Enantioselective syntheses of rigidiusculamides A and B: Revision of the relative stereochemistry of rigidiusculamide A

Article abstract of DOI:10.1002/asia.201100809

The first enantioselective synthesis of cytotoxic natural products rigidiusculamides A (ent-21) and B (8) has been achieved by two synthetic routes. The first one is convergent based on the common intermediate 11, obtained through a high yielding SmI₂-mediated Reformatsky-type reaction. A highly diastereoselective one-pot Dess-Martin periodinane-mediated bis-oxidation allowed the direct conversion of the diastereomeric mixture of 11 into rigidiusculamide B (8). Isolation of minor diastereomer 21, in combination with computational work, allowed us to suggest the structure of the natural rigidiusculamide A to be ent-21, as synthesized by the second route. Four diastereomers (7, ent-7, 22 a, and 22 b) and an enantiomer (21) of rigidiusculamide A (ent-21) have been synthesized. On the basis of literature precedents and computational work, a biosynthetic pathway for rigidiusculamides A and B was proposed to account for the opposite configuration at C-5 of those two congeners.

Full text of DOI:10.1002/asia.201100809

FULL PAPERS
DOI: 10.1002/asia.201100809
Enantioselective Syntheses of Rigidiusculamides A and B: Revision of the
Relative Stereochemistry of Rigidiusculamide A
Gui-Yang Chen, Huang Huang, Jian-Liang Ye, Ai-E Wang, Hui-Ying Huang,
Hong-Kui Zhang, and Pei-Qiang Huang*[a]
504
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Chem. Asian J. 2012, 7, 504 – 518

Abstract: The first enantioselective
synthesis of cytotoxic natural products
rigidiusculamides A (ent-21) and B (8)
has been achieved by two synthetic
routes. The first one is convergent
based on the common intermediate 11,
obtained through a high yielding SmI2-
mediated Reformatsky-type reaction.
sion of the diastereomeric mixture of
11 into rigidiusculamide B (8). Isola-
tion of minor diastereomer 21, in com-
bination with computational work, al-
lowed us to suggest the structure of the
natural rigidiusculamide A to be ent-
21, as synthesized by the second route.
Four diastereomers (7, ent-7, 22a, and
22b) and an enantiomer (21) of rigidi-
usculamide A (ent-21) have been syn-
thesized. On the basis of literature
precedents and computational work, a
biosynthetic pathway for rigidiuscula-
mides A and B was proposed to ac-
count for the opposite configuration at
C-5 of those two congeners.
Keywords: biosynthetic pathways ·
computational chemistry · natural
products · structure elucidation ·
total synthesis
A
highly diastereoselective one-pot
Dess–Martin periodinane-mediated
bis-oxidation allowed the direct conver-
Introduction
the isolation of rigidiusculamides A–D (7–10) from a crude
extract of the ascomycete fungus Albonectria rigidiuscula,[12]
and found that compounds 7 and 8 exhibited modest cyto-
toxicity against the human tumor cell lines HeLa and MCF-
7. The structure and related stereochemistry of rigidiuscula-
mide A were elucidated by NMR spectroscopy techniques,
including NOESY, and the absolute stereochemistry was de-
termined by the Snatzke circular dichroism technique.
Oxygenated pyrrolidines occur as key structural features in
many bioactive natural products, such as azasugars,[1] tetra-
mic acids (pyrrolidin-2,4-diones)/tetramates,[2] and g-hy-
droxy-g-lactams/g-alkylidene-g-lactams.[3] Although hydroxy-
lated pyrrolidin-2-ones are not yet recognized as a distinct
class of natural products, their bioactivity has attracted
much attention. For example, clausenamide (1),[4] isolated
from the leaves of Clausena lansium (Lour) Skeels, showed
remarkable nootropic activity,[4b] and is under clinical trial
for the treatment of Alzheimerꢁs disease.[4c] Moreover, the
discovery of lactacystin (2)[5] as a potent inhibitor of 20S
proteosome[6] has aroused interest in research on hydroxy-
lated pyrrolidin-2-ones (g-lactams).[7–11] More and more bio-
active hydroxylated g-lactams have been isolated from
sponges and microorganisms. The lactacystin series of lac-
tams (omuralide (3),[6a,d] salinosporamides A–J,[7] and so
on[8]) are of the most importance. Salinosporamide A (NPI-
0052; 4), which is a secondary metabolite of the marine acti-
nomycete Salinispora tropica, is reported to be approximate-
ly thirty-five times more effective than omuralide as a pro-
teosome inhibitor and is currently in clinical trials for the
treatment of cancer.[9] On the other hand, in addition to the
known dysidamide (5)[10a] and dysidamides B and C,[10b]
which were isolated from the marine sponge Dysidea herba-
cea, five new members of polychlorinated pyrrolidinones
have been isolated from the Red Sea marine sponge Lamel-
lodysidea herbacea.[10c] The X-ray crystallographic diffraction
analysis of compound 5 revealed the presence of two C-5
epimers in a ratio of 3:1. Structurally simple streptopyrroli-
dine (6), isolated from the fermentation broth of a marine
Streptomyces sp. KORDI-3973 from the deep sea sedi-
ment,[5] was shown to significantly block capillary tube for-
mation in cells.[11] Recently, Che and co-workers reported
[a] G.-Y. Chen, H. Huang, Dr. J.-L. Ye, Dr. A.-E Wang, H.-Y. Huang,
Prof. Dr. H.-K. Zhang, Prof. Dr. P.-Q. Huang
Department of Chemistry
In continuation of our studies on the asymmetric synthe-
ses of bioactive N-containing heterocycles,[13] in particular,
pyrrolidin-2-ones[14] and tetramic acids/tetramates,[15] we
have been engaged in the total synthesis of rigidiusculami-
des A and B. We now report the results of this study, which
include the first enantioselective and stereodivergent synthe-
sis of rigidiusculamide B (8) and the proposed structure of
and Key Laboratory for Chemical Biology of Fujian Province
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen, Fujian 361005 (P.R. China)
Fax : (+86)-592-2186400
E-mail: pqhuang@xmu.edu.cn
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rigidiusculamide A (7), as well as the revised structure of ri-
gidiusculamide A (ent-21). On the basis of NMR spectrosco-
py and computation studies, the relative stereochemistry of
the natural rigidiusculamide A was revised as 3S,4S,5R.
Results and Discussion
First Synthetic Route: Syntheses of Rigidiusculamide B (8)
and the Proposed Structure of Rigidiusculamide A (7)
Our retrosynthetic analysis suggested (5S)-4-hydroxypyrroli-
din-2-one (11) as a common intermediate for the synthesis
of rigidiusculamides A and B (7 and 8; Scheme 1). Com-
pound 11 would be available from compound 12 by cycliza-
Scheme 2. Synthesis of pyrrolidin-2-one 11 by the SmI2-mediated Refor-
matsky reaction. TFA=trifluoroacetic acid.
reomers of 11 could be separated into two fractions, 11a/
11b and 11c/11d, in a ratio of 84:16 by flash column chro-
1
matography. H NMR spectral analysis showed that the dia-
stereomeric ratio of fraction 11a/11b was 69:31 and that of
the fraction 11c/11d was 50:50. The diastereomeric ratio of
11 and its precursor 12 was thus determined to be 58:26:8:8.
With the key intermediate 11 in hand, we first carried out
the synthesis of 8. For this purpose, both stereoselective a-
hydroxylation and oxidation of the b-hydroxyl group were
required. In connection with our recent interest in step-
economy syntheses,[23,24] we anticipated to undertake a one-
pot conversion of the diastereomeric mixture of 11 to 16. In
this context, Kirsch has reported[25] an 2-iodylbenzoic acid
(IBX)-mediated one-pot a-hydroxylation of a-alkynyl alco-
hols.[26] In the total synthesis of decarbamoyloxysaxitoxin,
Nagasawa and co-workers also attempted a one-pot b-hy-
droxyl oxidation/N-a-hydroxylation on a specific substrate
by using IBX as an oxidant.[27]
To achieve our goal, and after unsuccessful trials with
IBX, we elected to use Dess–Martin periodinane (DMP) as
an oxidant.[28] It was hoped that the hydroxyl group could be
oxidized by DMP to give a 1,3-dicarbonyl intermediate (tet-
ramic acid), which would be further oxidized (hydroxyl-
ation) with DMP to give the desired product. To the best of
our knowledge, hydroxylation with DMP has not been re-
ported previously, whereas a-hydroxylation of 1,3-dicarbon-
yl compounds is well documented.[29] To our delight, expo-
sure of the 11a/11b fraction to DMP (4 equiv) in dimethyl-
sulfoxide (DMSO) at 508C for 12 hours produced the de-
sired compound 16 in 76% yield as the only isolable diaste-
reomer (Scheme 3).
Scheme 1. Retrosynthetic analysis of rigidiusculamide B (8) and the pro-
posed structure of rigidiusculamide A (7). Bn=benzyl, Boc=tert-buty-
loxycarbonyl.
tion, which in turn, could be accessed from 13 through
either propionate enolate addition[16] or a Reformatsky reac-
tion.[17,18] In view of the configurational instability of amino
aldehydes,[16,19] the milder SmI2-mediated[20] Reformatsky-
type reaction[18] was envisioned for the coupling of aldehyde
(S)-13 and ethyl 2-bromopropionate (14).
The configurationally labile a-amino aldehyde (S)-13 was
prepared by a known procedure from l-tyrosine in 65%
overall yield.[21] For the Reformatsky reaction, the SmI2-
mediated version developed by Molander and Etter was
used.[18a] By treating a solution of amino aldehyde (S)-13
and 14 in tetrahydrofuran (THF) with a freshly prepared
[22]
0.1m SmI2 (4.0 equiv) in THF at ꢀ258C for 0.5 hours pro-
duced the desired product 12 as a diastereomeric mixture in
91% yield (Scheme 2). The ratio of the four diastereomers
of compound 12 was not determined at this stage, but was
deduced from their cyclization products 11a–d.
As rigidiusculamides A and B were projected to be syn-
thesized from 11 by dehydration–diastereoselective dihy-
droxylation and bis-oxidation, respectively, in principle, all
four diastereomers of 11 can serve well for both purposes.
Thus, all four diastereomers of 12 could be used in the next
step without separation. Treatment of the diastereomeric
mixture of 12 successively with TFA and K2CO3 in toluene
provided pyrrolidin-2-one 11 in 86% yield. The four diaste-
The relative stereochemistry of compound 16 was deter-
mined by NOESY experiments. The correlations between
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Syntheses of Rigidiusculamides A and B
ered mesylate was in a diastereomeric ratio of 73:27, which
was similar to the original ratio of the starting mixture 11a/
11b (69:31). HPLC analysis of 18 on a chiral stationary
phase showed that the enantiomeric excess (ee) of 18
(½aꢁ2D0 =+146.6 (c=1.0, CHCl3)) was at least 95% (see Fig-
ure S-9 in the Supporting Information).
We next turned our attention to the diastereoselective cis-
dihydroxylation of 18. For the diastereoselective cis-dihy-
droxylation of g-substituted a,b-unsaturated lactams,[31,32]
both Upjohn (OsO4 (cat.), NMO, acetone/H2O))[31a] and
Mukaiyama conditions (KMnO4, [18]crown-6, CH2Cl2)[32a]
were generally adopted, both of which demonstrated com-
plete trans-diastereoselectivity directed by the substituent at
C-5 of the pyrrolidinones.[31b–d,32b,c] Recently, the Sharpless
modification of the Upjohn procedure,[33] which uses easy to
handle K2OsO2(OH)4 as a catalytic oxidant, has shown great
advantages in the cis-dihydroxylation of g-substituted a,b-
unsaturated lactams.[34] This high-yielding and highly diaste-
reoselective method was then applied. Treatment of a,b-un-
Scheme 3. Synthesis of rigidiusculamide B (8).
H-14 (Me at C-3), H-6, and H-8 indicated that the Me at C-
3 and the benzyloxybenzyl group at C-5 were on the same
face (see Figure S-2 in the Supporting Information). Thus,
the configuration of compound 16 was determined to be
3S,5S. Catalytic hydrogenolysis of 16 (H2, 1 atm, 10% Pd/C
(cat.)) provided the O-debenzylation product 8 as a color-
less oil in 94% yield. The physical (½aꢁ2D0 =ꢀ20.2 (c=1.0,
MeOH); lit.[12] ½aꢁ2D5 =ꢀ19.0 (c=1.5, MeOH)) and spectral
data of 8 are identical to those reported for the natural ri-
gidiusculamide B. Thus, both the structure and the stereo-
chemistry of rigidiusculamide B (8) have been confirmed.
We next investigated the synthesis of the proposed struc-
ture of rigidiusculamide A (7). The diastereomeric mixture
11a/11b (ratio: 69:31) was treated with methanesulfonyl
chloride (MsCl)/Et3N to give, after work up, crude mesylate
17, which, without purification, was treated with 1,8-
saturated lactam 18 with
a
catalytic amount of
K2OsO2(OH)4 (0.005 equiv), NMO (2.0 equiv), and citric
acid (2.0 equiv) in tBuOH/H2O (1:1, v/v) at room tempera-
ture for 8 hours produced diastereomer 19 in 94% yield,
along with 1% of diastereomer 20. Although vicinal cou-
pling constants are usually used as an empiric rule to deter-
mine the related stereochemistry of simple 5-alkyl-4-hydrox-
ypyrrolidin-2-ones, the observed anomalous small vicinal
coupling constants[35] of H-4/H-5 (J4,5 =1.5 Hz for trans-dia-
stereomer 19; J4,5 =3.5 Hz for cis-diastereomer 20) prevent-
ed a reliable assignment of the related stereochemistries of
19 and 20. Compounds 19 and 20 were then debenzylated to
give 7 and 21 in 95 and 99% yield, respectively, from which
the related stereochemistries of 19 and 20 could be deduced.
A thorough structural study was undertaken on synthetic
compounds 7 and 21. The skeleton of 7 was first confirmed
by NMR spectroscopy techniques (DEPT135, COSY,
HSQC, and HMBC). The relative stereochemistries of com-
pounds 7 and 21 were assigned by NOESY experiments. In
the NOESY spectrum of 7 (Figure 1), the observed correla-
tions between H-14 and H-6 as well as those between H-14
and H-4 indicated that the p-hydroxybenzyl group at C-5,
Me at C-3 (H-14), and H-4 were on the same face, which es-
tablished 3,4-cis-4,5-trans stereochemistry. The correlations
between H-4/H-5 and H-4/H-14 (Me at C-3) shown in the
NOESY spectrum of 21 indicate all-cis stereochemistry.
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU; 2 equiv) in CH2Cl2 at
reflux for 1.5 hours to afford racemic 3-pyrrolin-2-one[30] 18
in 91% yield (Scheme 4). To access to optically active prod-
uct, the elimination reaction with DBU was first run in an
ice-bath, then at room temperature for 5 hours, which gave
the elimination product 18 in 37% yield (91% yield based
on 62% of the recovered starting material 17). The recov-
Scheme 4. Syntheses of the proposed structure of rigidiusculamide A (7)
and its diastereomer 21. NMO=N-methylmorpholine N-oxide.
Figure 1. Observed key correlations in the NOESY spectra of compounds
7 and 21.
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The spectral data for synthetic compound 7 disagree with
those reported for the natural rigidiusculamide A, although
the magnitude of the optical rotation of 7 (½aꢁ2D0 =+14.9 (c=
1.0, MeOH)) was in agreement with that of the natural ri-
gidiusculamide A (lit.[12] ½aꢁ2D5 =ꢀ16.0 (c=0.1, MeOH)).
Nevertheless, both the optical rotation (½aꢁ2D0 =+19 (c=0.1,
MeOH)) and spectral data of compound 21 were in agree-
ment with those of the natural rigidiusculamide A, except
the sense of optical rotation.
It is noteworthy that in work of Che et al. the 4,5-trans
stereochemistry of rigidiusculamide A was assigned based
on the observed NOEs between H-4 and Me at C-3 (H-14),
as well as H-4 and benzene H-8.[12] However, no correlation
between H3-14 and H-6 has been reported, which is less con-
vincing for the assignment. Indeed, quantum chemical calcu-
lations on the assumed structure, ent-21, at the B3LYP/6-
31G* level showed that, in the most stable conformer of ent-
21 (Figure 2), the distance between H-4 and H-8, and H-4
and H3-14 was only 2.961 and 2.645 ꢂ, respectively, which is
within the range of observable NOEs. Thus, the deduction
of the 4,5-trans stereochemistry for rigidiusculamide A from
only the correlations between H-4/H3-14, and H-4/benzene
H-8 by Che et al. might have led to the wrong conclusion.
On the basis of the above-mentioned evidence and con-
siderations, natural rigidiusculamide A was tentatively de-
duced to have 3S,4S,5R configuration (ent-21).
Scheme 5. Retrosynthetic analysis of the revised structure of rigidiuscula-
mide A (ent-21) and other diastereomers.
Figure 2. Structure and optimized stable conformer of ent-21 at the
B3LYP/6-31G* level.
Second Synthetic Route: Synthesis of the Revised Structure
of Rigidiusculamide A (ent-21) and Diastereomers ent-7
and 22a,b
To further confirm the structure of rigidiusculamide A, the
synthesis of the revised structure of rigidiusculamide A (ent-
21) and three diastereomers (22a,b and ent-7) by a new syn-
thetic route was anticipated. The retrosynthetic analysis is
outlined in Scheme 5 and features the use of the Horner–
Wadsworth–Emmons (HWE) reaction and diastereoselec-
tive cis-dihydroxylation as the key steps.
The requisite protected a-amino aldehyde (R)-13 was pre-
pared from d-tyrosine by a known procedure.[21] The key
HWE reaction was undertaken under Masamune–Roush
conditions.[36] Thus, successive treatment of a-amino alde-
hyde (R)-13 with LiCl/DBU and 2-(diethoxyphosphoryl)pro-
panoate in CH3CN at 0–58C for 3 hours produced the de-
sired olefin as a separable geometric mixture of 23a and
Scheme 6. Syntheses of two diastereomers (22a,b) of rigidiusculamide A.
1
23b in a ratio of 83:17 (determined by H NMR spectrosco-
py) in 86% combined yield (Scheme 6). It should be men-
stereoselectivity (45% yield, 23a/23b=67:33). The geome-
tioned that use of nBuLi as the base gave a poorer yield and
tries of the olefins were determined by NOESY experi-
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Syntheses of Rigidiusculamides A and B
ments. A strong NOE correlation between the vinylic
proton (at C-3) and methyl-H at C-2 was observed in the
Z isomer, 23b, whereas no similar correlation was observed
for the E isomer, 23a.
no]propionate and KNACTHNGUTERN(NUG TMS)2 in the presence of an excess
of [18]crown-6 in THF at ꢀ788C, was treated with amino al-
dehyde (R)-13 to produce (Z)-enoate 23b as a single isomer
in 87% yield (Scheme 7). As for the cis-dihydroxylation,
mixed stereochemical outcomes[41] were usually obtained for
We next investigated the stereoselective cis-dihydroxyla-
tion of the major isomer (E)-23a. In sharp contrast to the
cyclic cases for which excellent trans selectivities were
always observed (see above), the catalytic cis-dihydroxyla-
tion of acyclic g-amido-(E)-enoates with OsO4/NMO
showed variable stereochemistries with poor to modest dia-
stereoselectivities.[37,38] The Sharpless asymmetric dihydroxy-
lation usually showed decreased reaction rates with mixed
results in terms of stereoselectivity.[37b,e–g,38] To get high ste-
reoselectivities in such cis-dihydroxylations, aryl ketimine
derivatives,[38a] bulky alkyl groups,[38b] and the OsO4/
N,N,N’,N’-tetramethylethane-1,2-diamine (TMEDA) oxida-
tion system[39] were introduced. For our particular substra-
te[37i] (E)-23a, the most convenient Sharpless modification of
Upjohn conditions was applied.[33,34] A solution of (E)-23a
in tBuOH/H2O (1:1, v/v) was treated with K2OsO2(OH)4
(cat.)/NMO in the presence of citric acid (2 equiv) and
stirred for 8 hours to give 24a and 24b as a chromatographi-
cally separable 75:25 diastereomeric mixture in 96% com-
bined yield (Scheme 6). The stereochemistry of the products
were difficult to determine at this stage due to rotation of
the Boc group, but could be deduced from derivatives 22a
and 22b (see below). Cleavage of the N-Boc group in 24a
with TFA followed by treatment of the crude product with
K2CO3 yielded the cyclization product 25a in 87% yield,
which gave 22a after O-debenzylation (10% Pd/C, H2;
Scheme 6). The structure of 22a was determined to be
3S,4R,5R by comprehensive NMR spectroscopy analysis (in-
cluding 1H, 13C, DEPT135, COSY, and NOESY). In the
NOESY spectrum of 22a (see Figure S-5 in the Supporting
Information), the observed correlations between H-4/H-6
and H-5/H-14 indicated that the p-hydroxybenzyl groups at
C-5 and H-4 were on the same face. Thus, all-trans stereo-
chemistry was established for 22a. Except for the optical ro-
tation data, the physical properties and spectral data for
compound 22a (½aꢁ2D0 =ꢀ17.6 (c=0.1, MeOH)) are different
from those of the natural product (lit.[12] ½aꢁD25 =ꢀ16.0 (c=
0.1, MeOH)), thus implying that compound 22a was not the
natural product (rigidiusculamide A). By the same proce-
dures, the minor diastereomer 24b was converted into 22b.
A 3,4-trans-4,5-cis stereochemistry was revealed from the
observed correlation between H-4/H-5 and H-6/H-14 in the
NOESY spectrum of 22b (see Figure S-5 in the Supporting
Information). All physical (½aꢁ2D0 =+5.5 (c=0.9, MeOH);
lit.[12] ½aꢁ2D5 =ꢀ16.0 (c=0.1, MeOH)) and spectral data of
compound 22b are different from those of rigidiusculami-
de A, indicating that compound 22b was also not the natural
product (rigidiusculamide A).
Scheme 7. Syntheses of the revised structure of rigidiusculamide A (ent-
21) and diastereomer ent-7. DMAP=4-(N,N-dimethylamino)pyridine.
N-Boc-protected g-amino-(Z)-enoates with OsO4/NMO as
an oxidation system. By changing the N-protecting groups,
stereoselection can be modulated.[42] In our case, the cis-di-
hydroxylation of (Z)-23b under Sharpless-modified Upjohn
conditions[33,34] proceeded smoothly to give 24c and 24d
(d.r.=17:83, determined after bis-acetylation, see below) as
a partially separable diastereomeric mixture in 96% yield,
which, after removal of the N-protecting group, cyclized
under basic conditions to afford the pyrrolidinones 26a/26b
as an inseparable diastereomeric mixture in 85% yield. O-
Debenzylation of pyrrolidinones 26a/26b gave two partially
We next focused on the synthesis of the revised structure
of rigidiusculamide A (ent-21). For this purpose, the Still–
Gennari Z-selective HWE reaction[40] was used for the ste-
reoselective synthesis of (Z)-enoate 23b. The carbanion gen-
erated in situ from ethyl 2-[bis(2,2,2-trifluoroethyl)phospho-
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separable diastereomers ent-21 and ent-7. A sample of the
major diastereomer ent-21 was isolated, the physical and
spectral data of which matched those reported for the natu-
ral rigidiusculamide A (½aꢁ2D0 =ꢀ19.2 (c=1.0, MeOH); lit.[12]
½aꢁ2D5 =ꢀ16.0 (c=0.1, MeOH) for natural rigidiusculami-
de A), thereby demonstrating that ent-21 is the natural rigid-
iusculamide A. To get complete separation of two diastereo-
mers, the mixture of 26a/26b was bis-acetylated to give 27a
and 27b (d.r.=17:83), which are separable by flash column
chromatography. By comparing the coupling constants be-
tween H-4 and H-5 in two diastereomers (27a: J4,5 =4.6 Hz;
27b: J4,5 =6.0 Hz), the stereochemistries of 27a and 27b
were assigned as 4,5-trans and 4,5-cis, respectively, which
was further confirmed by extensive NMR spectroscopy anal-
ysis (1H, 13C, DEPT135, COSY, and NOESY). There are
correlations between H-4/H-14 (Me at C-3) and H-4/H-6 in
the NOESY spectrum of 27a, while the correlation between
H-5/H-14 (Me at C-3) and H-5/H-4 were observed for dia-
stereomers 27b (Figure 3).
nificantly from one to another molecule for polysubstituted
cis (or trans) diastereomers.[38,42]
With the structure of rigidiusculamide B (8) confirmed as
3S,5S and the stereochemistry of rigidiusculamide A revised
as 3S,4S,5R, it is necessary to revise the biosynthesis of rigid-
iusculamides A–D proposed by Che et al.[12]
In fact, considerable efforts have been devoted to reveal
the biosynthesis of oxygenated pyrrolidin-2-ones, including
acyltetramic acids,[43] g-hydroxy-g-lactams/g-alkylidene-g-lac-
tams,[3,44] and other hydroxylated g-lactams.[45] In particular,
several biosynthetic pathways involving epimerization have
been suggested for different natural products. For example,
epimerization has also been suggested to account for the dif-
ferent configuration at C-8a of swainsonine (30), relative to
2-epi-lentiginosine (28) and slaframine (29), all of which are
produced by the fungus Rhizoctonia leguminicola.[46a] In ad-
dition, 2-epi-lentiginosine (28) has been reported to be a
late intermediate in the biosynthesis of slaframine (29) and
swainsonine (30) by Harris and co-workers.[46b] Epimeriza-
tion at C-8a is apparently involved in the last stages of the
biosynthesis of swainsonine, as well as in the oxidation of
the piperidine ring.[47] Epimerization at C-5 might occur in
the biosynthesis of natural dysidamide G (31), because it
exists as a 3:1 C-5 epimeric mixture.[10c] Moreover, natural
reutericyclin (32) is an R enantiomer,[48] whereas most natu-
rally occurring tetramic acids possess an S configuration at
C-5.[2]
Figure 3. Observed characteristic correlations in the NOESY spectra of
compounds 27a and 27b.
Catalytic hydrogenolysis of diastereomer 27a under acidic
conditions gave debenzylated and concomitantly deacetylat-
ed compound ent-7 in 70% yield (Scheme 7). Similarly, com-
pound ent-21 was produced from diastereomer 27b. Diaste-
reomer ent-21 showed correlations between H-4/H-14, H-5/
H-14, H-4/H-5, and H-4/H-8 in the NOESY spectrum
(Figure 4). The optical rotation (½aꢁ2D0 =ꢀ19.2 (c=1.0,
MeOH); lit.[12] ½aꢁ2D5 =ꢀ16.0 (c=0.1, MeOH)) and spectral
data of ent-21 were in agreement with those reported for the
natural rigidiusculamide A. Thus, the stereochemistry of the
natural rigidiusculamide A was revised as 3S,4S,5R.
At this stage, it is worthwhile to comment on the correla-
tion between the coupling constants J4,5 and the relative ste-
reochemistry of 5-alkyl-4-hydroxypyrrolidin-2-ones. From
Because rigidiusculamides A and B have the opposite
configuration at C-5, and so might rigidiusculamides C and
D, a simplified plausible biosynthetic pathway to rigidiuscu-
lamides A and B that involves an epimerization of tetramic
acid derivative is suggested in Scheme 8. As outlined in
Scheme 8, propionate-derived methylmalonyl coenzyme A
(CoA)[45] first condenses with l-tyrosine to yield the tetra-
mic acid derivative A,[43f,g] which is then oxidized to afford
rigidiusculamide B (8). Rigidiusculamide B (8) could epi-
merize at C-5 to give intermediate B, which is reduced ste-
reoselectively to produce the all-cis product rigidiusculami-
de A (ent-21). It is worth noting that the reduction of tetra-
mic acids with NaBH4 also gives 4,5-cis-lactams.[35a]
1
the H NMR spectroscopy data of all 5-alkyl-4-hydroxypyr-
rolidin-2-ones synthesized in
this work, we can conclude
without exception that the cis
diastereomer always displays a
larger coupling constant be-
tween H-4 and H-5 (J4,5) than
that of the corresponding trans
diastereomer. This conclusion
is in agreement with the previ-
Figure 4. Observed characteris-
tic correlations in the NOESY
ous empiric rule.[35] However,
It is interesting that dysidamide (5) and dysidamides B–F
spectrum of compound ent-21.
the values of J4,5 may vary sig-
also possess 4,5-cis stereochemistry.[10] Similar stereochemis-
510
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 504 – 518

Syntheses of Rigidiusculamides A and B
Conclusion
Starting from l-tyrosine, a divergent enantioselective syn-
thesis of rigidiusculamide B (8) and the proposed structure
of rigidiusculamide A (7) has been achieved in 9 steps, and
32% overall yield; starting from d-tyrosine, the revised
structure of the natural rigidiusculamide A (ent-21) has been
synthesized by another synthetic route in 11 steps with 22%
overall yield. Through this work, the configuration of 8 was
confirmed to be 3S,5S. By comparing the four diastereomers
(7, ent-7, 22a, and 22b) and the enantiomer (21) of rigidius-
culamine A (ent-21), the stereochemistry of natural rigidius-
culamide A was established to be 3S,4S,5R (ent-21) without
any ambiguity. A plausible biosynthesis of rigidiusculamide-
s A and B has been proposed to account for the opposite
configuration at C-5 of these two congeners. In addition, we
have demonstrated, for the first time, that DMP is an excel-
lent reagent for the direct bis-oxidation of b-hydroxy car-
bonyl compounds to give, in one-pot, the a-hydroxylation/b-
Scheme 8. A plausible biosynthesis of rigidiusculamides A and B.
try patterns can also be found in streptopyrrolidine (6),[11]
anisomycin (33; first isolated from the fermentation broths
of Streptomyces griseolus and Streptomyces roseochromo-
genes),[49] and preussin (34; a potent antifungal agent isolat-
ed from fermentation broths of Preussia sp. and Aspergillus
ochraceus);[50] the last two actually possess relative 2,3-cis
stereochemistry with opposite absolute configurations at
those carbon atoms.
hydroxyl oxidation product in
a highly diastereomeric
manner, and the power of computational chemistry in many
aspects of total synthesis.
Experimental Section
General
Optical rotations were recorded on a Perkin–Elmer 341 automatic polar-
1
imeter. H and 13C NMR data were acquired with Bruker (at 400 MHz or
600 MHz) or Varian (at 500 MHz) spectrometers by using solvent signals
([D6]acetone: dH =2.05/dC =29.8 ppm, 206.1 ppm; [D6]DMSO: dH =
2.50 ppm; CD3OD: dH =3.35 ppm; CDCl3: dH =7.26/dC =77.0 ppm) as
references.
To test the feasibility of the suggested epimerization from
8 to intermediate B, the energy difference between 8 and 5-
epi-8 was calculated (Scheme 9). As the computational re-
Tetrahydrofuran (THF) was distilled prior to use from sodium benzophe-
none ketyl. CH2Cl2 was distilled over calcium hydride under N2. DMSO
was distilled from calcium hydride. Column chromatography was per-
formed on silica gel eluting with EtOAc/petroleum ether (PE; 60–908C,
unless otherwise stated) and a mixture of EtOAc/hexane.
1
For molecules with Boc groups, H and 13C NMR spectra were complicat-
ed by rotation of the N-Boc moiety.
Synthesis of Compound 12
A mixture of freshly prepared (S)-13[21a] (739 mg, 2.0 mmol) and 14
(0.38 mL, 3.0 mmol) in THF (3 mL) was added to a 0.1n solution of SmI2
in THF (prepared freshly by the addition of iodine (2.98 g) to samarium
powder (2.04 g) in THF (80 mL)) and stirred at 608C for 2–3 h before
being cooled to ꢀ258C. The mixture was stirred for 10 min at ꢀ258C and
warmed to room temperature over 0.5 h. The reaction was quenched
with a 0.1m aqueous solution of HCl (30 mL) and extracted with EtOAc
(3ꢃ20 mL). The combined extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
Scheme 9. Calculated energy difference between rigidiusculamide B (8)
and 5-epi-8 at B3LYP/6-31G* level.
sults at the B3LYP/6-31G* level showed, rigidiusculamide B
(8) was more stable than 5-epi-8 only by 1.25 kcalmolꢀ1,
which, without taking kinetics into account, indicates that 8
and 5-epi-8 exist in a ratio of 8:1. This deduction is essential-
ly in agreement with the isolated yields of rigidiusculami-
des B and A (30 and 2 mg, respectively).[12] Thus, rigidiuscu-
lamide B (8) may be able to epimerize to intermediate B at
room temperature. In fact, easy racemization of 5-alkyltetr-
amic acids has been observed during the conversion of 5-al-
kyltetramic acids into the corresponding 5-alkyltetramate-
s.[35a,51]
(eluent: EtOAc/PE=1:3) to afford compound 12 as
a colorless oil
(857 mg, 91%) as a mixture of four diastereomers, which was used in the
next step without further separation. 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=1.06–1.60 (m, 15H; tBu, CHCH3, and CH2CH3), 2.40–3.01 (m,
5H; NCH3 and CHCH2), 3.15–3.26 (m, 1.2H; CHCH2 and OH), 3.60–
3.90 (m, 0.8H; OH), 4.05–4.25 (m, 3H; CH2CH3 and CH2CHCH), 5.05
(s, 2H; PhCH2), 6.85–6.95 (m, 2H; ArH), 7.05–7.20 (m, 2H; ArH), 7.26–
7.45 ppm (m, 5H; ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
9.3, 13.9, 14.0 (2C), 14.1, 15.2, 15.7, 27.9, 28.2, 33.6, 40.6, 53.3, 58.1, 60.6,
60.7, 60.8, 70.0, 79.6, 114.6, 114.7, 114.8, 127.3 (2C), 127.8, 128.4, 129.9
(2C), 130.0, 131.2, 137.1, 155.4, 155.9, 157.2, 157.3, 176.6 ppm; IR (film):
Chem. Asian J. 2012, 7, 504 – 518
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
511

P.-Q. Huang et al.
FULL PAPERS
n˜ =3458, 2977, 2933, 1731, 1692, 1668, 1511, 1454, 1391, 1367, 1242, 1177,
Compound 11d
1026 cmꢀ1
; HRMS (ESI): m/z calcd for C27H37NO6Na: 494.2519
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.15 (d, J=7.5 Hz, 1.5H;
CCH3), 2.67 (s, 1.5H; NCH3), 2.80 (dd, J=14.0, 6.6 Hz, 0.5H; H-6), 3.02–
3.12 (m, 1H; H-6), 3.71 (ddd, J=6.6, 6.6, 5.1 Hz; homodec at d=
3.99 ppm gave a dd, J5,6 =6.6, 6.6 Hz, 0.5H; H-5), 3.94–4.04 (m, 0.5H; H-
4), 5.03 (s, 1H; PhCH2), 6.91 (d, J=8.6 Hz, 1H; ArH), 7.20 (d, J=
8.6 Hz, 1H; ArH), 7.30–7.43 ppm (m, 2.5H; ArH).
[M+Na]+; found: 494.2510.
Procedure for the Preparation of Compound 11
TFA (0.76 mL, 10.2 mmol) was added to
a solution of 12 (0.32 g,
0.68 mmol) in CH2Cl2 (5 mL) and cooled on an ice/water bath. After
being stirred for 1 h at room temperature, the excess acid was removed
under reduced pressure to give the deprotected amine. The residue was
dissolved in toluene (4 mL) and treated with K2CO3 (1.66 g, 12 mmol).
The mixture was stirred overnight and then the solid was filtered off. The
filtrate was concentrated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (eluent: EtOAc/PE=
2:1) to give the diastereomeric mixtures of 11a/11b (159 mg, 74%, d.r.=
69:31, determined by 1H NMR spectroscopy) and 11c/11d (31 mg, 12%,
Synthesis of Compound 16
DMP (550 mg, 1.28 mmol) was added to a stirred solution of a diastereo-
meric mixture 11a/11b (105 mg, 0.32 mmol) in DMSO (1.5 mL) at room
temperature. Then the mixture was stirred at 558C for 12 h. After cooling
to room temperature, the reaction was quenched with H2O (15 mL). The
precipitate was filtered off and the filtrate was extracted with EtOAc (3ꢃ
8 mL). The combined extracts were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(eluent: EtOAc/PE=2:1) to afford compound 16 as a white solid (83 mg,
76%). M.p. 185.2–186.48C (EtOAc/PE); ½aꢁ2D0 =ꢀ18.3 (c=0.8 in acetone);
1H NMR (400 MHz, CDCl3, 258C, TMS): d=0.49 (s, 3H; CCH3), 2.99 (s,
3H; NCH3), 3.02 (d, J=4.3 Hz, 2H; H-6), 4.09 (t, J=4.3 Hz, 1H; H-5),
4.96 (s, 2H; PhCH2), 6.81 (d, J=8.7 Hz, 2H; ArH), 6.85 (d, J=8.7 Hz,
2H; ArH), 7.26–7.40 ppm (m, 5H; ArH); 13C NMR (100 MHz, CDCl3,
258C, TMS): d=20.0, 28.4, 33.9, 67.8, 70.0, 70.8, 115.4, 126.6, 127.4, 128.0,
128.6, 131.0, 136.6, 158.2, 173.1, 208.1 ppm; IR (KBr): n˜ =3305, 3030,
2924, 1777, 1672, 1610, 1511, 1252, 1125, 1039 cmꢀ1; HRMS (ESI): m/z
calcd (%) for C20H22NO4: 340.1549 [M+H]+; found: 340.1550.
1
d.r.=50:50, determined by H NMR spectroscopy).
Mixture of 11a/11b
White solid; m.p. 116.7–118.68C (EtOAc/PE); IR (KBr): n˜ =3375, 2923,
1666, 1611, 1511, 1454, 1401, 1241, 1025 cmꢀ1
.
Compound 11a
1H NMR (400 MHz, CDCl3, 258C, TMS) (data read from the spectrum
of the mixture): d=1.12 (d, J=7.4 Hz, 2.1H; CCH3), 2.25–2.36 (m, ho-
modec at d=1.12 ppm gave a d, J3,4 =5.7 Hz, 0.7H; H-3), 2.67 (dd, J=
14.0, 5.4 Hz, 0.7H; H-6), 2.81 (s, 2.1H; NCH3), 3.05 (dd, J=14.0, 7.6 Hz,
0.7H; H-6), 3.51 (ddd, J=7.6, 5.4, 5.1 Hz, 0.7H; H-5), 3.69 (dd, J=5.7,
5.1 Hz, 0.7H; H-4), 5.03 (s, 1.4H; PhCH2), 6.97 (d, J=8.6 Hz, 1.4H;
ArH), 7.12 (d, J=8.6 Hz, 1.4H; ArH), 7.29–7.43 ppm (m, 3.5H; ArH);
13C NMR (100 MHz, CDCl3, 258C, TMS) (data read from the spectrum
of the mixture): d=14.2, 27.9, 37.4, 45.1, 67.0, 70.0, 77.0 (observed in 13C
DEPT135), 115.3, 127.4, 127.9, 128.7, 128.9, 130.1, 136.8, 157.7,
175.2 ppm.
Synthesis of Compound 8
A solution of 16 (25 mg) in MeOH (1 mL) was added to a suspension of
10% Pd/C (15 mg) in MeOH (1 mL). The mixture was stirred under
1 atm of hydrogen for 6 h at room temperature. The mixture was filtered
and the filtrate concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (eluent: EtOAc/
PE=3:1) to give 8 as a colorless oil (17 mg, 94%). ½aꢁ2D0 =ꢀ20.2 (c=1.0
in MeOH) (lit.[12] [a]D25 =ꢀ19.0 (c 1.5, MeOH)); 1H NMR (500 MHz,
[D6]acetone, 258C, TMS): d=0.52 (s, 3H; CCH3), 3.01 (dd, J=14.6,
4.4 Hz, 1H; H-6), 3.04 (s, 3H; NCH3), 3.14 (dd, J=14.6, 4.4 Hz, 1H; H-
6), 4.22 (t, J=4.4 Hz, 1H; H-5), 6.74 (d, J=8.5 Hz, 2H; ArH), 6.89 ppm
(d, J=8.5 Hz, 2H; ArH); 13C NMR (125 MHz, [D6]acetone, 258C, TMS):
d=19.9, 28.1, 34.3, 68.0, 71.1, 116.1 (2C), 127.0, 132.0 (2C), 157.5, 173.3,
210.6 ppm; IR (film): n˜ =3300, 2928, 1775, 1686, 1613, 1515, 1444, 1228,
Compound 11b
1H NMR (400 MHz, CDCl3, 258C, TMS) (data read form the spectrum
of the mixture): d=1.09 (d, J=7.5 Hz, 0.9H; CCH3), 2.12–2.25 (m, ho-
modec at d=1.09 ppm gave a d, J3,4 =5.6 Hz, 0.3H; H-3), 2.64 (dd, J=
14.1, 5.1 Hz, 0.7H; H-6), 2.84 (s, 0.9H; NCH3), 3.05 (dd, J=14.1, 7.8 Hz,
0.7H; H-6), 3.56 (dd, J=7.8, 5.1 Hz, 0.3H; H-5), 4.07 (dd, J=5.6, 5.1 Hz,
0.3H; H-4), 5.02 (s, 0.6H; PhCH2), 6.91 (d, J=8.6 Hz, 0.6H; ArH), 7.05
(d, J=8.6 Hz, 0.6H; ArH), 7.29–7.43 ppm (m, 1.5H; ArH); 13C NMR
(100 MHz, CDCl3, 258C, TMS) (data read from the spectrum of the mix-
ture): d=8.3, 28.6, 35.5, 40.0, 68.9, 71.2, 77.0 (observed in 13C DEPT135),
115.1, 127.4, 127.9, 128.5, 128.9, 130.0, 136.8, 157.7, 175.3 ppm; MS (ESI):
m/z (%): 348 (100) [M+Na]+; elemental analysis calcd (%) for
C20H23NO3: C 73.82, H 7.12, N 4.30; found: C 73.68, H 7.38, N 4.46.
1122 cmꢀ1
; HRMS (ESI): m/z calcd (%) for C13H16NO4: 250.1079
[M+H]+; found: 250.1081.
Syntheses of Compounds 17 and 18
Freshly distilled Et3N (98 mL, 0.72 mmol) and MsCl (28 mL, 0.36 mmol)
were added successively to a solution of a diastereomeric mixture of 11a/
11b (40 mg, 0.12 mmol) in CH2Cl2 (3 mL) and was cooled on an ice/
water bath. After being stirred for 30 min, the reaction was quenched
with an aqueous solution of NaHCO3 and the organic phase was separat-
ed, and washed successively with water and brine. The combined extracts
were dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The crude mesylate 17 was used in the next step without
further purification.
Mixture of 11c/11d
White solid; m.p. 125.6–126.48C (EtOAc/PE); 13C NMR (100 MHz,
CDCl3, 258C, TMS): d=8.4, 13.2, 27.6, 28.9, 32.0, 32.8, 42.6, 43.4, 64.1,
64.3, 68.6, 70.0, 74.1, 115.0, 127.4, 127.9, 128.5, 129.4, 130.2, 130.3, 130.4,
136.9, 157.5 (2C), 175.4, 176.3 ppm; IR (KBr): n˜ =3376, 2930, 1672, 1610,
1511, 1454, 1401, 1240, 1177, 1109, 1080, 1025 cmꢀ1; MS (ESI): m/z (%):
348 (100) [M+Na]+; elemental analysis calcd (%) for C20H23NO3: C
73.82, H 7.12, N 4.30; found: C 73.68, H 7.38, N 4.46.
DBU (18 mL, 0.12 mmol) was added dropwise to a solution of the crude
mesylate 17 in CH2Cl2 (3 mL) at 08C. The reaction was stirred for 5 h at
room temperature, and then quenched with an aqueous solution of
NH4Cl at 08C. The mixture was extracted with EtOAc (3ꢃ5 mL). The
combined extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (eluent:
EtOAc/PE=1:2) to give the recovered compound 17 (31 mg, 62%) and
18 (14 mg, 37%, 91% yield based on recovered 17). The diastereomeric
mixture of 11c/11d was dehydrated in a similar manner to give the recov-
ered compound 17 (55%) and 18 (37%, 82% yield based on recovered
17).
Compound 11c
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.19 (d, J=7.4 Hz, 1.5H;
CCH3), 2.15–2.35 (m, homodec at d=1.19 ppm gave a d, J3,4 =5.1 Hz,
1.5H; H-3), 2.83 (s, 1.5H; NCH3), 2.92–3.03 (m, 1H; H-6), 3.62 (ddd, J=
9.0, 6.6, 3.8 Hz; homodec at d=3.99 ppm gave a dd, J5,6 =9.0, 6.6 Hz,
0.5H; H-5), 3.94–4.04 (m, 0.5H; H-4), 5.04 (s, 1H; PhCH2), 6.93 (d, J=
8.6 Hz, 1H; ArH), 7.23 (d, J=8.6 Hz, 1H; ArH), 7.30–7.43 ppm (m,
2.5H; ArH).
512
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 504 – 518

Syntheses of Rigidiusculamides A and B
Compound 17
Synthesis of Compound 7
Colorless oil; ½aꢁ2D0 =+29.7 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=0.95 (d, J=7.8 Hz, 2.2H; CHCH3), 1.05 (d, J=
7.3 Hz, 0.8H; CHCH3), 2.10 (dq, J=7.3, 3.2 Hz, 0.28H; CH3CH), 2.52
(dq, J=7.8, 3.2 Hz, 0.72H; CH3CH), 2.50–2.60 (m, 2.2H; SO2Me and
CHCH2), 2.63–2.75 (m, 1.8H; SO2Me and CHCH2), 2.80–2.88 (m, 3.25H;
NMe and CHCH2), 3.01 (dd, J=14.3, 4.8 Hz, 0.75H; CHCH2), 3.73–3.80
(m, 1H; CH2CH), 4.50 (dd, J=2.8, 2.8 Hz, 0.75H; CHCHCH), 4.88 (d,
J=6.1 Hz, 0.25H; CHCHCH), 4.99 (s, 0.5H; PhCH2), 5.05 (s, 1.5H;
PhCH2), 6.85–6.91 (m, 2H), 6.97–7.05 (m, 2H; ArH), 7.23–7.36 ppm (m,
5H; ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=8.9, 14.3, 18.3,
28.1, 28.4, 34.9, 36.1, 37.9, 38.6, 43.7, 58.2, 65.6, 66.8, 69.9, 79.6, 82.1,
115.4, 127.3, 127.4, 127.5, 127.9, 128.5, 130.2, 136.6, 157.9 (2C), 173.3,
Hydrogenolysis of 19 (18 mg, 0.05 mmol) by the procedure described for
8 produced compound 7, the proposed structure for rigidiusculamide A
20
(12 mg, 95%), as a white solid. M.p. 175.9–178.08C (EtOAc/PE); ½aꢁD
=
1
+14.9 (c=1.0 in MeOH); H NMR (400 MHz, [D6]acetone, 258C, TMS):
d=1.22 (s, 3H; CCH3), 2.77 (s, 3H; NCH3), 2.78 (dd, J=14.3, 7.4 Hz,
1H; H-6), 2.99 (dd, J=14.3, 5.6 Hz, 1H; H-6), 3.54 (ddd, J=7.4, 5.6,
3.4 Hz, 1H; H-5), 3.63 (d, J=3.4 Hz, 1H; H-4), 6.78 (d, J=8.5 Hz, 2H;
ArH), 7.09 ppm (d, J=8.5 Hz, 2H; ArH); 13C NMR (100 MHz,
[D6]acetone, 258C, TMS): d=23.6, 28.5, 36.6, 66.8, 73.5, 75.2, 116.1 (2C),
128.8, 131.2 (2C), 157.0, 175.1 ppm; MS (ESI): m/z (%): 274 (100)
[M+Na]+; IR (KBr): n˜ =3404, 2926, 1672, 1615, 1516, 1407, 1242,
1065 cmꢀ1
; HRMS (ESI): m/z calcd (%) for C13H17NO4K: 290.0795
173.7 ppm; IR (film): n˜ =2934, 1693, 1607, 1512, 1243, 1174, 1024 cmꢀ1
;
[M+K]+; found: 290.0793.
MS (ESI): m/z (%): 426 (100) [M+Na]+; elemental analysis calcd (%)
Synthesis of Compound 21
for C21H25NO5S: C 62.51, H 6.25, N 3.47; found: C 62.29, H 6.14, N 3.26.
Hydrogenolysis of 20 (1.6 mg, 4.7ꢃ10ꢀ3 mmol) by the procedure de-
scribed for 8 produced compound 21 (1 mg, 99%) as a colorless oil.
½aꢁD20 =+19 (c=0.1 in MeOH) (lit.[12] [a]2D5 =ꢀ16.0 (c=0.1 in MeOH));
1H NMR (600 MHz, [D6]acetone+D2O, 25 8C, TMS): d=1.25 (s, 3H;
CCH3), 2.76 (s, 3H; NCH3), 2.95–3.05 (m, 2H; H-6), 3.73 (d, J=4.4 Hz,
1H; H-4), 3.77 (dt, J=7.4, 4.4 Hz, 1H; H-5), 6.81 (d, J=7.9 Hz, 2H;
ArH), 7.22 ppm (d, J=7.9 Hz, 2H; ArH); 13C NMR (125 MHz,
[D6]acetone, 258C, TMS): d=21.7, 28.0, 33.1, 63.1, 73.1, 75.2, 116.0 (2C),
129.7, 131.4 (2C), 156.8, 175.4 ppm; IR (film): n˜ =3381, 2919, 1674, 1613,
Compound 18
Colorless oil; ½aꢁ2D0 =+146.6 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.83 (t, J=1.7 Hz, 3H; CHCCH3), 2.51 (dd, J=
13.5, 8.9 Hz, 1H; CHCH2), 3.01 (s, 3H; NMe), 3.11 (dd, J=13.5, 5.2 Hz,
1H; CHCH2), 3.98 (ddd, J=8.9, 5.2, 1.8 Hz, 1H; CHCH2), 5.06 (s, 2H;
PhCH2), 6.51 (dq, J=1.8, 1.7 Hz, 1H; CCHCH), 6.92 (d, J=8.6 Hz, 2H;
ArH), 7.08 (d, J=8.6 Hz, 2H; ArH), 7.31–7.45 ppm (m, 5H; ArH);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=11.2, 27.6, 37.0, 63.4, 70.0,
114.9 (2C), 127.4 (2C), 127.9, 128.5 (2C), 128.7, 130.1 (2C), 135.2, 136.9,
139.5, 157.7, 171.9 ppm; IR (film): n˜ =2918, 2847, 1677, 1640, 1503, 1387,
1250, 1026 cmꢀ1; MS (ESI): m/z (%): 330 (100) [M++Na]; HRMS (ESI):
m/z calcd (%) for C20H21NO2Na: 330.1470 [M+Na]+; found: 330.1466.
1515, 1407, 1259, 1095 cmꢀ1
; HRMS (ESI): m/z calcd (%) for
C13H17NO4Na: 274.1055 [M+Na]+; found: 274.1057.
Synthesis of Compounds 23a/23b
Method A: LiCl (404 mg, 9.63 mmol) and DBU (1.5 mL, 9.63 mmol)
were added to a solution of ethyl 2-(diethoxyphosphoryl)propanoate
(2.293 g, 9.63 mmol) in predried CH3CN (39 mL). The reaction mixture
was stirred at room temperature for 20 min until the LiCl dissolved com-
pletely. After being cooled to 08C, aldehyde (R)-13 (1.423 g, 3.85 mmol)
in CH3CN (4 mL) was added dropwise by means of a syringe and the re-
action mixture was stirred at 08C for 3 h. The reaction was quenched
with an aqueous solution of NH4Cl (30 mL) and extracted with Et2O (4ꢃ
20 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (eluent: EtOAc/hexane=1:30) to give 23a (1.253 g, 72%) and
23b (250 mg, 14%).
Synthesis of Compound 19
Compound 18 (172 mg, 0.56 mmol) and citric acid (212 mg, 1.12 mmol)
were dissolved in a 1:1 (v/v) mixture of tBuOH and H2O (8.0 mL). Aque-
ous K2OsO2(OH)4 (0.1 mL, 0.027m) was added followed by NMO
(130 mg, 1.12 mmol). The solution turned gray–green and, after stirring
for 8 h at room temperature, a nearly colorless solution formed. At that
point, the reaction was quenched with an excess of Na2S2O3 (5.0 g). The
solid was filtered off and the filtrate concentrated under reduced pres-
sure. The residue was purified by flash column chromatography on silica
gel (eluent: EtOAc/PE=3:1) to give a product that was recrystallized
from PE/EtOAc to give compound (3S,4S,5S)-19 (178 mg, 94%). The
mother liquid was subjected to flash column chromatography to afford
(3R,4R,5S)-20 (ca. 1.6 mg, 1%). White solid; m.p. 131.7–133.28C
(EtOAc/PE); ½aꢁ2D0 =+12.5 (c=1.0 in MeOH); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.36 (s, 3H; CCH3), 2.76 (dd, J=14.4, 8.2 Hz,
1H; H-6), 2.80 (s, 3H; NCH3), 2.98 (dd, J=14.4, 6.0 Hz, 1H; H-6), 3.31
(brs, 1H; CHOH), 3.61 (ddd, J=8.2, 6.0, 1.5 Hz, 1H; H-5), 3.72 (d, J=
1.5 Hz, 1H; H-4), 4.49 (brs, 1H; COH), 5.05 (s, 2H; PhCH2), 6.94 (d, J=
8.4 Hz, 2H; ArH), 7.11 (d, J=8.4 Hz, 2H; ArH), 7.30–7.43 ppm (m, 5H;
ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=23.8, 29.0, 36.5,
67.3, 70.0, 73.2, 74.4, 115.2 (2C), 127.4 (2C), 128.0, 128.6 (2C), 128.8,
130.1 (2C), 136.8, 157.8, 175.0 ppm; IR (KBr): n˜ =3370, 2927, 1678, 1610,
1511, 1241 cmꢀ1; MS (ESI): m/z (%): 364 (100) [M+Na]+; elemental
analysis calcd (%) for C20H23NO4: C 70.36, H 6.79, N 4.10; found: C
70.27, H 6.91, N 3.99.
Method B: A solution of ethyl 2-[bis(2,2,2-trifluoroethyl)phosphono]pro-
pionate (26 mg, 0.075 mmol) and [18]crown-6 (100 mg, 0.38 mmol) in an-
hydrous THF (1.5 mL) was cooled to ꢀ788C under nitrogen and treated
with KNACHTUNTGRNE(NUG TMS)2 (0.11 mL, 0.075 mmol, 0.7m in toluene). The aldehyde
(R)-13 (28 mg, 0.075 mmol) was then added and the resulting mixture
was stirred for 1 h at ꢀ788C. The reaction mixture was quenched with an
aqueous solution of NH4Cl (2 mL) and extracted with Et2O (4ꢃ5 mL).
The combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. The re-
sulting residue was purified by flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:20) to give 23b as a colorless viscous oil
(30 mg, 87%).
Compound 23a
Compound 20
Colorless viscous oil; ½aꢁ2D0 =+14.0 (c=1.0 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=1.26–1.34 (m, 12H; tBu and
CH2CH3), 1.78 (s, 3H; CCH3), 2.75 (brs, 4H; NCH3 and CH2CH), 2.88
(dd, J=13.9, 8.9 Hz, 1H; CH2CH), 4.20 (q, J=7.0 Hz, 2H; CH2CH3),
5.03 (s, 2H; PhCH2), 5.04 (brm, 1H; CH2CHCH), 6.74 (dd, J=8.4,
1.4 Hz, 1H; CH=C), 6.89 (d, J=8.5 Hz, 2H; ArH), 7.09 (brs, 2H; ArH),
7.31–7.43 ppm (m, 5H; ArH); 13C NMR (125 MHz, CDCl3, 258C, TMS):
d=12.7, 14.2, 28.2 (3C), 29.3, 37.9, 55. 4, 60.7, 70.0, 79.6, 114.8 (2C),
127.4 (2C), 127.8, 128.5 (3C), 130.0 (2C), 130.7, 137.1, 138.4, 155.1, 157.5,
167.8 ppm; IR (film): n˜ =2975, 2928, 1711, 1691, 1611, 1584, 1512, 1453,
1390, 1366, 1243, 1124, 1027, 862, 772, 743, 697 cmꢀ1; HRMS (ESI): m/z
calcd (%) for C27H35NO5Na: 476.2413 [M+Na]+; found: 476.2406.
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.26 (s, 3H; CCH3), 2.86 (s,
3H; NCH3), 2.95 (dd, J=13.1, 5.0 Hz, 1H; H-6), 3.09 (dd, J=13.1,
10.1 Hz, 1H; H-6), 3.60 (ddd, J=10.1, 5.0, 3.5 Hz, 1H; H-5), 3.72 (d, J=
3.5 Hz, 1H; H-4), 5.06 (s, 2H; PhCH2), 6.95 (d, J=8.6 Hz, 2H; ArH),
7.30 (d, J=8.6 Hz, 2H; ArH), 7.32–7.45 ppm (m, 5H; ArH); 13C NMR
(125 MHz, CDCl3, 258C, TMS): d=21.4, 27.9, 31.8, 62.5, 70.1, 71.7, 74.9,
115.0, 127.5, 128.0, 128.6, 129.2, 130.6, 137.0, 157.7, 175.4 ppm; IR (film):
n˜ =3337, 2930, 1678, 1610, 1512, 1241, 1075 cmꢀ1; HRMS (ESI): m/z
calcd (%) for C20H24NO4: 342.1705 [M+H]+; found: 342.1702.
Chem. Asian J. 2012, 7, 504 – 518
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
513

P.-Q. Huang et al.
FULL PAPERS
Compound 23b
[D6]DMSO+D2O, 25 8C, TMS): d=1.07 (s, 3H; CCH3), 2.69 (s, 3H;
NCH3), 2.86 (dd, J=14.4, 6.6 Hz, 1H; H-6), 2.92 (dd, J=14.4, 5.4 Hz,
1H; H-6), 3.29 (ddd, J=6.6, 5.4, 4.8 Hz, 1H; H-5), 3.59 (d, J=4.8 Hz,
1H; H-4), 5.07 (s, 2H; PhCH2), 6.96 (d, J=8.6 Hz, 2H; ArH), 7.18 (d,
J=8.6 Hz, 2H; ArH), 7.29–7.50 ppm (m, 5H; ArH); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=18.6, 28.0, 30.9, 36.9, 63.2, 70.1, 78.4,
115.3 (2C), 127.5 (2C), 128.0, 128.6 (2C), 128.9, 130.2 (2C), 136.9, 157.8,
175.2 ppm; IR (KBr): n˜ =3453, 2925, 1686, 1610, 1513, 1238, 990, 748,
700 cmꢀ1; HRMS (ESI): m/z calcd (%) for C20H24NO4: 364.1525 [M+H]+
; found: 364.1522.
Colorless viscous oil; ½aꢁ2D0 =ꢀ63.5 (c=1.0 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=1.26–1.34 (m, 12H; tBu and
CH2CH3), 1.93 (s, 3H; CCH3), 2.78 (brm, 5H; NCH3 and CH2CH), 4.21
(q, J=7.1 Hz, 2H; CH2CH3), 5.02 (s, 2H; PhCH2), 5.44 (brm, 1H;
CH2CHCH), 6.10 (brm, 1H; CH=C), 6.88 (d, J=8.6 Hz, 2H; ArH), 7.14
(m, 2H; ArH), 7.28–7.42 ppm (m, 5H; ArH); 13C NMR (125 MHz,
CDCl3, 258C, TMS): d=14.2, 20.5, 28.3 (3C), 29.6, 37.7, 56.3, 60.3, 69.9,
79.2, 114.6 (2C), 127.3 (2C), 127.8, 128.4 (3C), 130.0 (2C), 130.6, 137.1,
138.9, 155.4, 157.3, 167.1 ppm; IR (film): n˜ =2976, 2927, 1710, 1690, 1611,
1584, 1512, 1453, 1390, 1366, 1229, 1130, 1026, 860, 774, 739, 697 cmꢀ1
;
Synthesis of Compound 25b
HRMS (ESI): m/z calcd (%) for C27H35NO5Na: 476.2413 [M+Na]+;
A solution of 24b (50 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was cooled on
an ice/water bath and TFA (0.15 mL, 30% CH2Cl2) was added dropwise.
After 5 min, the cooling bath was removed and the reaction mixture was
stirred at room temperature for 3.5 h (monitored by TLC). The reaction
mixture was then concentrated under reduced pressure and the residue
was dissolved in toluene (1 mL). The mixture was cooled on an ice/water
bath and K2CO3 (140 mg, 1.0 mmol) was added. The reaction mixture
was stirred at room temperature for 16 h (monitored by TLC). The reac-
tion mixture was then concentrated under reduced pressure and the re-
sulting residue was dissolved in CH2Cl2 and H2O. The reaction mixture
was extracted with CH2Cl2 (5ꢃ20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: MeOH/CH2Cl2 =1:40) to
found: 476.2409.
Synthesis of Compounds 24a/24b
N-Methylmorpholine oxide (566 mg, 2.95 mmol), citric acid (345 mg,
2.95 mmol), and aqueous K2OsO2(OH)4 (0.3 mL, 0.027m) were added to
a solution of 23a (668 mg, 1.47 mmol) in tBuOH/H2O (1:1, 3 mL). The
mixture was stirred at room temperature for 8 h (monitored by TLC).
The reaction was quenched with Na2S2O3·5H2O and stirred for 0.5 h.
After removing the solid by filtration, the filtrate was concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (eluent: EtOAc/hexane=1:6) to give 24a
(514 mg, 72%) and 24b (171 mg, 24%).
Compound 24a
give 25b as
a white solid (28 mg, 80%). M.p. 169–1708C (MeOH/
Colorless viscous oil; ½aꢁ2D0 =+76.7 (c=1.2 in CHCl3); 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=1.20–1.46 (m, 15H), 2.04 (s, 1H),
2.38 (brs, 2H), 2.68–3.07 (m, 3H), 3.24 (brs, 1H), 3.59 (s, 1H), 4.12 (q,
J=7.2 Hz, 1H), 4.21–4.35 (m, 2H), 5.02 (s, 2H; PhCH2), 6.89 (d, J=
8.5 Hz, 2H; ArH), 7.09 (d, J=8.5 Hz, 2H; ArH), 7.29–7.43 ppm (m, 5H;
ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=14.1, 20.9, 22.2, 28.3
(3C), 32.3, 56.6, 60.3, 62.0, 62.4, 70.0, 77.5, 114.7 (2C), 127.3 (2C), 127.4,
127.8, 128.4 (2C), 129.9 (2C), 137.1, 155.1, 157.2, 175.7 ppm; IR (film):
n˜ =3456, 2977, 2931, 1732, 1690, 1666, 1611, 1584, 1511, 1454, 1391, 1366,
1242, 1175, 1024, 949, 863, 774, 739, 697 cmꢀ1; HRMS (ESI): m/z calcd
(%) for C27H37NO7Na: 510.2468 [M+Na]+; found: 510.2457.
CH2Cl2); ½aꢁ2D0 =+6.5 (c=0.5 in MeOH); 1H NMR (500 MHz,
CD3OD+D2O, 25 8C, TMS): d=1.31 (s, 3H; CCH3), 2.72 (s, 3H; NCH3),
2.86 (dd, J=13.5, 6.0 Hz, 1H; H-6), 3.04 (dd, J=13.5, 8.5 Hz, 1H; H-6),
3.82 (d, J=6.0 Hz, 1H; H-4), 3.93 (dt, J=8.5, 6.0 Hz, 1H; H-5), 5.06 (s,
2H; PhCH2), 6.94 (d, J=8.6 Hz, 2H; ArH), 7.23 (d, J=8.6 Hz, 2H;
ArH), 7.34–7.43 ppm (m, 5H; ArH); 13C NMR (125 MHz, CD3OD): d=
18.9, 29.0, 33.5, 64.5, 71.0, 75.2, 77.8, 116.0 (2C), 128.5 (2C), 128.8, 129.5
(2C), 131.5 (2C), 131.9, 138.9, 158.9, 177.4 ppm; IR (KBr): n˜ =3424,
2924, 1702, 1613, 1514, 1254, 1060, 740, 669 cmꢀ1; HRMS (ESI): m/z
calcd (%) for C20H24NO4: 364.1525 [M+H]+; found: 364.1521.
Synthesis of Compound 22a
Compound 24b
Colorless viscous oil; ½aꢁ2D0 =+71.3 (c=1.2 in CHCl3); 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=1.12–1.57 (m, 18H), 2.51 (brs, 2H),
2.72 (s, 1H), 2.85–2.92 (m, 1H), 3.58–3.80 (m, 2H), 4.23 (brm, 2H), 5.03
(s, 2H; PhCH2), 6.89 (d, J=8.5 Hz, 2H; ArH), 7.13 (d, J=8.5 Hz, 2H;
ArH), 7.29–7.43 ppm (m, 5H; ArH); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=14.0, 21.0, 28.3 (3C), 30.6, 34.7, 56.0, 60.3, 61.9, 62.6, 70.0, 80.6,
114.8 (2C), 127.4 (2C), 127.8, 128.5 (2C), 129.8, 130.0 (2C), 137.1, 157.4,
158.1, 176.2 ppm; IR (film): n˜ =3456, 2978, 2932, 1730, 1692, 1664, 1612,
1512, 1454, 1393, 1367, 1243, 1176, 1148, 1025, 949, 863, 774, 737,
Compound 25a (45 mg, 0.13 mmol) in MeOH (2 mL) was added to a sus-
pension of 10% Pd/C (25 mg) in MeOH (2 mL). The mixture was stirred
under 1 atm of hydrogen for 10 h at room temperature. The mixture was
filtered and the filtrate was concentrated under reduced pressure. The re-
sulting residue was purified by flash column chromatography on silica gel
(eluent: MeOH/CH2Cl2 =1:20) to give compound 22a as a white solid
(30 mg, 91%). M.p. 194–1968C (MeOH/CH2Cl2); ½aꢁ2D0 =ꢀ17.6 (c=1.0 in
MeOH); 1H NMR (500 MHz, [D6]acetone, 258C, TMS): d=1.20 (s, 3H;
CCH3), 2.76 (s, 3H; NCH3), 2.94 (dd, J=13.5, 6.8 Hz, 1H; H-6), 2.99 (dd,
J=13.5, 5.7 Hz, 1H; H-6), 3.42 (ddd, J=6.8, 5.7, 4.9 Hz, 1H; H-5), 3.83
(dd, J=5.2, 4.9 Hz, 1H; H-4), 4.21 (brm, 1H, D2O exchangeable; COH),
4.32 (d, J=5.2 Hz, 1H, D2O exchangeable; CHOH), 6.80 (d, J=8.5 Hz,
2H; ArH), 7.03 (d, J=8.5 Hz, 2H; ArH), 8.19 ppm (s, 1H; ArOH);
13C NMR (125 MHz, [D6]acetone, 258C, TMS): d=19.0, 28.3, 37.0, 66.1,
77.2, 77.7, 116.1 (2C), 129.6, 131.4 (2C), 156.9, 175.5 ppm; IR (KBr): n˜ =
3387, 2923, 1679, 1613, 1515, 1406, 1269, 1079, 619 cmꢀ1; HRMS (ESI):
m/z calcd (%) for C13H17NO4Na: 274.1055 [M+Na]+; found: 274.1051.
697 cmꢀ1
; HRMS (ESI): m/z calcd (%) for C27H37NO7Na: 510.2468
[M+Na]+; found: 510.2465.
Synthesis of Compound 25a
A solution of 24a (163 mg, 0.33 mmol) in CH2Cl2 (1.7 mL) was cooled on
an ice/water bath and TFA (0.51 mL, 30% CH2Cl2) was added dropwise.
After 5 min, the cooling bath was removed and the reaction mixture was
stirred at room temperature for 3.5 h (monitored by TLC). The reaction
mixture was then concentrated under reduced pressure and the residue
was dissolved in toluene (3.4 mL). The mixture was cooled with an ice/
water bath and K2CO3 (455 mg, 3.3 mmol) was added. The reaction mix-
ture was stirred at room temperature for 16 h (monitored by TLC). The
reaction mixture was then concentrated under reduced pressure and the
resulting residue was dissolved in CH2Cl2 and H2O. The reaction mixture
was extracted with CH2Cl2 (5ꢃ20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: MeOH/CH2Cl2 =1:40) to
Synthesis of Compound 22b
Compound 25b (27 mg, 0.079 mmol) in MeOH (1 mL) was added to a
suspension of 10% Pd/C (15 mg) in MeOH (1 mL). The mixture was
stirred under 1 atm of hydrogen for 10 h at room temperature. The mix-
ture was filtered and the filtrate was concentrated under reduced pres-
sure. The resulting residue was purified by flash column chromatography
on silica gel (eluent: MeOH/CH2Cl2 =1:20) to give 22b as a white solid
(18 mg, 90%). M.p. 193–1958C (MeOH/CH2Cl2); ½aꢁ2D0 =+5.5 (c=0.9 in
MeOH); 1H NMR (500 MHz, [D6]acetone, 258C, TMS): d=1.30 (s, 3H;
CCH3), 2.66 (s, 3H; NCH3), 2.82 (dd, J=13.6, 6.0 Hz, 1H; H-6), 3.05 (dd,
J=13.6, 8.2 Hz, 1H; H-6), 3.87 (dt, J=13.6, 6.0 Hz, 1H; H-5), 3.93 (t, J=
give 25a as
a white solid (99 mg, 87%). M.p. 154–1558C (MeOH/
CH2Cl2); ½aꢁ2D0 =ꢀ36.8 (c=1.0 in MeOH); 1H NMR (400 MHz,
514
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 504 – 518

Syntheses of Rigidiusculamides A and B
6.0 Hz; H-4), 4.23 (brm, 1H, D2O exchangeable; COH), 4.46 (d, J=
5.7 Hz, 1H, D2O exchangeable; CHOH), 6.77 (d, J=8.5 Hz, 2H; ArH),
7.17 (d, J=8.5 Hz, 2H; ArH), 8.23 ppm (s, 1H; ArOH); 13C NMR
(125 MHz, [D6]acetone, 258C, TMS): d=19.6, 28.6, 33.4, 63.8, 74.9, 77.0,
116.1 (2C), 130.5, 131.2 (2C), 156.8, 175.6 ppm; IR (KBr): n˜ =3436, 2927,
1679, 1613, 1517, 1403, 1234, 1099, 830, 796 cmꢀ1; HRMS (ESI): m/z
calcd (%) for C13H17NO4Na: 274.1055 [M+Na]+; found: 274.1051.
rated (10 mg, 69%) for characterization, and the remaining major part of
the mixture was separated by acetylation.
Compound ent-21
White solid; m.p. 182–1838C (MeOH/CH2Cl2); ½aꢁ2D0 =ꢀ19.2 (c=1.0 in
MeOH) (lit.[12] colorless oil, ½aꢁ2D5 =ꢀ16.0 (c=0.1 in MeOH)); 1H NMR
(500 MHz, [D6]acetone+D2O, 25 8C, TMS): d=1.19 (s, 3H; CCH3), 2.70
(s, 3H; NCH3), 2.92 (dd, J=13.3, 5.6 Hz, 1H; H-6), 2.97 (dd, J=13.3,
8.6 Hz, 1H; H-6), 3.66 (d, J=4.4 Hz, 1H; H-4), 3.68 (ddd, J=8.6, 5.6,
4.4 Hz, 1H; H-5), 6.75 (d, J=8.5 Hz, 2H; ArH), 7.17 ppm (d, J=8.5 Hz,
2H; ArH); 13C NMR (125 MHz, [D6]acetone, 258C, TMS): d=21.8, 28.0,
33.1, 63.2, 73.2, 75.2, 116.0 (2C), 129.8, 131.4 (2C), 156.8, 175.5 ppm; IR
(KBr): n˜ =3415, 2925, 1665, 1613, 1517, 1403, 1235, 1090, 848, 792, 713,
Synthesis of Compounds 24c and 24d
NMO (412 mg, 2.14 mmol), citric acid (450 mg, 2.14 mmol), and an aque-
ous solution of K2OsO2(OH)4 (0.2 mL, 0.027m) were added to a solution
of 23b (487 mg, 1.07 mmol) in tBuOH/H2O (1:1, 3 mL). The mixture was
stirred at room temperature for 8 h (monitored by TLC). The reaction
was quenched with Na2S2O3·5H2O and stirred for 0.5 h. After removing
the solid by filtration, the filtrate was concentrated under reduced pres-
sure. The resulting residue was purified by flash column chromatography
on silica gel (eluent: EtOAc/hexane=1:6) to give 24c/24d as an insepara-
ble mixture (500 mg, 96%, colorless viscous oil), which was used in the
next step without further purification. 1H NMR (500 MHz, CDCl3, 258C,
TMS) (data read from the spectrum of the mixture, M=major diastereo-
mer; m=minor diastereomer): d=1.24–1.50 (m, 15H, M+m), 1.73 (s,
1H, M+m), 2.16–2.38 (m, 2H, M+m), 2.58–2.90 (m, 3H, M+m), 3.20–
3.34 (m, 1H, M+m), 3.76–3.86 (m, 1H, M+m), 4.12–4.51 (m, 3H, M+m),
5.03 (s, 2H, M+m), 6.86–6.90 (m, 2H, M+m), 7.05–7.10 (m, 2H, M+m),
7.30–7.43 ppm (m, 5H, M+m); 13C NMR (125 MHz, CDCl3, 258C, TMS)
(data read from the spectrum of the mixture): d=14.1, 24.0, 28.3 (3C),
33.5, 58.3, 61.7, 62.2, 70.0, 75.6, 80.6, 114.8 (2C), 127.4 (2C), 127.8, 128.5
(2C), 129.8, 129.9 (2C), 137.1, 157.2, 157.4, 175.7 ppm.
628 cmꢀ1
; HRMS (ESI): m/z calcd (%) for C13H17NO4Na: 274.1055
[M+Na]+; found: 274.1048.
Synthesis of Compounds 27a and 27b
Triethylamine (0.10 mL, 0.66 mmol) was added dropwise to a solution of
mixture of 26a/26b (50 mg, 0.15 mmol) and DMAP (15 mg (cat.)) in
CH2Cl2 (3.7 mL). The reaction was cooled on an ice/water bath and
Ac2O (0.06 mL, 0.59 mmol) was added dropwise. After 5 min, the cooling
bath was removed and the reaction mixture was stirred at room tempera-
ture for 20 h. The reaction mixture was then concentrated under reduced
pressure and the resulting residue was purified by flash column chroma-
tography on silica gel (eluent: EtOAc/hexane=1:4) to give 27a (10 mg,
16%) and 27b (51 mg, 82%).
Compound 27a
Colorless oil; ½aꢁ2D0 =+32.6 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.27 (s, 3H; CCH3), 1.84 (s, 3H; CH3CO), 2.02
(s, 3H; CH3CO), 2.78 (dd, J=14.0, 7.3 Hz, 1H; H-6), 2.94 (s, 3H;
NCH3), 3.07 (dd, J=14.0, 4.6 Hz, 1H; H-6), 3.73 (dt, J=7.3, 4.6 Hz, 1H;
H-5), 4.85 (d, J=4.6 Hz, 1H; H-4), 5.04 (s, 2H; PhCH2), 6.90 (d, J=
8.5 Hz, 2H; ArH), 7.07 (d, J=8.5 Hz, 2H; ArH), 7.29–7.42 ppm (m, 5H;
ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=20.1, 20.4, 23.1,
28.7, 36.5, 64.1, 69.9, 73.5, 77.3, 115.1 (2C), 127.3 (2C), 127.6, 127.9, 128.5
(2C), 130.6 (2C), 136.8, 157.8, 169.5, 169.6, 171.6 ppm; IR (film): n˜ =
2924, 1747, 1711, 1610, 1512, 1243, 1072, 902, 798, 696 cmꢀ1; HRMS
(ESI): m/z calcd (%) for C24H27NO6Na: 448.1736 [M+Na]+; found:
448.1737.
Synthesis of Compounds 26a and 26b
TFA (0.35 mL, 30% CH2Cl2) was added dropwise to a cooled solution
(ice/water bath) of the mixture 24c/24d (115 mg, 0.24 mmol) in CH2Cl2
(1.2 mL). After 5 min, the cooling bath was removed and the reaction
mixture was stirred at room temperature for 3.5 h. The reaction mixture
was then concentrated under reduced pressure and the residue was dis-
solved in toluene (2.4 mL). The mixture was cooled on an ice/water bath
and K2CO3 (331 mg, 2.4 mmol) was added. The reaction mixture was
stirred at room temperature for 16 h. The reaction mixture was then con-
centrated under reduced pressure and resulting residue was dissolved in
CH2Cl2 and H2O. The reaction mixture was extracted with CH2Cl2 (5ꢃ
15 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
(eluent: MeOH/CH2Cl2 =1:40) to give 26a/26b as an inseparable mixture
(68 mg, 85%, white solid), which was used in the next step without fur-
ther purification. 1H NMR (500 MHz, CDCl3, 258C, TMS) (data read
from the spectrum of the mixture, M=major diastereomer; m=minor
diastereomer): d=1.29 (s, 0.42H; CCH3), 1.31 (s, 2.43H; CCH3), 2.83 (s,
0.45H, m; NCH3), 2.86 (s, 2.33H, M; NCH3), 2.98 (dd, J=13.2, 5.0 Hz,
1H, M+m; H-6), 3.12 (dd, J=13.2, 10.1 Hz, 1H, M+m; H-6), 3.31 (s,
0.78H, M; OH), 3.45 (s, 0.16H, m; OH), 3.63 (ddd, J=10.1, 5.0, 2.6 Hz,
1H, M+m; H-5), 3.75 (d, J=2.6 Hz, 1H, M+m; H-4), 4.55 (s, 0.58H, M;
OH), 4.66 (s, 0.19H, M; OH), 4.79 (s, 0.15H, m; OH), 5.08 (s, 2H, M+m;
PhCH2), 6.97 (d, J=8.6 Hz, 2H, M; ArH), 7.14 (d, J=8.6 Hz, 0.35H, m;
ArH), 7.29 (d, J=8.6 Hz, 1.66H, M; ArH), 7.31–7.47 ppm (m, 5H,
M+m; ArH); 13C NMR (125 MHz, CDCl3, 258C, TMS) (data read from
the spectrum of the mixture): d=21.3, 23.8, 27.9, 31.9, 36.5, 62.6, 67.3,
70.0, 72.1, 73.3, 74.6, 74.9, 114.9, 115.2, 127.4, 127.9, 128.5, 128.9, 129.3,
130.1, 130.5, 137.0, 157.6, 175.9 ppm.
Compound 27b
Colorless oil; ½aꢁ2D0 =ꢀ11.2 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.58 (s, 3H; CCH3), 2.00 (s, 3H; CH3CO), 2.08
(s, 3H; CH3CO), 2.76 (s, 3H; NCH3), 2.94 (d, J=6.4 Hz, 2H; H-6), 4.01
(dd, J=13.2, 6.4 Hz, 1H; H-5), 5.04 (s, 2H; PhCH2), 5.49 (d, J=6.4 Hz,
1H; H-4), 6.91 (d, J=8.6 Hz, 2H; ArH), 7.10 (d, J=8.6 Hz, 2H; ArH),
7.30–7.43 ppm (m, 5H; ArH); 13C NMR (100 MHz, CDCl3, 258C, TMS):
d=20.4, 20.9, 20.9, 29.0, 32.8, 60.5, 70.0, 71.7, 78.7, 115.1 (2C), 127.4
(2C), 127.9, 128.5 (2C), 129.4, 129.6 (2C), 136.8, 157.5, 169.1, 169.2,
171.0 ppm; IR (film): n˜ =2928, 1754, 1709, 1610, 1512, 1239, 1072, 859,
740, 698 cmꢀ1; HRMS (ESI): m/z calcd (%) for C24H27NO6Na: 448.1736
[M+Na]+; found: 448.1739.
Synthesis of Compound ent-7 (by Deacetylation of 27a)
Compound 27a (10 mg, 0.023 mmol) in MeOH (0.5 mL) was added to a
suspension of 10% Pd/C (10 mg) in MeOH (0.5 mL). The reaction was
cooled on an ice/water bath and AcCl (0.05 mL, 0.69 mmol) was added
dropwise. After 5 min, the cooling bath was removed and the reaction
mixture was stirred under 1 atm of hydrogen for 10 h at room tempera-
ture. The mixture was filtered and the filtrate was concentrated under re-
duced pressure. The resulting residue was purified by flash column chro-
matography on silica gel (eluent: MeOH/CH2Cl2 =1:20) to give com-
pound ent-7 (4 mg, 70%).
Synthesis of Compounds ent-21 and ent-7
The mixture of 26a/26b (20 mg, 0.06 mmol) in MeOH (1 mL) was added
to a suspension of 10% Pd/C (10 mg) in MeOH (1 mL). The mixture was
stirred under 1 atm of hydrogen for 10 h at room temperature. The mix-
ture was filtered and the filtrate concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (eluent: MeOH/CH2Cl2 =1:20) to give compounds ent-21 and
ent-7 as a mixture (3 mg, 21%), from which a sample of ent-21 was sepa-
Compound ent-7
Colorless oil; ½aꢁ2D0 =ꢀ12.9 (c=1.0 in MeOH); 1H NMR (400 MHz,
[D6]acetone+D2O, 25 8C, TMS): d=1.22 (s, 3H; CCH3), 2.75 (s, 3H;
Chem. Asian J. 2012, 7, 504 – 518
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
515

P.-Q. Huang et al.
FULL PAPERS
NCH3), 2.77 (dd, J=14.3, 7.4 Hz, 1H; H-6), 2.97 (dd, J=14.3, 5.6 Hz,
1H; H-6), 3.54 (ddd, J=7.4, 5.6, 3.4 Hz, 1H; H-5), 3.62 (d, J=3.4 Hz,
1H; H-4), 6.77 (d, J=8.5 Hz, 2H; ArH), 7.09 ppm (d, J=8.5 Hz, 2H;
ArH); 13C NMR (100 MHz, [D6]acetone, 258C, TMS): d=23.7, 28.5,
36.9, 67.0, 73.6, 75.6, 116.3 (2C), 129.2, 131.3 (2C), 157.1, 174.6 ppm; IR
(film): n˜ =3331, 2923, 1666, 1613, 1592, 1515, 1384, 852, 790 cmꢀ1; HRMS
(ESI): m/z calcd (%) for C13H17NO4Na: 274.1055 [M+Na]+; found:
274.1051.
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Synthesis of Compound ent-21 (by Deacetylation of 27b)
Compound 27b (40 mg, 0.094 mmol) in MeOH (1.5 mL) was cooled to
08C on an ice/water bath and added to a suspension of 10% Pd/C
(20 mg) in MeOH (1.5 mL). Subsequently, AcCl (0.2 mL, 2.76 mmol) was
added dropwise. After 5 min, the cooling bath was removed and the reac-
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Acknowledgements
We are grateful to the National Basic Research Program (973 Program)
of China (grant no. 2010CB833200), the NSF of China (20832005,
21072160), the NFFTBS (no. J1030415), and the NSF of Fujian Province
of China (2011J01056) for financial support. We thank Dr. Zhi-Hong
Guo for valuable discussions. We also thank Ming-Gui Lin for assistance
in the preparation of some starting materials.
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