Organocatalytic 1,4-conjugate addition of ascorbic acid to α,β-unsaturated aldehydes: Bio-inspired total syntheses of leucodrin, leudrin and proposed structure of dilaspirolactone

Article abstract of DOI:10.1039/c3ob00046j

The organocatalytic additions of ascorbic acid to various α,β-unsaturated aldehydes via tandem 1,4-conjugate addition/hemiacetalization/hemiketalization were developed, which provided a rapid entry into the 5-5-5 spirodilactone cores of a family of ascorbylated natural products. Based on the described chemistry, total syntheses of leucodrin, leudrin and the proposed structure of dilaspirolactone were achieved. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob00046j

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Table of Content: The organocatalytic conjugate addition of ascorbic acid to α, β−unsaturated
aldehyde is developed, which paves the way to the total synthesis of several ascorbylated natural
products.

Organic & Biomolecular Chemistry
Page 2 of 5
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Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Organocatalytic 1,4-Conjugate Addition of Ascorbic Acid to
Unsaturated Aldehydes: Bio-inspired Total Syntheses of Leucodrin,
Leudrin and Proposed Structure of Dilaspirolactone†
Zhaofeng Wang,a,b,§ Kun Zhao,a,§ Junkai Fu,b Junlin Zhang,b Weiyu Yinb and Yefeng Tang*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The organocatalytic additions of ascorbic acid to various
unsaturated aldehydes via tandem 1,4-conjugate
addition/hemiacetalization/hemiketalization were developed,
10 which provided a rapid entry into the 5-5-5 spirodilactone
cores of a family of ascorbylated natural products. Based on
the described chemistry, total syntheses of leucodrin, leudrin
and the proposed structure of dilaspirolactone were achieved.
Over the past decade, organocatalytic tandem or cascade
15 reactions have grown into one of the most powerful tools for
carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds
formation.[1] Owing to their abilities of enabling rapid generation
of complex molecular architectures from simple starting materials,
as well as their exceptional functional group compatibility,
20 operational simplicity and environmentally benign nature, they
represent an ideal approach for today’s chemists to pursue the so-
called “ideal synthesis”.[2] However, compared with the
tremendous progresses made on the methodology developments,
their true synthetic utilities in complex target synthesis have yet
25 to be demonstrated. In this context, inventions and applications of
new organocatalytic tandem or cascade transformations for the
syntheses of bioactive natural products and pharmaceuticals
remain as an area of intense interests.[3]
Ascorbic acid (vitamin C), is a naturally occurring substance
30 that plays essential roles in the biological systems. In addition, it
can incorporate into some other natural substances via covalent
bonds to generate the so-called ascorbylated products, which
usually display increasing molecular complexity and diverse
biological profiles.[4] As a paradigmatic example, structure 1-6[5]
35 (Fig.1) represent a group of ascorbylated natural products, among
which 1-4 feature a highly congested 5-5-5 spirodilactone core
bearing five continuous stereogenic centers, whereas 5-6 are
50
Fig.1 Representative ascorbylated natural products 1-6
characterized by a relevant 5-5 spirodilactone skeleton with the c-
ring existing in its open form. Notably, dichotomain B (2), which
was isolated by Sun and co-workers from the fronds of
55 dicranopteris dichotomain, exhibited promising anti-HIV activity
in the preliminary biological evaluations.[5d]
Biogenetically, the 5-5-5 spirodilactone core of 1-4, as
represented by 7, is assumed to be generated from ascorbic acid
(9) and coumaric acid (10a) (or its ester derivative) through a
60 sequential
1,4-conjugate
addition,
lactonization
and
hemiketalization (Scheme 1). Inspired by the hypothesis, Poss
and co-workers reported a concise synthesis of 7 (Scheme 1)
starting from ascorbic acid and coumaric acid ester derivative
10b.[6] The salient of their synthesis embodied the utilization of
65 10b as the surrogate of coumaric acid (10a) and a p-quinone
methide was assumed as the key intermediate. This method,
albeit very concise, suffered from several issues including the
extremely long reaction time, modest yield and limited substrate
scope.[7] To circumvent these problems, we envisioned that it
70 would be an alternative way to employ cinnamaldehyde (10c) in
the transformation, since it is well-known that -unsaturated
aldehyde is much more reactive Michael acceptor than the
corresponding acid or ester derivatives. Moreover, significant
progresses have been made in the field of organocatalytic
75 conjugate addition of -unsaturated aldehydes with various
nucleophiles,[8,9] and thus we assumed such strategy could be
implanted to the current scenarios. If it turns out to be true, 8
a The Comprehensive AIDS Research Center, Department of
40 Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua
University, Beijing 100084, China. Fax: +86 10 62797732; Tel: +86 10
62798236; E-mail: yefengtang@tsinghua.edu.cn
b Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University of Shenzhen Graduate School,
45 Shenzhen, 518055, China
§ These authors contributed equally to this work
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Page 3 of 5
Organic & Biomolecular Chemistry
Table 1 Condition screening of organocatalytic addition of ascorbic acid
with cinnamaldehyde
View Article Online
HO
O

9
Ph
Me
N
Ar
O
catalyst/additive
Ar
OTMS
: Ar = Ph

HO

N
(1:1, 20%)
t-Bu
O
H
Ph

50 oC, 10-12 h
Bn
N
H
C
O
A
B
O
H
O
: Ar = 3,5-(CF3)2-C6H3
H
11a
12a
HO
Entrya
Cat.
Additive Solvent
Yield
of 2ab
20
48
54
55
88
90
1c
2
3
4
5
6
7
8
9
10
11
12
13
14 d
15 e
none
piperidine
pyrrolidine AcOH
none
H2O/MeOH
AcOH
H2O/MeOH
H2O/MeOH
H2O/MeOH
H2O/MeOH
H2O/MeOH
Proline
None
BA
BA
Scheme 1 Bio-inspired strategy for the synthesis of the 5-5-5
spirodilactone core of 1-4.
A
B
C
C
C
C
C
C
C
C
C
BA
H2O/MeOH 92
PNBA
TFA
HClO4
BA
H2O/MeOH
H2O/MeOH
H2O/MeOH
H2O/CH3CN 88
H2O/dioxane 53
90
43
30
would be generated from 9 and 10c via an organocatalytic tandem
1,4-conjugate addition/hemiacetalization/hemiketalization. Next,
8 could be converted to 7 via selective oxidation of the resulting
hemiacetal motif to the corresponding lactone (Scheme 1).[10]
To validate the above hypothesis, a systematic condition
screening was performed with cinnamaldehyde (11a) as the
5
BA
BA
H2O/THF
91
85
87
BA
BA
H2O/MeOH
H2O/MeOH
10 model substrate. The first reaction was performed by stirring a
mixture of ascorbic acid and cinnamaldehyde in CH3OH/H2O
(4:1) at 50 oC for 24 h without addition of any catalyst or additive.
It was found that the desired product 12a was generated in a poor
yield, with most of the starting material recovered (entry 1).
15 Extending reaction time or elevating reaction temperature has
little influence on the outcomes. Given that iminium activation of
unsaturated aldehyde towards conjugate addition has been
well established,[11] we then tried several commonly used
secondary amine catalysts in the reaction. To our delight, we
20 found that both piperidine/AcOH and pyrrolidine/AcOH
combinations could notably improve the reaction by affording
12a in yield of 48% and 54%, respectively (entries 2 and 3).
Comparable result was obtained when proline was used (entry 4).
Strikingly, when chiral catalyst A12 was employed together with
25 benzoic acid (BA) as co-catalyst, 12a was isolated in an excellent
yield of 88% (entry 5). More encouraging outcomes were
obtained with chiral catalyst B13 and C,14 which afforded 12a in
yields of 90% and 92%, respectively (entries 6-7). Having the
optimal catalyst identified, we then evaluated the effect of the
30 additives on this reaction. It was shown that while p-nitro-benzoic
acid (PNBA) performed as well as benzoic acid, TFA and HClO4
failed to provide satisfactory results (entries 8-10). Furthermore,
the solvent effect was also examined. Both CH3CN/H2O and
THF/H2O proved to be suitable solvent system (entries 11 and
35 13), while dioxane/H2O led to modest result (entry 12). Finally,
we found that the transformation could proceed smoothly even at
room temperature or with less catalyst loading, and only a
slightly decreased yield of 12a was obtained (entries 14 and 15).
Notably, although four stereogenic centers (C-9, C-5, C-4 and C-
40 2) were generated in the reaction, 12a was only obtained as a
mixture of C-2 diastereoisomers (-isomer/-isomer = 7/1).15
With the optimal conditions in hand, the scope of the reaction
with respect to the Michael acceptor partners was explored. As
shown in Table 2, those substrates with either electron-neutral
45 groups (4-Me, 11b, entry 2) or electron-withdrawing groups (4-Cl,
4-Br, 4-F, 4-CF3, and 4-NO2, 11c-g, entries 3-7) on the para-
position of phenyl ring afforded the corresponding products in
50 a The reaction was run with 11a (1.5 mmol) and 9 (1.0 mmol) in 2.5 mL
solvents (H2O/organic solvent = 1:4). Refers to isolated yield. The
reaction stopped after 72 h. dThe reaction was run at 25 oC. e 10% catalyst
was used.
b
c
good to excellent yields. Similarly, 11h bearing two MeO- groups
55 on the meta-positions was also tolerated well (entry 8). In
contrast, for those substrates having electron-rich groups located
on the para-position (11i-k, entries 9-11), the reactions became
sluggish and only resulted in moderate yields (50-60%) even after
long reaction time (48 h). Fortunately, we found those reactions
60 could be improved by employing catalyst B rather than catalyst C,
and as results, 12i-k were obtained in excellent yields (82%-85%).
Not surprisingly, those substrates bearing other aromatic rings,
such as naphthyl- (11l) and furan- (11m) ring, were also proved
to be suitable substrates for the reaction (entries 12-13). Notably,
65 the structure of 12j, which was employed as a key precursor in
the following synthetic studies, was unambiguously confirmed by
the x-ray crystallographic study (Fig.2).[16]
Having established the method of organocatalytic conjugate
addition of ascorbic acid with various cinnamaldehyde
70 derivatives, we then explored the feasibility of selective oxidation
of the hemiacetal motif without protecting the free alcohol at C-
12. After extensive tries, we were pleased to find that the desired
transformation could be realized by using the combination of
NIS/TBAI.[17] Under this condition, 12a could be converted into
75 13a in yield of 80%. Moreover, this protocol could be extended
to substrates 12b-l, and all of them gave satisfactory results. The
only exception was the reaction with 12m, which resulted in
decomposition of the starting material.
With the core skeleton of 1-6 prepared in a scalable manner,
80 we then moved towards their total syntheses. At the outset,
leucodrin (5) and leudrin (6) were prepared from 13j and 13k
respectively, based on the method developed by Poss and co-
workers.[6] Thus, reduction of the hemiketal moiety of 13j and
13k with diborane in reflux THF followed by global deprotection
85 of the benzyl groups with hydrogenation afforded 5 and 6 in 72%
and 61% overall yields, respectively (Scheme 2).
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Organic & Biomolecular Chemistry
Page 4 of 5
Table 2. Organocatalytic Addition of Ascorbic acid with ,-
unsaturated aldehydes and selective oxidation of the hemiketal moiety.
spectroscopic evidence (for details, see Supporting Information).
30 Notably, although 16 was well-known for its superior reactivity
View Article Online
for glycosylation of sterically hindered alcohols, no 9-OH
O
HO
O
9
glycoside was isolated in our case. Moreover, efforts to improve
the reaction by employing large excesses amount of 16 or
elevating reaction temperature were failed, indicating that the 9-
35 OH of 13j was rather inert toward the glycosylation under the
currently examined conditions.
Ar
H
Cat. C/BA
(1:1, 20%)
O
HO
O
HO
O
NIS, TBAI
Ar
Ar
O
DCM, 25 oC
O
H2O/CH3OH
(1:4)
O
O
O
H
H
HO
11
HO
12
13
Entrya Ar
Yield of 12 (%)b Yield of 13 (%)
1
2
3
4
5
6
7
8
C6H5(11a)
91(12a)
87(12b)
82(12c)
85(12d)
85(12e)
95(12f)
93(12g)
80(13a)
61(13b)
66(13c)
69(13d)
64(13e)
70(13f)
76(13g)
65(13h)
75(13i)
80(13j)
77(13k)
66(13l)
messy
4-Me-C6H5(11b)
4-Cl-C6H5(11c)
4-Br-C6H5(11d)
4-F-C6H5(11e)
4-NO2-C6H5(11f)
4-CF3-C6H5(11g)
3,5-(MeO)2-C6H4(11h) 91(12h)
9c
10c
11c
12
13
4-MeO-C6H5(11i)
4-BnO-C6H5(11j)
3,4-(BnO)2-C6H5(11k)
Naphthyl(11l)
82(12i)
85(12j)
85(12k)
75(12l)
70(12m)
Furanyl-(11m)
a Each reaction was run with 11 (1.5 mmol), 9 (1.0 mmol) and catalyst
C/BA (0.2 mmol) in 2.5 mL solvent at 50 oC for 12 h. b Each of 12a-m
5 was isolated as a mixture of C-2 diastereoisomers (the ratio of -
isomer:-isomer varied from 1:5 to 1:7. c Catalyst B was used.
Scheme 3 Synthetic efforts towards total synthesis of viburnolide A (3)
With compound 17 in hands, we were allowed to attempt the
40 total synthesis of dilaspirolactone (4). However, when we tried to
remove the 2-chloro-2-methylpropanoic ester group of 17 using
the standard condition (MeOH/K2CO3), we were disappointed to
find that the desired product 18 could not be identified, and the
starting material was gradually decomposed under this condition.
Fig.2 X-ray crystal structure of 12j
45
To address this issue, glycoside donor 19[22] was employed,
considering that the benzyl group might be easily removed under
milder condition. Thus, treatment of 13j with two equivalents of
19 and catalytic amount of TMSOTf in DCM for 12 h afforded
two major products in yield of 35% and 18%, whose structure, on
50 the basis of extensive spectroscopic analysis, were assigned as -
glycoside 20a and -glycoside 20b, respectively (for details, see
Supporting Information). As expected, the global deprotection of
20a and 20b were easily achieved with hydrogenation (Pd-C/H2,
EtOAc) to provide the corresponding product 4 and 21 in
55 quantitatively yields (Scheme 4). However, we were surprised to
find that the spectrum data of the synthetic 4 did not match the
reported one. Since the structure of 4 was fully established on the
basis of extensive NMR studies, we came to realize that the
structure of dilaspirolactone could be incorrectly assigned in the
60 original isolation paper. Furthermore, we noticed that the
structure of dilaspirolactone was also challenged by M. Kikuchi
and co-workers in their seminal publication,[5c] where they
pointed out that viburnolide A (3), a natural product isolated in
their laboratory, bear the same spectrum data as that of
65 dilaspirolactone originally reported by Iwagawa and co-
workers.[5b] Thus, they deduced that dilaspirolactone and
viburnolide A in reality shared the same molecular architecture,
as represented by structure 3. Such assumption, although has
been overlooked for a long time by the following researchers,[4] is
70 now experimentally validated by our synthetic studies.
10 Scheme 2 Total synthesis of leucodrin (5) and leudrin (6)
Having achieved the syntheses of 5 and 6, we devoted to the
more challenging targets 1-4. Notably, although much effort has
been directed towards the synthesis of the aglycon of 1-4,[6,18]
their total syntheses have yet to be achieved, probably due to the
15 anticipated synthetic challenges associated with the installation of
the sugar unit to its corresponding parental scaffold. Indeed, the
glycosylation of the tertiary alcohol at C-9 might be rather
challenging due to the huge steric hindrance. Besides, the regio-
and diastereoselectivity of the glycosylation could also be very
20 complicated (e.g. 9-OH glycoside vs 12-OH glycoside and -
glycoside vs -glycoside). Keeping these concerns in mind, we
attempted several glycoside donors in the transformation,
including 14,[19] 15[20] and 16[21] (Scheme 3). It turned out that the
best result was obtained by using the condition reported by T.
25 Bach and co-workers.[21c] Thus, treatment of 13j with 2.0 equiv of
16 and catalytic amount of TBSOTf in a mixture of DCM/Hexane
(4:1) for 24 h provided 17 as the sole regio- and diastereoisomer
in 46% yield, whose structure was established by extensive
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Page 5 of 5
Organic & Biomolecular Chemistry
O
O
Zheng, W. L. Xiao, Y. Zhao, G. Xu, Y. Lu, Y. Chang, Q. T. Zheng,
Q. S. Zhao and H. D. Sun, Org. Lett., 2006, 8, 1937-1940.
OBn
O
13j, TMSOTf
DCM, 12 h
BnO
BnO
OBn
6
7
a) A. J. Poss and R. K. Belter, Tetrahedron Lett. 1987, 28, 2555-
HO
O
View Article Online
O
(20a/20b = 2/1)
53%
45
2558; b) A. J. Poss and R. K. Belter, J. Org. Chem., 1988, 53, 1535-
1540.
BnO
O
NH
CCl3
O
H
12
OBn
19
In Poss’s studies, only substrates bearing an electro-donating group
on the para position of phenyl ring were amenable to their method,
which limited its application for the synthesis of other analogues.
J. L. Vicario, D. Bada, L. Carillo and E. Reyes, Organocatalytic
Enantioselective Conjugate Addition Reactions: A Powerful Tool for
the Stereocontrolled Synthesis of Complex Molecules, RSC
Publishing, Cambridge, 2010.
O
O
1'
HMBC
BnO
BnO
2'
OBn
20a: ( glycoside, JH1'-H2' = 3.8 Hz)
20b: ( glycoside, JH1'-H2' = 7.6 Hz)
50 8
95%
(from 20a)
Pd(OH)2, H2
EA, 12 h
95%
(from 20b)
9
For selected reviews, see: a) A. Erkkilä, I. Majander and P. M.
Pihko, Chem. Rev., 2007, 107, 5416-5470; b) D. Almasi, D. A.
Alonso and C. Nájera, Tetrahedron: Asymmetry, 2007, 18, 299-365;
c) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701-1716; d) C.
Pankaj and S. C. Swapandeep, RSC Advances, 2012, 2, 6117-6134;
e) D. Roca-Lopez, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero and
P. Merino, Tetrahedron: Asymmetry, 2010, 21, 2561-2601; e) R.
Dalpozzo, G. Bartoli and G. Bencivenni, Symmetry, 2011, 3, 84-125.
O
O
55
O
OH
HO
O
O
O
OH
HO
O
O
O
H
O
OH
O
O
H
60
O
O
OH
HO
HO
HO
10 Conjugate addition of ascorbic acid with acrolein was reported,
however, a 6-5-5 instead of 5-5-5 tricyclic adduct was obtained. For
reference, see: G. Fodor, R. Arnold, T. Mohacsi, Tetrahedron 1983,
39, 2137-2145.
11 For representative examples，see: a) N. A. Paras and D. W. C.
MacMillan, J. Am. Chem. Soc., 2001, 123, 4370-4371; b) S.
Brandau, A. Landa, J. Franzén, M. Marigo and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2006, 45, 4305–4309; c) M. Rueping, E.
Sugiono and E. Merino, Chem. Eur. J., 2008, 14, 6329-6332; d) Y.
Wang, P. Li, X. Liang, J. Ye, Adv. Synth. Catal., 2008, 350, 1383-
1389; e) M. Rueping, E. Merino, E. Sugiono, Adv. Synth. Catal.,
2008, 350, 2127-2131; f) S. Zhang, Y. Zhang, Y. Ji, H. Li, W. Wang,
Chem. Commun., 2009, 4886-4888.
HO
dilaspirolactone (4)
(proposed structure)
HO
HO
21
Scheme 4 Synthesis of proposed structure of dilaspirolactone (4)
65
70
In summary, we have developed a novel organocatalytic
addition of ascorbic acid to unsaturated aldehydes via
tandem 1,4-conjugate addition/hemiacetalization/hemiketaliza-
tion reaction. The developed chemistry provides a rapid entry into
the characteristic 5-5-5 spirodilactone cores of a group of
ascorbylated natural products. To showcase the synthetic utility
of this methodology, we accomplished the total synthesis of
5
75 12 Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem. Int.
Ed., 2005, 44, 4212-4215.
13 M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jøgensen,
Angew. Chem., Int. Ed., 2005, 44, 794-797.
10 leucodrin (5), leudrin (6) and the proposed structure of
dilaspirolactone (4). Further synthetic efforts towards the total
synthesis of 1-3 are underway in this laboratory.
14 J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124,
Acknowledgements
80
85
1172-1173.
15 For details of rationalization for the high diastereoselectivity of the
reaction, see Supporting Information.
16 CCDC 918562 (3) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
17 J. D. Prugh, C. S. Rooney, A. A. Deana and H. G. Ramjit, J. Org.
Chem., 1986, 51, 648-657.
18 A. J. Poss and M. S. Smyth, Tetrahedron Lett. 1987, 28, 5469-5472.
This work was financially supported by the National Science of
15 Foundation of China (21102081, 21272133), New Teachers' Fund
for Doctor Stations (20110002120011), Scientific Research
Foundation for the Returned Overseas Chinese Scholars, Ministry
of Education, and Opening Foundation of Laboratory of
Chemical Genomics, Peking University of Shenzhen Graduate
20 School.
Crystallographic
Data
Centre
via
90 19 a) S. J. Deng, B. Yu, J. M. Xie, Y. Z. Hui, J. Org. Chem., 1999, 64,
7265-7266; b) B. N. A. Mbadugha, F. M. Menger, Org. Lett., 2006,
8, 1937-1940.
Notes and references
20 a) Y. Li, X. Y. Yang, Y. P. Liu, C. S. Zhu, Y. Yang and B. Yu,
Chem. Eur. J. 2010, 16, 1871-1882; b) Y. Li，Y. Yang and B. Yu,
1
For representative reviews, see: (a) H. C. Guo and J. A. Ma, Angew.
Chem., Int. Ed., 2006, 45, 354-366; (b) D. Enders, G. Grondal and
M. R. M. Hüttl, Angew.Chem.Int. Ed., 2007, 46, 1570-1581; (c) D.
Enders, C. Wang and J. W. Bats, Angew. Chem. Int. Ed., 2008, 47,
7539-7542; (d) X. Yu and W. Wang, Org.Biomol. Chem., 2008, 6,
2037-2046; (e) A. Alba, X. Companyo, M. Viviano and R. Rios,
Curr. Org. Chem., 2009, 13, 1432-1474.
95
Tetrahedron Lett., 2008, 49, 3604-3608.
21 For a review, see: a) Chem. Commun., 2010, 46, 4668-4679. For
synthesis of 16 and its application, see: b) A. M. Szpilman and E. M.
Carreira, Org. Lett., 2006, 8, 1937-1940; c) P. Lu and T. Bach,
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