Total synthesis of hyacinthacines B3, B4, and B 5 and purported hyacinthacine B7, 7-epi-hyacinthacine B7, and 7a-epi-hyacinthacine B3 from a common precursor

Article abstract of DOI:10.1021/jo5005923

The total synthesis of hyacinthacines B₃, B₄, and B₅ and purported hyacinthacine B₇, 7-epi-hyacinthacine B₇, and 7a-epi-hyacinthacine B₃ from a common anti-1,2-amino alcohol precursor is described. These syntheses confirmed that the proposed structures and absolute configurations of hyacinthacines B ₃, B₄, and B₅ were correct and disclosed that the proposed structure of hyacinthacine B₇ was incorrect. Our synthetic and spectroscopic studies suggest that the natural hyacinthacines B₅ and B₇ are the same compounds; however, without access to authentic samples this cannot be unequivocally proven.

Full text of DOI:10.1021/jo5005923

Article
pubs.acs.org/joc
Total Synthesis of Hyacinthacines B3, B4, and B5 and Purported
Hyacinthacine B7, 7-epi-Hyacinthacine B7, and 7a-epi-Hyacinthacine
B3 from a Common Precursor
Kongdech Savaspun, Christopher W. G. Au, and Stephen G. Pyne*
School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
S
* Supporting Information
ABSTRACT: The total synthesis of hyacinthacines B3, B4, and B5 and purported
hyacinthacine B7, 7-epi-hyacinthacine B7, and 7a-epi-hyacinthacine B3 from a common
anti-1,2-amino alcohol precursor is described. These syntheses confirmed that the
proposed structures and absolute configurations of hyacinthacines B3, B4, and B5 were
correct and disclosed that the proposed structure of hyacinthacine B7 was incorrect.
Our synthetic and spectroscopic studies suggest that the natural hyacinthacines B5 and
B7 are the same compounds; however, without access to authentic samples this cannot
be unequivocally proven.
INTRODUCTION
■
The hyacinthacine alkaloids are a relatively recent addition to
the group of polyhydroxylated 3-(hydroxymethyl)pyrrolizidine
natural products.1,2 These alkaloids, along with the other
related polyhydroxylated pyrrolidine, piperidine, indolizidine,
and nortropane alkaloids, often have specific glycosidase
inhibitory activities. Some of these, and their more druglike
derivatives, have been identified as potential antiviral,
anticancer, antidiabetic, and antiobesity drugs.1 Nineteen
hyacinthacine alkaloids of general structure 1 (Figure 1) have
been isolated. The first came from the Hyacinthaceae family of
plants (Hyacinthoides nonscripta, the common bluebell)3a while
the others have been isolated from the bulb extracts of Muscari
armeniacum,3b Scilla campanulata,3a S. sibirica,3c and S. socialis.3d
Related alkaloids, having extended side chains at C-5, have been
isolated from S. peruviana.3e In general, these alkaloids show
relatively weak glycosidase inhibitory activities with the best
only having moderate activities (IC50 ca. 5−20 M) against α-
and β-glucosidases, β-galactosidases, and amylglucosidases.3a−d
These alkaloids have been classified as hyacinthacines A1−7
,
B
1−7, and C1−5 based on their total number of hydroxy and
hydroxymethyl groups in the ring B.3a−d The structures and
relative configurations of these natural products have been
assigned based solely on NMR and MS spectroscopic analysis
with the only X-ray crystallographic study made on synthetic
material.4 The synthesis of these alkaloids has confirmed many
of these structures and allowed assignment of their absolute
configurations. Most of these syntheses have involved starting
materials from Nature’s chiral pool (carbohydrates,5a−o amino
acids,5p−r and diethyl tartrate5s−u). Others include an enzymatic
resolution step followed by diastereoselective synthesis,4,6 a [2
Figure 1. General structure of the hyacinthacine alkaloids and target
molecules.
+ 2]-cycloaddition approach using a chiral auxiliary7 and a
chemoenzymatic synthesis using an aldolase.8 The synthesis of
epimers9 and a racemic synthesis have also been reported.10
Received: March 13, 2014
Published: April 28, 2014
© 2014 American Chemical Society
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Synthetic studies have revealed that the proposed structures of
boronic acid Mannich reaction conditions14 to give the 1,2-anti-
amino alcohol 7.11 However, we found that this method was
not readily amenable to the scale up synthesis of 7 that was
required here and the best overall yield of 7 that we could
obtain on a several hundred milligram scale was 37% for the
two steps. We thus devised an alternative synthesis of the
aldehyde 8 from the alkene 12.
The ADH reactions of the alkene 12 using AD-mix-β (1 mol
% of (DHQD)2PHAL, t-BuOH/H2O (1:1), methanesulfona-
mide (1 molar equiv)) at rt or at 3 °C over 3 d gave the desired
diol 13, but in poor yields (15% and 24%, respectively) with no
diastereoselectivity (dr = 1:1) (Scheme 2). The dr of 13 was
9f
hyacinthacines B7,11 C3,5q and C5 are incorrect. Thus, new
methods for the synthesis of these compounds are important
not only to confirm their structures but also to provide
analogues for structure−activity relationship studies. In a
previous communication, we reported the development of a
new synthetic strategy toward these alkaloids and the first
synthesis of hyacinthacine B3 (2) from (2S)-4-penten-2-ol.11
This synthesis confirmed the structural identity and the
absolute configuration of this alkaloid. The synthesis of the
proposed structure of hyacinthacine B7 (3), the C-5 epimer of
hyacinthacine B3, was also described starting from (2R)-4-
penten-2-ol, which indicated that the structure proposed for the
natural product was incorrect.11 We report here the full details
of the synthesis of these compounds and the synthesis of
hyacinthacine B5 (5) and the analogue 7-epi-hyacinthacine B7
(6), a possible correct structure for natural hyacinthacine B7,
from (2S)-4-penten-2-ol as a common chiral synthetic
precursor. Two side products from the synthesis of 5 were
hyacinthacine B4 (4) and 7a-epi-hyacinthacine B3. These
syntheses confirmed the structures and absolute configurations
of natural hyancinthacines B3, B4, and B5. From further analysis
of their NMR spectroscopic data, and those of the other
epimeric compounds that we have prepared, we propose that
the structure of naturally occurring hyacinthacine B7 has been
missassigned and is actually hyacinthacine B5.. Unfortunately,
the unavailabilty of these natural products does not allow us to
be unequivocal about this structural reassignment.
Scheme 2. Synthesis of the anti-1,2-Amino Alcohol 7
RESULTS AND DISCUSSION
■
Synthesis of Hyacinthacine B3. Our retrosynthetic
analysis of hyacinthacines B3, B5, B7, and 7-epi-hyacinthacine
B7 suggested that the 1,2-anti-amino alcohol 7, which we used
earlier as a precursor for the total synthesis of hyacinthacine B3
(2),11 could serve as a useful common intermediate to the total
synthesis of all four target compounds (Scheme 1). We
Scheme 1. Retrosynthetic Analysis of Targets 2, 3, 5, and 6
1
conveniently determined by H NMR analysis, and the desired
2R diastereomer showed a resolved doublet resonance at δ 4.54
(J 11.5 Hz, OCHHPMP) while the undesired 2S diastereomer
had a resolved doublet resonance at δ 4.57 (J 11.5 Hz,
OCHHPMP). The yields and diastereoselectivities were
enhanced significantly when DHQD-IND or (DHQD)2PYR
were used instead of (DHQD)2PHAL as the chiral ligand at 3
°C over 3 d (65% yield, dr = 3:1 and 61% yield and dr = 4:1,
respectively).15 However, the yield of the diol 13 was nearly
quantitative (99%) when the latter reaction was run at 3 °C for
3 d in t-BuOH/H2O (1:2) without compromising the
diastereoselectivity (dr = 4:1). While these diastereomeric
diols could be separated by careful column chromatography, it
proved more convenient to take the diastereomeric mixture
through to the 1,2-anti-amino alcohol 7 and purify the reaction
product mixture at this stage. Thus, the diol 13 (dr = 4:1) was
oxidized with TEMPO and sodium hypochlorite in a two phase
system (satd aqueous NaHCO3/CH2Cl2) at 0 °C for 30 min16
to give a product mixture which we assumed was a mixture of
hemiacetals 14 since NMR analysis showed no aldehyde signals
(Scheme 2). The unpurified material was then immediately
treated with β-styrenyl boronic acid 9 and the chiral allylic
anticipated that the configurations at C-2 and/or C-4 in 7 could
be sequentially inverted to allow ready access to each of these
related synthetic targets. In our earlier synthesis of
hyacinthacine B3 (2), the α-hydroxy aldehyde 8, or its cyclic
acetal derivative, was prepared by an asymmetric dihydrox-
ylation (ADH) reaction of the vinyl sulfone 11 (Scheme 1).11,12
This aldehyde was not isolated but treated with a mixture of β-
styrenyl boronic acid 9 and the chiral allylic amine 1013 under
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amine 10 in CH2Cl2 solution at rt for 2 d.14 The crude reaction
mixture was purified by column chromatography to give the
1,2-anti-amino alcohol 7 in 73% overall yield for the two steps
as essentially a single diastereomer (dr = 95:5, Scheme 2). The
minor diastereomer of 7, which could possibly arise from the
reaction of 2S-13 with 9 and 10, could not be isolated from the
96% yield. We previously explained this high level of
diastereoselectivity based on stereoelectronic effects and an
examination of the HOMO of 16 about the alkene moiety.11
The nonbonding orbital bearing the electron pair on the N
atom overlaps more effectively with the π-system of the alkene
moiety on the concave face (α-face) of the molecule, making
this more hindered face more prone to dihydroxylation.18b,c
The β-benzyloxymethyl substituent at C-5 also contributes
partially to the diastereofacial selectivity, since the DH of a
similar substrate which lacked this C-5 substituent was less
diastereoselective.19 Importantly, the pyrrolo[1,2-c]oxazol-3-
one 16 has allowed us to secure the desired 2,3-diol
configuration of the alkaloid 2 on essentially a trans-2,5-
disubstituted 2,5-dihydropyrrole A-ring precursor, which would
otherwise be expected to be problematic. Compound 17 was
readily converted to the amino diol 20 (Scheme 3) by three
efficient consecutive reactions: (i) a bis-O-benzylation reaction
to give 18 (100% yield); (ii) O-PMB deprotection of 18 with
DDQ under aqueous conditions11 to give 19 (89% yield); and
(iii) base hydrolysis of 19 under microwave heating (96% yield
of 20). Treatment of 20 with 1.05 equiv of MsCl4 under basic
conditions (Et3N) at 0 °C gave the pyrrolizidine 21 in 100%
yield. Debenzylation of 21 under hydrogenolysis conditions
1
above-mentioned column chromatography. The H and 13C
NMR spectra of 7 matched closely with those of compound 7
that we prepared earlier starting from the vinyl sulfone 11.11
In order to prepare the A-ring of hyacinthacine B3 (2), via a
ring-closing metathesis (RCM) reaction of the diene 7, the 1,2-
amino alcohol moiety of 7, which may deactivate the ruthenium
catalyst by coordination, was protected first as its oxazolidinone
derivative 15 (66% yield) by treatment with triphosgene/Et3N
(Scheme 3). 1H NMR analysis of 15 showed J4,5 = 8.1 Hz, and
Scheme 3. Synthesis of Hyacinthacine B3 2
17
using PdCl2/H2 gave hyacinthacine B3 (2) in 68% yield after
purification and neutralization by basic ion-exchange chroma-
tography (Scheme 3). The overall yield of 2 from 12 was 24%.
The 1H and 13C NMR spectral data of this compound matched
very closely to those reported in the literature (see the
Supporting Information).3b The configuration assigned to this
compound was confirmed by NOESY NMR studies (see the
Supporting Information). The optical rotation of this
compound ([α]2D3 +10.8 (c 0.33, H2O)) was larger in magnitude
but of the same sign to that reported (lit.3b [α]D +3.3 (c 0.31,
H2O)). Thus, this synthesis confirms the proposed structure
and absolute configuration of hyacinthacine B3 2.
Synthesis of the Purported Structure of Hyacintha-
cine B7 and 7-epi-Hyacinthacine B7. The proposed
structure of hyacinthacine B7 (3) was prepared from 19
according to Scheme 4 (a). The unprotected secondary alcohol
of 19 was converted to the 4-nitrobenzoate derivative 22, with
inversion of configuration, under Mitsunobu reaction con-
ditions.20 Base hydrolysis of both the ester and oxazolidinone
moieties of 22 was achieved under microwave heating
conditions, which furnished the amino diol 23 in 97% yield.
This compound was identical to the compound we prepared in
our earlier synthesis of 23 starting from (2R)-4-penten-2-ol.11
Treatment of 23 with 1.05 equiv of MsCl under basic
conditions (Et3N) at 0 °C gave the pyrrolizidine 24 in 77%
yield after purification by column chromatography. Debenzy-
the magnitude of this vicinal coupling constant was consistent
with the 4,5-cis relative stereochemistry of 15.14c This
assignment was further established from the NOESY
correlation between H4 and H5 (Scheme 3). These results
also confirmed the anti-configuration assigned to the 1,2-amino
alcohol moiety in 7 which was expected based upon
mechanistic considerations and literature precedent (see
intermediate A in Scheme 2)14
A ruthenium-catalyzed RCM reaction of 15, using 5 mol % of
Grubbs’ second-generation catalyst, gave the pyrrolo[1,2-
c]oxazol-3-one 16 in 90% yield. Based on our previous
work,17,18a and that of Parsons,18b,c we expected that the syn-
dihydroxylation (DH) of 16 would furnish the corresponding
6α,7α-diol 17 with the desired configuration for the synthesis of
the target alkaloid. In the event, the Os(VIII)-catalyzed syn-DH
of 16 provided the desired diol 17 as a single diastereoisomer in
14
lation of 24 under hydrogenolysis conditions using PdCl2/H2
gave the purported structure of hyacinthacine B7 (3) in 84%
yield after purification and neutralization by basic ion-exchange
chromatography (Scheme 4 (a)). Of significant concern was
1
that the H and 13C NMR spectral data of synthetic 3 did not
match with those reported for hyacinthacine B7 (see the
Supporting Information).3d Further, its specific rotation [α]2D4
+
31.2 (c 0.20, H2O) was significantly different and of the
opposite sign to that of the natural product ([α]D − 4.4 (c 0.20,
H2O).3d NOESY NMR analysis of our synthetic compound
clearly indicated that it had the correct relative configuration;
significantly, a NOESY correlation was observed between H-5
and H-7 in 3 (see ref 11 for details), but this was not reported
for hyacinthacine B7 in the original isolation paper.
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those of hyacinthacine B7 than to those of synthetic 3, they
were nonetheless not identical (see the Supporting Informa-
tion).
Scheme 4. (a) Synthesis of the Purported Structure of
Hyacinthacine B7 (3) and (b) 7-epi-Hyacinthacine B7 (4)
Synthesis of Hyacinthacines B4 and B5 and 7a-epi-
Hyacinthacine B3. While the above synthetic strategies readily
provided the three desired target molecules, our synthesis of
hyacinthacine B5 (5) did not proceeded as efficiently as
planned. Our plan was to oxidize the secondary alcohol of 21 to
the corresponding C-7 ketone and then convert this to the C-7
α-carbinol 28 by a diastereoselective reduction with L-
Selectride using the conditions we had successfully employed
in Scheme 4 (b). Compound 28 would then be de-O-
benzylated to give hyacinthacine B5 (5). Surprisingly, the Swern
oxidation of alcohol 21 gave the unexpected lactam-carboxylic
acid 27 as the major oxidation product along with an
inseparable mixture that comprised three other products from
1H NMR analysis (Scheme 5 (a)). MS analysis of this mixture
Scheme 5. Synthesis of Hyacinthacine B4 (4), Hyacinthacine
B5 (5), and 7a-epi-Hyancinthacine B3 (33)
Unfortunately, a sample of natural hyacinthacine B7 was no
longer available from the authors for comparison with our
synthetic product.11 However, as communicated earlier, a GC−
MS analysis of the crude extract of the same S. socialis plants
used in the original isolation paper showed no hyacinthacine
corresponding to the retention time of 10.71 min for the tetra-
TMS derivative of 3 (base ion at 388 amu (100%)) while four
hyacinthacines in the S. socialis extract showed the same
fragmentation pattern suggesting they were epimers of 3.11 This
analysis strongly suggested that 3 does not occur in that plant,
although epimers of 3 clearly do.
This information, and the differences in NOESY correlations
between H-5 and H-7 in synthetic 3 and natural hyacinthacine
B7, suggested to us that the natural product might be 7-epi-
hyacinthacine B7 (6), since the other possible A-ring epimer,
hyacinthacine B5 (5), had already been reported as a natural
product.3c To examine this possibility, compound 6 was
prepared from the pyrrolizidine 24 according to Scheme 4
(b). Thus, the unprotected secondary alcohol in pyrrolizidine
24 was oxidized under Swern oxidation conditions21 to give the
ketone 25 in 63% yield. A diastereoselective reduction of this
ketone with L-Selectride from the less hindered convex face (β-
face) of the pyrrolizidine structure gave the alcohol 26, which
was epimeric at C-7 with its precursor 24. Debenzylation of 26
indicated that one of the components of this mixture might
have been the desired ketone. The yield of 27 was 16% when
the reaction mixture was held at −78 °C for 1 h and 38% when
the oxidation mixture was treated with Et3N at −78 °C and
then warmed to rt for 1 h. When the crude oxidation product
mixture from the former oxidation reaction conditions (−78 °C
for 1 h) was treated with L-Selectride, and then separated by
column chromatography, four new compounds could be
17
over PdCl2/H2 gave 7-epi-hyacinthacine B7 (6) in 84% yield
after purification and neutralization by basic ion-exchange
1
chromatography (Scheme 4 (b)). While the H and 13C NMR
spectroscopic data for this compound were a closer match to
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isolated, all in low yields, and identified. One product was the
lactam-alcohol 31 (8% yield), while the diastereomeric alcohols
28 (7%), and 30 (4%) and the ketone 29 (7%) comprised the
other three products (Scheme 5 (b)). The configurations of the
products 28, 29, and 30 were determined from NOESY NMR
experiments, and their structures were further supported by
their conversions to, hyacinthacine B5 (5) via hydrogenolysis,
hyacinthacine B4 (4) via a diastereoselective L-Selectride
reduction to alcohol 32 and then hydrogenolysis, and 7a-epi-
hyacinthacine B3 33 via hydrogenolysis, respectively (Scheme 5
dimethylchlorosulfonium species (Me2SCl+)21 would lead to
the N-sulfonium intermediate A which upon base-assisted
fragmentation could give rise to the iminum ion B (Scheme 6).
DMSO-assisted cyclization of B could lead to the bicyclic
intermediate C which upon base-promoted elimination−
fragmentation would give the resonance-stabilized cation
intermediate D. Quenching of the reaction mixture with
water could give rise to the aminal F, which could give the
lactam 27 upon chromatography on silica gel. Reduction of F
with an excess amount of L-Selectride could give alcohol 31
(Scheme 6).
1
(c)). The H and 13C NMR spectroscopic data of synthetic
The alcohol 28, however, clearly arises from reduction of the
expected and desired C-7 ketone 34, which could not be
isolated in pure form, while alcohol 30 seems to have formed
from reduction of ketone 35, the C-7a epimer of ketone 34
(Scheme 7 (a)). Such an epimerization process would seem
compounds 4 and 5 matched very closely to those reported for
these individual natural products, respectively (see the
Supporting Information).3c The configurations assigned to
these synthetic compounds were confirmed by NOESY NMR
studies (see the Supporting Information). The optical rotation
of 5 ([α]2D5 −21.6°, c 0.08, H2O) matched well with that of
natural hyacinthacine B5 ([α]D −25.4°, c 0.26, H2O)3c as did
that of 4 ([α]2D5 −7.7, c 0.18, H2O) and natural hyacinthacine B4
([α]D −6.7, c 1.19, H2O).3c Thus, these syntheses confirm the
proposed structures and absolute configurations of hyacintha-
cines B4 and B5.
Scheme 7. Proposed Intermediates and Mechanisms
A possible mechanistic scheme for the formation of the B-
ring fragmented products 27 and 31 is outlined in Scheme 6.
This mechanism is also consistent with the finding that 27 was
inert to reduction when treated with an excess amount of L-
Selectride under the reaction conditions indicated in Scheme 5
(b). Reaction of 21, via its tertiary nitrogen atom, with the
Scheme 6. Proposed Mechanism for the Formation of Ring-
Fragmented Products 27 and 31
likely as it would relieve unfavorable steric interactions between
the substituents at C-1, C-2, and C-5 on the more crowded
concave face of 34 (Scheme 7 (a)). In the C-7a epimeric
ketone 35 these substituents are now on the less crowded
convex face of the molecule. The isolation of ketone 29 in
Scheme 5 (b) suggests that this compound was protected from
reduction with L-Selectride by formation of its corresponding
enolate anion. A tentative mechanism to support such an
enolate intermediate, which also accounts for the inversion of
configuration at C-1, is shown in Scheme 7 (b). This
mechanism involves formation of the enone G which upon
1,4-reduction by L-Selectride, with addition of hydride at C-1
from the stereoelectronically favored pseudoaxial direction,
would give an enolate anion which upon quenching with water
and protonation at C-7a, from the stereoelectronically favored
pseudoaxial direction, would give 29 (Scheme 7 (b)).
The relatively more straightforward oxidation of alcohol 24
to its desired ketone 25 (Scheme 4 (b)) is likely a consequence
of the C-5 β-methyl substituent, which would sterically hinder
the formation of an intermediate analogous to A in Scheme 6
(Scheme 8).
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Scheme 8
Attempts to prepare the C-7-inverted alcohol 28 more
efficiently by SN2 inversion reactions of the alcohol 21 were
also unsuccessful (Scheme 9). The Mitsunobu reaction of 21
Scheme 9. Attempts To Invert the Configuration at C-7 of
Alcohol 21
Figure 2. 13C NMR chemical shifts (rounded to the nearest whole
integer) of compounds 2−6 and natural hyacinthacine B7.
Interestingly, the 13C NMR chemical shifts for C-3, C-5, C-8,
and C-9 of hyacinthacine B4 4, the C-1 epimer of 5, and 5 are
also nearly the same.
Compounds 2 and 3, with a β-hydroxy group at C-7, have
nearly the same 13C NMR chemical shifts for C-1, C-7, and C-
7a. This is also observed for compounds 5 and 6, having an α-
hydroxy group at C-7. In compounds 2 and 3, C-7a resonates at
δ 75−76, downfield of the signals for C-1 and C-7 (δ 71−74),
while in the 13C NMR spectra of compounds 5 and 6, the
reverse trend is observed (C-7a, δ 70−71 and C-1 and C-7 (δ
75−76).
In light of this analysis, an examination of the 13C NMR
chemical shifts for C-3, C-5, C-8, and C-9 of natural
hyacinthacine B7 (Figure 2) would indicate the α-configuration
of the C-5 methyl group rather than the assigned β-
configuration. Further, if one assumes that the chemical shifts
of C-1 (reported as δ 77.9) and C-2 (reported as δ 74.9) have
been missassigned in natural hyacinthacine B7 [these chemical
shifts are not consistent with those of the other hyacinthacine
alkaloids (in compounds 2−6, the 13C NMR chemical shift of
C-2 is always downfield of that of C-1; see the Supporting
Information)], then this compound should have the α-
configuration at C-1 and not the initially assigned β-
configuration. This analysis suggests that natural hyacinthacine
B7 is actually hyacinthacine B5 (5). Further, analysis of Table 1
indicates a close match between their 13C NMR chemical shifts.
gave the p-nitrobenzoate 36 in very poor yield (8%) and with
retention of configuration at C-7. The O-mesylate derivative 37
of 21 gave a more respectable yield of the benzoate 38 upon
treatment with CsOBz,22 but again with retention of
configuration at C-7. The configurations of esters 36 and 38
were confirmed from their base hydrolysis back to the alcohol
21. While the Mitsunobu reaction of hindered alcohols can
proceed with retention of configuration by direct O-acylation of
the alcohol by [ArCO2PPh3]+,23 we suspect that the aziridinium
ion intermediate H24 is formed in these reactions leading to C-
7 esters with overall retention of configuration (Scheme 9).
A comparison of the 13C NMR chemical shifts (rounded up
to the nearest whole integer) of synthetic compounds 2, 3, 5,
and 6 (all with the same configurations at C-1−C-3 and C-7a)
and those of natural hyacinthacine B7 is shown in Figure 2.
Compounds 2 and 5, with an α-methyl group at C-5, have
nearly the same 13C NMR chemical shifts for C-3, C-5, C-8,
and C-9. This is also true for compounds 3 and 6, having a β-
methyl group at C-5. However, these particular chemical shifts
observed for compounds 3 and 6 are significantly downfield of
those of their corresponding carbons seen in the 13C NMR
spectra of compounds 2 and 5, except for the chemical shift of
C-8 which is insensitive to the configuration at C-5.
1
A comparison of the H NMR chemical shifts and coupling
constants for these two alkaloids shows close agreement for the
protons H-1, H-2, H-6β, H-7, H-8, and H-9 (Table 2) and a
consistent difference of ca. 0.2 ppm for the protons H-3, H-5,
H-6α, H-7a, and H-8′. Considering that the chemical shifts of
these types of compounds are sensitive to pH and
concentration effects,4 these NMR data would seem to be a
good match and support our proposal that they are the same
compound (hyacinthacine B5). Their specific rotations,
however, are of the same sign but differ significantly in
magnitude (hyacinthacine B5: [α]D−25.4 (c 0.26, H2O);3c
natural hyacinthacine B7: [α]D−4.4 (c 0.20, H2O)3b). However,
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NMR) and 77.16 ppm (for 13C NMR), respectively. All signals which
were recorded in CD3OD were relative to the CD2HOD signal for 1H
NMR and the CD3OD for 13C NMR, referenced at 3.31 and 49.00
ppm, respectively. All signals which were recorded in D2O were
Table 1. Comparison of Literature 13C NMR Chemical Shifts
(125 MHz, D2O) of Natural Hyacinthacine B73d and Natural
Hyacinthacine B5
3c
1
3d
3c
relative to the D2O signal for H NMR, referenced at 4.49 ppm. For
natural hyacinthacine B7 δC
natural hyacinthacine B5 δC
13C NMR spectra in D2O the referencing of peaks is relative to internal
carbon
(ppm)
(ppm)
MeOH (49.50 ppm). In some cases, the 13C NMR spectral data were
referenced to sodium 3-(trimethylsilyl)propionate (TSP) at δ −2.19 in
D2O. In order to compare our 13C NMR data recorded in D2O (and
referenced to internal MeOH) with those of the literature which were
run in D2O and referenced to TSP at δ 0.00 we have added 2.19 ppm
to our observed 13C NMR chemical shifts in the 13C NMR comparison
tables (Supporting Information). NMR assignments were based upon
gCOSY, APT, gHSQC, gHMBC, and NOESY experiments. In some
cases, 13C NMR signals which were absent in the standard 13C NMR
spectrum were identified using gHSQC and gHMBC experiments.
Petrol refers to the hydrocarbon fraction of bp. 40−60 °C.
Compounds are named using systematic nomenclature. The NMR
assignments made to pyrrolizidine compounds are based on the
numbering system of the hyacinthacine alkaloids and not the
systematic name.
1
2
3
5
6
7
7a
8
9
77.9
74.9
66.2
57.7
45.2
76.5
69.9
66.8
18.4
74.8
76.9
65.5
58.5
43.9
75.0
70.1
64.7
17.9
Table 2. Comparison of Literature 1H NMR Chemical Shifts
(500 MHz, D2O) of Natural Hyacinthacine B73d and Natural
Hyacinthacine B5
3c
3d
3c
Synthesis of Hyacinthacine B3 (2). (2R,4S)-4-(4-Methoxy-
benzyloxy)pentane-1,2-diol (13). A solution of 12 (2.58 g, 12.49
mmol) in tert-butyl alcohol (20 mL) was slowly added dropwise into a
solution of potassium ferric cyanide (12.34 g, 37.48 mmol), potassium
carbonate (5.18 g, 37.48 mmol), methanesulfonamide (1.19 g, 12.49
mmol), potassium osmate dihydrate (55 mg, 0.150 mmol), and
(DHQD)2PYR (0.110 g, 0.125 mmol) in H2O (40 mL) which was
cooled in an ice bath. The reaction mixture was stirred at 3−5 °C (in a
cold room) for 2 d. The reaction was quenched with sodium sulfite
(9.44 g, 74.94 mmol) and then allowed to warm to rt (21 °C), stirred
for 30 min, and then extracted with EtOAc (3 × 100 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (increasing
polarity from 0:100 to 4:96 of MeOH/CH2Cl2) gave the title
compound as a colorless oil (2.736 g, 99%, dr = 4:1). Rf 0.50 (10:90
MeOH/CH2Cl2). [α]D25 −46.5 (c 1.64, CHCl3). IR νmax (cm−1): 3396,
2925, 1614, 1512, 1244, 1031, 818. NMR δH (500 MHz, CDCl3):
(major diastereomer) 7.25 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8
Hz), 4.54 (1H, d, J = 11.2 Hz), 4.36 (1H, d, J = 11.2 Hz), 3.96 (1H, s
(br), H2), 3.87−3.82 (1H, m, H4), 3.78 (3H, s), 3.56 (1H, dd, J =
10.8, 9.8 Hz, H1A), 3.43 (1H, dd, J = 9.8, 7.3 Hz, H1B), 1.74−1.65
(1H, m, H3A), 1.55 (1H, ddd, J = 10.7, 7.8, 2.9 Hz, H3B), 1.24 (3H, d,
J = 6.3 Hz, H5). (minor diastereomer, in part) 4.59 (1H, d, J = 11.2
Hz), 4.34 (1H, d, J = 11.2 Hz). NMR δC (125 MHz, CDCl3): (major
diastereomer) 159.3 (ArC), 130.4 (ArC), 129.5 (2 × ArCH), 114.0 (2
× ArCH), 72.2 (C4), 70.3 (OCH2PMP), 69.3 (C2), 66.9 (C1), 55.3
(OCH3), 39.3 (C3), 19.5 (C5). (minor diastereomer, in part) 132.1
(ArC), 131.9 (ArC), 114.4 (ArCH), 71.9 (C4), 70.1 (OCH2PMP),
66.7 (C1), 33.9 (C3), 19.7 (C5). ESIMS m/z: 263 (100) [M + Na]+.
HRESIMS: found 263.1258, calcd for C13H20O4Na 263.1259 [M +
Na]+.
Oxidation of Diol 13. A mixture of 13 (208 mg, 0.87 mmol),
2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) (3 mg,
0.02 mmol), potassium bromide (113 mg, 0.95 mmol), anhydrous
CH2Cl2 (9.5 mL), and saturated aqueous NaHCO3 solution (3.8 mL)
was cool to 0 °C. Commercial sodium hypochlorite solution (0.4 M,
3.0 mL, 1.21 mmol) was added slowly dropwise and stirred at 0 °C for
30 min. Saturated aqueous sodium thiosulfate solution (8.6 mL) was
added at 0 °C. The reaction mixture was extracted with EtOAc (3 ×
100 mL), dried (MgSO4), and concentrated in vacuo to give a white
solid which was used in the subsequent Petasis reaction without
further puricication.
(3S,4R,6S,E)-3-((S)-1-(Benzyloxy)but-3-en-2-ylamino)-6-(4-me-
thoxybenzyloxy)-4-methoxy-1-phenylhept-1-en-4-ol (7). A solution
of 10 (183 mg, 1.03 mmol) in anhydrous CH2Cl2 (0.5 mL) was added
to a solution of the above crude oxidation product and (E)-2-
phenylvinylboronic acid (153 mg, 1.03 mmol) in 1,1,1,3,3,3-
hexafluoro-2-propanol/CH2Cl2 (1:9, 3.5 mL) under a nitrogen
atmosphere. The reaction mixture was stirred at rt (32 °C) for 2 d,
natural hyacinthacine B7
natural hyacinthacine B5
δH
δH
proton
(ppm)
mult, J (Hz)
t (4.4)
(ppm)
mult, J (Hz)
dd (4.4, 4.2)
1
4.35
3.97
3.29
3.22
1.68
2.16
4.50
3.45
3.57
3.63
1.25
4.37
4.08
3.48
3.44
1.86
2.22
4.55
3.66
3.70
3.73
1.32
2
dd (7.6, 4.4)
dd (8.0, 4.2)
ddd (5.1, 4.6, 4.2)
m
3
ddd (7.6, 5.5, 3.5)
5
m
6α
6β
7
m
ddd (12.5, 10.0, 8.0)
ddd (12.5, 6.4, 6.0)
ddd (8.0, 7.6, 6.4)
dd (7.6, 4.4)
dd (12.0, 5.1)
dd (12.0, 4.6)
d (7.0)
m
m
7a
8
dd (7.6, 4.4)
dd (11.5, 3.5)
dd (11.5,5.5)
d (7.0)
8′
9
without having authentic samples of these two natural products
in hand it is impossible to either verify or disprove our proposal
and thus unequivocally demonstrate the correct structure of
natural hyacinthacine B7.
CONCLUSIONS
■
In conclusion, the total synthesis of hyacinthacines B3, B4, and
B5 and purported hyacinthacine B7, 7-epi-hyacinthacine B7, and
7a-epi-hyacinthacine B3 from a common anti-1,2-amino alcohol
precursor (7) has been achieved. These syntheses have
confirmed that the proposed structures and absolute config-
urations of hyacinthacines B3, B4, and B5 are correct and
disclosed that the proposed structure of natural hyacinthacine
B7 was incorrect. Our synthetic and spectroscopic studies
suggest that the natural hyacinthacines B5 and B7 are the same
compound; however, without access to authentic samples this
cannot be unequivocally proven.
EXPERIMENTAL SECTION
■
General Methods. Flash column chromatography packed with
Merck Kieselgel 60 PF254 was used for purification. A single
quadrupole mass spectrometer was used for obtaining the LRESIMS.
Quadrupole time-of-flight mass spectrometers were used for acquiring
HRESIMS and HRASAPMS. IR spectra were run on neat samples. 1H
(500 or 300 MHz) and 13C NMR (125 or 75 MHz) NMR spectra
were recorded in deuterochloroform (CDCl3), deuterium oxide
(D2O), or deuterated methanol-d4 (CD3OD) solution. All signals
which were recorded in CDCl3 were relative to the tetramethylsilane
1
(TMS) signal and the CDCl3 signal, referenced at 0.00 ppm (for H
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diluted with EtOAc (25 mL), and washed with 0.5 M NaOH solution
(3 × 25 mL). The organic layer was dried (MgSO4) and concentrated
in vacuo to give a dark brown oil. Purification by flash column
chromatography (0:100 to 40:60 EtOAc/CH2Cl2 as eluent) gave the
title compound (314 mg, 73%, two steps) as a brown oil. Rf 0.45 (5:95
MeOH/CH2Cl2). [α]D25 +11.9 (c 0.56, CHCl3). IR νmax (cm−1): 3438,
3066, 3027, 2905, 2860, 1648, 1611, 1511, 1452, 1245, 1076, 1035,
975, 925, 818, 746, 696. NMR δH (500 MHz, CDCl3): 7.36−7.19
(12H, m), 6.8 (2H, d, J = 8.3, Hz), 6.43 (1H, d, J = 16.1 Hz, H1), 6.08
(1H, dd, J = 16.1, 8.3 Hz, H2), 5.63−5.56 (1H, m, H2′), 5.21 (1H, d, J
= 17.1 Hz, H3′trans), 5.17 (1H, d, J = 10.2 Hz, H3′cis), 4.51 (1H, d,, J
= 11.2 Hz), 4.49 (2H, s), 4.37 (1H, d, J = 11.2 Hz), 4.02 (1H, s (br),
H4), 3.84−3.81 (1H, m, H6), 3.75 (3H, s), 3.49−3.42 (3H, m), 3.24
(1H, dd, J = 8.3, 3.4 Hz, H3), 1.58 (2H, dd, J = 6.4, 5.4 Hz, H5), 1.21
(3H, d, J = 6.4 Hz, H7). NMR δC (125 MHz, CDCl3): 159.1 (ArC),
138.2 (ArC), 138.0 (CH=), 136.9 (ArC), 132.8 (C1), 130.9 (ArC),
129.3 (2 × ArCH), 128.5 (2 × ArCH), 128.4 (2 × ArCH), 128.1 (C2),
127.7 (2 × ArCH), 127.5 (2 × ArCH), 126.4 (2 × ArCH), 117.9
(=CH2), 113.8 (2 × ArCH), 73.4 (CH2), 73.0 (OCH2Ph), 72.2 (C6),
70.4 (OCH2PMP), 70.4 (C4), 62.3 (C3), 58.0 (CH), 55.3 (OCH3),
40.2 (C5), 19.8 (C7). ESIMS m/z: 502 (100%) [M + H]+. HRESIMS:
found 502.2954, calcd for C32H40NO4, 502.2957 [M + H]+.
(4S,5R)-3-((S)-1-(Benzyloxy)but-3-en-2-yl)-5-((S)-2-(4-methoxy-
benzyloxy)propyl)-4-styryloxazolidin-2-one (15). Small-Scale Reac-
tion. Triphosgene (6 mg, 0.020 mmol) was slowly added to the
solution of the 1,2-amino alcohol 7 (20 mg, 0.040 mmol) and
triethylamine (11 μL, 0.080 mmol) in anhydrous CH2Cl2 (3 mL) at 0
°C under a nitrogen atmosphere. After being stirred for 15 min, the
reaction mixture was allowed to warm to rt, stirred for 18 h, and then
concentrated in vacuo to give a yellow solid. Purification by flash
column chromatography (increasing polarity from 0:100 to 1:99 of
MeOH/CH2Cl2 as eluent) gave the title compound (17 mg, 81%) as a
colorless oil. Larger scale reaction: Using triphosgene (0.186 g, 0.625
mmol), 7 (625 mg, 1.25 mmol), and triethylamine (697 μL, 4.99
mmol) the title compound (0.435 g, 66%) was obtained as a colorless
oil. Rf 0.66 (2:98 MeOH/CH2Cl2). [α]2D5 +20.9 (c 0.05, CHCl3). IR
νmax (cm−1): 3028, 2966, 2929, 2865, 1743, 1612, 1512, 1453, 1402,
1246, 1072, 1033, 977, 932, 820, 753, 695, 608. NMR δH (500 MHz,
CDCl3): 7.33−7.23 (12H, m), 6.86 (2H, d, J = 8.3 Hz), 6.30 (1H, d, J
= 15.9 Hz), 6.00 (1H, dd, J = 15.9, 9.8 Hz), 5.86−5.78 (1H, m), 5.25
(1H, d, J = 16.1 Hz), 5.18 (1H, d, J = 10.2 Hz), 4.86 (1H, ddd, J =
10.3, 8.8, 1.5 Hz), 4.61 (1H, d, J = 11.7 Hz), 4.52 (1H, d, J = 10.7 Hz),
4.47 (1H, d, J = 11.7 Hz), 4.37−4.40 (2H, m), 4.34 (1H, d, J = 10.7
Hz), 3.89 (1H, dd, J = 10.0, 9.3 Hz), 3.83−3.81 (1H, m), 3.79 (3H, s),
3.61 (1H, dd, J = 10.0, 4.9 Hz), 1.70 (1H, td, J = 11.9, 2.0 Hz), 1.60
(1H, dd, J = 11.9, 11.2 Hz), 1.19 (3H, d, J = 6.3 Hz). NMR δC (75
MHz, CDCl3): 159.3 (ArC), 157.5 (CO), 138.0 (ArC), 135.8 (ArC),
135.2 (CHPh), 133.9 (CH), 130.8 (ArC), 129.6 (2 × ArCH),
128.8 (ArCH), 128.6 (2 × ArCH), 128.5 (ArCH), 128.1 (2 × ArCH),
128.0 (2 × ArCH), 126.8 (2 × ArCH), 125.1 (CH), 118.6 (
CH2), 114.0 (2 × ArCH), 74.9 (C5), 73.2 (CH2), 71.5 (CH), 71.1
(CH2), 69.1 (CH2), 61.4 (C4), 56.4 (CH), 55.4 (OCH3), 38.8 (CH2),
20.3 (Me). ESIMS m/z: 550 (80%) [M + Na]+, 528 (18%) [M + H]+.
HRESIMS: found 528.2737, calcd for C33H38NO5 528.2750 [M + H]+.
(1R,5S,7aS)-5-(Benzyloxymethyl)-1-((S)-2-(4-methoxybenzyloxy)-
propyl)-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one (16). A solution
of the oxazolidinone 15 (239 mg, 0.45 mmol) and Grubbs’ II
ruthenium catalyst (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (8 mL)
under a nitrogen atmosphere was heated at reflux for 18 h. The
reaction mixture was cooled to rt and was then concentrated in vacuo
to give a black semisolid. Purification by flash column chromatography
with increasing polarity from 0:100 to 30:70 of EtOAc/petrol as eluent
gave the title compound (172 mg, 90%) as a yellow oil. Rf 0.24 (30:70
EtOAc/petrol). [α]D25 −22.5 (c 0.12, CHCl3). IR νmax (cm−1): 2967,
2864, 1745, 1610, 1513, 1454, 1375, 1246, 1213, 1072, 820, 746, 697,
608. NMR δH (500 MHz, CDCl3): 7.34−7.23 (7H, m), 6.86 (2H, d, J
= 8.3 Hz), 5.99 (1H, d, J = 5.9 Hz), 5.89 (1H, d, J = 5.9 Hz), 4.98 (1H,
td, J = 9.3, 3.4 Hz), 4.80−4.76 (2H, m), 4.55 (1H, d, J = 11.2 Hz), 4.54
(2H, s), 4.33 (1H, d, J = 11.2 Hz), 3.79−3.75 (1H, m), 3.78 (3H, s),
3.52 (2H, d, J = 4.5 Hz), 1.72 (1H, ddd, J = 12.4, 10.7, 3.4 Hz), 1.62
(1H, ddd, J = 10.7, 9.3, 2.9 Hz), 1.21 (3H, d, J = 5.8 Hz). NMR δC
(125 MHz, CDCl3): 162.4 (C3), 159.3 (ArC), 138.0 (ArC), 132.9
(C7), 130.6 (ArC), 129.5 (2 × ArCH), 128.5 (C6), 128.4 (2 ×
ArCH), 127.7 (ArCH), 127.6 (2 × ArCH), 113.9 (2 × ArCH), 76.4
(C1), 73.3 (OCH2Ph), 71.4 (CH2), 71.2 (CH), 70.9 (CH2), 68.2
(C5), 67.0 (C7a), 55.3 (OCH3), 40.1 (CH2), 20.0 (Me). ESIMS m/z:
446 (100%) [M + Na]+. HRESIMS: found 446.1956, calcd for
C25H29NO5Na 446.1943 [M + Na]+.
(1R,5R,6R,7S,7aS)-5-(Benzyloxymethyl)-6,7-dihydroxy-1-((S)-2-(4-
methoxybenzyloxy)propyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-
one (17). N-Methylmorpholine N-oxide (335 mg, 2.86 mmol) and
potassium osmate dihydrate (26 mg, 0.07 mmol) were added to a
solution of 16 (605 mg, 1.43 mmol) in 3:1 acetone/water (18 mL).
The reaction mixture was stirred at 35 °C for 18 h, concentrated in
vacuo, diluted with H2O, and extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo to afford a black oil. Purification by flash column
chromatography (0:100 to 3:97 MeOH/CH2Cl2 as eluent) gave the
title compound (629 mg, 96%) as a yellow oil. Rf 0.18 (60:40 EtOAc/
petrol). [α]2D5 +6.2 (c 0.14, CHCl3). IR νmax (cm−1): 3402, 2931, 2863,
1723, 1612, 1513, 1455, 1370, 1303, 1245, 1176, 1121, 1061, 1031,
950, 821, 741, 698. NMR δH (500 MHz, CDCl3): 7.31−7.20 (5H, m),
6.85−6.84 (2H, m), 4.86−4.83 (1H, m), 4.60−4.51 (3H, m), 4.30
(1H, d, J = 10.7 Hz) 4.24 (1H, s (br)), 3.91 (1H, s (br)), 3.78 (3H, s),
3.76−3.74 (1H, m), 3.69−3.67 (1H, m), 3.65−3.63 (3H, m), 2.35
(1H, ddd, J = 10.5, 8.8, 3.4 Hz), 1.92 (1H, td, J = 10.5, 4.4 Hz), 1.22
(3H, d, J = 4.9 Hz). NMR δC (125 MHz, CDCl3): 163.0 (C3), 159.3
(ArC), 138.0 (ArC), 130.6 (ArC), 129.6 (2 × ArCH), 128.5 (2 ×
ArCH), 127.8 (ArCH), 127.7 (2 × ArCH), 113.9 (2 × ArCH), 76.0
(C7), 74.0 (C1), 73.5 (CH2), 72.3 (C6), 72.2 (CH), 70.7 (CH2), 70.3
(CH2), 65.2 (C7a), 62.5 (C5), 55.4 (OCH3), 37.5 (CH2), 20.0 (Me).
ESIMS m/z: 480 (100%) [M + Na]+, 458 (10%) [M + H]+.
HRESIMS: found 458.2187, calcd for C25H32NO7 458.2179 [M + H]+.
(1R,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-1-((S)-
2-(4-methoxybenzyloxy)propyl)tetrahydropyrrolo[1,2-c]oxazol-
3(1H)-one (18). A solution of the diol 17 (18 mg, 0.039 mmol) and
tetrabutylammonium iodide (TBAI) (1 mg, 0.004 mmol) in
anhydrous THF (5 mL) was stirred at rt (18 °C) for 15 min under
a nitrogen atmosphere. Benzyl bromide (20 μL, 0.157 mmol) was
added, and then the solution was cooled to 0 °C. Sodium hydride
(50% dispersion in mineral oil, 6 mg, 0.117 mmol) was slowly added,
and the reaction mixture was allowed to warm to rt and was stirred for
18 h. Quenching with H2O (50 mL) gave a cloudy mixture, which was
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo to give a light yellow
solid. Purification by flash column chromatography (0:100 to 30:70
EtOAc/petrol as eluent) gave the title compound (25 mg, 100%) as a
colorless oil. Rf 0.70 (60:40 EtOAc/petrol). [α]2D5 +29.1 (c 0.14,
CHCl3). IR νmax (cm−1): 3031, 2929, 2862, 1750, 1611, 1513, 1455,
1390, 1359, 1303, 1246, 1228, 1065, 1031, 821, 736, 698. NMR δH
(500 MHz, CDCl3): 7.32−7.18 (17H, m), 6.84 (2H, d, J = 7.3 Hz),
4.99 (1H, d, J = 11.2 Hz), 4.77 (1H, dt, J = 7.8, 6.6 Hz), 4.58−4.48
(4H, m), 4.40 (1H, d, J = 12.2 Hz), 4.37 (1H, d, J = 12.2 Hz), 4.22
(1H, d, J = 10.7 Hz), 4.15 (1H, dd, J = 7.8, 1.5 Hz), 3.97 (1H, dd, J =
7.8, 2.4 Hz), 3.93 (1H, s (br)), 3.77−3.75 (1H, m), 3.73 (3H, s),
3.66−3.61 (2H, m), 3.56 (1H, dd, J = 10.2, 2.0 Hz), 2.09 (1H, dd, J =
14.2, 7.1 Hz), 1.79−1.75 (1H, m), 1.07 (3H, d, J = 5.9 Hz). NMR δC
(125 MHz, CDCl3): 162.1 (C3), 159.4 (ArC), 138.3 (ArC), 138.1
(ArC), 137.7 (ArC), 130.7 (ArC), 129.6 (2 × ArCH), 128.6 (2 ×
ArCH), 128.5 (2 × ArCH), 128.4 (2 × ArCH), 128.1 (ArCH), 127.8
(5 × ArCH), 127.5 (ArCH), 127.3 (2 × ArCH), 114.0 (2 × ArCH),
83.3 (C6), 77.2 (C7), 73.9 (C1), 73.4 (CH2), 73.3 (CH2), 73.0
(CH2), 72.3 (CH), 70.8 (CH2), 69.3 (CH2), 64.4 (C7a), 61.1 (C5),
55.4 (OCH3), 37.4 (CH2), 19.9 (Me). ESIMS m/z: 660 (70%) [M +
Na]+, 638 (3%) [M + H]+. HRESIMS: found 638.3093, calcd for
C39H44NO7 638.3118 [M + H]+.
(1R,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-1-((S)-
2-hydroxypropyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (19).
Dichloro-5,6-dicyanobenzoquinone (103 g, 0.45 mmol) was added
to a solution of 18 (131 mg, 0.21 mmol) in CH2Cl2/H2O (8:1, 9 mL).
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The reaction mixture was stirred at rt (26 °C) until TLC analysis
(50:50 EtOAc/petrol) showed complete consumption of 18 (4 h).
Purification by flash column chromatography (increasing polarity from
50:50 to 80:20 of EtOAc/petrol as eluent) gave the title compound
(94 mg, 89%) as a yellow oil. Rf 0.23 (50:50 EtOAc/petrol). [α]D25
+19.7 (c 0.08, CHCl3). IR νmax (cm−1): 3452, 2972, 2864, 1742, 1511,
1397, 1361, 1231, 1206, 1127, 1071, 739, 699. NMR δH (500 MHz,
CDCl3): 7.33−7.23 (15H, m), 5.04 (1H, d, J = 11.7 Hz), 4.79 (1H,
ddd, J = 12.7, 8.3, 2.9 Hz), 4.65 (1H, d, J = 11.7 Hz), 4.57−4.50 (3H,
m), 4.40 (1H, d, J = 12.2 Hz), 4.28 (1H, d, J = 7.8 Hz), 4.03 (1H, s),
3.99−3.98 (1H, m), 3.92−3.88 (1H, m), 3.76 (1H, dd, J = 10.2, 2.4
Hz), 3.73 (1H, d, J = 7.8 Hz), 3.60 (1H, dd, J = 10.2, 2.4 Hz), 2.09
(1H, ddd, J = 14.4, 8.3, 2.4 Hz), 1.64 (1H, ddd, J = 14.4, 9.8, 4.4 Hz),
1.07 (3H, d, J = 6.4 Hz). NMR δC (125 MHz, CDCl3): 162.2 (C3),
138.2 (ArC), 138.1 (ArC), 137.7 (ArC), 128.6 (2 × ArCH), 128.5 (2
× ArCH), 128.4 (2 × ArCH), 128.1 (ArCH), 127.8 (5 × ArCH), 127.6
(ArCH), 127.4 (2 × ArCH), 83.4 (C6), 76.9 (C7), 74.0 (C1), 73.4 (2
× CH2), 73.0 (CH2), 69.4 (CH2), 65.2 (CH), 64.4 (C7a), 61.1 (C5),
38.3 (CH2), 24.5 (Me). ESIMS m/z: 540 (100%) [M + Na]+, 518
(48%) [M + H]+. HRESIMS: found 518.2523, calcd for C31H36NO6
518.2543 [M + H]+.
General Method for Hydrolysis of Oxazolidinones. (1R,3S)-1-
((2R,3S,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-2-
yl)butane-1,3-diol (20). Sodium hydroxide (38 mg, 1.66 mmol) and 3
drops of H2O were added to a solution of 19 (171 mg, 0.33 mmol) in
ethanol (3 mL). The reaction mixture was stirred and irradiated in a
CEM microwave reactor (the temperature control was set at 110 °C
and the maximum applied power at 200 W) for 1 h. After the reaction
mixture had cooled to rt it was concentrated in vacuo to give a yellow
semisolid. Purification by flash column chromatography (increasing
polarity from 0:100 to 8:92 of MeOH/CH2Cl2 as eluent) gave the title
compound (156 mg, 96%) as a colorless oil. Rf 0.32 (7.5:92.5 MeOH/
CH2Cl2). [α]2D5 +31.3 (c 0.06, CHCl3). IR νmax (cm−1): 3355, 3029,
2894, 2858, 1494, 1451, 1405, 1344, 1208, 1145, 1084, 1051, 731, 694,
656. NMR δH (500 MHz, CDCl3): 7.35−7.24 (15H), 4.85 (1H, d, J =
11.2 Hz), 4.60 (1H, d, J = 12.2 Hz), 4.55 (1H, d, J = 12.2 Hz), 4.53
(1H, d, J = 11.2 Hz), 4.49 (1H, d, J = 11.7 Hz), 4.43 (1H, d, J = 11.7
Hz), 4.15−4.12 (2H, m, J = 5.0 Hz), 3.99−3.96 (1H, m), 3.90 (1H,
dd, J = 5.4, 5.0 Hz), 3.53−3.47 (2H, m), 3.46−3.44 (1H, m), 3.10
(1H, dd, J = 8.3, 5.4 Hz), 1.71 (1H, ddd, J = 14.4, 5.4, 2.4 Hz), 1.65
(1H, ddd, J = 14.4, 8.8, 5.8 Hz), 1.18 (3H, d, J = 6.4 Hz). NMR δC (75
MHz, CDCl3): 138.0 (ArC), 137.9 (ArC), 137.8 (ArC), 128.6 (2 ×
ArCH), 128.5 (4 × ArCH), 128.2 (3 × ArCH), 128.1 (3 × ArCH),
128.0 (ArCH), 127.9 (2 × ArCH), 80.6 (C4), 79.8 (C3), 73.4 (CH2),
73.3 (CH2), 72.6 (CH2), 70.4 (CH), 69.8 (CH2), 65.3 (CH), 63.1
(C2), 60.7 (C5), 44.6 (CH2), 23.9 (Me). ESIMS m/z: 492 (100%) [M
+ H]+. HRESIMS: found 492.2758, calcd for C30H38NO5 492.2750 [M
+ H]+.
General Method for Mesylation−Cyclization. (1R,3R,5R,6R,-
7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-methylhexa-
hydro-1H-pyrrolizin-1-ol (21). Triethylamine (40 μL, 0.25 mmol) was
slowly added to a solution of 20 (140 mg, 0.25 mmol) in CH2Cl2
(12.8 mL) at 0 °C under a nitrogen atmosphere followed by a 0.13 M
solution of methanesulfonyl chloride in anhydrous CH2Cl2 (2.2 mL,
0.28 mmol MeSO2Cl). The reaction mixture was stirred at 0 °C for 1.5
h and quenched with saturated aqueous NaHCO3 solution (3.5 mL)
and extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to give a
yellow oil. Purification by flash column chromatography (increasing
polarity from 2:98 to 10:90 of MeOH/CH2Cl2 as eluent) gave
compound 21 (134 mg, 100%) as a colorless oil. Rf 0.22 (5:95
MeOH/CH2Cl2). [α]D25 +16.5 (c 0.26, CHCl3). IR νmax (cm−1): 3354,
2913, 2865, 1453, 1360, 1207, 1139, 1090, 1026, 732, 696. NMR δH
(500 MHz, CDCl3): 7.33−7.27 (15H, m), 4.71 (1H, d, J = 12.2 Hz),
4.66 (1H, dd, J = 8.8, 4.4 Hz), 4.58−4.50 (5H, m), 4.14 (1H, dd, J =
5.4, 4.9 Hz), 3.90 (1H, dd, J = 5.0, 4.4 Hz), 3.70−3.67 (1H, m), 3.58
(1H, dd, J = 4.9, 4.4 Hz), 3.45−3.43 (1H, m), 3.39−3.36 (2H, m),
1.85 (2H, dd, J = 7.3, 5.4 Hz), 1.17 (3H, d, J = 6.8 Hz). NMR δC (125
MHz, CDCl3): 138.4 (ArC), 138.3 (ArC) 138.2 (ArC), 128.5 (2 ×
ArCH), 128.4 (4 × ArCH), 127.9 (5 × ArCH), 127.8 (3 × ArCH),
127.7 (ArCH), 81.2 (C2), 76.6 (C1), 75.8 (C7a), 73.5 (CH2), 73.1
(CH2), 72.2 (CH2), 71.8 (C8), 71.3 (C7), 60.2 (C3), 56.9 (C5), 42.4
(C6), 16.2 (C9). ESIMS m/z: 474 (100%) [M + H]+. HRESIMS:
found 474.2624, calcd for C30H36NO4 474.2644 [M + H]+.
General Method for Hydrogenolysis of Benzyl Ethers.
(1S,2R,3R,5R,7R,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (Hyacinthacine B3) (2). PdCl2 (7 mg, 0.04
mmol) was added to a N2-flushed solution of 21 (17 mg, 0.036 mmol)
in MeOH (4 mL). The reaction mixture was stirred at rt under a H2
atmosphere (balloon) for 8 h and then filtered through a pad of Celite
and washed with MeOH (10 mL). The combined filtrates were
concentrated in vacuo to give a colorless film which was dissolved in
water (2 mL) and held for 15 min in a column containing Amberlyst
A-26 (OH−) ion-exchange resin (1 g). Elution with water (3 × 5 mL)
followed by evaporation in vacuo gave the title compound (5 mg,
68%) as a colorless film. [α]2D3 +10.8 (c 0.33, H2O) [lit.3b [α]D + 3.1 (c
0.33, H2O), temperature not reported]. IR νmax (cm−1): 3317, 2960,
2929, 2878, 1652, 1338, 1133. NMR δH (500 MHz, CD3OD): 4.52
(1H, m, H7), 4.04 (1H, t, J = 4.4 Hz, H1), 3.91 (1H, dd, J = 4.2, 7.3
Hz, H2), 3.57 (1H, dd, J = 4.9, 11.0 Hz, H8A), 3.53 (1H, dd, J = 4.5,
11.1 Hz, H8B), 3.50 (1H, m, H5), 3.30 (1H, t, J = 4.6 Hz, H7a), 3.10
(1H, ddd, J = 4.7, 4.9 7.3 Hz, H3), 1.86−1.82 (2H, m, H6α and H6β),
1.19 (3H, d, J = 6.9 Hz, H9). NMR δH (75 MHz, CD3OD): 76.5 (C2),
76.2 (C7a), 71.4 (C1), 70.6 (C7), 64.2 (C8), 63.0 (C3), 56.4 (C5),
43.5 (C6), 16.7 (C9). ESIMS m/z: 204 (100%) [M + H]+. HRMS
found 204.1232, calcd for C9H18NO4 204.1236 [M + H]+.
Synthesis of Hyacinthacine B7 (3) and 7-epi-Hyacinthacine
B7 (6). General Method for the Mitsunobu Reaction. (R)-1-
((1R,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
oxohexahydropyrrolo[1,2-c]oxazol-1-yl)propan-2-yl 4-Nitroben-
zoate (22). A solution of 19 (455 mg, 0.88 mmol), triphenylphosphine
(1038 mg, 3.96 mmol), and p-nitrobenzoic acid (662 mg, 3.959 mmol)
in toluene (9 mL) was cooled to 0 °C, and diisopropyl
azodicarboxylate (0.78 mL, 3.96 mmol) was added. The reaction
mixture was allowed to warm to rt (27 °C) and stirred for 24 h. The
volatiles were removed in vacuo, extracted with CH2Cl2 (3 × 30 mL),
dried (MgSO4), and concentrated in vacuo to give a dark brown oil.
Purification by flash column chromatography (increasing polarity from
0:100 to 10:90 of MeOH/CH2Cl2 as eluent) gave the title compound
(498 mg, 85%) as a yellow oil. Rf 0.30 (30:70 EtOAc/petrol). [α]D25
−26.6 (c 0.64, CHCl3). IR νmax (cm−1): 2934, 2864, 1752, 1719, 1525,
1346, 1274, 1100, 737. NMR δH (500 MHz, CDCl3): 8.24 (2H, d, J =
8.8 Hz), 8.13 (2H, d, J = 8.8 Hz), 7.35−7.20 (15H, m), 5.27−5.21
(1H, m), 5.10 (1H, d, J = 11.7 Hz), 4.72 (1H, dt, J = 7.3, 6.6 Hz), 4.66
(1H, d, J = 11.7 Hz), 4.57 (1H, d, J = 11.7 Hz), 4.52 (1H, d, J = 11.7
Hz), 4.51 (1H, d, J = 11.7 Hz), 4.38 (1H, d, J = 11.7 Hz), 4.32 (1H,
dd, J = 7.8, 2.0 Hz), 4.07 (1H, s, H7), 4.00 (1H, dt, J = 7.8, 2.9 Hz),
3.76 (2H, d, J = 8.3 Hz), 3.59 (1H, J = 10.3, 2.4 Hz), 2.42 (1H, dt, J =
14.6, 7.8 Hz), 2.07 (1H, dt, J = 14.6, 4.4 Hz), 1.31 (3H, d, J = 6.4 Hz).
NMR δC (125 MHz, CDCl3): 164.2 (CO), 161.8 (C3), 150.6 (ArC),
138.1 (ArC), 137.8 (ArC), 137.4 (ArC), 135.7 (ArC), 130.8 (2 ×
ArCH), 128.6 (2 × ArCH), 128.5 (2 × ArCH), 128.4 (2 × ArCH),
128.2 (ArCH), 127.8 (6 × ArCH), 127.7 (2 × ArCH), 127.4 (2 ×
ArCH), 123.6 (2 × ArCH), 83.3 (C6), 76.7 (C7), 73.4 (2 × CH2),
73.0 (CH2), 72.8 (C1), 70.3 (CH), 69.2 (CH2), 63.9 (C7a), 61.1
(C5), 35.5 (CH2), 22.1 (Me). ESIMS m/z: 667 (100%) [M + H]+.
HRASAPMS: found 667.2671, calcd for C38H39N2O9 667.2656 [M +
H]+
(1R,3R)-1-((2R,3S,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-
pyrrolidin-2-yl)butane-1,3-diol (23). Following the general method
for hydrolysis of an oxazolidinone, compound 22 (167 mg, 0.25
mmol) was treated with sodium hydroxide (58 mg, 2.51 mmol) in
ethanol (3 mL) and 3 drops of H2O at 110 °C in a CEM microwave
reactor. Purification by flash column chromatography (0:100 to 5:95
MeOH/CH2Cl2 as eluent) gave the title compound (120 mg, 97%) as
a colorless oil. Rf 0.30 (5:95 MeOH/CH2Cl2). [α]2D5 +18.7 (c 0.83,
CHCl3). IR νmax (cm−1): 3323, 3030, 2864, 1496, 1453, 1360, 1208,
1075, 915, 835, 736, 640. NMR δH (500 MHz, CDCl3): 7.33−7.27
(15H), 4.88 (1H, d, J = 11.7 Hz), 4.61 (1H, d, J = 11.7 Hz), 4.56 (1H,
d, J = 11.7 Hz), 4.53 (1H, d, J = 11.7 Hz), 4.50 (1H, d, J = 12.2 Hz),
4577
dx.doi.org/10.1021/jo5005923 | J. Org. Chem. 2014, 79, 4569−4581

The Journal of Organic Chemistry
Article
4.44 (1H, d, J = 12.2 Hz,), 4.17 (1H, t, J = 4.4 Hz), 4.08−4.05 (1H,
m), 4.03−4.01 (1H, m), 3.89 (1H, dd, J = 5.8, 4.4 Hz), 3.54 (1H, dd, J
= 11.2, 5.4 Hz), 3.48−3.46 (2H, m), 3.02 (1H, dd, J = 7.3, 4.4 Hz),
1.72 (1H, d, J = 14.2 Hz), 1.44 (1H, dt, J = 14.2, 9.8 Hz), 1.16 (3H, d,
J = 5.8 Hz). NMR δC (125 MHz, CDCl3): 138.1 (ArC), 138.0 (ArC),
137.9 (ArC), 128.7 (2 × ArCH), 128.5 (2 × ArCH), 128.2 (2 ×
ArCH), 128.1 (3 × ArCH), 128.0 (3 × ArCH), 127.8 (3 × ArCH),
81.3 (C4), 79.2 (CH), 73.5 (CH2), 73.3 (CH2), 72.9 (C3), 72.8
(CH2), 70.2 (CH2), 68.3 (CH), 63.1 (C2), 60.4 (C5), 42.6 (CH2),
23.8 (Me). ESIMS m/z: 492 (100%) [M + H]+. HRESIMS: found
492.2765, calcd for C30H38NO5 492.2750 [M + H]+.
(1R,3S,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methylhexahydro-1H-pyrrolizin-1-ol (24). Following the general
method for mesylation−cyclization, compound 23 (259 mg, 0.53
mmol) was treated with triethylamine (73 μL, 0.53 mmol) and 0.13 M
solution of methanesulfonyl chloride in anhydrous CH2Cl2 (4.04 mL,
0.53 mmol MeSO2Cl) in CH2Cl2 (28 mL) at 0 °C for 1.5 h.
Purification by flash column chromatography (0:100 to 10:90 MeOH/
CH2Cl2 as eluent) gave the title compound (198 mg, 77%) as a
colorless oil. Rf 0.30 (5:95 MeOH/CH2Cl2). [α]2D5 +21.7 (c 1.03,
CHCl3). IR νmax (cm−1): 3360, 3030, 2922, 2862, 1469, 1452, 1359,
1310, 1208, 1094, 1048, 1027, 914, 735, 696. NMR δH (500 MHz,
CDCl3): 7.32−7.27 (15H, m), 4.74 (1H, J = 11.7 Hz), 4.67 (1H, td,
7.8, 6.6), 4.55−4.48 (5H, m), 4.06 (1H, t, J = 4.6 Hz), 3.92 (1H, dd, J
= 5.6, 4.4 Hz), 3.45−3.41 (3H, m), 3.09 (1H, dd, J = 10.1, 5.6 Hz),
3.06−3.02 (1H, m), 2.27 (1H, dt, J = 11.9, 6.1 Hz), 1.59 (1H, td, J =
11.9, 9.8 Hz), 1.14 (3H, d, J = 6.1 Hz). NMR δC (75 MHz, CDCl3):
138.7 (ArC), 138.5 (ArC) 138.2 (ArC), 128.5 (4 × ArCH), 128.4 (2 ×
ArCH), 127.9 (4 × ArCH), 127.8 (2 × ArCH), 127.7 (3 × ArCH),
82.0 (C2), 77.6 (C1), 73.4 (CH2), 73.3 (C7a), 73.2 (CH2), 72.4
(CH2), 71.7 (C8), 71.0 (C7), 68.2 (C3), 62.4 (C5), 44.0 (C6), 22.0
(C9). ESIMS m/z: 474 (100%) [M + H]+. HRESIMS: found
474.2665, calcd for C30H36NO4 474.2644 [M + H]+.
(1S,2R,3S,5R,7R,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (Putative Hyacinthacine B7) (3). Following the
general method for hydrogenolysis of benzyl ethers, the alcohol 24 (27
mg, 0.059 mmol) was treated with PdCl2 (16 mg, 0.09 mmol) and
MeOH (2 mL) at rt for 3 h. The title compound (10 mg, 84%) was
obtained as a colorless film. [α]2D4 +31.2 (c 0.20, CHCl3). NMR δH
(500 MHz, D2O): 4.60 (1H, ddd, J = 5.8, 7.0, 9.2 Hz), 4.13 (1H, app.
t, J = 4.0 Hz), 4.03 (1H, dd, J = 4.0, 9.1 Hz), 3.74 (1H, dd, J = 4.9, 11.7
Hz), 3.70 (1H, dd, J = 4.9, 11.7 Hz), 3.32 (1H, dd, J = 4.0, 5.8 Hz),
3.06−2.97 (1H, m), 2.81 (1H, app. dd, J = 4.9, 9.1 Hz), 2.38 (1H, ddd,
J = 5.0, 7.0, 12.2 Hz), 1.60 (1H, ddd, J = 9.3, 11.0, 12.2 Hz), 1.17 (1H,
d, J = 6.3 Hz). NMR δC (125 MHz, D2O): 80.3 (C2), 75.8 (C1), 74.0
(C3), 73.5 (C7), 77.6 (C7a), 67.8 (C8), 67.4 (C5), 48.4 (C6), 24.7
(C9). ESIMS m/z: 204 (100%) [M + H]+.
General Method for Swern Oxidation. (3S,5R,6R,7S,7aS)-6,7-
Bis(benzyloxy)-5-(benzyloxymethyl)-3-methylhexahydro-1H-pyrroli-
zin-1-one (25). Oxalyl chloride (79 μL, 0.92 mmol) was added
dropwise via syringe in to a stirred solution of DMSO (130 μL, 1.84
mmol) in CH2Cl2 (5 mL) at −78 °C. The solution was stirred at −78
°C for 5 min, and then a solution of 24 (43 mg, 0.09 mmol) in CH2Cl2
(2 mL) cooled to −78 °C was added dropwise via syringe, followed by
Et3N (513 μL, 3.68 mmol). The reaction mixture was stirred at −78
°C for 1 h and then poured into H2O (40 mL) and extracted with
Et2O (3 × 30 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated in vacuo to give a yellow oil.
Purification by flash column chromatography (increasing polarity from
0:100 to 10:90 of MeOH/CH2Cl2 as eluent) gave the title compound
25 (27 mg, 63%) as a colorless oil and recovered 24 (13.2 mg, 30%).
Rf 0.61 (5:95 MeOH/CH2Cl2). [α]2D5 +28.2 (c 0.32, CHCl3). IR νmax
(cm−1): 3030, 2864, 1750, 1698, 1452, 1361, 1270, 1207, 1098, 736,
661. NMR δH (500 MHz, CDCl3): 7.32−7.23 (15H, m), 4.65 (1H, d, J
= 11.7 Hz), 4.60 (1H, d, J = 12.2 Hz), 4.59 (1H, d, J = 11.7 Hz), 4.51
(1H, d, J = 12.2 Hz), 4.50 (1H, d, J = 11.7 Hz), 4.36 (1H, d, J = 11.7
Hz), 4.18 (1H, t, J = 3.4 Hz), 3.91 (1H, dd, J = 8.8, 3.4 Hz), 3.69 (1H,
d, J = 3.4 Hz), 3.63 (1H, dd, J = 9.8, 3.4 Hz), 3.56 (1H, dd, J = 9.8, 4.9
Hz), 3.50−3.46 (1H, m), 3.35 (1H, dt, J = 8.8, 4.4 Hz), 2.61 (1H, dd, J
= 17.6, 6.8 Hz), 2.10 (1H, dd, J = 17.6, 8.3 Hz), 1.21 (3H, d, J = 5.9
Hz). NMR δC (125 MHz, CDCl3): 214.7 (C7), 138.5 (ArC), 138.4
(ArC), 137.9 (ArC), 128.5 (2 × ArCH), 128.4 (4 × ArCH), 128.0 (3
× ArCH), 127.9 (4 × ArCH), 127.8 (2 × ArCH), 83.4 (C2), 78.8
(C1), 73.8 (CH2), 73.5 (CH2), 73.1 (CH2), 72.0 (C8), 71.8 (C7a),
69.1 (C3), 60.7 (C5), 46.6 (C6), 22.5 (C9). ESIMS m/z: 472 (100%)
[M + H]+. HRASAPMS: found 472.2494, calcd for C30H34NO4
472.2488 [M + H]+.
General Method for the Reduction of a Ketone to a
Secondary Alcohol with L-Selectride. (1S,3S,5R,6R,7S,7aR)-6,7-
Bis(benzyloxy)-5-(benzyloxymethyl)-3-methylhexahydro-1H-pyrroli-
zin-1-ol (26). A solution of the cyclic ketone 25 (63 mg, 0.13 mmol)
in THF (5 mL) was cooled to −78 °C, and then L-Selectride (1.0 M
solution in THF, 536 μL, 0.54 mmol) was slowly added dropwise. The
reaction mixture was stirred at −78 °C for 1 h, warmed to rt (22 °C),
and stirred for 2 h. Ammonia solution (1.0 M, 24 mL) was added, and
the resulting mixture was extracted with EtOAc (3 × 50 mL). The
combined organic extracts was washed with brine, dried (K2CO3), and
concentrated in vacuo to give a light brown film. Purification by flash
column chromatography (increasing polarity from 0:100 to 10:90 of
MeOH/CH2Cl2 as eluent) gave the title compound (44 mg, 70%) as a
colorless oil. Rf 0.34 (5:95 MeOH/CH2Cl2). [α]2D5 +36.2 (c 1.26,
CHCl3). IR νmax (cm−1): 3415, 3030, 2864, 1696, 1452, 1363, 1204,
1098, 1024, 736, 697. NMR δH (500 MHz, CDCl3): 7.33−7.28 (15H,
m), 4.74 (1H, d, J = 11.6 Hz), 4.59 (2H, s), 4.53 (2H, s), 4.48 (1H, d, J
= 11.6 Hz), 4.37−4.33 (2H, m), 4.02 (1H, dd, J = 5.4, 4.9 Hz), 3.80
(1H, s (br)), 3.53 (1H, s (br)), 3.47−3.41 (2H, m), 3.33 (1H, s (br)),
2.08 (1H, dd, J = 12.7, 5.4 Hz), 1.60−1.56 (1H, m), 1.20 (3H, d, J =
4.4 Hz). NMR δC (125 MHz, CDCl3): 138.2 (ArC), 137.6 (ArC),
137.5 (ArC), 128.8 (2 × ArCH), 128.7 (2 × ArCH), 128.6 (2 ×
ArCH), 128.3 (2 × ArCH), 128.1 (4 × ArCH), 128.0 (ArCH), 127.8
(2 × ArCH), 80.6 (C2), 78.6 (C1, br), 73.6 (CH2), 73.5 (CH2), 73.2
(C7), 72.9 (CH2), 71.2 (C8, br), 70.1 (C7a), 69.3 (C3), 62.3 (C5, br),
45.0 (C6), 21.4 (C9, br). ESIMS m/z: 474 [M + H]+. HRASAPMS:
found 474.2642, calcd for C30H36NO4 474.2644 [M + H]+.
(1S,2R,3R,5S,7S,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (7-epi-Hyacinthacine B7) (6). Following the
general method for hydrogenolysis of benzyl ethers, the alcohol 26 (38
mg, 0.08 mmol) was treated with PdCl2 (22 mg, 0.12 mmol) and
MeOH (6 mL) at rt for 3 h. The title compound (14 mg, 84%) was
obtained as a colorless film. [α]2D5 +18.5 (c 0.14, H2O). IR νmax (cm−1):
3287, 2929, 1589, 1381, 1344, 1199, 1127, 1081. NMR δH (500 MHz,
D2O): 4.59 (1H, t, J = 4.9 Hz, H7), 4.41 (1H, dd, J = 5.4, 4.9 Hz, H1),
3.99 (1H, dd, J = 7.3, 4.9 Hz, H2), 3.71 (1H, dd, J = 11.7, 5.4 Hz,
H8A), 3.67 (1H, dd, J = 11.7, 5.8 Hz, H8B), 3.58 (1H, t, J = 5.4 Hz,
H7a), 3.40−3.32 (1H, m, H5), 3.04 (1H, app. dt, J = 6.3, 5.4 Hz, H3),
2.11 (1H, dd, J = 13.7, 5.8 Hz, H6β), 1.71 (1H, ddd, J = 13.7, 10.2, 4.9
Hz, H6α), 1.18 (3H, d, J = 5.9 Hz, H9). NMR δH (125 MHz, D2O):
77.8 (C2), 75.7 (C7), 75.3 (C1), 73.3 (C3), 70.6 (C7a), 65.5 (C8),
64.2 (C5), 46.5 (C6), 22.8 (C9). ESIMS m/z: 204 [M + H]+.
HRASAPMS: found 204.1239, calcd for [C9H18NO4]+, 204.1236 [M +
H]+.
Synthesis of Hyacinthacine B4 (4), Hyacinthacine B5 (5), and
7a-epi-Hyacinthacine B3 (33). Swern Oxidation of 18. (R)-3-
((2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-oxopyrroli-
din-1-yl)butanoic Acid (27). The title compound was prepared
following the general method for Swern oxidation using 21 (107 mg,
0.23 mmol), oxalyl chloride (195 μL, 2.27 mmol), DMSO (322 μL,
4.54 mmol), and Et3N (1.26 mL, 9.08 mmol) in CH2Cl2 (17 mL).
Purification by flash column chromatography (0:100 to 15:85 MeOH/
CH2Cl2 as eluent) gave the title compound 27 (17 mg, 16%), a
mixture of three unknown ketones (16 mg, 15%), and recovered 21
(41.4 mg, 39%), all as colorless oils. Rf 0.50 (10:90 MeOH/CH2Cl2).
[α]D25 +33.3 (c 0.33, CHCl3). IR νmax (cm−1): 3062, 3030, 2931, 2867,
1696, 1495, 1452, 1354, 1307, 1102, 1026, 774, 657. NMR δH (500
MHz, CDCl3): 7.36−7.26 (13H, m), 7.16 (2H, d, J = 7.5 Hz), 4.87
(1H, d, J = 12.2 Hz), 4.71 (1H, d, J = 12.2 Hz), 4.63 (1H, d, J = 12.2
Hz), 4.54 (1H, d, J = 12.2 Hz), 4.43 (1H, d, J = 11.7 Hz), 4.39 (1H, d,
J = 11.7 Hz), 4.22 (1H, d, J = 5.4 Hz), 4.05−3.98 (1H, m), 3.94 (1H,
d, J = 5.4 Hz), 3.63 (1H, s (br)), 3.48 (1H, dd, J = 10.2, 4.4 Hz), 3.47
(1H, dd, J = 10.2, 3.4 Hz), 2.96 (1H, dd, J = 16.1, 7.3 Hz), 2.76 (1H,
4578
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dd, J = 16.1, 6.8 Hz), 1.31 (3H, d, J = 2.9 Hz). NMR δC (75 MHz,
CDCl3): 174.9 (CO), 172.6 (CO), 137.8 (2 × ArC), 137.5 (ArC),
128.6 (2 × ArCH), 128.5 (4 × ArCH), 128.3 (2 × ArCH), 128.1 (2 ×
ArCH), 128.0 (2 × ArCH), 127.9 (ArCH), 127.7 (2 × ArCH), 75.9
(CH), 75.7 (CH), 73.4 (CH2), 72.7 (CH2), 71.9 (CH2), 68.5 (CH2),
62.1 (CH), 47.4 (CH), 38.3 (CH2), 18.2 (Me). ESIMS m/z: 526
(100%) [M + Na]+. HRASAPMS: found 504.2407, calcd for
C30H34NO6 504.2386 [M + H]+.
Swern Oxidation of 21 Followed by Reduction of Ketone to
Secondary Alcohols with L-Selectride. (1S,3R,5R,6R,7S,7aR)-6,7-
Bis(benzyloxy)-5-(benzyloxymethyl)-3-methylhexahydro-1H-pyrroli-
zin-1-ol (28), (3R,5R,6R,7R,7aS)-6,7-Bis(benzyloxy)-5-(benzyloxy-
methyl)-3-methylhexahydro-1H-pyrrolizin-1-one (29), (1R,3R,5R,-
6R,7S,7aS)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-methylhexa-
hydro-1H-pyrrolizin-1-ol (30), and (3R,4R,5R)-3,4-Bis(benzyloxy)-5-
(benzyloxymethyl)-1-((R)-4-hydroxybutan-2-yl)pyrrolidin-2-one
(31). Step 1: Following the general method for the Swern oxidation
using DMSO (778 μL, 10.96 mmol), oxalyl chloride (470 μL, 5.48
mmol), alcohol 18 (259 mg, 0.55 mmol), anhydrous CH2Cl2 (30 mL),
and Et3N (3.04 mL, 21.92 mmol) at −78 °C, a yellow oil was obtained
which was used without further purification in the next reaction with
L-Selectride.
Step 2: Following the general method for reduction of a ketone to a
secondary alcohol with L-Selectride, the above Swern oxidation crude
product in THF (20 mL) was treated with L-Selectride (1.0 M
solution in THF, 2.19 mL, 2.19 mmol). Purification by flash column
chromatography (2:98−15:85 MeOH/CH2Cl2 as eluent) gave
compounds 28 (11.7 mg, 4%), 29 (18.0 mg, 7%), 30 (20.5 mg,
7%), and 31 (17.8 mg, 8%) and recovered 21 (18.1 mg, 7%).
28. Rf 0.44 (10:90 MeOH/CH2Cl2). [α]2D5 +11.5 (c 0.33, CHCl3).
IR νmax (cm−1): 3350, 3030, 2919, 2868, 1690, 1452, 1363, 1097, 1026,
735, 644. NMR δH (500 MHz, CDCl3): 7.34−7.26 (15H, m), 4.81
(1H, d, J = 11.7 Hz), 4.61 (1H, d, J = 11.7 Hz), 4.59 (1H, d, J = 11.7
Hz), 4.55 (1H, d, J = 11.7 Hz), 4.54 (2H, s), 4.44−4.39 (1H, m), 4.34
(1H, dd, J = 5.4, 4.9 Hz), 4.04 (1H, dd, J = 5.8, 4.4 Hz), 3.83 (1H, s
(br)), 3.68−3.66 (1H, m), 3.60−3.55 (2H, m), 3.46−3.43 (1H, m),
2.17 (1H, dt, J = 12.2, 6.3 Hz), 1.69−1.78 (1H, m), 1.28 (3H, d, J =
6.8 Hz). NMR δC (75 MHz, CDCl3): 138.1 (ArC), 137.5 (ArC), 137.3
(ArC), 128.8 (4 × ArCH), 128.6 (2 × ArCH), 128.4 (2 × ArCH),
128.3 (2 × ArCH), 128.2 (2 × ArCH), 128.1 (2 × ArCH), 128.0
(ArCH), 81.4 (C2), 78.3 (C1), 73.6 (2 × CH2), 73.0 (CH2), 71.4 (C7,
absent), 70.8 (C8, observed in HSQC), 68.3 (C7a), 61.2 (C3), 56.6
(C5, observed in HSQC), 43.0 (C6), 16.8 (C9). ESIMS m/z: 474
(100%) [M + H]+. HRASAPMS: found 474.2649, calcd for
C30H36NO4 474.2644 [M + H]+.
observed in HMBC), 62.0 (C3), 50.2 (C5, observed in HMBC), 46.6
(C6, br), 29.8 (C9). ESIMS m/z: 474 (100%) [M + H]+.
HRASAPMS: found 474.2635, calcd for C30H36NO4, 474.2644 [M +
H]+.
31. Rf 0.54 (5:95 MeOH/CH2Cl2). [α]2D5 +77.2 (c 0.95, CHCl3). IR
νmax (cm−1): 3400, 2929, 2866, 1645, 1452, 1359, 1259, 1101, 1025,
697. NMR δH (500 MHz, CDCl3): 7.38−7.16 (15H, m), 4.93 (1H, d, J
= 12.2 Hz), 4.76 (1H, d, J = 12.2 Hz), 4.70 (1H, d, J = 12.2 Hz), 4.53
(1H, d, J = 12.2 Hz), 4.42 (2H, s), 4.36 (1H, d, J = 4.9 Hz), 4.33−4.26
(1H, m), 4.01 (1H, d, J = 4.9 Hz), 3.57 (2H, s (br)), 3.52 (1H, s (br)),
3.48 (1H, dd, J = 10.2, 2.9 Hz), 3.44 (1H, dd, J = 10.2, 4.9 Hz), 1.74−
1.70 (2H, m), 1.17 (1H, d, J = 7.3 Hz). NMR δC (125 MHz, CDCl3):
173.8 (CO), 137.9 (2 × ArC), 137.3 (ArC), 128.7 (2 × ArCH), 128.5
(2 × ArCH), 128.4 (2 × ArCH), 128.2 (2 × ArCH), 128.1 (ArCH),
128.0 (2 × ArCH), 127.9 (ArCH), 127.8 (3 × ArCH), 76.9 (CH), 76.2
(CH), 73.6 (CH2), 72.7 (CH2), 72.3 (CH2), 69.1 (CH2), 59.9 (CH),
58.6 (CH2), 45.1 (CH), 36.1 (CH2), 19.8 (Me). ESIMS m/z: 512
(100%) [M + Na]+. HRESIMS: found 512.2413, calcd for
C30H35NO5Na 512.2413 [M + Na]+.
(1S,3R,5R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methylhexahydro-1H-pyrrolizin-1-ol (32). Following the general
method for the reduction of a ketone to a secondary alcohol with L-
Selectride, the ketone 29 (16 mg, 0.034 mmol) in THF (6 mL) was
treated with L-Selectride (1.0 M solution in THF (136 μL, 0.14
mmol). Purification by flash column chromatography (2:98 to 10:90
MeOH/CH2Cl2 as eluent) gave the title compound (9 mg, 58%) as a
colorless oil. Rf 0.54 (10:90 MeOH/CH2Cl2). [α]2D5 −16.5 (c 0.47,
CHCl3). IR νmax (cm−1): 3369, 3063, 3032, 2927, 2865, 1690, 1454,
1365, 1207, 1099, 1028, 740, 670. NMR δH (500 MHz, CDCl3):
7.31−7.24 (15H, m), 4.61 (1H, d, J = 11.6 Hz), 4.56 (1H, d, J = 11.7
Hz), 4.55 (1H, d, J = 11.7 Hz), 4.50 (1H, d, J = 12.0 Hz), 4.46 (1H, d,
J = 11.6 Hz), 4.44 (1H, d, J = 12.0 Hz), 4.28 (1H, s (br)), 4.18 (1H,
s), 4.09 (1H, s), 3.70 (1H, br), 3.50 (1H, s (br)), 3.45 (1H, dd, J = 9.1,
8.8 Hz), 3.38 (1H, s (br)), 3.20 (1H, s (br)), 2.24 (1H, dt, J = 12.5, 5.9
Hz), 1.37 (1H, dd, J = 12.5, 10.5 Hz), 1.24 (3H, d, J = 6.6 Hz). NMR
δC (125 MHz, CDCl3): 138.4 (ArC), 138.2 (ArC), 137.2 (ArC), 128.8
(2 × ArCH), 128.6 (4 × ArCH), 128.3 (3 × ArCH), 128.0 (2 ×
ArCH), 127.9 (3 × ArCH), 127.8 (ArCH), 85.6 (C2), 82.6 (C1, br),
73.7 (C7), 73.5 (C7a, observed in the HSQC), 73.4 (CH2), 72.8 (C8,
observed in the HSBC), 71.8 (2 × CH2), 62.5 (C3, br), 54.6 (C5, br),
42.9 (C6, br), 17.0 (C9, br). ESIMS m/z: 474 (100%) [M + H]+.
HRASAPMS: found 474.2652, calcd for C30H36NO4 474.2644 [M +
H]+.
(1S,2R,3R,5R,7S,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (Hyacinthacine B5) (5). Following the general
method for hydrogenolysis of benzyl ethers, the alcohol 28 (11.7 mg,
0.03 mmol) was treated with PdCl2 (6.6 mg, 0.04 mmol) and MeOH
(2 mL) at rt (19 °C) for 3 h. The title compound (1.5 mg, 21%) was
obtained as a colorless film. [α]2D5 −21.6 (c 0.08, H2O) [lit.3c [α]D
−25.4 (c 0.26, H2O), temperature not reported]. IR νmax (cm−1):
3299, 2953, 1587, 1555, 1399, 1044, 839, 760, 692. NMR δH (500
MHz, D2O): 4.55 (1H, td, J = 7.1, 6.8 Hz, H7), 4.34 (1H, dd, J = 4.4,
3.9 Hz, H1), 4.04 (1H, dd, J = 7.3, 4.4 Hz, H2), 3.69 (1H, dd, J = 11.2,
4.4 Hz, H8A), 3.65 (1H, dd, J = 11.2, 5.4 Hz, H8B), 3.52 (1H, dd, J =
6.9, 4.4 Hz, H7a), 3.39 (1H, td, J = 6.1, 5.3 Hz, H3), 3.34−3.30 (1H,
m, H5), 2.19 (1H, dt, J = 12.7, 6.3 Hz, H6β), 1.79 (1H, dt, J = 12.7, 8.3
Hz, H6α), 1.29 (3H, d, J = 6.8 Hz, H9). NMR δC (75 MHz, D2O):
77.6 (C2), 75.6 (C7), 75.1 (C1), 69.7 (C7a), 66.0 (C8), 65.3 (C3),
57.7 (C5), 44.3 (C6), 18.1 (C9). ESIMS m/z: 204 (100%) [M + H]+.
HRASAPMS: found 204.1249, calcd for C9H18NO4, 204.1236 [M +
H]+.
29. Rf 0.32 (5:95 MeOH/CH2Cl2). [α]2D5 −62.5 (c 0.81, CHCl3). IR
νmax (cm−1): 3031, 2926, 2870, 1717, 1452, 1361, 1267, 1097, 737,
697. NMR δH (500 MHz, CDCl3): 7.32−7.24 (13H, m), 7.20 (2H, d, J
= 7.0 Hz), 4.55 (2H, d, J = 12.0 Hz), 4.45 (1H, J = 12.0 Hz), 4.43 (2H,
d, J = 12.0 Hz), 4.34 (1H, J = 12.0 Hz), 4.15 (1H, s), 3.99 (1H, s),
3.71−3.67 (2H, m), 3.54−3.48 (3H, m), 2.25−2.13 (2H, m), 1.36
(3H, d, J = 6 0.7 Hz). NMR δC (125 MHz, CDCl3): 218.0 (C7), 138.4
(ArC), 137.6 (2 × ArC), 128.7 (2 × ArCH), 128.6 (2 × ArCH), 128.5
(2 × ArCH), 128.0 (2 × ArCH), 127.8 (4 × ArCH), 127.6 (3 ×
ArCH), 84.0 (C1), 83.0 (C2), 76.4 (C7a), 73.3 (CH2), 73.0 (C8),
71.6 (CH2), 70.9 (CH2), 62.7 (C3), 54.5 (C5), 43.1 (C6), 17.2 (C9).
ESIMS m/z: 472 (100%) [M + H]+. HRASAPMS: found 472.2469,
calcd for C30H34NO4, 472.2488 [M + H]+.
30. Rf 0.69 (20:80 MeOH/CH2Cl2). [α]2D5 +30.3 (c 0.12, CHCl3).
IR νmax (cm−1): 3271, 3030, 2919, 2861, 1454, 1364, 1206, 1102, 1035,
665, 645. NMR δH (500 MHz, CDCl3): 7.35−7.18 (15H, m), 4.71
(1H, d, J = 12.7 Hz), 4.68 (1H, d, J = 12.7 Hz), 4.56 (2H, s), 4.45 (1H,
d, J = 11.7 Hz), 4.39(1H, d, J = 11.7 Hz), 4.20 (1H, dd, J = 7.3, 4.9
Hz), 4.07−4.04 (2H, m), 3.85 (1H, s (br)), 3.71 (1H, dd, J = 10.5, 2.9
Hz), 3.48 (1H, s (br)), 3.33 (1H, dd, J = 10.5, 2.0 Hz), 3.24−3.20
(1H, m), 2.05 (1H, dd, J = 12.7, 5.4 Hz), 1.72 (1H, td, J = 12.7, 3.4
Hz), 1.30 (3H, d, J = 5.8 Hz). NMR δC (125 MHz, CDCl3): 138.8
(ArC), 136.9 (2 × ArC), 128.7 (2 × ArCH), 128.5 (2 × ArCH), 128.3
(2 × ArCH), 128.1 (2 × ArCH), 127.9 (2 × ArCH), 127.7 (2 ×
ArCH), 84.1 (C7, observed in HMBC), 75.6 (C1, br), 73.7 (CH2),
73.3 (C2, br), 72.2 (CH2), 71.8 (CH2), 71.6 (C7a, br), 68.0 (C8,
(1R,2R,3R,5R,7S,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (Hyacinthacine B4) (4). Following the general
method for hydrogenolysis of benzyl ethers, the alcohol 32 (8.4 mg,
0.018 mmol) was treated with PdCl2 (4.8 mg, 0.027 mmol) and
MeOH (1.4 mL) at rt (22 °C) for 3 h. The title compound (3.6 mg,
100%) was obtained as a colorless film. [α]2D5 −7.7 (c 0.18, H2O) [lit.3c
[α]D −6.7 (c 1.19, H2O), temperature not reported]. IR νmax (cm−1):
3291, 2930, 2882, 1637, 1592, 1384, 1343, 1137, 1064, 612. NMR δH
(500 MHz, D2O): 4.44 (1H, td, J = 6.4, 5.7 Hz, H7), 4.16 (1H, dd, J =
4579
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7.8, 7.3 Hz, H1), 3.97 (1H, dd, J = 7.8, 7.0 Hz, H2), 3.69 (2H, d, J =
5.4 Hz, H8), 3.30 (1H, dd, J = 7.3, 6.8 Hz, H7a), 3.28−3.24 (1H, m,
H5), 3.14 (1H, dt, J = 7.8, 5.4 Hz, H3), 2.14 (1H, dt, J = 13.2, 5.7 Hz,
H6β), 1.71 (1H, ddd, J = 13.2, 7.3, 6.4 Hz, H6α), 1.26 (3H, d, J = 7.3
Hz, H9). NMR δC (125 MHz, D2O): 82.0 (C2), 77.1 (C1), 73.1 (C7),
72.9 (C7a), 66.0 (C8), 64.5 (C3), 57.0 (C5), 42.7 (C6), 19.0 (C9).
ESIMS m/z: 204 (100%) [M + H]+. HRASAPMS: found 204.1246,
calcd for C9H18NO4 204.1236 [M + H]+.
(1S,2R,3R,5R,7R,7aS)-3-(Hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2,7-triol (7a-epi-Hyacinthacine B3) (33). Following the
general method for hydrogenolysis of benzyl ethers, the alcohol 30
(2.3 mg, 0.005 mmol) was treated with PdCl2 (1.3 mg, 0.008 mmol),
and MeOH (0.5 mL) at rt (24 °C). The title compound (1.0 mg,
100%) was obtained as a colorless film. [α]2D5 −5.3 (c 0.11, H2O). IR
νmax (cm−1): 3294, 2967, 1649, 1552, 1405, 1083, 1044. NMR δH (500
MHz, D2O): 4.38 (1H, t, J = 3.9 Hz, H7), 4.26 (1H, dd, J = 4.4, 3.9
Hz, H1), 4.08 (1H, dd, J = 7.3, 4.9 Hz, H2), 3.97 (1H, dd, J = 12.7, 6.8
Hz, H8A), 3.89 (1H, dd, J = 12.7, 3.9 Hz, H8B), 3.59 (1H, dd, J = 4.4,
3.9 Hz, H7a), 3.51, (1H, ddd, J = 5.9, 4.4, 3.9 Hz, H5), 3.23 (1H, ddd,
J = 6.8, 4.9, 3.9 Hz, H3), 2.05 (1H, ddd, J = 13.2, 4.4, 3.9 Hz, H6β),
1.71 (1H, ddd, J = 13.2, 11.2, 4.4 Hz, H6α), 1.22 (3H, d, J = 5.9 Hz,
H9). NMR δC (125 MHz, D2O): 77.5 (C7a), 76.4 (C2), 72.1 (C7),
72.0 (C1), 66.8 (C3), 61.4 (C8), 55.2 (C5), 46.3 (C6), 22.0 (C9).
ESIMS m/z: 204 (100%) [M + H]+. HRASAPMS: found 204.1234,
calcd for C9H18NO4, 204.1236 [M + H]+.
(1R,3R,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methylhexahydro-1H-pyrrolizin-1-yl 4-nitrobenzoate (36). Follow-
ing the general method for the Mitsunobu reaction, the alcohol 21
(144 μg, 0.30 mmol) was treated with triphenylphosphine (354 mg,
1.35 mmol), p-nitrobenzoic acid (226 mg, 1.35 mmol), and
diisopropyl azodicarboxylate (266 μL, 3.96 mmol) in toluene (3
mL) at 80 °C for 2 d. Purification by flash column chromatography
(20:70 to 50:50 EtOAc/petrol as eluent) gave the title compound (ca.
70% pure) (40 mg) as a yellow film, and recovered 21 (45.5 mg, 32%)
was also isolated. Rf 0.60 (5:95 MeOH/CH2Cl2). IR νmax (cm−1):
2921, 2854, 1722, 1527, 1347, 1273, 1103, 1027, 736, 697. NMR δH
(500 MHz, CDCl3): 8.28 (2H, d, J = 8.8 Hz), 8.16 (2H, d, J = 8.8 Hz),
7.37−7.22 (15H, m), 5.77 (1H, dt, J = 7.3, 4.1 Hz), 4.75 (1H, d, J =
11.7 Hz), 4.64−4.47 (5H, m), 4.19 (1H, dd, J = 5.3, 4.1 Hz), 3.93 (1H,
s (br)), 3.78 (1H, dd, J = 5.3, 3.2 Hz), 3.68−3.60 (1H, m), 3.42 (3H, s
(br)), 2.01 (2H, m), 1.27 (3H, d, J = 6.2 Hz). NMR δC (125 MHz):
164.4 (CO), 150.6 (ArC), 138.3 (2 × ArC), 138.2 (ArC), 135.7
(ArC), 130.8 (2 × ArCH), 128.7 (2 × ArCH), 128.5 (4 × ArCH),
127.9 (3 × ArCH), 127.8 (5 × ArCH), 127.7 (2 × ArCH), 123.6
(ArCH), 81.4 (C2), 76.9 (C1), 76.1 (C7, br), 73.5 (CH2), 73.4 (CH2),
72.6 (CH2), 72.4 (C8), 60.1 (C3), 56.7 (C5), 39.8 (C6), 22.1 (C1).
ESIMS m/z: 623 (100%) [M + H]+. HRESIMS: found 623.2737, calcd
for C37H39N2O7 623.2757 [M + H]+.
(1R,3R,5R,6R,7S,7aS)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methylhexahydro-1H-pyrrolizin-1-yl Methanesulfonate (37). Fol-
lowing the general method for mesylation−cyclization, the alcohol 21
(16.8 mg, 0.034 mmol) was treated with triethylamine (81 μL, 0.58
mmol), methanesulfonyl chloride (184 μL, 2.38 mmol), and CH2Cl2
(1.5 mL) at rt for 24 h. Purification by flash column chromatography
(0:100 to 5:95 MeOH/CH2Cl2 as eluent) gave the title compound
(16.5 mg, 87%) as a colorless oil. Rf 0.67 (5:95 MeOH/CH2Cl2). [α]D25
−10.5 (c 0.16, CHCl3). IR νmax (cm−1): 3063, 3030, 2929, 2866, 1453,
1351, 1174, 1116, 1026, 935, 895, 697. NMR δH (500 MHz, CDCl3):
7.35−7.25 (15H, m), 5.50−5.49 (1H, m), 4.59−4.44 (6H, m), 4.22
(1H, dd, J = 5.9, 4.9 Hz), 3.89 (1H, s (br)), 3.66−3.64 (1H, m), 3.56−
3.49 (1H, m), 3.33 (1H, dd, J = 8.5, 4.4 Hz), 3.28−3.25 (1H, m), 3.20
(1H, dd, J = 8.5, 7.8 Hz), 2.81 (3H, s), 2.06 (1H, dd, J = 13.7, 4.9 Hz),
1.93−1.86 (1H, m), 1.19 (3H, d, J = 6.8 Hz). NMR δC (75 MHz,
CDCl3): 138.3 (ArC), 137.9 (2 × ArC), 132.2 (2 × ArCH), 128.5
(ArCH), 128.2 (4 × ArCH), 128.0 (2 × ArCH), 127.9 (4 × ArCH),
127.8 (2 × ArCH), 83.3 (C7), 79.2 (C2), 77.2 (C1), 73.6 (CH2), 73.4
(C7a), 72.9 (CH2), 72.4 (C8), 71.6 (CH2), 60.6 (C3), 56.8 (C5), 39.9
(C6), 37.7 (Me), 15.5 (C9). ESIMS m/z: 552 (100%) [M + H]+.
HRESIMS: found 552.2418, calcd for C31H38NO6S 552.2420 [M +
H]+.
(1R,3R,5R,6R,7S,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methylhexahydro-1H-pyrrolizin-1-yl Benzoate (38). A solution of
the mesylate 36 (31 mg, 0.06 mmol) in DMSO (6 mL) was stirred at
rt for 5 min, and then cesium benzoate (26 mg, 0.11 mmol) was
added. The reaction mixture was stirred at 70 °C for 2 d. After the
reaction mixture had cooled to rt, a satd aq solution of Na2CO3 (5
mL) was added and then extracted with Et2O (3 × 20 mL), dried
(MgSO4), and concentrated in vacuo to give a light brown film.
Purification by flash column chromatography (increasing polarity from
5:95 to 20:80 of EtOAc/CH2Cl2 as eluent) gave the title compound
(14 mg, 42%) as a colorless film. Rf 0.20 (2:98 MeOH/CH2Cl2). [α]D25
−18.7 (c 0.28, CHCl3). IR νmax (cm−1): 3063, 3031, 2924, 2862, 1715,
1452, 1358, 1273, 1111, 1025, 736, 696. NMR δH (500 MHz, CDCl3):
8.01 (2H, d, J = 7.8 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.42 (2H, dd, J = 7.8,
7.3 Hz), 7.33−7.22 (15H, m), 5.75−5.72 (1H, m), 4.74 (1H, d, J =
11.7 Hz), 4.67 (1H, d, J = 11.7 Hz), 4.62 (1H, d, J = 11.7 Hz), 4.56
(1H, d, J = 12.2 Hz), 4.51 (1H, d, J = 11.7 Hz), 4.49 (1H, d, J = 12.2
Hz), 4.18 (1H, dd, J = 4.9, 3.9 Hz), 3.92 (1H, t, J = 3.9 Hz), 3.78 (1H,
s (br)), 3.66−3.62 (1H, m), 3.43 (3H, s (br)), 2.02−2.00 (2H, m),
1.22 (3H, d, J = 6.8 Hz). NMR δC (125 MHz, CDCl3): 166.4 (CO),
138.6 (2 × ArC), 138.4 (ArC), 133.0 (2 × ArCH), 130.7 (ArC), 129.7
(2 × ArCH), 128.4 (4 × ArCH), 127.9 (2 × ArCH), 127.8 (4 ×
ArCH), 127.7 (2 × ArCH), 127.6 (2 × ArCH), 81.7 (C2), 76.9 (C1),
75.6 (C7), 73.5 (CH2), 73.3 (CH2), 72.5 (C7a and CH2), 72.2 (C8),
59.9 (C3), 56.4 (C5), 39.9 (C6), 16.2 (C9). ESIMS m/z: 578 [M +
H]+. HRESIMS: found 578.2902, calcd for C37H40NO5 578.2906 [M +
H]+.
ASSOCIATED CONTENT
■
S
* Supporting Information
Comparative tables of the 1H and 13C NMR spectroscopic data
of synthetic and natural samples of compounds 2−6, copies of
1
the H and 13C NMR spectra of all new compounds, and
NOESY spectra of compounds 2−6 and 33. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: spyne@uow.edu.au.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is funded by the Australian Research Council.
K.S. thanks The Royal Thai Government under The Ministry
of Science and Technology scholarship for full financial support
of his Ph.D. program.
REFERENCES
■
(1) (a) Asano, N. In Modern Alkaloids: Structure, Isolation, Synthesis
and Biology; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH
Verlag: Weinheim, 2008; pp 111−138. (b) Nash, R. J.; Kato, A.; Yu,
C.; Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513−1521.
(2) For reviews on their synthesis, see: (a) Pyne, S. G.; Tang, M.
Curr. Org. Chem. 2005, 9, 1393−1418. (b) Lopez, M. D.; Cobo, J.;
Nogeuras, M. Curr. Org. Chem. 2008, 12, 718−750. (c) Ritthiwigrom,
T.; Au, C. W. G.; Pyne, S. G. Curr. Org. Synth. 2012, 9, 583−612.
(3) (a) 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, 95−103. (b) Asano, N.;
Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1−8. (c) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002,
65, 1875−1881. (d) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.;
Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R. J. J. Nat.
4580
dx.doi.org/10.1021/jo5005923 | J. Org. Chem. 2014, 79, 4569−4581

The Journal of Organic Chemistry
Article
Prod. 2007, 70, 993−997. (e) Asano, N.; Ikeda, K.; Kasahara, M.; Arai,
Y.; Kizu, H. J. Nat. Prod. 2004, 67, 846−850.
Org. Chem. 2006, 71, 7097−7099. (d) Ritthiwigrom, T.; Willis, A. C.;
Pyne, S. G. J. Org. Chem. 2010, 75, 815−824. (e) Jiangseubchatveera,
N.; Bouillon, M. E.; Liawruangrath, B.; Liawruangrath, S.; Nash, R. J.;
Pyne, S. G. Org. Biomol. Chem. 2013, 11, 3826−3833. (f) Bouillon, M.
E.; Pyne, S. G. Tetrahedron Lett. 2014, 55, 475−478.
(4) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.;
Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615−3618.
(5) (a) Ramabaud, L.; Compain, P.; Martin, O. R. Tetrahedron:
Asymmetry 2001, 12, 1807−1809. (b) Izquierdo, I.; Plaza, M. T.;
Robles, R.; Franco, F. Tetrahedron: Asymmetry 2002, 13, 1581−1585.
(c) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A.
Tetrahedron Lett. 2003, 44, 2315−2318. (d) Izquierdo, I.; Plaza, M. T.;
Franco, F. Tetrahedron: Asymmetry 2003, 14, 3933−3935. (e) Des-
(15) Crispino, G. A.; Jeong, K.; Kolb, H. C.; Wang, Z.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785−3786.
(16) Siedlecka, R.; Skarzewski, J.; Mlochowshi, J. Tetrahedron Lett.
1990, 31, 2177−2180.
(17) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818−7824.
(18) (a) Davis, A. S.; Gates, N. J.; Lindsay, K. B.; Tang, M.; Pyne, S.
G. Synlett 2004, 49−52. (b) Murray, A. J.; Parsons, P. J.; Greenwood,
E. S.; Viseux, E. M. E. Synlett 2004, 1589−1591. (c) Murray, A. J.;
Parsons, P. J.; Hitchcock, P. B. Tetrahedron 2007, 63, 6485−6492.
(19) Machan, T.; Davis, A. S.; Liawruangrath, B.; Pyne, S. G.
Tetrahedron 2008, 64, 2725−2732.
́
vergnes, S.; Py, S.; Valee, Y. J. Org. Chem. 2005, 70, 1459−1462.
(f) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587−
2590. (g) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Sanchaz-Cantalejo,
F. Tetrahedron: Asymmetry 2007, 18, 2211−2217. (h) Izquierdo, I.;
Plaza, M. T.; Tamayo, J. A.; Yanez, V.; Re, D. L.; Sanchaz-Cantalejo, F.
Tetrahedron 2008, 64, 4613−4618. (i) Zhang, T.-X.; Zhou, L.; Cao, X.-
P. Chem. Res. Chin. Univ. 2008, 24, 469−472. (j) Izquierdo, I.; Plaza,
M. T.; Tamayo, J. A.; Franco, F.; Sanchaz-Cantalejo, F. Tetrahedron
2010, 66, 3788−3794. (k) Delso, I.; Tejero, T.; Goti, A.; Merino, P.
Tetrahedron 2010, 66, 1220−1227. (l) Hu, X.-G.; Jia, Y.-M.; Xiang, J.;
Yu, C.-Y. Synlett 2010, 982−986. (m) Tamayo, J. A.; Franco, F.;
(20) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 3017−3020.
(21) Mancuso, A. J.; Swern, D. Synthesis 1981, 3, 165−185.
(22) Dijkstra, G.; Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem.
1987, 52, 4230−4234.
(23) (a) Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67,
1751−1753. (b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.;
Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551−2651.
(24) For the formation of aziridinium ion intermediates in related
systems, see: Krow, G. R.; Edupuganti, R.; Gandla, D.; Choudhary, A.;
Lin, G.; Sonnet, P. E.; De Brosse, C.; Ross, C. W.; Cannon, K. C.;
Raines, R. T. J. Org. Chem. 2009, 74, 8232−8242.
́
Saanchez-Cantalejo, F. Tetrahedron 2010, 66, 7262−7267. (n) Zhang,
W.; Sato, K.; Kato, A.; Jia, Y.; Hu, X.; Wilson, F. X.; Well, R.; Horne,
G.; Fleet, G. W. J.; Nash, R. J.; Yu, C. Org. Lett. 2011, 13, 4414−4417.
(o) D’Adamio, G.; Goti, A.; Parmeggiani, C.; Moreno-Clavijo, E.;
Robina, I.; Cardona, F. Eur. J. Org. Chem. 2011, 7155−7162.
(p) Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.; Yoda, H.
Tetrahedron 2008, 64, 8052−8058. (q) Sengoku, T.; Satoh, Y.;
Takahashi, M.; Yoda, H. Tetrahedron Lett. 2009, 50, 4937−4940.
(r) Ribes, C.; Falomir, E.; Murga, J.; Carda, M.; Marco, J. A.
Tetrahedron 2009, 65, 6965−6971. (s) Chandrasekhar, S.; Parida, B.
B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826−7828. (t) Liu, X.-K.;
Qiu, S.; Xiang, Y.-G.; Ruan, Y.-P.; Zheng, X.; Huang, P.-Q. J. Org.
Chem. 2011, 76, 4952−4963. (u) Brock, E. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem. 2013, 11, 3187−
3202.
(6) Dewi-Wulfing, P.; Blechert, S. Eur. J. Org. Chem. 2006, 1852−
̈
1856.
(7) (a) Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.;
Delair, P. Org. Biomol. Chem. 2008, 6, 1170−1172. (b) Reddy, P. V.;
Koos, P.; Veyron, A.; Greene, A. E.; Delair, P. Synlett 2009, 1141−
1143. (c) Reddy, P. V.; Smith, J.; Kamath, A.; Jamet, H.; Veyron, A.;
Koos, P.; Philouze, C.; Greene, A. E.; Delair, P. J. Org. Chem. 2013, 78,
4840−4849.
(8) Calveras, J.; Casas, J.; Parella, T.; Joglar, J.; Clapes
́
, P. Adv. Synth.
Catal. 2007, 349, 1661−1666.
(9) (a) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2002, 13, 1581−1585. (b) Izquierdo, I.; Plaza, M. T.; Franco, F.
Tetrahedron: Asymmetry 2004, 15, 1465−1469. (c) Izquierdo, I.; Plaza,
M. T.; Tamayo, J. A.; Rodriguez, M.; Martos, A. Tetrahedron 2006, 62,
6006−6011. (d) Zhou, L.; Chen, J.; Cao, X.-P. Synthesis 2007, 1359−
1365. (e) Kaliappan, K. P.; Das, P. Synlett 2008, 6, 841−844.
́
(f) Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo, F. Eur. J. Org. Chem.
2011, 7182−7188. (g) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org.
Chem. 2013, 1749−1757. (h) Martella, D.; Cardona, F.; Parmeggiani,
C.; Franco, F.; Tamayo, J. A.; Robina, I.; Moreno-Clavijo, E.; Moreno-
Vargas, A. J.; Goti, A. Eur. J. Org. Chem. 2013, 4047−4056.
(i) Marjanovic, J.; Divjakovic, V.; Matovic, R.; Ferjancic, Z.; Saicic,
R. N. Eur. J. Org. Chem. 2013, 5555−5560.
(10) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem.
2005, 70, 7297−7304.
(11) Au, C. W. G.; Nash, R. J.; Pyne, S. G. Chem. Commun. 2010, 46,
713−715.
(12) Evans, P.; Leffray, M. Tetrahedron 2003, 59, 7973−7987.
(13) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968−5976.
(14) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120,
11798−11799. (b) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A.
H. J. Org. Chem. 2004, 69, 3139−3143. (c) Au, C. W. G.; Pyne, S. G. J.
4581
dx.doi.org/10.1021/jo5005923 | J. Org. Chem. 2014, 79, 4569−4581