Stereoselective formal total synthesis of (-)-didemniserinolipid B

Article abstract of DOI:10.1055/s-0029-1217976

A formal total synthesis of (-)-didemniserinolipid B from l-(+)-tartaric acid is presented. Key features of the synthesis include construction of the bicyclic acetal core from bisdimethyl amide of tartaric acid and further elaboration by cross metathesis.

Full text of DOI:10.1055/s-0029-1217976

LETTER
2593
Stereoselective Formal Total Synthesis of (–)-Didemniserinolipid B
F
ormal Total Synt
a
hesis of (–)
-
v
Didemniserinolipid
r
B
ayani R. Prasad,* Vasudeva Rao Gandi
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
E-mail: prasad@orgchem.iisc.ernet.in
Received 11 June 2009
OH
Abstract: A formal total synthesis of (–)-didemniserinolipid B
from L-(+)-tartaric acid is presented. Key features of the synthesis
include construction of the bicyclic acetal core from bisdimethyl
amide of tartaric acid and further elaboration by cross metathesis.
O
NaO3SO
O
13
O
OEt
NH2
2
H
O
Key words: didemniserinolipid B, marine natural product, stereo-
(+)-didemniserinolipid B (1)
selective synthesis, tartaric acid
O
O
OH
O
O
H
OH
hydroxy-exo-brevicomin (1b)
2-hydroxy-exo-brevicomin (1a)
Alkylated 6,8-dioxabicyclo[3.2.1]octane structural units
are widespread in bioactive natural products. Pine beetle
pheromones such as brevicomins contain simple 6,8-di-
oxabicyclo[3.2.1]octane unit while didemniserinolipids
that originate from marine sources possess complex sys-
tems with the same bicylic core.1 Didemniserinolipid B
(1, Figure 1) isolated from the marine tunicate belonging
to the genus Didemnum sp. by Gonzalez et al.2 possess the
6,8-dioxabicyclo[3.2.1]octane framework with an extend-
ed alkyl chains, containing a 2-aminopropane 1,3-diol
ether, and a a,b-unsaturated ester. Although didemniser-
inolipid B showed no appreciable bioactivity, interesting
bioactive profile of related didemniserinolipids as inhibi-
tors of HIV-1 integrase3 has invigorated the attention of
synthetic chemists. Ley’s group has synthesized natural
didemniserinolipid B and also revised the structure and
absolute configuration of the natural product.4a Burke’s
group recently reported the synthesis of didemniserinolip-
id B employing their ketalization–ring-closing-metathesis
strategy,4b,c while a formal synthesis of 1 by Ramana and
Induvadana involving a Pd-mediated alkynediol cyclo-
isomerization was disclosed.4d Our own interest in the
synthesis of 6,8-dioxabicyclo[3.2.1]octane-containing
natural products and other oxygenated natural products,
culminated in enantiodivergent synthesis of hydroxy-exo-
brevicomin, hydroxy brevicomin from chiral-pool tartaric
acid.5 In continuation of our efforts, herein we report a
stereoselective formal total synthesis of the antipode of
natural didemniserinolipid B from L-(+)-tartaric acid.
Figure 1 Natural products possessing 6,8-dioxabicyclo[3.2.1]octa-
ne framework
OH
O
O
OSO3Na
13
EtO2C
O
NH2
4
(−)- 1
Williamson
etherification
OH
O
O
Boc
7
3
O
N
EtO2C
O
4
cross-metathesis
hydrogenation
Wittig
olefination
18
OBn
HO
O
OBn
O
3
5
BnO
O
O
11
5
7
O
O
O
O
NMe2
OBn
Me2N
Me2N
4
O
O
O
O
3
2
Scheme 1 Retrosynthesis for (–)-didemniserinolipid
amide 3 derived from tartaric acid6 is envisioned
(Scheme 1).
Our approach for the synthesis of (–)-1 is based on the
elaboration of bicyclic acetal 11. Installation of the C15
side chain is planned by cross metathesis followed by hy-
drogenation, while formation of the a,b-unsaturated ester
is envisaged by Wittig olefination. Synthesis of the bicylic
acetal 11 is anticipated by intramolecular ketalization of
the masked triol 7, the synthesis of which from the keto
Accordingly, the synthetic sequence commenced with the
addition of 1.5 equivalents of 4-benzyloxy-butylmagne-
sium bromide to the bisdimethylamide derived from tar-
taric acid 2 resulting in the ketoamide 3 in 86% yield.7
Reduction of the ketone in 3 with NaBH4/CeCl3 furnished
the alcohol 4 in 93% yield,8 which under Barton–McCom-
bie deoxygenation9 conditions afforded the amide 5 in
72% yield for two steps. Addition of 3-butenylmagnesium
bromide to amide 5 produced the corresponding ketone in
86% yield, which on reduction with K-Selectride in THF
at –78 °C furnished the alcohol 6 as a single diastereomer
SYNLETT 2009, No. 16, pp 2593–2596
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.09.2009
DOI: 10.1055/s-0029-1217976; Art ID: D15609ST
© Georg Thieme Verlag Stuttgart · New York

2594
K. R. Prasad, V. R. Gandi
LETTER
O
O
O
O
NaBH4, CeCl3
MeOH, −78 °C
2 h, 93%
BnO
MgBr
2
NMe2
OBn
Me2N
Me2N
3
THF, −15 °C, 0.5 h
86%
O
O
O
O
3
2
BrMg
i)
i) NaH/CS2, MeI, THF
r.t. to reflux, 3 h, 84%
O
O
O
O
THF, 0 °C, 15 min, 86%
OBn
OBn
Me2N
Me2N
3
ii) K-Selectride, THF
5
ii) n-Bu3SnH, AIBN
benzene, reflux, 2 h
91%
O
−78 °C, 1.5 h, 98%
O
OH
O
5
4
i) Ph3P, DIAD, PNBA
THF, 0 °C to r.t., 3 h, 92%
ii) K2CO3, MeOH
HO
O
HO
NaH, BnBr
DMF, 0 °C, 2 h
81%
OBn
OBn
5
5
O
r.t., 1 h, 97%
O
6
7
MgBr
i)
i) OsO4, NMO, THF.H2O
r.t., 3 h, 89%
BnO
O
BnO
O
THF, 0 °C, 0.5 h, 74%
O
OBn
OBn
5
ii) IBX, EtOAc, reflux
4 h, 86%
5
ii) Pb(OAc)4, CH2Cl2
r.t., 0.5 h, 89%
O
O
9
8
OBn
BnO
O
.
FeCl3 6H2O
CH2Cl2, r.t.
15 min, 92%
O
OBn
5
BnO
O
O
O
11
10
Scheme 2 Synthesis of 6,8-dioxabicyclo[3.2.1]octane fragment of didemniserinolipid B
in 98% yield. Mitsunobu inversion of the secondary hy- inane oxidation followed by Wittig olefination with the
droxy group in 6 with DIAD, Ph3P, and p-nitrobenzoic ac- ylide 17 resulted in the known a,b-unsaturated ester 18 in
id, and subsequent hydrolysis of the p-nitrobenzoyl ester 59% yield. Conversion of 18 to didemniserinolipid B is
furnished the epimerized alcohol 7 in 94% yield for two reported by Burke et al. The present sequence thus consti-
steps. The free hydroxy group in 7 was protected as the tutes a formal total synthesis of (–)-didemniserinolipid B
corresponding benzyl ether 8 using standard conditions in (Scheme 3).
81% yield. Osmium-mediated dihydroxylation of the alk-
In conclusion, a stereoselective formal total synthesis of
ene furnished the corresponding diol which on treatment
(–)-didemniserinolipid B from the bisdimethylamide of
with Pb(OAc)4 produced the aldehyde 9 in 89% yield for
tartaric acid was presented. Key features of the synthetic
two steps. Addition of 5-hexenylmagnesium bromide to
sequence include the formation of the 6,8-dioxabicyc-
the aldehyde 9 furnished a diastereomeric mixture of the
lo[3.2.1]octane core by intramolecular ketalization of a
keto triol derived from tartaric acid and the installation of
the alkyl chain on the bicylic acetal via cross metathesis
followed by hydrogenation. The synthetic sequence de-
corresponding alcohol in 74% yield, which was subjected
to oxidation with IBX to yield the ketone 10 in 86% yield.
Treatment of 10 with FeCl3 smoothly furnished the bicy-
clic acetal 11 in 92% yield (Scheme 2).10
picted is amenable for the synthesis of a number of ana-
Reaction of the bicyclic acetal 11 with 10-undecenoic acid logues.
methyl ester mediated by Grubbs’ second-generation cat-
alyst was facile affording the product 12 in 80% yield.11
Acknowledgment
Hydrogenation of the alkene in 12 with Pd/C followed by
reduction with LiAlH4 produced the alcohol 1312 in al-
We thank the Department of Science and Technology (DST), New
Delhi for funding this project through a Swarnajayanthi fellowship
to K.R.P. V.R.G. thanks CSIR for a research fellowship. We also
most quantitative yield. Alcohol 13 was transformed into
the mesylate, which on further reaction with L-serinol de-
thank Dr. C. V. Ramana for sharing the experimental details and
rivative 14 afforded 15 in 56% yield for two steps. Deben-
data for the compounds 15–18.
zylation of the bisbenzylether 15 produced the diol 16 in
95% yield. Subjecting the diol 16 to Dess–Martin period-
Synlett 2009, No. 16, 2593–2596 © Thieme Stuttgart · New York

LETTER
Formal Total Synthesis of (–)-Didemniserinolipid B
2595
R.; Gandi, V. Tetrahedron: Asymmetry 2008, 19, 2616.
(f) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72,
6312. (g) Prasad, K. R.; Dhaware, M. Synthesis 2007, 3697.
(h) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643.
O
OBn
OMe
7
O
4
Grubbs II (15 mol%)
CH2Cl2, reflux, 24 h, 80%
BnO
O
5
(7) Formation of minor amount (8%) of diketone resulting from
the addition of Grignard reagent to both amide groups is
observed.
11
i) H2, Pd/C, NaHCO3
hexane, 5 h, 76%
OBn
O
(8) Diastereomeric ratio of the product alcohol was estimated to
be >95:5 within detectable limits by 1H NMR. Alcohols
were inseparable at this stage. However, stereochemistry of
the alcohol is of no consequence because it is deoxygenated
in the next step.
O
OMe
ii) LiAlH4, THF, 0 °C
1 h, 96%
4
8
BnO
BnO
O
12
5
OBn
i) MsCl, Et3N, CH2Cl2, 0 °C, 0.5 h
(9) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
O
ii)
NaH, DMSO
0 °C to r.t., 5 h
56% for two steps
OH
HO
Boc
13
(10) For FeCl3-mediated deprotection of acetals, see: (a) Sen,
S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J.
J. Org. Chem. 1997, 62, 6684. (b) Prasad, K. R.;
O
O
N
5
13
14
Chandrakumar, A. Tetrahedron: Asymmetry 2005, 16,
1897. (c) Ref. 5 and 6
OBn
H2, Pd(OH)2/C
(11) It was cumbersome to purify the cross-metathesis product 12
by column chromatography from traces of an unidentified
impurity. However, this was of no consequence in the next
reaction sequence, and pure 13 was isolated after the
reduction of the olefin and the ester.
(12) All new compounds exhibited satisfactory spectral data. In
the NMR data that follow, * indicates rotamer peaks.
Compound 3: [a]D +8.7 (c 1.3, CHCl3). IR (neat): 2940,
2863, 1716, 1652, 1506, 1374 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.40–7.24 (m, 5 H), 5.13 (d, J = 6.0 Hz, 1 H),
4.78 (d, J = 5.7 Hz, 1 H), 4.90 (s, 2 H), 3.47 (t, J = 6.0 Hz, 2
H), 3.13 (s, 3 H), 2.98 (s, 3 H), 2.83–2.56 (m, 2 H), 1.79–1.55
(m, 4 H), 1.42 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
209.2, 168.1, 138.5, 128.3, 128.3, 127.6, 127.5, 112.1, 82.1,
74.9, 72.9, 69.9, 39.2, 37.0, 36.0, 29.1, 26.4, 26.0, 19.8.
HRMS: m/z calcd for C18H25NO5 + Na: 386.1943; found:
386.1925
O
EtOAc, 1 h
95%
O
Boc
13
O
O
N
BnO
HO
4
15
16
OH
i) DMP, CH2Cl2, 0 °C, 2.5 h
O
ii)
OEt
O
Ph3P
13
O
O
N
17
O
4
Boc
benzene, reflux, 1 h
OH
ref. 4b
1
O
O
13
O
O
N
Boc
CO2Et
18
Compound 13: [a]D –21.2 (c 3, CHCl3). IR (neat): 3448,
2926, 1455, 1097, 734 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.50–7.10 (m, 10 H), 4.62 (s, 2 H), 4.5 (s, 2 H), 4.17 (br
s, 1 H), 3.90–3.73 (m, 1 H), 3.63 (t, J = 6.6 Hz, 2 H), 3.46 (t,
J = 6.6 Hz, 2 H), 3.29 (br s, 1 H), 2.30 (t, J = 7.5 Hz, 2 H),
2.00–1.15 (m, 40 H). 13C NMR (75 MHz, CDCl3): d = 138.7,
138.5, 128.37, 128.32, 127.63, 127.58, 127.47, 109.3, 80.0,
77.8, 72.8, 72.3, 70.3 (2 C), 63.1, 37.4, 35.3, 32.8, 30.7, 29.8,
29.62, 29.58, 29.41, 26.1, 25.7, 25.4, 22.8, 22.0. HRMS:
m/z calcd for C40H62O5 + Na: 645.4495; found: 645.4484.
Compound 15: [a]D –18.3 (c 0.3, CHCl3). IR (neat): 3069,
2927, 1700, 1454, 1388, 734 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.50–7.20 (m, 10 H), 4.61 (s, 2 H), 4.49 (s, 2 H),
4.17 (br s, 1 H), 4.10–3.85 (m, 3 H), 3.85–3.70 (m, 1 H),
3.70–3.30 (m, 6 H), 3.29 (br s, 1 H), 2.00–1.15 (m, 55 H).
13C NMR (100 MHz, CDCl3): d = 152.2/151.7*, 138.7/
138.5*, 128.4, 128.35, 127.66, 127.60, 127.5, 109.3, 93.7/
93.3*, 80.1/79.7*, 80.0, 77.8, 72.9, 72.3, 71.4, 70.3 (2 C),
70.1/69.3*, 65.7/65.4*, 56.5/56.4*, 37.43, 35.3, 30.8, 29.8,
29.7, 29.64, 29.60, 29.5, 28.48, 28.43, 27.5/26.8*, 26.11,
26.06, 25.43, 24.4/23.1*, 22.8, 21.96. HRMS: m/z calcd for
C51H81NO8 + Na: 858.5860; found: 858.5861.
Scheme 3 Formal total synthesis of (–)-didemniserinollipid B
References and Notes
(1) Kiyota, H. Top. Heterocycl. Chem. 2006, 5, 65.
(2) Gonzalez, N.; Rodriguez, J.; Jimenez, C. J. Org. Chem.
1999, 64, 5705.
(3) Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J.
Org. Lett. 2000, 2, 1605.
(4) (a) Kiyota, H.; Dixon, D. J.; Luscombe, C. K.; Hettstedt, S.;
Ley, S. V. Org. Lett. 2002, 4, 3223. (b) Marvin, C. C.;
Voight, E. A.; Burke, S. D. Org. Lett. 2007, 9, 5357.
(c) Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.;
Burke, S. D. J. Org. Chem. 2008, 73, 8452. (d) Ramana, C.
V.; Induvadana, B. Tetrahedron Lett. 2009, 50, 271.
(5) (a) Prasad, K. R.; Anbarasan, P. Tetrahedron Lett. 2006, 47,
1433. (b) Prasad, K. R.; Anbarasan, P. Tetrahedron:
Asymmetry 2006, 17, 850. (c) Prasad, K. R.; Anbarasan, P.
Tetrahedron 2006, 62, 8303. (d) Prasad, K. R.; Anbarasan,
P. Synlett 2006, 2087.
(6) (a) For a general approach to the synthesis of g-keto amides
from tartaric acid, see: Prasad, K. R.; Chandrakumar, A.
Tetrahedron 2007, 63, 1798. (b) Prasad, K. R.; Gholap, S.
L. J. Org. Chem. 2008, 73, 1. (c) Prasad, K. R.; Gholap, S.
L. J. Org. Chem. 2008, 73, 2916. (d) Prasad, K. R.; Swain,
B. Tetrahedron: Asymmetry 2008, 19, 1134. (e) Prasad, K.
Compound 16: [a]D –41.4 (c 1.2, CHCl3) [Lit.4d [a]D +36.3
(c 0.2, CHCl3 for the enantiomer)]. IR (CHCl3): 3463, 2928,
1700, 1389, 1366, 1088, 770 cm–1. 1H NMR (400 MHz,
CDCl3): d = 4.07 (br s, 1 H), 4.05–3.96 (m, 1 H), 3.95–3.86
(m, 3 H), 3.65 (t, J = 6.5 Hz, 2 H), 3.62–3.55 (m, 1 H), 3.54–
3.37 (m, 2 H), 3.36–3.14 (m, 2 H), 2.52–2.30 (m, 1 H), 2.10–
1.81 (m, 1 H), 1.79–1.41 (m, 30 H), 1.38–1.22 (m, 25 H).
13C NMR (100 MHz, CDCl3): d = 152.2/151.7*, 109.6, 93.7/
Synlett 2009, No. 16, 2593–2596 © Thieme Stuttgart · New York

2596
K. R. Prasad, V. R. Gandi
LETTER
93.3*, 82.4, 80.3/79.7*, 77.8, 71.4, 70.0/69.3*, 66.3, 65.7/
65.4*, 56.5/56.3*, 37.5, 35.2, 32.7, 30.2, 29.8, 29.7 (2 C),
29.6 (2 C), 29.5, 28.48/28.43*, 27.5/26.8*, 26.1, 25.6, 25.3,
25.1, 24.4/23.1*, 23.0. HRMS: m/z calcd for C37H69NO8 +
Na: 678.4921; found: 678.4935.
3.81 (m, 3 H), 3.61 (br s, 1 H), 3.59–3.24 (m, 4 H), 2.50–2.26
(m, 1 H), 2.19 (q, J = 7.0 Hz, 2 H), 2.16–1.36 (m, 25 H),
1.35–1.21 (m, 33 H). 13C NMR (100 MHz, CDCl3): d =
166.7, 152.5/151.7*, 148.8, 121.4, 109.6, 93.7/93.2*, 82.3,
80.3/79.7*, 77.6, 71.3, 69.97/69.19*, 66.2, 65.6/65.3*, 60.1,
56.4/56.3*, 37.4, 35.0, 32.0, 30.0, 29.7, 29.4, 28.7/28.4*,
27.8, 27.4/26.7*, 26.0, 25.0, 24.3/23.0*, 22.9, 14.2. HRMS:
m/z calcd for C41H73NO9 + Na: 746.5183; found: 746.5188.
Compound 18: [a]D –29.3 (c 0.3, CHCl3) [Lit.4b [a]D +37.6
(c 0.98, CHCl3)]. 1H NMR (400 MHz, CDCl3): d = 6.95 (dt,
J = 15.5, 7.0 Hz, 1 H), 5.80 (d, J = 15.6 Hz, 1 H), 4.17 (q,
J = 7.2 Hz, 2 H), 4.06 (br s, 1 H), 4.02–3.96 (m, 1 H), 3.95–
Synlett 2009, No. 16, 2593–2596 © Thieme Stuttgart · New York