Synthesis of the proposed structure of pentahydroxylated pyrrolizidine hyacinthacine C5 and Its C6,C7 epimer

Article abstract of DOI:10.1002/ejoc.201101126

The synthesis of two pentahydroxylated pyrrolizidines, hyacinthacine C ₅ (1) and 6,7-di-epi-hyacinthacine C₅ (12), from an orthogonally protected pyrrolidine of 2,5-dideoxy-2,5-imino-D-mannitol configuration (i.e., 7) is described. T

Full text of DOI:10.1002/ejoc.201101126

FULL PAPER
DOI: 10.1002/ejoc.201101126
Synthesis of the Proposed Structure of Pentahydroxylated Pyrrolizidine
Hyacinthacine C5 and Its C6,C7 Epimer
Juan A. Tamayo,*[a] Francisco Franco,*[a] and Fernando Sánchez-Cantalejo[a]
Keywords: Azasugars / Hyacinthacines / Enantioselectivity / Synthetic methods / Inhibitors
The synthesis of two pentahydroxylated pyrrolizidines, hya- pounds. On this respect, additional studies on chemical de-
cinthacine C5 (1) and 6,7-di-epi-hyacinthacine C5 (12), from
rivatives of synthetic 1 support our initially proposed struc-
an orthogonally protected pyrrolidine of 2,5-dideoxy-2,5-
ture and establish the absolute configuration of putative (+)-
imino-D-mannitol configuration (i.e., 7) is described. The an- hyacinthacine C5 as that shown in 1. These studies lead us
alytical and spectroscopic data of synthetic 1 present some
differences with those of natural hyacinthacine C5 that ex-
ceed the previously observed variations in similar com-
to conclude that the natural compound originally labeled as
(+)-hyacinthacine C5 might be a different isomer.
Introduction
Hyacinthacine C5 (1) was first isolated by Kato et al.[1]
in 2007 from the bulbs of Scilla Socialis and has shown
moderate inhibitory activity against rat intestinal maltase,
Caldocellum saccharolyticum β-glucosidase, and Aspergillus
niger amiloglucosidase with an IC50 value of 77, 48, and
57 μm, respectively. This natural compound belongs to one
of the five structural classes utilized to classify imi-
nosugars:[2] polyhydroxylated pyrrolizidines. Hyacinthac-
ines C, a subclass of this group, present the characteristic
five hydroxy groups along their bicyclic ring, one of them
being a hydroxymethyl group adjacent to the ring nitrogen
at C-3 (Figure 1). Not many hyacinthacines C have been de-
scribed to date,[1,3] and only six compounds presenting a
substitution pattern similar to that of hyacinthacine C5 (1)
and hyacinthacine C1 (2) have been published, including a
very recent synthesis of proposed 1.[1,3a,3b,3d–3f] Recently, we
described the synthesis of two pentahydroxylated pyrrolizi-
dines (compounds 4 and 5), which are epimers of hya-
cinthacine C1, by using suitably protected α,β-unsaturated
ketone 6 as the starting material.[3a] This ketone was in turn
obtained from a 2,5-dideoxy-2,5-imino-d-altritol (DALDP)
derivative.[4] In our synthesis, a highly stereoselective bis-
hydroxylation of ketone 6 was the key step to achieve highly
functionalized hyacinthacine C1 epimers 4 and 5.
Figure 1. Some examples of hyacinthacine C1 and C5-type alkaloids
1–5.
Related to this work, and as part of our studies con-
cerned with the synthesis of polyhydroxylated pyrrolizidines
alkaloids (PHPAs),[3a,5] we decided to approach the synthe-
sis of hyacinthacine C5 (1). In this case, an orthogonally
protected pyrrolidine of DMDP (2,5-dideoxy-2,5-imino-d-
mannitol) configuration (i.e., 7),[5e,6] previously used by our
group for the synthesis of (+)-casuarine (8),[5e] was the in-
termediate chosen as the starting material. Orthogonally
[a] Department of Medicinal and Organic Chemistry,
Faculty of Pharmacy, University of Granada,
Campus de Cartuja s/n, 18071 Granada, Spain
Fax: +34-958-243845
E-mail: jtamayo@ugr.es
ffranco@ugr.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101126.
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Synthesis of Hyacinthacine C5 and Its C6,C7 Epimer
protected α,β-unsaturated ketone 9, derived from 7, would work of Yu, that the natural compound initially labeled as
be a desirable intermediate that, when subjected to dihy- (+)-hyacinthacine C5 is in fact a different isomer.
droxylation, could led us to pentahydroxylated pyrrolidines
10 and 11, which are precursors of the desired hyacinthac-
Results and Discussion
ine C5-type bicyclic ring when subjected to the appropriate
chemical transformations (Scheme 1). In this article, we re-
port on the synthesis of putative (+)-hyacinthacine C5 (1)
and (+)-6,7-di-epi-hyacinthacine C5 (12) by using the or-
thogonally protected pyrrolidine of DMDP configuration
(i.e., 7) as the starting chiral building block. Following the
synthesis of putative hyacinthacine C5 (1) and 6,7-di-epi-
hyacinthacine C5 (12), we describe an exhaustive structural
study by NMR spectroscopic analysis of final compound 1
and its hydrochloride salt, as well as some of its chemical
precursors and derivatives. Analytical and spectroscopic
data for synthetic 1 and its hydrochloride salt, however, did
not match those reported by Kato for the natural product,[1]
but did however match those reported by Yu in a recent
synthesis of ent-1.[3a] Moreover, NOE studies on synthetic
1 and 1·HCl together with those of the chemical precursors
of synthetic 1 prompt us to conclude, together with the
According to the retrosynthetic analysis shown in
Scheme 1, the synthesis started with previously described
pyrrolidine 7.[5e,6] Oxidation of the free OH group in 7 pro-
duced aldehyde 13,[5e] which was treated in situ with 1-tri-
phenylphosphoranylidene-2-propanone to afford key inter-
mediate α,β-unsaturated ketone 9 (Scheme 2). Dihydrox-
ylation of 9 with aqueous 1% OsO4 yielded diol intermedi-
ates 10/11 as a 1.4:1 mixture[7] that was easily separated by
flash chromatography. The configurations of the two new
generated stereogenic centers were not established at this
point but later in the synthesis, because their 1H NMR
spectra appeared as an irresolvable mixture of rotamers.
Catalytic hydrogenation of 10 and 11 in the presence of Pd/
C yielded pyrrolizidines 14 and 15, respectively, as the only
isomers (Scheme 3). The absolute configurations of 14 and
15 were established on the basis of spectroscopic analysis
carried out on their corresponding O-desilylation deriva-
tives 16 and 17, respectively (Scheme 3). Their proposed
structures were confirmed by NOE experiments, which
showed positive interactions between 1-H–7-H, 6-H–7a-H,
6-H–Me, 1-H–5-H, and 5-H–7-H in 16 and between 1-H–
3-H, 1-H–5-H, 5-H–6-H, and 7-H–7a-H in 17 (Figure 2).
Scheme 2. Synthesis of pyrrolidines 10 and 11.
In this sense, it is worth noting the stereoselectivity ob-
served in the hydrogenation reactions of 10 and 11. As sug-
gested by Scheme 3, initial N-Cbz removal affords interme-
diates A and AЈ, which upon intramolecular reductive
amination form intermediate bicyclic iminium ions B and
BЈ. Highly stereoselective hydrogenation of such intermedi-
ates through the α-face yields pyrrolizidines 14 and 15,
which both present the S configuration at C-5 (Figure 3).
According to this description, the stereochemistry at C-6
remains unaffected during the reaction, and consequently
pyrrolizidine 14 shows a trans disposition between the OH
group at C-6 and the Me group at C-5, and pyrrolizidine
15 adopts a cis disposition. These experimental facts
Scheme 1. Previous synthesis of (+)-casuarine (8) from DMDP pre-
cursor 7 and retrosynthetic analysis of hyacinthacine C5 (1) and
6,7-di-epi-C5 (12).
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J. A. Tamayo, F. Franco, F. Sánchez-Cantalejo
FULL PAPER
prompt us to state that iminium intermediates B and BЈ are
the chemical species subjected to hydrogenation and there-
fore to conclude that α,β-dihydroxylated ketone 10 is the
precursor of 14 having the 1ЈS,2ЈR configuration, whereas
11, with a 1ЈR,2ЈS configuration, is the precursor of 15.
To finish the synthesis, the transformation of 16 and 17
into target molecules 1 and 12 was achieved by O-debenz-
ylation to proposed hyacinthacine C5 (1) and 6,7-di-epi-hya-
cinthacine C5 (12, Scheme 3).
The analytical and spectroscopic data of compounds 1
and 12 were established by careful studies and confirmed
by extensive 1H, 13C, and NOE NMR experiments. As pre-
viously described by different authors,[8] analytical and
spectroscopic data of synthetic alkaloids can vary with
those of natural compounds. Metal ions, ionic strength of
the solvent, pH, and purification methodology can be re-
sponsible for these differences, especially in their NMR
chemical shift values.
In our case, the analytical and spectroscopic data of syn-
thetic 1 and 1·HCl are inconsistent with those data de-
1
scribed for natural hyacinthacine C5. H and 13C NMR ex-
periments carried out on synthetic 1 and 1·HCl under the
same conditions as those described by Kato[1] [D2O and 3-
(trimethylsilyl)propionate (TSP) as an internal standard, see
the Supporting Information] do not match those reported
for hyacinthacine C5 (see Tables 1 and 2). Especially signifi-
cant are the 13C NMR spectroscopic data. In both com-
pounds, the chemical shifts of C-2 and C-8 appear upfield
with respect to those of natural hyacinthacine C5 (Table 2,
Table 1. 1H NMR spectroscopic data of synthetic 1, 1·HCl, and
natural 1 at 500 MHz in D2O.[a]
Scheme 3. Synthesis of pyrrolizidines 1 and 12 from pyrrolidines
10 and 11 respectively.
Entry
Proton
1·HCl
Synthetic 1
Natural 1
1
2
3
4
5
6
7
8
9
1-H
2-H
3-H
5-H
6-H
7-H
7a-H
8-H
8Ј-H
4.42
4.15
3.73
3.64
3.93–3.96
4.38
3.82–3.86
3.93–3.96
3.82–3.86
4.19
3.99
2.97–2.93
2.97–2.93
3.72–3.66
4.15
3.08
3.72–3.66
3.72–3.66
4.01
3.80
3.01
2.81
3.60
3.99
3.24
3.50
3.55
[a] Chemical shifts are expressed in ppm downfield from sodium
TSP.
Figure 2. Main NOE interactions in 16 and 17.
Table 2. 13C NMR spectroscopic data of synthetic 1, 1·HCl, and
natural 1 at 125 MHz in D2O.[a]
Entry Carbon 1·HCl
(x)
Synthetic 1
(y)
Natural 1
(z)
(x – z)
(y – z)
1
2
3
4
5
6
7
8
9
C-1
C-2
C-3
C-5
C-6
C-7
C-7a
C-8
C-9
80.0
79.1
76.6
71.1
82.5
79.5
76.1
60.9
17.0
+1.8
–1.9
79.6
78.7
65.3
70.4
82.3
79.0
70.5
62.2
17.2
+1.4
–2.3
+0.2
+9
+0.6
+1.2
+1.3
–3.5
+1.5
78.2
81.0
65.1
61.4
81.7
77.8
69.2
65.7
15.7
+11.5
+9.7
+0.8
+1.7
+6.9
–4.8
+1.3
Figure 3. Proposed iminium intermediates B and BЈ in the catalytic
hydrogenation of 10 and 11.
[a] Chemical shifts are expressed in ppm downfield from sodium
TSP.
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Synthesis of Hyacinthacine C5 and Its C6,C7 Epimer
Entries 2 and 8), whereas the rest of the carbon atoms are data of compounds 1 and 12 were established by extensive
moved downfield. In addition, C-5 in synthetic 1 and 1·HCl 1H, 13C, and NOE NMR experiments. Some differences ex-
shows a 9 and 9.7 ppm downfield shift, respectively, to that ist between the analytical and spectroscopic data of natural
of C-5 in natural hyacinthacine C5 (Table 2, Entry 4), hyacinthacine C5 (1) and synthetic 1, which, although to a
whereas the shift for the rest of the carbon atoms ranges certain point expected, exceed the previously observed vari-
from 0.2 to 6.9 ppm (see Table 2). As explained above, cer- ations in similar compounds.[8] On this respect, additional
tain shifts can be expected between synthetic and natural studies on chemical derivatives of synthetic 1 support the
alkaloids; still, those differences vary evenly for all the sig- initially proposed structure and establish the absolute con-
nals, which is not the case here. Also significant are the figuration of putative hyacinthacine C5 as that of structure
specific rotation values of both synthetic 1 {[α]3D0 = +8 (c = 1. These results, together with those recently published by
1, H2O)} and 1·HCl {[α]2D8 = +18 (c = 1, H2O)}, which in Yu, lead us to conclude that the natural compound initially
concordance with the NMR results do not match those re- labeled as (+)-hyacinthacine C5 might be a different isomer.
ported for natural 1 {ref.[1] [α]D = +1.5 (c = 0.22, H2O)}.
These results prompted us to consider that the com-
pound initially assigned as hyacinthacine C5 could be a dif-
ferent isomer. To support this conclusion we decided to
carry out additional experiments. In this sense, pyrrolizid-
ines 14 and 16, chemical precursors of synthetic 1, and syn-
thetic 1 itself were acetylated to 18, 19, and peracetylated
20, respectively (Scheme 4). NOE studies on these com-
Experimental Section
General Remarks: Solutions were dried with MgSO4 before concen-
tration under reduced pressure. The 1H and 13C NMR spectra were
recorded with Varian Direct Drive 400 and 500 MHz spectrometers
for solutions in CDCl3 (internal Me4Si). Splitting patterns are des-
ignated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
pounds showed positive interactions between 1-H–7-H, 1-
H–5-H, and 5-H–7-H in all three derivatives 18, 19, and
20.[9] These results definitely support the stereochemistry
initially assigned by us to synthetic 1 confirming its struc-
ture as the one depicted in Scheme 3 and proving that the
natural compound originally described as (+)-hyacinthac-
ine C5 is in fact a different isomer.[3a]
multiplet, and br., broad. IR spectra were recorded with a Perkin–
Elmer FTIR Spectrum One instrument, and mass spectra were re-
corded with a Hewlett–Packard HP-5988-A and Fisons mod. Plat-
form II and VG Autospec-Q mass spectrometers or a NALDI ion-
ization–time-of-flight (NALDI-TOF) mass spectrometer and EI
mass spectrometer. Optical rotations were measured for solutions
in CHCl3 (1-dm tube) with a Jasco DIP-370 polarimeter. TLC was
performed on precoated silica gel 60 F254 aluminum sheets and
detection by employing a mixture of 10% ammonium molybdate
(w/v) in 10% aqueous sulfuric acid containing 0.8% cerium sulfate
(w/v) and heating. Column chromatography was performed on sil-
ica gel (Merck, 7734). All compounds were shown to be homogen-
eous by chromatographic methods and characterized by NMR
spectroscopy and MS and HRMS.
(E)-4-[(2ЈR,3ЈR,4ЈR,5ЈR)-3Ј,4Ј-Dibenzyloxy-N-benzyloxycarbonyl-
5Ј-tert-butyldiphenylsilyloximethylpyrrolidin-2Ј-yl]but-3-en-2-one
(9): To a solution of 7 (1.01 g, 1.4 mmol) in dry DCM (15 mL)
was added activated powdered 4 Å molecular sieves (200 mg), N-
methylmorpholine N-oxide (250 mg, 2.1 mmol), and tetraprop-
ylammonium perruthenate (TPAP, 100 mg), and the reaction mix-
ture was kept at room temperature for 1 h. TLC (Et2O/hexane, 3:2)
then showed a faster-running compound. The reaction was diluted
with Et2O (30 mL), filtered through a bed of Silica gel 60 (230–
400 mesh), and thoroughly washed with Et2O. The combined fil-
trate and washings were concentrated to aldehyde 13 (955 mg,
95%), which was used in the next step. IR (KBr, neat): ν = 3063
˜
and 3029 (Ph), 1735 (CHO), 1724 (C=O, Cbz) cm–1. A solution
of 13 (955 mg, 1.34 mmol) and 1-(triphenylphosphoranylidene)-2-
propanone (1.35 g, 4.2 mmol) in dry toluene (15 mL) was heated
at reflux for 24 h. TLC then showed a slower-running compound.
The solvent was eliminated, and the residue was submitted to col-
umn chromatography (Et2O/hexane, 3:2) to afford syrup 9 (870 mg,
Scheme 4. Synthesis of acetylated derivatives 18, 19, and 20.
86%, from 7). [α]3D0 = +8, [α]30 +7 (c = 1, CHCl ). IR (neat): ν =
˜
405
3
3032 and 2930 (Ph), 1704 and 1677 (C=O) cm–1
.
1H NMR
Conclusions
(400 MHz, CDCl3): δ = 7.73–7.12 (2 m, 25 H, 5Ph), 6.69 (ddd, J3,4
= 16.1 Hz, J4,5Ј = 7.7 Hz, 1 H, 4-H, two rotamers), 6.04 (2 d, 1 H,
3-H, two rotamers), 5.22–4.87 (4 d, J = 12.1 Hz, 2 H, CH2Ph, two
rotamers), 4.74–3.72 (br. m, 10 H, 2 CH2Ph, 2Ј,3Ј,4Ј,5Ј,2ЈЈa,2ЈЈb-
H,), 2.19 and 2.01 (2 s, 3 H, 1,1,1-H, two rotamers), 1.11 and 1.06
(2 s, 9 H, CMe3, two rotamers) ppm. 13C (125 MHz, CDCl3): δ =
We describe herein the synthesis of two pentahydroxyl-
ated pyrrolizidines, putative hyacinthacine C5 (1) and 6,7-
di-epi-hyacinthacine C5 (12), from an orthogonally pro-
tected pyrrolidine of DMDP configuration (i.e., 7) as start-
ing chiral building block. The analytical and spectroscopic 198.2 (C-2), 154.5 (Cbz), 145.2, 144.9, 137.5, 135.5, 133.3, 131.4,
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J. A. Tamayo, F. Franco, F. Sánchez-Cantalejo
FULL PAPER
129.7, 127.9, 86.4, and 85.5 (C-3Ј, two rotamers), 82.4 and 81.4 (C- (Me), 19.2 (CMe3) ppm. HRMS (NALDI-TOF): calcd. for
4Ј, two rotamers), 71.8, 71.7, 71.4 and 71.2 (2 CH2Ph, two rota-
mers), 67.3, 67.1 (Cbz, two rotamers), 65.4 and 65.4 (C-2Ј, two
rotamers), 65.1 (C-5Ј), 62.1 and 61.4 (C-5ЈЈ, two rotamers), 27.0,
26.9 (CMe3, two rotamers), 19.4 and 19.2 (Me, two rotamers) ppm.
HRMS (NALDI-TOF): calcd. for C47H51NO6NaSi [M + H]+
776.3383; found 776.3381 (deviation +0.3 ppm).
C39H48NO5Si [M + H]+ 638.3302; found 638.3307 (deviation
+0.5 ppm).
(1R,2R,3R,5S,6S,7S,7aR)-1,2-Dibenzyloxy-6,7-dihydroxy-3-
hydroxymethyl-5-methylpyrrolizidine (16): To a stirred solution of
14 (51 mg, 0.08 mmol) in THF (2.5 mL) was added TBAF·3H2O
(76 mg, 0.24 mmol). The mixture was kept at 50 °C for 16 h. TLC
(AcOEt/H3CCN/MeOH/H2O, 70:10:10:5) then showed a new
slower-running compound. The reaction mixture was evaporated
and subjected to chromatography (AcOEt/H3CCN/MeOH/H2O,
95:10:4:2) to afford pure 16 (30 mg, 94%). [α]2D8 = –14 (c = 1,
(2R,3R,4R,5R)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-2-tert-
butyldiphenylsilyloxymethyl-5-[(1ЈS,2ЈR)-1Ј-2Ј-dihydroxy-3Ј-oxo-
butyl]pyrrolidine (10) and (2R,3R,4R,5R)-3,4-Dibenzyloxy-N-benz-
yloxycarbonyl-2-tert-butyldiphenylsilyloxymethyl-5-[(1ЈR,2ЈS)-1Ј-2Ј-
dihydroxy-3Ј-oxobutyl]pyrrolidine (11): To a stirred solution of 9
(855 mg, 1.13 mmol) in acetone/water (8:1, 13.5 mL) was added
NMO (332 mg, 2.83 mmol) and aqueous 1% OsO4 (2.5 mL). The
mixture was left at room temperature for 20 h. TLC (Et2O/hexane,
3:2) then revealed the presence of two new products of lower mo-
bility. The mixture was concentrated to a residue that was submit-
ted to chromatography (Et2O/hexane, 1:1) to afford first 10 as a
CHCl ). IR (neat): ν = 3368 (OH) cm–1 1H NMR (400 MHz,
.
˜
3
CDCl3): δ = 7.37–7.23 (m, 10 H, 2 Ph), 4.63 and 4.60 (2 d, J =
3.1 Hz, 2 H, CH2Ph), 4.52 and 4.47 (2 d, J = 11.8 Hz, 2 H, CH2Ph),
4.10 (t, J1,7a = J1,2 = 3.7 Hz, 1 H, 1-H), 4.00 (t, J6,7 = J7,7a
=
7.55 Hz, 1 H, 7-H), 3.96 (t, J2,3 = 3.7 Hz, 1 H, 2-H), 3.86 (br. s, 1
H, OH), 3.73 (t, J5,6 = 7.55 Hz, 1 H, 6-H), 3.59–3.43 (m, 3 H,
7a,8,8Ј-H), 3.19 (m, 1 H, 3- H), 2.96 (m, 1 H, 5-H), 1.21 (d, JMe,5
= 6.22 Hz, 3 H, Me) ppm. 13C NMR (125 MHz, CDCl3): δ = 131.2,
131.2, 130.6, 130.5, 130.5, 130.3 (Ph), 89.4 (C-1), 87.9 (C-2), 85.2
(C-6), 82.7 (C-7), 74.9 (CH2Ph), 74.6 (C-7a), 74.5 (CH2Ph), 73.7
(C-3), 67.5 (C-5), 63.3 (C-8), 20.9 (Me) ppm. HRMS (NALDI-
TOF): calcd. for C23H30NO5 [M + H]+ 400.2124; found 400.2115
(deviation –2.2 ppm).
syrup. Yield: 328 mg (37%). [α]2D4 = –25 (c = 1, CHCl3). IR (neat):
1
ν = 3435 (OH), 1702 and 1679 (C=O) cm–1. H NMR (500 MHz,
˜
CDCl3): δ = 7.73–7.07 (2 m, 25 H, 5Ph), 5.06–4.85 (m, 2 H,
CH2Ph), 4.69–4.02 (2 br. m, 11 H, 2CH2Ph, 3Ј,4Ј,5Ј,2ЈЈa,2ЈЈb,3,4-
H), 3.92 (dd, 1 H, OH, two rotamers), 3.82–3.66 (m, 1 H, 2Ј-H),
3.53 (dd, 1 H, OH, two rotamers), 2.25 and 1.79 (2 s, 3 H, 1,1,1-
H, two rotamers), 1.08 and 1.01 (2 s, 9 H, CMe3, two rotamers)
ppm. 13C NMR (125 MHz, CDCl3): δ = 208.1 (C-2), 155.4 (Cbz),
137.7, 136.7, 135.9, 135.5, 133.3, 129.8, 128.2, 127.8, 82.1 (C-3Ј),
81.3 (C-4Ј), 78.3 (C-3), 71.6 (C-4), 69.8 (C-2Ј), 68.0 (C-5Ј), 67.3,
65.2 and 61.8 (2CH2Ph and Cbz), 26.8 (CMe3), 25.9 (Me) and 19.2
(CMe3) ppm. HRMS (NALDI-TOF): calcd. for C47H54NO8Si [M
(1R,2R,3R,5S,6S,7S,7aR)-1,2,6,7-Tetrahydroxy-3-hydroxymethyl-
5-methylpyrrolizidine [(+)-hyacinthacine C5, 1]: Compound 16
(41 mg, 0.10 mmol) in MeOH (4.5 mL) and conc. HCl (four drops)
was hydrogenated (70 psi H2) in the presence of 10% Pd/C (16 mg)
for 27 h. The catalyst was filtered off, washed with MeOH, and the
combined filtrate and washings were treated with Amberlite IRA-
400 resin (OH– form). Evaporation of the solvent afforded pure 1
(16 mg, 73%) as a colorless viscous syrup. [α]2D8 = +8 (c = 1, H2O).
+ H]+ 788.3619; found 788.3607 (deviation –1.5 ppm). Eluted sec-
27
ond was 11 (246 mg, 28%) as a syrup. [α]2D6 = –5, [α] = –6 (c 1,
546
CHCl ). IR (neat): ν = 3389 (OH), 1721 and 1672 (C=O) cm–1. 1H
˜
3
IR (neat): ν = 3363 (OH) cm–1. 1H NMR (500 MHz, D2O): δ =
˜
NMR (400 MHz, CDCl3): δ = 7.61–7.12 (2 m, 25 H, 5Ph), 5.00
(m, 2 H, CH2Ph), 4.63 (m, 2 H, CH2Ph), 4.50 (m, 2 H, 3,4-H), 4.40
(m, 2 H, CH2Ph), 4.17 (m, 3 H, 2ЈЈa,2ЈЈb,3Ј-H), 4.04 (m, 1 H, 2Ј-
H), 3.78 (m, 2 H, 4Ј,5Ј-H), 2.01 (s, 3 H, Me), 1.04 (s, 9 H, CMe3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 207.0 (C-2), 157.9 (Cbz),
137.6, 137.5, 135.6, 135.4, 133.4, 133.3, 129.8, 128.5, 127.7, 82.6
(C-3Ј), 81.7 (C-4Ј), 78.4 (C-3), 74.6 (C-4), 71.5 and 71.1 (C-2Ј, two
rotamers), 67.8 (C-5Ј), 67.6, 65.2 and 61.7 (2 CH2Ph, Cbz), 26.8
(CMe3), 25.0 (Me) and 19.2 (CMe3) ppm. HRMS (NALDI-TOF):
calcd. for C47H54NO8Si [M + H]+ 788.3619; found 788.3616 (devia-
tion –0.4).
4.19 (t, J1,2 = J1,7a = 6.9 Hz, 1 H, 1-H), 4.15 (t, J6,7 = J7,7a = 6.9 Hz,
1 H, 7-H), 3.99 (t, J2,3 = 6.9 Hz, 1 H, 2-H), 3.72–3.66 (m, 3 H,
6,8,8-H), 3.08 (t, 1 H, 7a-H), 2.97–2.93 (m, 2 H, 3,5-H), 1.24 (d,
JMe,5 = 6.3 Hz, 3 H, Me) ppm. 13C NMR (125 MHz, D2O): δ =
82.3 (C-6), 79.6 (C-1), 79.0 (C-7), 78.7 (C-2), 70.5 (C-7a), 70.4 (C-
5), 65.3 (C-3), 62.2 (C-8), 17.2 (Me) ppm. HRMS (NALDI-TOF):
calcd. for C9H18NO5 [M + H]+ 220.1185; found 220.1182 (devia-
tion –1.4 ppm).
(1R,2R,3R,5S,6S,7S,7aR)-1,2,6,7-Tetrahydroxy-3-hydroxymethyl-
5-methylpyrrolizidine Hydrochloride [1·HCl]: Conc. HCl (three
drops) was added to a solution of 1 (16 mg, 0.073 mmol) in H2O
(4 mL). Evaporation of the solvent afforded 1·HCl (18 mg, quanti-
(1R,2R,3R,5S,6S,7S,7aR)-1,2-Dibenzyloxy-3-tert-butyldiphenyl-
silyloxymethyl-6,7-dihydroxy-5-methylpyrrolizidine (14): Com-
pound 10 (230 mg, 0.29 mmol) in MeOH (4 mL) was hydrogenated
(60 psi H2) in the presence of 10% Pd/C (35 mg) overnight. TLC
(AcOEt/hexane, 3:1) then showed a slower-running compound. The
catalyst was filtered off, washed with MeOH, and the combined
filtrate and washings were concentrated to a residue that was sub-
mitted to chromatography (AcOEt/hexane, 1:1) to afford pure 14
(121 mg, 65%) as a colorless viscous syrup. [α]2D5 = –5 (c = 1,
1
tative). [α]2D8 = +18 (c = 1, H2O). H NMR (500 MHz, D2O): δ =
4.42 (t, J1,2 = J1,7a = 5.1 Hz, 1 H, 1-H), 4.38 (t, J6,7 = J7,7a = 6.6 Hz,
1 H, 7-H), 4.15 (t, J2,3 = 5.2 Hz, 1 H, 2-H), 3.96–3.93 (m, 2 H, 6,8-
H), 3.86–3.82 (m, 2 H, 7a,8Ј-H), 3.73 (m, 1 H, 3-H), 3.64 (quint.,
J5,6 = 6.9 Hz, 1 H, 5-H), 1.50 (d, JMe,5 = 6.8 Hz, 3 H, Me) ppm.
13C NMR (125 MHz, D2O): δ = 82.5 (C-6), 80.0 (C-1), 79.5 (C-7),
79.1 (C-2), 76.6 (C-3), 76.1 (C-7a), 71.1 (C-5), 60.9 (C-8), 17.0 (Me)
ppm.
CHCl ). IR (neat): ν = 3368 (OH) cm–1 1H NMR (400 MHz,
.
˜
3
CDCl3): δ = 7.70–7.22 (2 m, 20 H, 4Ph), 4.52 (2 d, 4 H, 2CH2Ph),
4.23 (t, J1,2 = J2,3 = 2.3 Hz, 1 H, 2-H), 4.13–4.07 (m, 1 H, 1-H),
3.99 (t, J6,7 = J7,7a = 7.5 Hz, 1 H, 7-H), 3.72–3.56 (m, 3 H, 6,8,8Ј-
(1R,2R,3R,5S,6R,7R,7aR)-1,2-Dibenzyloxy-3-tert-butyldiphenyl-
silyloxymethyl-6,7-dihydroxy-5-methylpyrrolizidine (15): Com-
pound 11 (200 mg, 0.25 mmol) in MeOH (3.5 mL) was hydroge-
H), 3.40 (m, 1 H, 7a-H), 3.18 (m, 1 H, 3-H), 2.95 (m, 1 H, 5-H), nated (60 psi H2) in the presence of 10% Pd/C (40 mg) overnight.
1.08 (d, JMe,5 = 6.2 Hz, 3 H, Me), 1.04 (s, 9 H, CMe3) ppm. 13C TLC (AcOEt/hexane, 3:1) then showed a slower-running com-
NMR (125 MHz, CDCl3): δ = 138.0, 135.6, 135.6, 133.6, 133.5,
129.6, 129.6, 128.4, 128.4, 127.7, 127.6, 127.6, 127.5, 87.1 (C-1),
86.0 (C-2), 83.0 (C-6), 80.1 (C-7), 72.8 (C-7a), 71.6 (CH2Ph), 71.5
pound. The catalyst was filtered off, washed with MeOH, and the
combined filtrate and washings were concentrated to a residue that
was submitted to chromatography (AcOEt/hexane, 3:2) to afford
(CH2Ph), 71.3 (C-3), 65.2 (C-5), 65.1 (C-8), 26.9 (CMe3), 19.2 pure 15 (91 mg, 56%) as a colorless viscous syrup. [α]2D5 = +14 (c
7186
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7182–7188

Synthesis of Hyacinthacine C5 and Its C6,C7 Epimer
= 1, CHCl ). IR (neat): ν = 3459 (OH) cm–1. 1H NMR (400 MHz): (400 MHz, CDCl3): δ = 7.67–7.62 and 7.40–7.22 (2 m, 20 H, 4 Ph),
˜
3
δ = 7.70–7.24 (2 m, 20 H, 4 Ph), 4.58 and 4.56 (2 d, J = 12.0 Hz,
2 H, CH2Ph), 4.50 (t, J = 12.0 Hz, 2 H, CH2Ph), 4.36 (m, 1 H, 2- 5.9 Hz, 1 H, 6-H), 4.59–4.46 (m, 4 H, 2CH2Ph), 4.23 (br. t, J1,2
5.29 (dd, J6,7 = 6.7 Hz, J7,7a = 5.6 Hz, 1 H, 7-H), 4.97 (dd, J5,6
=
=
H), 4.28 (m, 1 H, 1-H), 4.01 (m, 1 H, 7-H), 3.97 (m, 1 H, 7a-H),
3.86 (m, 1 H, 6-H), 3.76 (t, J = 10.0 Hz, 1 H, 8-H), 3.61 (m, 1 H,
8Ј-H), 3.41 (d, 1 H, OH), 3.19 (m, 1 H, 3-H), 3.13 (m, 1 H, 5-H),
J1,7a = 3.3 Hz, 1 H, 1 H, 1-H), 4.12 (br. t, J2,3 = 3.0 Hz, 1 H, 2-
H), 3.68 (dd, J8,8Ј = 9.9 Hz, J3,8 = 7.7 Hz, 1 H, 8-H), 3.58 (dd, J3,8Ј
= 6.3 Hz, 1 H, 8Ј-H), 3.45 (dd, 1 H, 7a-H), 3.24 (quint., J5,9
=
1.06 (s, 9 H, CMe3), 1.01 (d, JMe,5 = 6.5 Hz, 3 H, Me) ppm. 13C 5.9 Hz, 1 H, 5-H), 3.19 (m, 1 H, 3-H), 2.04 and 1.99 (2 s, 6 H,
NMR (125 MHz): δ = 140.5, 139.5, 138.2, 136.4, 136.2, 132.3, 2Ac), 1.04 (d, JMe,5 = 6.1 Hz, 3 H, Me), 1.03 (s, 9 H, CMe3) ppm.
132.2, 131.3, 131.1, 130.8, 130.5, 130.3, 130.3, 130.2, 87.7 (C-2),
85.1 (C-1), 83.8 (C-6), 79.7 (C-7), 75.8 (C-7a), 74.5 and 74.5 (2 140.6, 138.3, 131.0, 130.3, 130.2 (Ph), 89.7 (C-1), 88.6 (C-2), 84.6
13C NMR (125 MHz, CDCl3): δ = 173.2 and 173.0 (C=O), 140.8,
CH2Ph), 73.4 (C-3), 67.9 (C-8), 65.5 (C-5), 29.5 (CMe3), 21.9 (Me),
17.6 (CMe3) ppm. HRMS (NALDI-TOF): calcd. for C39H48NO5Si
[M + H]+ 638.3302; found 638.3311 (deviation +1.4 ppm).
(C-6), 82.1 (C-7), 74.8 (C-7a), 74.5 (CH2Ph), 74.4 (CH2Ph), 73.3
(C-3), 68.2 (C-8), 66.4 (C-5), 29.5 (CMe3), 23.6 (2 CH3CO), 22.0
(Me), 21.9 (CMe3) ppm. HRMS (NALDI-TOF): calcd. for
C
43H52NO7Si [M + H]+ 722.3505; found 722.3513 (deviation
(1R,2R,3R,5S,6R,7R,7aR)-1,2-Dibenzyloxy-6,7-dihydroxy-3-
hydroxymethyl-5-methylpyrrolizidine (17): To a stirred solution of
15 (86 mg, 0.13 mmol) in THF (3 mL) was added TBAF·3H2O
(106 mg, 0.34 mmol). The mixture was kept at 55 °C for 4 h. TLC
(AcOEt/MeCN/MeOH/H2O, 70:10:5:5) then showed a new slower-
running compound. The reaction mixture was evaporated and sub-
jected to chromatography (AcOEt/MeCN/MeOH/H2O, 70:10:5:5)
to afford pure 17 as a syrup (41 mg, 76%). [α]2D8 = +39 (c = 1,
+1.1 ppm).
(1R,2R,3R,5S,6S,7S,7aS)-6,7-Di-O-acetyl-3-acetyloxymethyl-1,2-di-
benzyloxy-6,7-dihydroxy-5-methylpyrrolizidine (19): Compound 16
(46 mg, 0.115 mmol) was acetylated in dry pyridine (2 mL), acetic
anhydride (87 μL, 0.92 mmol), and DMAP (cat.) at room tempera-
ture for 1 h. TLC (AcOEt/hexane, 2:1) then showed a faster-run-
ning compound. The reaction mixture was supported on silica gel
and chromatographed (AcOEt/hexane, 1:3) to afford pure 19
(31 mg, 51%) as a colorless viscous syrup. [α]2D7 = +2 (c = 1,
CHCl ). IR (neat): ν = 3391 (OH) cm–1 1H NMR (400 MHz,
.
˜
3
CDCl3): δ = 7.39–7.22 (m, 10 H, 2 Ph), 4.73 and 4.62 (2 d, J =
11.8 Hz, 2 H, CH2Ph), 4.58 and 4.52 (2 d, J = 11.5 Hz, 2 H,
CH2Ph), 4.45 (t, J1,2 = J1,7a = 5.9 Hz, 1 H, 1-H), 4.15 (m, 1 H, 2-
H), 4.00 (m, 1 H, 7-H), 3.94 (m, 1 H, 6-H), 3.71 (t, J7,7a = 5.9 Hz,
1 H, 7a-H), 3.65 (dd, J3,8 = 3.9 Hz, J8,8Ј = 11.4 Hz, 1 H, 8-H), 3.56
(dd, J3,8Ј = 4.1 Hz, 1 H, 8Ј-H), 3.20 (m, 1 H, 5-H), 2.99 (m, 1 H,
3-H), 1.19 (d, JMe,5 = 6.7 Hz, 3 H, Me) ppm. 13C (125 MHz,
CDCl3): δ = 138.2, 127.9, 127.6, 127.5, 127.3, 127.2 (Ph), 84.8 (C-
2), 80.7 (C-6), 80.4 (C-1), 75.9 (C-7), 72.2 (CH2Ph), 71.8 (CH2Ph),
71.1 (C-7a), 70.6 (C-3), 63.4 (C-5), 60.3 (C-8), 13.4 (Me) ppm.
HRMS (NALDI-TOF): calcd. for C23H30NO5 [M + H]+ 400.2124;
found 400.2116 (deviation –0.8 ppm).
CHCl ). IR (neat): ν = 1742 (C=O) cm–1. 1H NMR (400 MHz,
˜
3
CDCl3): δ = 7.35–7.29 (m, 10 H, 2 Ph), 5.29 (t, J6,7 = J7,7a = 5.9 Hz,
1 H, 7-H), 5.02 (t, J5,6 = 6.1 Hz, 1 H, 6-H), 4.61 and 4.51 (2 d, J
= 11.9 Hz, 2 H, CH2Ph) 4.55 and 4.47 (2 d, J = 11.8 Hz, 2 H,
CH2Ph), 4.23 (t, J1,2 = J1,7a = 3.5 Hz, 1 H, 1-H), 4.02 (m, 2 H,
8,8Ј-H), 3.91 (t, J2,3 = 3.3 Hz, 1 H, 2-H), 3.53 (br. dd, 1 H, 7a-H),
3.28 (m, 1 H, 3-H), 3.20 (quint., 1 H, 5-H), 2.05, 2.01 and 2.00 (3
s, 9 H, 3Ac), 1.13 (d, JMe,5 = 6.1 Hz, 3 H, Me) ppm. 13C NMR
(150 MHz, CDCl3): δ = 173.4, 173.2 and 172.9 (C=O), 140.4,
131.10, 131.08, 130.5, 130.4, 130.3 (Ph), 88.8 (C-1), 88.2 (C-2), 84.2
(C-6), 81.8 (C-7), 74.66 (CH2Ph), 74.55 (C-7a), 74.51 (CH2Ph), 70.5
(C-3), 67.9 (C-8), 66.5 (C-5), 23.62 and 23.60 (2 CH3CO), 22.0 (Me)
ppm. HRMS (NALDI-TOF): calcd. for C29H36NO8 [M + H]+
526.2441; found 526.2417 (deviation –4.6 ppm).
(1R,2R,3R,5S,6R,7R,7aR)-1,2,6,7-Tetrahydroxy-3-hydroxymethyl-
5-methylpyrrolizidine [(+)-6,7-Di-epi-hyacinthacine C5, 12]: Com-
pound 17 (44 mg, 0.11 mmol) in MeOH (4 mL) and conc. HCl
(four drops) was hydrogenated (70 psi H2) in the presence of 10%
Pd/C (20 mg) for 20 h. The catalyst was filtered off, washed with
MeOH, and the combined filtrate and washings were treated with
Amberlite IRA-400 resin (OH– form). Evaporation of the solvent
(1R,2R,3R,5S,6S,7S,7aS)-1,2,6,7-Tetra-O-acetyl-3-acetyloxy-
methyl-1,2,6,7-tetrahydroxy-5-methylpyrrolizidine (20): Compound
1 (40 mg, 0.812 mmol) was acetylated in dry pyridine (3 mL), acetic
anhydride (258 μL, 2.74 mmol), and DMAP (cat.) at room tem-
perature for 1.5 h. TLC (AcOEt/hexane, 2:1) then showed a faster-
running compound. The solvent was evaporated, and the residue
was supported on silica gel and chromatographed (AcOEt/hexane,
afforded pure 12 (24 mg, 99%) as a colorless viscous syrup. [α]3D0
=
˜
=
+8 (c = 1, H2O) {ref.[1] [α]D = +1.5 (c = 0.22, H O)}. IR (neat): ν
2
1
= 3363 (OH) cm–1. H NMR (500 MHz, D2O): δ = 4.31 (t, J1,2
J1,7a = 7.5 Hz, 1 H, 1-H), 4.24 (m, 1 H, 7-H), 4.15 (m, 1 H, 6-H),
3.99 (br. t, J2,3 = 7.5 Hz, 1 H, 2-H), 3.80 (br. dd, J3,8 = 4.0 Hz, J8,8Ј
= 11.9 Hz, 1 H, 8-H), 3.71 (br. dd, J3,8Ј = 4.7 Hz, 1 H, 8Ј-H), 3.49
(m, 1 H, 7a-H), 3.16 (m, 1 H, 5-H), 2.81 (m, 1 H, 3-H), 1.19 (d,
JMe,5 = 6.7 Hz, 1 H, Me) ppm. 13C NMR (125 MHz, D2O): δ =
79.7 (C-6), 78.7 (C-2), 74.3 (C-7), 73.1 (C-1), 70.6 (C-3), 69.1 (C-
7a), 62.7 (C-5), 61.6 (C-8), 14.0 (Me) ppm. HRMS (NALDI-TOF):
calcd. for C9H17NO5Na [M + Na]+ 242.1004; found 242.1012 (de-
viation +3.3 ppm).
1:2) to afford pure 20 (61 mg, 78%) as a colorless viscous syrup.
[α]2D9 = +9.3 (c = 1, CHCl ). IR (neat): ν = 1743 (C=O) cm–1. H
1
˜
3
NMR (400 MHz, CDCl3): δ = 5.36 (t, J1,2 = J1,7a = 4.7 Hz, 1 H,
1-H), 5.29 (t, J7,7a = J6,7 = 5.0 Hz, 1 H, 7-H), 5.18 (t, J2,3 = 4.6 Hz,
1 H, 2-H), 5.04 (dd, J5,6 = 6.5 Hz, 1 H, 6-H), 4.04 (d, J3,8 = 6.6 Hz,
2 H, 8,8-H), 3.45 (t, 1 H, 7a-H), 3.29 (dt, 1 H, 3-H), 3.16 (quint.,
JMe,5 = 6.5 Hz, 1 H, 5-H), 2.09, 2.08, 2.07, 2.07 and 2.06 (5 s, 15
H, 5Ac), 1.16 (d, 3 H, Me) ppm. 13C NMR (150 MHz, CDCl3): δ
= 170.8, 170.5, 170.2, 170.2 and 169.9 (C=O), 81.5 (C-6), 79.5 (C-
1), 79.25 (C-2), 78.6 (C-7), 71.9 (C-7a), 67.5 (C-3), 64.8 (C-8), 64.5
(C-5), 21.08, 21.06 and 20.97 (5 CH3CO), 19.4 (Me) ppm. HRMS
(NALDI-TOF): calcd. for C19H28NO10 [M + H]+ 430.1713; found
430.1707 (deviation –1.4 ppm).
(1R,2R,3R,5S,6S,7S,7aS)-6,7-Di-O-acetyl-1,2-dibenzyloxy-3-tert-
butyldiphenylsilyloxymethyl-6,7-dihydroxy-5-methylpyrrolizidine
(18): Compound 14 (43 mg, 0.067 mmol) was acetylated in dry pyr-
idine (1.5 mL), acetic anhydride (32 μL, 0.337 mmol), and DMAP
(cat.) at room temperature for 1.5 h. TLC (AcOEt/hexane, 2:1) then
showed a faster-running compound. The reaction mixture was sup-
ported on silica gel and chromatographed (AcOEt/hexane, 1:5) to
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the H and 13C NMR spectra of compounds 9, 10,
1
1
afford pure 18 (17 mg, 35%) as a colorless viscous syrup. [α]3D0
=
11, 14, and 15 and copies of the H, 13C, COSY, HSQC, and NOE
–3 (c = 1, CHCl ). IR (neat): ν = 1743 (C=O) cm–1. 1H NMR of compounds 16, 17, 18, 19, 20, 1, and 12.
˜
3
Eur. J. Org. Chem. 2011, 7182–7188
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7187

J. A. Tamayo, F. Franco, F. Sánchez-Cantalejo
FULL PAPER
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Acknowledgments
Major support for this project was provided by the Ministerio de
Educación y Ciencia of Spain (Project Ref. No. CTQ2006-14043).
Additional support was provided by Junta de Andalucía (Group
BIO-250). We also acknowledge Fundación Ramón Areces for a
grant (F.S.-C.).
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Received: July 31, 2011
Published Online: October 17, 2011
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Eur. J. Org. Chem. 2011, 7182–7188