Stereoselective synthesis of the a,e-ring bicyclic core of calyciphylline b-Type alkaloids

Article abstract of DOI:10.1055/s-0039-1690721

A stereoselective synthesis of the bicyclic unit constituting the A and E rings of calyciphylline B-Type alkaloids is disclosed. The propionate ester of (1 R)-cyclohex-2-en-1-ol, obtained by enzymatic resolution, is subjected to an Ireland-Claisen rearrangement. Subsequent reduction of the acid, Mitsunobu reaction to introduce a nitrogen functionality, oxidative cleavage to a dialdehyde, and intramolecular aldol and aza-Michael reactions afford the bicyclic subunit.

Full text of DOI:10.1055/s-0039-1690721

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
B. S. Kumar, S. Raghavan
Letter
Synlett
Stereoselective Synthesis of the A,E-Ring Bicyclic Core of Calyci-
phylline B-Type Alkaloids
Balagani Satish Kumar
Me
H
Enzymatic
resolution
Sadagopan Raghavan*
Ireland–
Claisen
OH
N
Department of Organic Synthesis and Process Chemistry, Indian
Institute of Chemical Technology, Hyderabad 500007, India
sraghavan@iict.res.in
H
P
rearrangement
H
O
Aza-
Michael
NHNs-p
O
Me
Aldol
reaction
Mitsunobu
reaction
Received: 12.09.2019
Accepted after revision: 07.10.2019
Published online: 22.09.2019
Morita and Kobayashi in 2003.1 Subsequently, deoxycalyci-
phylline B (2) and deoxyisocalyciphylline B (3) were isolat-
ed from the stems of D. subverticillatum.2 Hao and co-work-
ers elucidated the structure of daphlongamine H (4).3
Calyciphylline B-type alkaloids contain a penta- or hex-
acyclic framework with eight or nine stereogenic centers,
including one quaternary center, and a tertiary nitrogen. Al-
kaloids of this class possess a wide range of biological activ-
ities including cytotoxicity against murine lymphoma
L1210 cells1 and inhibition of platelet aggregation induced
by platelet-activating factor.4
DOI: 10.1055/s-0039-1690721; Art ID: st-2019-d0485-l
Abstract A stereoselective synthesis of the bicyclic unit constituting
the A and E rings of calyciphylline B-type alkaloids is disclosed. The pro-
pionate ester of (1R)-cyclohex-2-en-1-ol, obtained by enzymatic resolu-
tion, is subjected to an Ireland–Claisen rearrangement. Subsequent re-
duction of the acid, Mitsunobu reaction to introduce a nitrogen
functionality, oxidative cleavage to a dialdehyde, and intramolecular al-
dol and aza-Michael reactions afford the bicyclic subunit.
Key words asymmetric synthesis, alkaloids, chiral resolution, electro-
The first synthesis of isodaphlongamine H (5), possess-
ing cis-fused B,C rings, was disclosed by Hanessian and co-
workers.5 Recently, Sarpong’s group reported total synthe-
ses of daphlongamine H and isodaphlongamine H.6 The
synthesis of the ABE core of these alkaloids was reported by
Belanger in 2017.7 We envisaged the synthesis of deoxyca-
lyciphylline B by following the retrosynthetic strategy de-
cyclic reaction, Michael addition, Mitsunobu reaction
Calyciphylline B-type alkaloids constitute a subclass of
calyciphylline alkaloids that belong to the large family of
Daphniphyllum alkaloids. Calyciphylline B (1; Figure 1) was
isolated from the leaves of Daphniphyllum calycinum by
Me 20
H
Me
Me
H
H
H
H
3
2
18
19
4
A 1
E
13
14
22
O
N
N
N
8
5
H
B
F
H
9
H
H
H
H
15
7
O
O
O
O
O
O
Me6
Me
Me
C
16
D
H
H
H
21
12
10
17
11
H
Deoxyisocalyciphylline B (3)
Calyciphylline B (1)
Deoxycalyciphylline B (2)
Me
Me
H
H
H
H
N
N
H
H
H
H
O
O
O
O
Me
Me
H
H
Daphlongamine H (4)
Isodaphlongamine H (5)
Figure 1 Representative calyciphylline B-type alkaloids
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. S. Kumar, S. Raghavan
Letter
Synlett
Me
H
Me
Me
H
H
H
H
8
OP
N
N
N
H
H
H
P
OP
P
O
+
O
H
O
O
O
O
Me
H
H
H
H
2
7
6
Me
H
OH
P = Protecting group
NHP
9
10
Scheme 1 Retrosynthetic disconnection of deoxycalyciphylline B
picted in Scheme 1. The target compound 2 might be ob-
tained from ketone 6 by elaboration of the lactone ring, fol-
lowed by C–N bond formation by means of the Appel
reaction. We surmised that ketone 6 might be obtained by
combining aldehyde 7 and ester 8, followed by oxidation of
the resulting alcohol to a -keto ester and the creation of
the quaternary center by means of the Stolz allylation pro-
tocol. We proposed to synthesize aldehyde 7 by organoca-
talysis and to prepare ester 8 from the cyclohexene deriva-
tive 9, which, in turn, might be obtained from the cyclohex-
enol 10.
Here, we report the synthesis of the A,E bicyclic core 8,
which is common to all calyciphylline B-type alkaloids. The
synthesis commenced from (1R)-cyclohex-2-en-1-ol (10),
obtained by enzymatic resolution following a reported pro-
cedure.8 Esterification with propanoyl chloride furnished
ester 11 (Scheme 2). The trimethylsilyl ketene acetal ob-
tained from ester 11 on warming underwent Ireland–
LDA, THF, –78 °C, 1 h
then TMS-Cl, HMPA, 1 h,
65 °C, 6 h, 50%
OP
NBS, CHCl3,
rt, 4 h, 74%
+
83% brsm
H
H
Cl
10, P =H
11, P = C(O)Et
CO2H
CO2H
Me
O
Me
Et3N, CH2Cl2,
0 °C, 1 h, 98%
12
13
PPh3, DIAD,
NsNH2, THF, rt,
24 h, 65%
Br
H
Br
Zn, EtOH,
80 °C, 2 h, 80%
H
+
O
O
H
Me
13, R = CO2H
H
H
H
R
Me
Me
Me
O
O
15
14
17
NHNs
LAH, THF, 0 °C,
30 min, 70%
LDA, THF, –78 °C, 1 h,
16, R = CH2OH
EtO2C
quench
EtO2C
Me
H
Me
H
OsO4, NaIO4,
2,6-lutidine, THF,
H2O, 0 °C, 2 h, 85%
NaClO2, NaH2PO4,
MeCH=CMe2, t-BuOH,
0 °C, 1 h, 95%
CHO
H
N
Ns
H
N Ns
H
NNs
O
AllBr, Et3N,
CH2Cl2, rt,
30 min, 80%
H
AcOH, toluene,
100 °C, 1 h, 45%
O
O
N
Me
H
8
18
18
OTMS
Me
O
Me
H
O
CO2H
TMSO
Me
(I)
(II)
12
(Z)-enolate
Major pathway
(E)-enolate
Major pathway
OTMS
O
Me
H
O
TMSO
Me
(IV)
CO2H
(III)
Me
(Z)-enolate
Minor pathway
13
(E)-enolate
Minor pathway
Scheme 2 Synthesis of the bicyclic subunit 8; brsm = based on recovered starting material Ns = (4-nitrobenzene)sulfonyl.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
B. S. Kumar, S. Raghavan
Letter
Synlett
Claisen rearrangement to yield a 5:1 mixture of acids 12
and 13, respectively.9,10 The formation of acid 12 can be ra-
tionalized by invoking boat-like (I) and chair-like transition
states (II) in the Claisen rearrangement of the (Z)- and (E)-
silyl ketene acetal, respectively. The acids, on bromolacton-
ization, furnished a separable mixture of bromolactones 14
and 15. The lactone 14 was isomerized by enolization fol-
lowed by quenching with diethyl malonate to furnish lac-
tone 15.11 Reductive cleavage of lactone 15 by treatment
with Zn/EtOH afforded the acid 13, which was reduced to
alcohol 16.
(5) (a) Chattopadhyay, A. K.; Ly, V. L.; Jakkepally, S.; Berger, G.;
Hanessian, S. Angew. Chem. Int. Ed. 2016, 55, 2577.
(b) Chattopadhyay, A. K.; Menz, H.; Ly, V. L.; Dorich, S.;
Hanessian, S. J. Org. Chem. 2016, 81, 2182. (c) Chattopadhyay, A.
K.; Berger, G.; Hanessian, S. J. Org. Chem. 2016, 81, 5074.
(6) Hugelshofer, H. C. L.; Palani, V.; Sarpong, R. J. Am. Chem. Soc.
2019, 141, 8431.
(7) Boissarie, P.; B́elanger, G. Org. Lett. 2017, 19, 3739.
(8) Kolodiazhna, O. O.; Kolodiazhna, A. O.; Kolodiazhnyi, O. I. Russ.
Chem. Bull. 2012, 61, 2175.
(9) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868. (b) Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org.
Chem. 1991, 56, 3572.
The sulfonamide 17 was prepared in a straightforward
manner by following a Mitsunobu protocol.12,13 Subjecting
the cyclohexene group of 17 to oxidative cleavage by means
of Jin’s protocol14 afforded a dialdehyde that, without fur-
ther purification, was treated with piperidinium acetate to
furnish aldehyde 18. Aldehyde 18 is probably formed by an
intramolecular aldol reaction followed by an aza-Michael
reaction or, alternatively, by a Mannich reaction. Pinnick
oxidation15 of aldehyde 18 afforded the corresponding acid
that, on reaction with allyl bromide in the presence of tri-
ethylamine, gave the bicyclic compound 8 corresponding to
the A and E rings of calyciphylline B-type alkaloids.16
In summary a short stereoselective synthesis of the bi-
cyclic subunit of calyciphylline B-type alkaloids is dis-
closed. Enzymatic resolution, Ireland–Claisen rearrange-
ment, Mitsunobu reaction, and an intramolecular aldol re-
action followed by an aza-Michael reaction are the key
steps in this synthetic protocol.
(10) The structure assigned to acids 12 and 13 is based on their con-
version into lactones 14 and 15, respectively, and a comparison
of their spectra with known iodolactones; see: Bartlett, P. A.;
Pizzo, C. F. J. Org. Chem. 1981, 46, 3896.
(11) Among the various proton sources used for quenching (which
included acetic acid, pivalic acid, and methyl salicylate), diethyl
malonate was found to afford lactone 15 selectively.
(12) (a) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar,
K. V. P. P. Chem. Rev. 2009, 109, 2551.
(13) N-[(1S)-1-Cyclohex-2-en-1-ylpropyl]-4-nitrobenzenesulfon-
amide (17)
To a solution of alcohol 16 (1.4 g, 10 mmol) in anhyd THF (200
mL) were added Ph3P (5.24 g, 20 mmol), (4-nitrobenzene)sul-
fonamide (4.04 g, 20 mmol), and DIAD (3.16 mL, 20 mmol) at
0 °C, and the mixture was stirred for 12 h at rt. H2O (100 mL) was
added and the layers were separated. The aqueous layer was
extracted with EtOAc (3 × 20 mL), and the combined organic
extracts were washed with brine (20 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The crude product was puri-
fied by column chromatography [silica gel (100–200 mesh), 10%
EtOAc–hexane] to give a colorless solid; yield: 2.21 g (6.5 mmol,
20
65%); mp 98–100 °C; []D –15.3 (c 0.31, CHCl3); Rf = 0.2 (15%
Funding Information
EtOAc–hexane).
IR (neat): 3282, 2926, 2850, 1608, 1530, 1351, 1156, 753, 611
Funding Information: Science and Engineering Research Board, DST,
cm–1 1H NMR (400 MHz, CDCl3):  = 8.37 (d, J = 8.8 Hz, 2 H),
.
New Delhi, (Grant / Award Number: 'PDF/2017/001254')
S
c
i
e
n
c
e
a
n
d
E
n
g
i
n
e
eri
n
g
R
esearc
h
B
o
ard(P
D
F/2
0
1
7/0
0
1
2
5
4)
8.05 (d, J = 8.9 Hz, 2 H), 5.74 (ddd, J = 9.7, 6.5, 2.9 Hz, 1 H), 5.43
(d, J = 10.2 Hz, 1 H), 4.65 (t, J = 6.1 Hz, 1 H), 3.07–2.98 (m, 1 H),
2.92–2.83 (m, 1 H), 2.18–2.07 (m, 1 H), 2.00–1.89 (m, 2 H),
1.77–1.68 (m, 1 H), 1.67–1.59 (m, 2 H), 1.53–1.41 (m, 1 H),
1.31–1.13 (m, 1 H), 0.88 (d, J = 6.9, Hz, 3 H).13C{1H} NMR (100
MHz, CDCl3):  = 150.1, 146.0, 129.2, 128.6, 128.31, 124.4, 46.8,
38.1, 37.6, 25.7, 25.2, 22.1, 14.8. MS (ESI–TOF): m/z = 325 [M +
H]+; HRMS (ESI–TOF): m/z [M + H]+ calcd for C15H21N2O4S:
325.1222; found: 325.1227..
Acknowledgement
B.S.K is grateful to DST for a postdoctoral fellowship. Manuscript
Communication No. IICT/Pubs/2019/281.
Supporting Information
(14) Wensheng, Y.; Yan, M.; Ying, K.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(15) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690721.
S
u
p
p
orit
n
gInformati
o
n
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p
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orti
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o
n
(16) Allyl Ester 8
References and Notes
Et3N (80 L, 0.56 mmol) and allyl bromide (25 L, 0.28 mmol)
were added to a solution of acid 19 (50 mg, 0.14 mmol) in
anhyd CH2Cl2 (1.5 mL) cooled to 0 °C. The mixture was stirred
for 30 min at rt then concentrated in vacuo and extracted with
EtOAc (3 × 5 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by column chromatogra-
phy [silica gel (100–200 mesh), 10% EtOAc–hexanes] to give a
colorless solid; yield: 44 mg (0.11 mmol, 80%); mp 124–126 °C;
[]D20 +2.6 (c 1.3, CHCl3); Rf = 0.6 (20% EtOAc–hexane).
(1) Morita, H.; Kobayashi, J. Org. Lett. 2003, 5, 2895.
(2) Yang, S.-P.; Yue, J.-M. J. Org. Chem. 2003, 68, 7961.
(3) Li, C.-S.; Di, Y.-T.; Zhang, Q.; Zhang, Y.; Tan, C.-J.; Hao, X.-J. Helv.
Chim. Acta 2009, 92, 653.
(4) Mu, S.-Z.; Wang, J.-S.; Yang, X.-S.; He, H.-P.; Li, C.-S.; Di, Y.-T.;
Wang, Y.; Zhang, Y.; Fang, X.; Huang, L.-J.; Hao, X.-J. J. Nat. Prod.
2008, 71, 564.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
B. S. Kumar, S. Raghavan
Letter
Synlett
IR (KBr): 3096, 2927, 2860, 1727, 1531, 1351, 1167, 1115, 1026,
613 cm–1. 1H NMR (500 MHz, CDCl3):  = 8.42 (d, J = 8.8 Hz, 2 H),
8.07 (d, J = 8.8 Hz, 2 H), 5.99 (ddd, J = 17.2, 10.7, 5.7 Hz, 1 H),
5.40 (dd, J = 17.2, 1.5 Hz, 1 H), 5.31 (dd, J = 10.4, 1.2 Hz, 1 H),
4.70–4.66 (m, 2 H), 4.12 (dd, J = 9.0, 3.8 Hz, 1 H), 3.73 (dd, J = 9.3,
6.3 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.57 (t, J = 9.3 Hz, 1 H), 2.21–
2.11 (m, 2 H), 1.99–1.90 (m, 2 H), 1.83–1.75 (m, 1 H), 1.55–1.50
(m, 1 H), 0.86 (d, J = 6.6 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3):
 = 174.0, 150.3, 141.4, 132.2, 129.3, 124.3, 118.4, 67.0, 65.5,
57.5, 51.7, 38.0, 30.4, 30.0, 16.5. MS (ESI–TOF): m/z = 395 [M +
H]+. HRMS (ESI–TOF): m/z [M + H]+ calcd for C18H23N2O6S:
395.1277; found: 395.1275.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D