A carbohydrate-based approach for the total synthesis of sawaranospirolide C

Article abstract of DOI:10.1016/j.tetlet.2021.153072

A diastereoselective carbohydrate-based synthesis of the oxaspirolactone sawaranospirolide C was accomplished by utilizing one-pot cascade of acetonide deprotection/hemiacetal formation/spirolactonization as the key step.

Full text of DOI:10.1016/j.tetlet.2021.153072

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A carbohydrate-based approach for the total synthesis of
sawaranospirolide C
Shuai Yu a,b, Yinxin Liu b, Chengxiang Shang a,b, Yuguo Du a,b, Jun Liu a,b,
⇑
a The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Beijing 100085, China
b Department of Chemistry, University of Chinese Academy of Science, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective carbohydrate-based synthesis of the oxaspirolactone sawaranospirolide C was
accomplished by utilizing one-pot cascade of acetonide deprotection/hemiacetal formation/spirolac-
tonization as the key step.
Received 26 February 2021
Revised 26 March 2021
Accepted 6 April 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Sawaranospirolide
[6,5]-oxaspirolactone
Total synthesis
Carbohydrate
Introduction
bioactive spiroacetals from naturally abundant carbohydrates, [5]
we envisioned that the stereoselective synthesis of sawara-
The family of sawaranospirolides A-D (1–4) has been isolated
by Hasegawa et al. from the heartwood of the Japanese ‘Sawara’
tree Chamaecyparis pisifera [1,2]. The structure and relative stereo-
chemistry of sawaranospirolides were established based on exten-
sive spectroscopic analysis and the absolute configuration was
further confirmed by chemical conversion and degradation. Archi-
tecturally, sawaranospirolides family possess unique [6,5]-oxas-
nospirolides A and C could be derived from the simple and natural
L-sorbose, and the advantage of the existing chirality transfer will
be elaborated in the rapid asymmetric synthesis.
Results and discussion
Structurally, sawaranospirolides A and C share the same [6,5]-
oxaspirolactone backbone, except for the different stereochemistry
pirolactone
skeleton
bearing
a
highly
oxygenated
tetrahydropyran ring system and a
c
-butyrolactone. These natu-
of p-hydroxyphenyl group at C-3 position of the
ring. Structural comparison indicated that the similarities between
the natural carbohydrate, -sorbose and the highly oxygenated
c-butyrolactone
rally occurring oxaspirolactones [3] contain five contiguous stere-
ogenic centers at C3-C7 and are epimeric with one another at C-
3 or C-5.
L
tetrahydropyran ring system (C4-C8) of sawaranospirolides A and
C. Accordingly, we hypothesized that sawaranospirolides A and C
In 2010, the first synthesis of ent-sawaranospirolides C and D
was completed by Robertson and co-workers [4]. The absolute
configurations were also confirmed by the synthesis and illustrated
in Figure 1. The utilization of m-CPBA mediated oxidative spirolac-
tonization enable the successful [6,5]-oxaspirolactone formation
and guarantee the total synthesis of ent-sawaranospirolide C and
D. Although much research has been conducted to date, the
biological activities of sawaranospirolides still remain undeter-
mined. As part of our continuing interest in the synthesis of
could be prepared from the same precursor, -sorbose.
L
Retrosynthetic analysis of sawaranospirolides A (1) and C (3) is
summarized in Scheme 1. We envisaged that sawaranospirolides A
and C could be generated from multi-functionalized
a,b-unsatu-
rated ester 6 via hydrogenation, acetonide deprotection, hemiac-
etal formation, and spirolactonization cascade (Scheme 1). The
key precursor,
a,b-unsaturated ester 6, which contains three
desired contiguous stereogenic hydroxyl groups, could be readily
accessible from 2,3,4,6-Di-O-isopropylidene- -sorbofuranose 7 via
L
multiple functional group transformations.
⇑
Corresponding author at: The State Key Laboratory of Environmental Chemistry
and Ecotoxicology, Research Center for Eco-Environmental Sciences, Beijing
100085, China.
Subsequently, the synthesis of the key precursor 6 from
bose is outlined in Scheme 2. The known aldehyde 8 was easily
obtained from -sorbose in excellent yield according to a known
L
-sor-
E-mail address: junliu@rcees.ac.cn (J. Liu).
L
https://doi.org/10.1016/j.tetlet.2021.153072
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Yu, Y. Liu, C. Shang et al., A carbohydrate-based approach for the total synthesis of sawaranospirolide C, Tetrahedron Letters,
https://doi.org/10.1016/j.tetlet.2021.153072

S. Yu, Y. Liu, C. Shang et al.
Tetrahedron Letters xxx (xxxx) xxx
The stereochemistry of ester 6 was confirmed on the basis of its
NOESY correlations.
With the key precursor 6 in hand, we then focused on the final
stage of the total synthesis of sawaranospirolides A (1) and C (3)
OH
O
OH
HO
OH
O
HO
OH
O
5
7
O
O
O
1
3
according to the retrosynthetic design. Hydrogenation of
a,b-
unsaturated ester 6 over palladium on activated charcoal (Pd/C,
10%) under high pressure hydrogen atmosphere (4 atm) removed
the benzyl group and reduced the conjugate double bond to afford
the saturated ester 11 along with significant quantities of a bypro-
duct 12, which is the partial hydrolysis product of the acetonide
group. [10] It was noteworthy that 3R isomer of the saturated ester
was obtained as a single diastereomer. The excellent selectivity
probably originated from the steric interactions of two adjacent
bulky cyclic acetonides. Facial selective hydrogenation of the dou-
HO
HO
(1)
Sawaranospirolide A
(2)
B
Sawaranospirolide
OH
OH
HO
OH
O
HO
OH
O
O
O
O
O
ble bond proceeded only on the less hindered face of the
a, b-
unsaturated ester to give exclusively 3R isomer.
HO
Sawaranospirolide C
HO
Sawaranospirolide
Finally, one-pot acetonide deprotection/ hemiacetal formation /
spirolactonization was achieved with 70% TFA via spirohemiacetal
intermediates (5a-b), delivering the [6,5]-oxaspirolactone sawara-
nospirolide C (3) in 67% overall yield (Scheme 3). The optical rota-
tion and spectroscopic data (1H and 13C NMR, HRMS) of our
synthetic sample were in good agreement with natural product
sawaranospirolide C [1,11].
In view of the structural similarities between sawara-
nospirolides A and C, we designed the divergent synthesis of both
natural products from the same precursor 6. Results were detailed
in Table 2. We began our investigation by the reduction of 6 with
metal hydride species (e.g. NaBH4-NiCl2, [12] NaBH4-CuCl2 and
Mg-MeOH [13], entries 5–6, Table 2), however only complex mix-
ture was obtained or low conversion was observed with recovered
starting materials. Other reaction conditions were also attempted,
such as hydosilylation, Crabtree’s reduction, and Stryker’s reduc-
tion [Ph3PCuH]6, [14] no desired product was observed. (entries
7–8, Table 2)
(3)
(4)
D
Fig. 1. Structures of Sawaranospirolides A–D.
procedure [6,7]. Aryllithium reagent, which is in situ generated
from 4-benzyloxybromobenzene and n-BuLi, was added to alde-
hyde 8 to give diastereomeric alcohol 9 as an inseparable mixture.
[8] However, in the case of the nucleophilic addition by Grignard
reagent, which is also derived from 4-benzyloxybromobenzene,
lower yield (<40%) was obtained. Dess-Martin oxidation of the
resulting secondary alcohol of 9 gave the corresponding ketone
10 in 71% yield over three steps. Homologation of the ketone 10
by Horner-Wadsworth-Emmons [9] reaction with triethyl phos-
phonoacetate in the presence of a variety of bases (eg. Ba(OH)2,
DBU, t-BuOK or LiHMDS) were explored; however, the desired
a,
b-unsaturated ester 6 was formed in a very low yield and signifi-
cant substrate decomposition was observed. Alternatively, when
the ketone 10 was subjected to Wittig olefination with, the corre-
Since the previous synthetic strategy for sawaranospirolide A
was failed, we then revised our plan at this stage. The conjugate
addition of organometallic reagents to electron-deficient alkenes
might be a possible solution due to its high electrophilic reactivity.
Robertson and co-workers reported the synthesis of sawara-
nospirolides with the similar synthetic strategy to introduce the
sponding
a,b-unsaturated ester 6 was successfully synthesized in
69% isolated yield (Table 1). Due to the low reactivity of this stabi-
lized ylide prolonged heating up to 125 °C for several days was
necessary, during which considerable decomposition occurred.
OH
HO
OH
O
5
7
O
O
1
3
HO
O
OH
O
OMe
OMe
(1)
(3)
HO
A
Sawaranospirolide
OH
OH OH
5a
O
O
OH
OH
5b
OH
HO
HO
OH
O
HO
OH
O
O
HO
Sawaranospirolide C
BnO
O
O
O
OMe
OH
OH
O
OH
O
O
7
O
HO
OH
OH
O
O
O
O
O
L-Sorbose
6
Scheme 1. Retrosynthetic analysis of sawaranospirolides A (1) and C (3).
2

S. Yu, Y. Liu, C. Shang et al.
Tetrahedron Letters xxx (xxxx) xxx
BnO
O
OH
OH
O
O
O
O
8
a
b
OH
O
O
O
9
HO
OH
O
O
OH
O
O
L-Sorbose
BnO
O
BnO
O
O
OMe
c
d
O
O
O
O
69%
71%
O
O
O
O
O
10
6
Scheme 2. Synthesis of 6. Reagents and conditions: (a) Ref 6; (b) 4-benzyloxybromobenzene, n-BuLi, then 8, THF, À78 °C; (c) Dess-Martin periodinane, NaHCO3, DCM, 71% over
three steps; (d) See Table 1, Ph3P = CHCO2Me, Toluene, 125 °C, 110 h, 69%.
p-hydroxyphenyl substituent at the 3-position of the oxaspirolac-
tone backbone. In their study, [4] they used Meyers’ dienyloxazo-
line chiral auxiliary with p-(benzyloxy)phenyllithium for the key
Table 1
Homologation of ketone 10 under various conditions.
conjugate addition. Accordingly,
a,b-unsaturated ester 14, readily
BnO
BnO
prepared from 7, was used as an appropriate substrate for this
addition. One-pot oxidation/olefination of the primary alcohol in
7 using Dess-Martin periodinane and the stabilized ylide (Ph3-
P = CH2CO2Me) furnished the unsaturated ester 14 in 71% yield
[15]. Initially, the conjugate addition of 4-(benzyloxy)phenyl-
lithium to ester 14 in THF at low temperature led to unidentified
decomposition products along with the 1,2-addition product (10–
20%) (Scheme 4). Treatment of ester 14 with corresponding phenyl
Grignard reagent in the presence of cuprous chloride salt was also
unfruitful. In 2012, Fukuyama et al. [16] reported an elegant total
synthesis of the indole alkaloid isoschizogamine. One of the key
steps in their synthesis is a Rh (I)-catalyzed Michael addition of
arylboronic acid to a, b-unsaturated lactone. Encouraged by their
result, we decided to extend the Rh (I)-catalyzed strategy to our
substrate 14. Unfortunately, the conjugate addition reactions of
arylboronic acids to acyclic a, b-unsaturated ester 14 did not yield
the 1,4-addition product under various conditions, only resulted in
unidentified decomposition product and the recovery of major
O
O
OMe
O
O
O
O
O
O
O
O
O
O
10
6
Entry Reagents and conditions
Time
Yield
a
1
2
3
4
triethyl phosphonoacetate, Ba(OH)2, THF, rt to reflux 62 h
triethyl phosphonoacetate, DBU, THF, rt 56 h
triethyl phosphonoacetate, tBuOK, THF, 0 °C to reflux 40 h
-
-
a
<5%b
<5%b
triethyl phosphonoacetate, LiHMDS, THF, À78 °C to
5 h
rt
5
6
methyl (triphenylphosphoranylidene) acetate, DCM, 80 h
40 °C
methyl (triphenylphosphoranylidene) acetate,
toluene, 125 °C
9%
110 h 69%
a
No reaction occured with complete recovery of the starting material.
With considerable unidentified decomposition products.
b
starting material. These results demonstrate that a, b-unsaturated
BnO
O
HO
HO
O
O
O
O
OMe
OMe
OMe
f
3R
g
+
O
O
O
O
O
O
HO
O
O
O
O
O
HO
11
6
12
OH
O4
O
1
OH
O
HO
HO
OH
O
OMe
8
4
OMe
HO
H+
6
O1
8
OH
O
O
OH OH
1
8
OH
4
HO
6
OH
5b
HO
OH
5a
Sawaranospirolide C (3)
Scheme 3. Synthesis of sawaranospirolide C (3). Reagents and conditions: (f) H2 (4 atm), 10% Pd/C, EtOAc, MeOH, 30 h; (g) 70% trifluoroacetic acid, rt, 67% over two steps.
3

S. Yu, Y. Liu, C. Shang et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Reduction of
a, b-unsaturated ester 6 under various conditions.
BnO
HO
HO
HO
O
O
O
O
O
O
OMe
OMe
OMe
OMe
+
+
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
O
O
O
HO
11a
11
6
12
Entry
Reagents and conditions
Time
Product (Yield)
1
2
3
4
5
6
7
8
H2 (1 atm), Pd/C, EtOAc, MeOH
12 h
12 h
12 h
30 h
24 h
24 h
24 h
24 h
11a (99%)
H2 (1 atm), Pd(OH)2/C, EtOAc, MeOH
H2 (4 atm), Pd/C, EtOAc, MeOH
H2 (4 atm), Pd/C, EtOAc, MeOH
11a (95%)
11 (>40%)a
11 + 12 (>90%)
b
NaBH4-NiCl2 or NaBH4-CuCl2, À40 °C to rt
-
-
-
-
c
Mg-MeOH, 0 °C to rt
d
[Ir(cod)(Py)(PCy3)]PF6, H2 (1 atm), DCM
Stryker’s reagent, PhSiH3, 0 °C to rt
c
a
With debenzylation product 11a in 50%.
b
c
No reaction occured with complete recovery of the starting material.
Starting material 6was recovered with unidentified mixtures.
No desired product was observed.
d
OH
BnO
RO
HO
OH
O
O
O
OMe
OMe
H
h
O
O
O3S
O
O
O
O
O
O
O
O
HO
Sawaranospirolide
O
6
(1)
13
A
O
OMe
OH
O
O
O
i
O
O
O
O
O
O
O
7
14
Scheme 4. Attempted synthesis of sawaranospirolide A (1). Reagents and conditions: (h) See the text; (i) Dess-Martin periodinane, solid NaHCO3, then Ph3P = CHCO2Me, DCM,
71%.
ester 14 is exceptionally sterically hindered thus the desired conju-
Acknowledgements
gate addition is highly impeded and challenging.
This work was supported by the National Key Research and
Development Program of China (2016YFA0203102) and the STS
Project of Chinese Academy of Sciences (KFJ-STS-QYZD-201-5-1).
We thank Dr. Miao Chen and Xinyi Zhang for HRMS measurements.
Conclusion
In summary, an efficient total synthesis of spiroacetal butyro-
lactone sawaranospirolide C was achieved in seven linear steps
Appendix A. Supplementary data
from -sorbose. Our highly efficient synthesis demonstrated the
L
powerful application of easily accessible carbohydrate as chiral
pool. Synthetic efforts toward sawaranospirolide A were also
described. However, the effort was compromised by the inability
to effect reduction or conjugate addition of the remarkably unreac-
tive intermediates (6 or 14). Further studies toward the synthesis
of other sawaranospirolides are currently in progress and will be
reported in due course.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153072.
References
[1] S. Hasegawa, H. Koyanagi, Y. Hirose, Phytochemistry 29 (1990) 261–266.
[2] S. Hasegawa, Y. Hirose, H. Erdtman, Phytochemistry 27 (1988) 2303–2307.
[3] (a) S. Thorat, R. Kontham, Org. Biomol. Chem. 17 (2019) 7270–7292;
(b) F.-M. Zhang, S.-Y. Zhang, Y.-Q. Tu, Nat. Prod. Rep. 35 (2018) 75–104.
[4] J. Robertson, P. Chovatia, T. Fowler, J. Withey, D. Woollaston, Org. Biomol.
Chem. 8 (2010) 226–233.
Declaration of Competing Interest
[5] (a) Y. Feng, J. Liu, Y.P. Carrasco, J.B. MacMillan, J.K. De Brabander, J. Am. Chem.
Soc. 138 (2016) 7130–7142;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(b) J. Li, C. Zhao, J. Liu, Y. Du, Tetrahedron 71 (2015) 3885–3889;
(c) C. Zhang, J. Liu, Y. Du, Tetrahedron Lett. 54 (2013) 3278–3280;
4

S. Yu, Y. Liu, C. Shang et al.
Tetrahedron Letters xxx (xxxx) xxx
(d) J. Liu, J.K. De Brabander, J. Am. Chem. Soc. 131 (2009) 12562–12563;
(e) Y. Du, J. Liu, R. J., Linhardt,, J. Org. Chem. 72 (2007) 3952–3954.
[6] C. Reilly, C. Brien, P.V. Murphy, Tetrahedron Lett. 50 (2009) 4427–4429.
[7] (a) D.B. Dess, J.C. Martin, J. Am. Chem. Soc. 113 (1991) 7277–7287;
(b) Y. Gao, J. Liu, J. Qiao, Y. Liu, P. He, Y. Du, Tetrahedron Lett. 59 (2018) 291–
294.
[8] H. Müller, V. Gabrielli, O. Agoglitta, R. Holl, Eur. J. Med. Chem. 110 (2016) 340–
375.
[9] W.S. Wadsworth, W.D. Emmons, J. Am. Chem. Soc. 83 (1961) 1733–1738.
[10] (a) C. Murali, M.S. Shashidhar, C.S. Gopinath, Tetrahedron 63 (2007) 4149–
4155;
of synthetic and natural sawaranospirolide C. The observed optical rotation
values for our synthetic sawaranospirolide C ([
the same sign as the isolated sawaranospirolide C ([
a
]D25 -19.4(c 0.1, MeOH)) was
]D25 -36 (c 2.25, MeOH))
a
1 and opposite to Robertson’s synthetic ent-sawaranospirolide C ([
a]D23
+40.5 (c 1.4, MeOH))4.
[12] (a) M. Narisada, I. Horibe, F. Watanabe, K. Takeda, J. Org. Chem. 54 (1989),
5308-5303;
(b) C. Chang, J. Geng, Y. Liu, Y. Du, J. Liu, Z.B. Dong, Synthesis 52 (2020) 1576–
1584.
[13] G.H. Lee, I.K. Youn, E.B. Choi, H.K. Lee, G.H. Yon, H.C. Yang, C.S. Pak, Curr. Org.
Chem. 8 (2004) 1263–1287.
(b) D. Artner, C. Stanetty, K. Mereiter, A. Zamyatina, P. Kosma, Carbohydr. Res.
346 (2011) 1739–1746.
[14] P. Chiu, Z. Li, K.C.M. Fung, Tetrahedron Lett. 44 (2003) 455–457.
[15] A.C.M. Barrett, D. Hamprecht, M. Ohkubo, J. Org. Chem. 62 (1997) 9376–9378.
[16] (a) Y. Miura, N. Hayashi, S. Yokoshima, T. Fukuyama, J. Am. Chem. Soc. 134
(2012) (1997) 11995–12001;
[11] Our synthetic sawaranospirolide
C
exhibited physical properties that
and Robertson’s
consistent with that for natural sawaranospirolide
C
synthetic sawaranospirolide C. See Supporting Information for detailed
spectroscopic comparisons (1H, 13C NMR and COSY in CD3OD or DMSO-d6)
(b) R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem. 68 (2003) 6000–6004.
5