added dropwise
2.0 mL of n-BuLi (2.5 M in hexanes, 5.0 mmol). The solution was allowed to warm to 0 °C over 30
min and then degassed by three freeze-thaw cycles. A 0.440-mL (0.44 mmol) portion of this LDA
solution was added to a degassed solution of amino-nitriles 13 (89 mg, 0.22 mmol) in THF (1.1 mL)
at –60 °C and the mixture was stirred for 15 min. Benzyl chloromethyl ether (0.093 mL, 0.105 g,
0.67 mmol) was then added at –60 °C and stirring was continued for 30 min before the addition of
saturated aqueous NH4Cl. The reaction mixture was allowed to warm to 20 °C and was extracted
with ethyl acetate. The combined organic phases were washed with water and brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting, unstable crude
1
product 18 was directly used without purification: H NMR (400 MHz, Toluene-d8) δ 0.31 (s, 3 H,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
5
6
7
8
9
H), 0.34 (s, 3 H), 0.89 (B of ABX, J = 14.6, 9.9 Hz, 1 H), 1.12 (A of ABX, J = 14.6, 5.0 Hz, 1 H),
1.45 – 1.36 (m, 1 H), 1.75 – 1.64 (m, 1 H), 2.14 – 2.05 (m, 1 H), 2.25 – 2.17 (m, 1 H), 2.98 (B of
AB, J = 9.1 Hz, 1 H), 3.20 (A of AB, J = 9.1 Hz, 1 H), 3.40 (ddd, J = 6.9, 6.9, 5.0 Hz, 1 H), 4.03 (dd,
J = 5.9, 5.0 Hz , 1 H), 4.05 (ddd, J = 9.9, 5.0, 3.2 Hz, 1 H), 4.19 (dd, J = 5.9, 3.2, 1 H), 4.22 (B of
AB, J = 12.2 Hz, 1 H), 4.27 (A of AB, J = 12.2 Hz, 1 H), 5.60 (s, 1 H), 7.27 – 7.16 (m, 10 H), 7.49 –
7.43 (m, 3 H),7.78 – 7.73 (m, 2 H); 13C NMR (100 MHz, Toluene-d8) δ -2.4 (CH3), -2.2 (CH3), 24.1
(CH2), 24.3 (CH2), 37.6 (CH2), 64.1 (CH), 66.0 (C), 66.9 (CH), 73.57 (CH2), 76.4 (CH2), 82.2 (CH),
90.8 (CH), 106.9 (CH), 120.0 (C), 127.8 (CH), 127.9 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH),
128.6 (CH), 129.2 (CH), 129.5 (CH), 134.0 (CH), 136.7 (C), 138.3 (C), 139.6 (C); MS (ESI) m/z 498
[M-CN]+, 525 [M+H]+.To a solution of the crude product in anhydrous MeOH (1.0 mL) at 0 °C was
added NaBH4 (42 mg, 1.11 mmol). The reaction mixture was stirred for 1 h at this temperature and
then water was added and the aqueous phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by chromatography on silica gel with MeOH saturated
with NH3 in EtOAc (2-10%) to give 54 mg (49%, 55% brsm, 2 steps) of ether 19, along with 9 mg of
amino-nitrile 13. Ether 19: [α]25D +15 (c 1.2, CHCl3); IR (film) 3373, 2918, 2845, 1665, 1455, 1110
cm-1; 1H NMR (300 MHz, CDCl3) δ 0.29 (s, 3 H), 0.33 (s, 3 H), 0.87 (A of ABX, J = 14.5, 9.4 Hz, 1
H), 1.10 (B of ABX, J = 14.5, 5.9 Hz, 1 H), 1.66 – 1.53 (m, 1 H), 1.77 – 1.66 (m, 1 H), 1.98 – 1.82
(m, 1 H), 3.16 – 3.08 (m, 1 H), 3.20 (B of ABX, J = 9.1, 6.1 Hz, 1 H), 3.38 (A of ABX, J = 9.1, 6.2
Hz, 1 H), 3.46 – 3.33 (m, 1 H), 3.60 (dd, J = 9.4, 5.9 Hz, 1 H), 4.26 (B of AB, J = 12.1 Hz, 1 H),
4.31 (A of AB, J = 12.1 Hz, 1 H), 5.73 (s, 1 H), 4.50 – 4.43 (m, 2 H), 7.40 – 7.27 (m, 10 H), 7.57 –
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.47 (m, 5 H); C NMR (75 MHz, CDCl3) δ -2.4 (CH3), -2.3 (CH3), 17.0 (CH2), 22.0 (CH2), 31.3
(CH2), 56.6 (CH), 58.1 (CH), 66.5 (CH), 73.2 (2 CH2), 80.8 (CH), 91.8 (CH), 105.4 (CH), 126.9
(CH), 127.5 (CH), 127.7 (CH), 127.9 (CH), 128.3 (CH), 128.4 (CH), 128.9 (CH), 129.2 (CH), 133.7
24
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
(CH), 137.2 (C), 138.7 (C), 139.7 (C); MS (ESI) m/z 500.2 (MH+); HRMS (ESI) calcd for
4
5
C31H38NO3Si: 500.2615. Found: 500.2618 (MH+).
6
7
8
9
((2S,3aR,4R,6S,8aR,8bS)-6-(Benzyloxymethyl)-2-phenylhexahydro-4H-[1,3]dioxolo[4,5-
a]pyrrolizin-4-yl)methanol (20). 30% KH in mineral oil (27 mg, 0.20 mmol) under Ar was washed
with pentane and DMF (0.250 mL) was added. The mixture was cooled to 0 °C and carefully treated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
t
with a solution of BuOOH (0.021 mL, 6.0 M in decane, 0.13 mmol) and, after 10 min, with a
solution of 19 (10.5 mg, 0.021 mmol) in DMF (0.150 mL) and a solution of TBAF (0.042 mL, 1.0 M
in THF, 0.04 mmol). After 1 h at 0 °C, the reaction mixture was allowed to warm to 20 °C and was
stirred for 1 h. Saturated aqueous Na2S2O3 was then added and the aqueous phase was extracted with
EtOAc. The combined organic phases were washed with water and brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product.
Chromatography on silica gel with MeOH saturated with NH3 in dichlormethane (1:10) afforded 11
mg (> 100%) of alcohol 20: [α]25 +35.7 (c 0.8, CHCl3); IR (film) 3375, 2926, 2853, 1674, 1403,
D
1086 cm-1;1H NMR (400 MHz, CDCl3) δ 1.62 – 1.81 (m, 2 H), 1.81 – 1.92 (m, 1 H), 2.01 – 2.16 (m,
1 H), 3.31 – 3.40 (m, 2 H), 3.40 – 3.47 (m, 1 H), 3.51 – 3.62 (m, 2 H), 3.66 (ddd, J = 6.3, 4.6, 1.5 Hz,
1 H), 3.78 – 3.70 (m, 1 H), 4.28 (B of AB, J = 11.9 Hz, 1 H), 4.34 (A of AB, J = 11.9 Hz, 1 H), 4.64
13
– 4.57 (m, 2 H), 5.84 (s, 1 H), 7.45 – 7.27 (m, 8 H), 7.55 – 7.47 (m, 2 H); C NMR (100 MHz,
CDCl3) δ 23.8 (CH2), 30.6 (CH2), 60.9 (CH), 62.4 (CH2), 63.6 (CH), 67.2 (CH), 71.8 (CH2), 73.2
(CH2), 82.6 (CH), 86.8 (CH), 105.6 (CH), 126.5 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 128.5
(CH), 129.3 (CH), 136.6 (C), 138.2 (C); MS (ESI) m/z (MH+); HRMS (ESI) calcd for C23H28NO4:
382.2013; Found: 382.2017 (MH+).
(+)-Hyacinthacine B2 (3). To a solution of alcohol 20 (8.0 mg, 0.021 mmol) in ethanol (0.300
mL) and THF (0.050 mL) was added 10% Pd/C (2.0 mg) and 6 N HCl (5 drops). The reaction
mixture was stirred at 20 °C for 16 h under hydrogen. The mixture was then filtered through a plug
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
7
of Celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure and
the residue was placed on a column of Dowex resin (H+ form), which was washed successively with
MeOH, water, and concentrated aqueous NH4OH. The aqueous NH4OH fractions were concentrated
8
9
1
under reduced pressure to give 5.2 mg of protonated hyacinthacine B2: H NMR (400 MHz, D2O) δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.81 (m, 2H, H6 and H7), 1.91 (m, 1H, H6), 2.07 (m, 1H, H7), 3.58 – 3.51 (m, 1H, H3), 3.66 – 3.59
(m, 1H, H5), 3.71 (B of ABX, J = 12.8, 2.4 Hz, 1H, H8), 3.74 (s, 1H, H9b), 3.76 (s, 1H, H9a), 3.91 (A
of ABX, J = 12.8, 3.1 Hz, 1H, H8), 4.13 – 4.06 (m, 2H, H1 and H2), 4.15 (ddd, J = 8.5, 4.3, 4.1 Hz,
13
1H, H7a); C NMR (100 MHz, D2O) δ 25.0 (CH2), 29.9 (CH2), 58.2 (CH2), 60.2 (CH2), 64.6 (CH),
69.3 (CH), 71.8 (CH), 72.8 (CH), 73.6 (CH). This material was placed on a column of Dowex resin
(OH- form), which was then washed with water to give 3.8 mg (89%, 2 steps) of (+)-hyacinthacine
B2 (3): [α]23D +25 (c 0.32, H2O); IR (film) 3344, 2925, 2883, 1661, 1401, 1035 cm-1; 1H NMR (400
MHz, D2O) δ 1.72 – 1.84 (m, 1 H), 1.94 – 2.09 (m, 3 H), 3.27 (ddd, J = 8.6, 6.4, 4.3 Hz, 1 H), 3.33
(pseudo-q, J = 5.1 Hz, 1 H), 3.66 (ddd, J = 7.0, 7.0, 3.9 Hz, 1 H), 3.73 (dd, J = 11.5, 6.4 Hz, 1 H),
3.81 – 3.91 (m, 3 H), 4.07 (dd, J = 3.9, 3.9 Hz, 1 H), 4.11 (dd, J = 8.6, 3.9 Hz, 1 H); 13C NMR (100
MHz, D2O) δ 79.4 (CH), 74.6 (CH), 69.3 (CH), 66.8 (CH2), 64.5 (CH2), 64.3 (CH), 64.2 (CH), 33.1
(CH2), 25.0 (CH2); MS (ESI) m/z 204 (MH+); HRMS (ESI) calcd for C9H18NO4: 204.1230; Found:
204.1229 (MH+).
Acknowledgment. We thank the CNRS and the Université Joseph Fourier (UMR 5616, FR 2607)
for financial support, the French Ministry for a doctoral fellowship (to J.S.), and Professor N. Asano
for a comparison sample of natural hyacinthacine B1.
Supporting Information Available: X-ray crystallographic analysis data for single crystal of
1
compound 12, H, 13C and COSY NMR spectra of compounds 2, 3, 8 – 17, 19, 20 and NOESY
26
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
spectra of compounds 9 (minor), 14 and 15a. This material is available free of charge via the
4
5
Internet at http://pubs.acs.org.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
i Wardrop, D. J.; Waidyarachchi, S. L. Nat. Prod. Rep. 2010, 27, 1431.
ii
(a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645. (b) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683. (c) Robina, I.;
Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab. 2004, 5, 329. (d) Borges de
Melo, E.; da Silveira Gomes, A.; Carvalho, I. Tetrahedron 2006, 62, 10277. (e) Gerber-Lemaire, S.;
Juillerat-Jeanneret, L. Mini Rev. Med. Chem. 2006, 6, 1043.
iii Winchester, B. G. Tetrahedron: Asymmetry 2009, 20, 645.
iv Iminosugars; Compain, P.; Martin, O. R., Ed.; John Wiley and Sons, Ltd., West Sussex, 2007.
v For a review on polyhydroxylated pyrrolizidines, see: (a) Yoda, H.; Curr. Org. Chem. 2002, 6, 223.
For reviews on pyrrolizidines, see: (b) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. (c) Liddell, J. R.
Nat. Prod. Rep. 2001, 18, 441. (d) Liddell, J. R. Nat. Prod. Rep. 2000, 17, 455. (e) Liddell, J. R.
Nat. Prod. Rep. 1999, 16, 499. (f) Liddell, J. R. Nat. Prod. Rep. 1998, 15, 363. (g) Nash, R. J.;
Watson, A. A.; Asano, N. In Alkaloids: Chemical & Biological Perspectives; Pelletier, S. W., Ed.;
Elsevier Science, Ltd.: Oxford, 1996, vol. 11, 345.
vi
Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.; Watson, A. A.;
Nash, R. J.; Wormald, M. R.; Fleet, G. W. J.; Asano, N. Carbohydr. Res. 1999, 316, 95.
vii
(a) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W.; Kuriyama, C.; Ikeda, K.; Asano
N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993. (b) Ritthiwigrom, T.; Au, C. W. G.; Pyne, S. G. Curr.
Org. Synth. 2012, 9, 583.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
viii
For recent examples, see: (a) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587. (b)
4
5
6
7
8
Desvergenes, S.; Py, S.; Vallée, Y. J. Org. Chem. 2005, 70, 1459. (c) Donohoe, T. J.; Sintim, H. O.;
Hollinshead, J. J. Org. Chem. 2005, 70, 7297. (d) Dewi-Wülfing, P.; Blechert, S. Eur. J. Org. Chem.
2006, 1852. (e) Donohoe, T. J.; Thomas, R. E. Chem. Rec. 2007, 7, 180. (f) Izquierdo, I.; Plaza, M.
T.; Tamayo, J. A.; Yanez, V.; Lo Re, D.; Sanchez-Cantalejo, F. Tetrahedron 2008, 64, 4613. (g)
Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.; Linney, I. D. Org. Lett.
2008, 10, 3615. (h) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826. (i)
Delso, I.: Tejero, T.; Goti, A.; Merino, P. Tetrahedron 2010, 66, 1220. (j) Izquierdo, I.; Plaza, M. T.;
Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo, F. Tetrahedron 2010, 66, 3788. (k) Hu, X-G.; Jia, Y-
M.; Xiang, J.; Yu, C-Y. Synlett 2010, 982. (l) Liu, W-J.; Ye, J-L.; Huang, P-Q. Org. Biomol. Chem.
2010, 8, 2085. (m) Liu, X-K.; Qiu, S.; Xiang, Y-G.; Ruan, Y-P.; Zheng, X.; Huang, P-Q. J. Org.
Chem. 2011, 76, 4952. (n) D'Adamio, G.; Goti, A.; Parmeggiani, C.; Moreno-Clavijo, E.; Robina, I.;
Cardona, F. Eur. J. Org. Chem. 2011, 7155. (o) Royzen, M.; Taylor, M. T.; DeAngelis, A.; Fox, J.
M. Chem. Sci. 2011, 2, 2162. (p) Liao, J-C.; Xiao, K-J.; Zheng, X.; Huang, P-Q. Tetrahedron 2012,
68, 5297.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ix
For recent work on groups B and C, see: (a) Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.;
Yoda, H. Tetrahedron 2008, 64, 8052. (b) Au, C. W. G.; Nash, R. J.; Pyne, S. G. Chem. Commun.
2010, 46, 713. (c) Zhang, W.; Sato, K.; Kato, A.; Jia, Y-M.; Hu, X-G.; Wilson, F. X.; van Well, R.;
Horne, G.; Fleet, G. W. J.; Nash, R. J.; Yu, C-Y. Org. Lett. 2011, 13, 4414. (d) Tamayo, J. A.;
Franco, F.; Sanchez-Cantalejo, F. Eur. J. Org. Chem. 2011, 7182.
x Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008,
6, 1170.
xi Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525.
28
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
xii 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, J-F.; Greene, A. E. Synlett 2005, 1413.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
xiii
Indolizidines: (a) Pourashraf, M.; Delair, P.; Rasmussen, M.; Greene, A. E. J. Org. Chem. 2000,
65, 6966. (b) Rasmussen, M.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66, 5438. (c) Ceccon, J.;
Poisson, J-F.; Greene, A. E. Org. Lett. 2006, 8, 4739. (d) Ceccon, J.; Danoun, G.; Greene, A. E.;
Poisson, J-F. Org. Biomol. Chem. 2009, 7, 2029.
xiv
Pyrrolizidines: (a) Roche, C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5, 1741. (b) Roche, C.;
Kadlecíková, K.; Veyron, A.; Delair, P.; Philouze, C.; Greene, A. E.; Flot, D.; Burghammer, M. J.
Org. Chem. 2005, 70, 8352.
xv
For a more recent non-chiral pool/non-enzymatic (formal) approach to hyacinthacine A1 that
features an efficient asymmetric aziridination, see: Kondo, Y.; Suzuki, N.; Takahashi, M.;
Kumamoto, T.; Masu, H.; Ishikawa, T. J. Org. Chem. 2012, 77, 7988.
xvi For a preliminary communication on the synthesis of hyacinthacine B1, see : Reddy, P. V.; Koos,
P.; Veyron, A.; Greene, A. E.; Delair, P. Synlett 2009, 7, 1141.
xvii
(a) Bruylants, P. Bull. Soc. Chim. Belges 1924, 33, 467. For mechanistic studies, see: (b)
Beaufort-Droal, V.; Pereira, E.; Théry, V.; Aitken, D. J. Tetrahedron 2006, 62, 11948. For recent
applications in synthesis, see: (c) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337. (d)
Agami, C.; Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org. Chem., 2003, 2062. (e) Reimann,
E.; Ettmayr, C. Monatsh. Chem., 2004, 135, 1289. (f) Hu, X-G.; Jia, Y-M.; Xiang, J.; Yu, C-Y.
Synlett, 2010, 982.
29
ACS Paragon Plus Environment