Total synthesis of (+)-hyacinthacine A6 and (+)-hyacinthacine A7

Article abstract of DOI:10.1055/s-0033-1340107

(+)-Hyacinthacines A₆ and A₇ have been synthesized from a common, late-stage intermediate, prepared in high yield through stereoselective [2+2] cycloaddition of dichloroketene to a chiral enol ether. The flexibility of aminonitrile chemistry is central to the approach. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340107

LETTER
▌209
letter
Total Synthesis of (+)-Hyacinthacine A6 and (+)-Hyacinthacine A7
(+)-Hyacinthacine A6 and (+)-Hyacinthacine A7
Julien Smith, Anushree Kamath, Andrew E. Greene, Philippe Delair*
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, 38041 Grenoble, France
Fax +33(4)76514494; E-mail: philippe.delair@ujf-grenoble.fr
Received: 22.08.2013; Accepted after revision: 06.10.2013
OH
OH
H
H
N
Abstract: (+)-Hyacinthacines A6 and A7 have been synthesized
from a common, late-stage intermediate, prepared in high yield
through stereoselective [2+2] cycloaddition of dichloroketene to a
chiral enol ether. The flexibility of aminonitrile chemistry is central
to the approach.
7
1
7a
2
3
6
B
OH
OH
A
N
5
Me
OH
OH
(+)-hyacinthacine A1 (1)
(+)-hyacinthacine A6 (2)
Key words: asymmetric synthesis, cycloaddition, glycosidase in-
hibitors, aminonitriles, iminosugars
OH
H
OH
H
OH
N
OH
N
Me
Iminosugars are carbohydrate analogues in which the ring
oxygen has been replaced with nitrogen.1 Their resem-
blance to carbohydrates and the presence of the endocy-
clic nitrogen make them powerful glycosidase inhibitors.2
Theses enzymes, which catalyze the hydrolysis of oligo-
saccharides and glycoconjugates, are involved in a large
array of biological processes (cell–cell and cell–virus in-
teractions, for example).3 Inhibitors of these enzymes are
thus potential drugs against various human pathologies.4
Me
OH
OH
OH
(+)-hyacinthacine A7 (3)
(–)-α-5-C-(3-hydroxybutyl)-
hyacinthacine A1 (4)
Figure 1 Examples of group A hyacinthacines
protected dihydroxypyrrolizidinone 7 from (S)-(–)-steri-
col 5, an efficient and commercially available chiral aux-
iliary.17 Benzylidene diol protection was chosen not only
for its general ease of introduction and removal, but also
because of the expected stereochemical directing effect of
the endo phenyl group (Scheme 1).
Among the different naturally occurring iminosugars, the
hyacinthacine alkaloids have received particular attention
over the past few years due to their selective inhibition
profile.5 These polyhydroxylated pyrrolizidines are char-
acterized by the presence of an hydroxymethyl substituent
at C-3 and are designated A, B, or C on the basis of the
number of hydroxyl and hydroxymethyl substituents pres-
ent on ring B of the pyrrolizidine skeleton (Figure 1).6
Most of the synthetic effort reported to date toward the hy-
acinthacines has focused on the A group members hyacin-
thacines A1 (1) and A2.7 The other members of the A
group are synthetically more challenging C-3 and C-5 di-
substituted pyrrolizidines (e.g., 2–4), and they have, per-
haps as a consequence, received much less attention. In
this communication, a highly stereocontrolled, nonchiral
pool, nonenzymatic approach to hyacinthacines A6 and A7
is described.8
Ar
O
Ph
O
H
N
7
Me
Me
O
HN
Ar
OH
O
O
SiMe2Ph
(S)-(–)-stericol 5
Ar = 2,4,6-triisopropylphenyl
6
Scheme 1 Preparation of protected dihydroxypyrrolizidinone 715c
To obtain hyacinthacine A6 from pyrrolizidinone 7, a
methyl group needed to be introduced at C-5 on the more
crowded endo face of the tricyclic structure. It appeared
that this might prove feasible through methylation–reduc-
tion of the corresponding aminonitrile.15c Reductive cya-
nation (partial hydride reduction18 of the lactam, followed
by TMSCN treatment) was thus effected to produce in
high yield an inconsequential mixture of the two epimeric
aminonitriles 8. Deprotonation of this mixture with LDA,
in the absence of all oxygen,19 followed by addition of ex-
cess methyl iodide, then yielded a mixture of the corre-
sponding methylated aminonitriles 9. This crude material
was not stable toward purification and was therefore di-
rectly reduced with sodium borohydride to generate a
somewhat disappointing 3:1 mixture of the desired meth-
yl-substituted pyrrolizidine 10 and its C-5 epimer. Fortu-
nately, however, a much improved 10:1 ratio was
produced by using Super-Hydride as the reducing agent
The published9,10 syntheses of hyacinthacines A6 and A7
have all relied on chiral-pool material or enzymatic tech-
niques for chirality. We believed that our asymmetric di-
chloroketene–chiral
enol
ether
cycloaddition
methodology,11 previously applied for the preparation of
a variety of alkaloids,12–15 coupled with flexible aminoni-
trile chemistry,16 might offer attractive alternative access
to these two diastereomeric C-3,C-5-disubstituted hyacin-
thacines. The syntheses began with the previously report-
ed,15c highly stereoselective preparation of benzylidene-
SYNLETT 2014, 25, 0209–0212
Advanced online publication: 21.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340107; Art ID: ST-2013-D0812-L
© Georg Thieme Verlag Stuttgart · New York

210
J. Smith et al.
LETTER
and the major isomer 10 could be isolated in 78% overall Smitrovich and Woerpel conditions21 to pyrrolizidinone 7
yield (Scheme 2).
to give in 70% yield the C-3 hydroxymethyl derivative,
which was smoothly protected as the benzyl ether 11 by
using sodium hydride and benzyl bromide (83%). The
new aminonitriles 12 were then prepared by reductive cy-
anation in 68% yield (Scheme 3).
Ph
Ph
O
O
O
H
H
a
b
O
O
7
N
N
NC
Me
NC
SiMe2Ph
SiMe2Ph
Ph
Ph
O
O
H
N
H
N
8
9
c
a, b
O
O
7
Ph
O
OH
H
H
N
c
d, e
NC
O
OH
OH
OBn
OBn
N
11
12
Me
Me
SiMe2Ph
Scheme 3 Reagents and conditions: (a) KH, t-BuOOH, TBAF,
DMF, 70%; (b) NaH, DMF, BnBr, TBAI, 83%; (c) DIBAL-H, n-BuLi,
THF, TMSCN, 68%.
10
hyacinthacine A6 (2)
Scheme 2 Reagents and conditions: (a) DIBAL-H, n-BuLi, THF,
TMSCN, 97%; (b) LDA, THF, MeI; (c) LiEt3BH, THF (dr = 10:1),
SiO2, 78% (2 steps); (d) KH, t-BuOOH, TBAF, DMF, 70%; (e) HCl,
MeOH, 73%.
In the key event, treatment of these aminonitriles 12, first
with AgBF4 and then with MeMgBr, did indeed afford the
corresponding methylated derivative in an improved 2:1
ratio of diastereomers, but this was nevertheless still un-
acceptably low (not shown).
The C-3 hydroxymethyl substituent was next unmasked
by Tamao–Fleming oxidation,20 without concomitant for-
mation of the N-oxide, under the basic conditions de-
scribed by Smitrovich and Woerpel.21 Acid cleavage of
the acetal then completed the synthesis of hyacinthacine
A6, which was isolated in 73% yield after basic resin col-
umn chromatography. The spectroscopic data provided by
the synthetic material were in accordance with those re-
ported for natural hyacinthacine A6 {[α]D +18.0, lit.8 [α]D
+16.3}.
In order to further differentiate the levels of face–reagent
steric interaction, the use of a bulky methyl equivalent
was next considered. In view of the efficient protodesi-
lylation procedure developed by Roush and coworkers,24
the dimethylphenylsilylmethyl group appeared to be a
perfect candidate. Most gratifyingly, when the aminoni-
trile epimers 12 were subjected to the Bruylants reaction
with dimethylphenylsilylmethylmagnesium bromide,
without prior iminium formation with silver tetrafluoro-
borate, an excellent level of diastereoselectivity was in
fact realized (>20:1). The major isomer 13 could be isolat-
ed in 69% yield (Scheme 4).
It was hoped that hyacinthacine A7 might be accessed
from the same mixture of aminonitriles 8 by using a
Bruylants reaction,22 since in this reaction attack of an al-
kyl Grignard reagent would be expected to occur on the
exo face, opposite the phenyl. Yu and coworkers,23 how-
ever, had found that methyl Grignard lacks sufficient re-
activity in this type of reaction and requires initial
formation of the iminium salt for a successful application.
Therefore, the aminonitriles 8 were treated first with sil-
ver tetrafluoroborate and then with methylmagnesium
bromide, which indeed provided the expected methylated
pyrrolizidines but, to our dismay, as a nearly equimolar
mixture of isomers (≤3:2, Equation 1).
Ph
O
H
N
O
a
b
12
PhMe2Si
OBn
13
Ph
O
OH
O
H
N
H
N
c
OH
Ph
O
H
Me
Me
AgBF4, CH2Cl2, r.t.;
MeMgBr, THF, –78 °C
OBn
OH
O
14
(+)-hyacinthacine A7 (3)
8
N
Scheme 4 Reagents and conditions: (a) Me2PhSiCH2MgBr, THF (dr
>20:1), SiO2, 69%; (b) TBAF·H2O, DMF, 80 °C, 83%; (c) H2, Pd/C,
EtOH, 6 M HCl, 74%.
Me
SiMe2Ph
≤ 3:2
Equation 1
After some experimentation, it was found that protodesi-
lylation of silane 13 could be cleanly accomplished in
pure DMF in the presence of TBAF to afford the exo
methyl derivative 14 in 83% yield after silica gel purifica-
tion. Concomitant deprotection of the three hydroxyl
groups was then readily achieved through hydrogenolysis
in acidic medium to provide (+)-hyacinthacine A7 in 74%
This poor facial discrimination led us to reduce the steric
impediment of the C-3 exo substituent in 8 by performing
the Tamao–Fleming oxidation before introduction of the
C-5 methyl. This steric modification (a protected hy-
droxymethyl in place of the bulky dimethylphenylsilyl-
methyl) could be readily achieved by applying the
Synlett 2014, 25, 209–212
© Georg Thieme Verlag Stuttgart · New York

LETTER
(+)-Hyacinthacine A6 and (+)-Hyacinthacine A7
211
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yield. The synthetically derived hyacinthacine A7 fur-
nished 1H NMR and 13C NMR data consistent with those
of the natural material.25
In conclusion, (+)-hyacinthacine A6 and (+)-hyacintha-
cine A7 have been efficiently synthesized in high enantio-
meric purity from a common, late-stage intermediate. The
approach, based on an asymmetric [2+2] cycloaddition of
dichloroketene to a chiral enol ether, allows flexible and
highly stereocontrolled introduction of each of the C-5
epimeric substituents. The approach is thus particularly
well suited for the preparation of other C-5-substituted
hyacinthacines, such as the hydroxybutyl hyacinthacine
A1 derivative26 4 (Figure 1).27
Acknowledgment
We thank Professors N. Asano, G. W. J. Fleet, and R. Nash for hel-
pful correspondence. Financial support from the CNRS and the
Université Joseph Fourier and a doctoral fellowship (to J.S.) from
the French Ministry are gratefully acknowledged.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(b) Rasmussen, M.; Delair, P.; Greene, A. E. J. Org. Chem.
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Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem.
2008, 6, 1170. (b) Reddy, P. V.; Koos, P.; Veyron, A.;
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indicated it would lead to natural hyacinthacine A6.
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M. D.; van der Marel, G. A.; Aerts, J. M.; Overkleeft, H. S.
Org. Biomol. Chem. 2011, 9, 5908. (c) Wardrop, D. J.;
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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.
(5) (a) Ritthiwigrom, T.; Au, C. W. G.; Pyne, S. G. Curr. Org.
Synth. 2012, 9, 583. For a review on polyhydroxylated
pyrrolizidines, see: (b) Yoda, H. Curr. Org. Chem. 2002, 6,
223. For reviews on pyrrolizidines, see: (c) Liddell, J. R.
Nat. Prod. Rep. 2002, 19, 773. (d) Nash, R. J.; Watson, A.
A.; Asano, N. In Alkaloids: Chemical and Biological
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 209–212

212
J. Smith et al.
LETTER
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.
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Chem. 2004, 135, 1289; and ref. 23.
(dddd, J = 12.0, 7.6, 7.6, 7.6 Hz, 1 H), 1.86 (dddd, J = 11.5,
7.6, 6.3, 5.3 Hz, 1 H), 1.96 (dddd, J = 12.0, 8.5, 5.3, 5.3 Hz,
1 H), 3.05 (ddddd, J = 7.6, 6.3, 6.3, 6.3, 6.3 Hz, 1 H), 3.47
(ddd, J = 8.5, 6.4, 1.9 Hz, 1 H), 3.50 (ddd, J = 7.6, 5.3, 5.3
Hz, 1 H), 4.44 (dd, J = 6.2, 1.9 Hz, 1 H), 4.54 (dd, J = 6.2,
5.3 Hz, 1 H), 5.75 (s, 1 H), 7.29–7.44 (m, 6 H), 7.47–7.59 (m,
4 H). 13C NMR (100 MHz, CDCl3): δ = –2.4 (CH3), 18.1
(CH3), 20.1 (CH2), 23.2 (CH2), 34.7 (CH2), 54.5 (CH), 57.9
(CH), 66.3 (CH), 81.9 (CH), 91.2 (CH), 105.5 (CH), 126.7
(CH), 127.7 (CH), 128.2 (CH), 128.7 (CH), 129.0 (CH),
133.6 (CH), 136.8 (C), 139.5 (C). ESI-MS: m/z = 394
[MH+]. ESI-HRMS: m/z calcd for C24H32NO2Si: 394.2197;
found: 394.2194 [MH+].
(23) Hu, X.-G.; Jia, Y.-M.; Xiang, J.; Yu, C.-Y. Synlett 2010,
982.
(24) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.;
Tinsley, J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
(25) Our synthetic hyacynthacine A7 is dextrorotatory {[α]D +48},
as was Donohoe’s9b (but not Izquierdo’s10) with the same
indicated absolute stereochemistry. Based on the reported8
levorotation {[α]D –52} of natural hyacynthacine A7 and the
dextrorotation of natural and synthetic hyacynthacine A6, the
two alkaloids, most surprisingly, would appear to belong to
different enantiomeric series. Previous workers9b have
reached the same conclusion from the rotational data.
(26) Asano, N.; Ikeda, K.; Kasahara, M.; Arai, Y.; Kizu, H.
J. Nat. Prod. 2004, 67, 846.
(2S,3aR,4R,6S,8aR,8bS)-4-(Benzyloxymethyl)-6-methyl-
2-phenylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine
(14)
To a solution of pyrrolizidine 13 (15.0 mg, 0.030 mmol) in
anhydrous DMF (0.30 mL) was added solid TBAF·H2O (84
mg, 0.30 mmol), and the reaction mixture was heated at
80 °C for 16 h. An additional portion of solid TBAF·H2O
(42 mg, 0.15 mmol) was then added, and the resulting
mixture was stirred at 80 °C for 8 h. After the addition of sat.
aq NH4Cl, the reaction mixture was processed with EtOAc.
The resulting crude material was purified by silica gel
chromatography (0–5% MeOH saturated with NH3 in
CH2Cl2) to afford 9.1 mg (83%) of 14: [α]D25 +32 (c 0.9,
CHCl3). IR (film): 3027, 2921, 2850, 1456 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.06 (d, J = 5.9 Hz, 3 H), 1.51 (dddd,
J = 11.9, 9.5, 9.5, 9.5 Hz, 1 H), 1.94 (dddd, J = 12.8, 9.5, 9.5,
2.4 Hz, 1 H), 2.06 (dddd, J = 11.9, 9.5, 5.9, 2.4 Hz, 1 H), 2.22
(dddd, J = 12.8, 9.5, 9.5, 4.9 Hz, 1 H), 3.32 (ddddd, J = 9.5,
5.9, 5.9, 5.9, 5.9 Hz, 1 H), 3.38–3.47 (m, 2 H), 3.50–3.57 (m,
1 H), 3.83 (ddd, J = 9.5, 4.9, 4.9 Hz, 1 H), 4.52 (A of AB,
J = 12.0 Hz, 1 H), 4.59 (B of AB, J = 12.0 Hz, 1 H), 4.64 (dd,
J = 6.1, 4.9 Hz, 1 H), 4.85 (d, J = 6.1 Hz, 1 H), 5.77 (s, 1 H),
7.27–7.30 (m, 1 H), 7.31–7.36 (m, 4 H), 7.37–7.42 (m, 3 H),
7.44–7.50 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 21.2
(CH3), 22.9 (CH2), 34.9 (CH2), 60.6 (CH), 66.0 (CH), 67.5
(CH), 72.9 (CH2), 73.3 (CH2), 85.0 (CH), 87.6 (CH), 105.7
(CH), 126.8 (CH), 127.5 (CH), 128.3 (CH), 128.4 (CH),
129.4 (CH), 136.3 (C), 138.3 (C). ESI-MS: m/z = 366
[MH+]. ESI-HRMS: m/z calcd for C23H28NO3: 366.2064;
found: 366.2069 [MH+].
(27) Experimental Procedures for Methyl Introductions
(2S,3aR,4S,6R,8aR,8bS)-4-{[Dimethyl(phenyl)silyl]-
methyl}-6-methyl-2-phenylhexahydro-3aH-
[1,3]dioxolo[4,5-a]pyrrolizine (10)
To a degassed solution of aminonitriles 8 (14.7 mg, 0.035
mmol) in THF (1.0 mL) at –60 °C was added a degassed
solution of LDA (1.0 M, 0.073 mL). After 15 min, MeI
(0.011 mL, 0.177 mmol) was added, and the resulting
solution was stirred at –60 °C for 30 min before the addition
of sat. aq NH4Cl. After being allowed to warm to r.t., the
reaction mixture was processed with EtOAc to give 17 mg of
crude aminonitriles 9, which were used without further
purification. To a solution of this material in anhydrous THF
(0.21 mL) at 0 °C was added dropwise a solution of LiBHEt3
(1.0 M in THF, 0.17 mL, 0.17 mmol). The reaction mixture
was stirred for 30 min at this temperature and then quenched
with H2O and processed with EtOAc. The resulting crude
product was purified by silica gel chromatography (2–5%
MeOH saturated with NH3 in EtOAc) to afford 13.0 mg
(78%) of 10: [α]D21 –4 (c 1.2, CHCl3). IR (film): 3065, 3022,
2950, 2915, 1660 cm–1. 1H NMR (400 MHz, CDCl3): δ =
0.34 (s, 3 H), 0.36 (s, 3 H), 0.95 (d, J = 6.3 Hz, 3 H), 0.97 (A
of ABX, J = 14.6, 8.6 Hz, 1 H), 1.07 (B of ABX, J = 14.6,
6.4 Hz, 1 H), 1.48 (dddd, J = 11.5, 8.5, 7.6, 7.6 Hz, 1 H), 1.60
Synlett 2014, 25, 209–212
© Georg Thieme Verlag Stuttgart · New York

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