Divergent synthesis of lamellarin α 13-sulfate, 20-sulfate, and 13,20-disulfate

Article abstract of DOI:10.3987/COM-09-S(S)100

A divergent synthesis of three sulfate derivatives of lamellarin α, namely, lamellarin α 13-sulfate (2), 20-sulfate (1), and 13,20-disulfate (4) has been achieved via a common intermediate (6) in which 13-OH and 20-OH of the lamellarin core are differentially protected by MOM and benzyl groups, respectively. Compound (6) in turn was prepared using sequential Suzuki-Miyaura coupling of 3,4-dihydroxypyrrole bistriflate (7) as a key reaction.

Full text of DOI:10.3987/COM-09-S(S)100

HETEROCYCLES, Vol. 80, No. 2, 2010
841
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 841 - 846. © The Japan Institute of Heterocyclic Chemistry
Received, 31st July, 2009, Accepted, 4th September, 2009, Published online, 14th September, 2009
DOI: 10.3987/COM-09-S(S)100
DIVERGENT SYNTHESIS OF LAMELLARIN ꢀ 13-SULFATE,
20-SULFATE,ꢀand 13,20-DISULFATE
Tsutomu Fukuda,a Takeshi Ohta,a Sho Saeki,a and Masatomo Iwaob*
b
aGraduate School of Science and Technology, and Department of Applied
Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan, e-mail: iwao@nagasaki-u.ac.jp
Abstract – A divergent synthesis of three sulfate derivatives of lamellarin ꢀ,
namely, lamellarin ꢀ 13-sulfate (2), 20-sulfate (1), and 13,20-disulfate (4) has
been achieved via a common intermediate (6) in which 13-OH and 20-OH of the
lamellarin core are differentially protected by MOM and benzyl groups,
respectively.
Compound (6) in turn was prepared using sequential
Suzuki-Miyaura coupling of 3,4-dihydroxypyrrole bistriflate (7) as a key reaction.
Lamellarins and the related marine pyrrole alkaloids have attracted considerable attention due to their
unique structures and highly useful biological activities.1 Lamellarin ꢀ 20-sulfate (1) was isolated from
the unidentified ascidian collected from the Arabian Sea near Trivandrum, India, by Faulkner and
co-workers.2 They demonstrated that 1 inhibits HIV-1 integrase selectively and growth of the HIV-1
virus in cell culture.2 Because cytotoxicity of 1 is quite low, this natural product has been regarded as a
new type of lead compound for development of anti-HIV agents. An attempted synthesis of lamellarin
ꢀ 20-sulfate (1) and 13-sulfate (2) from lamellarin ꢀ (3) by titration with DMF-SO3 complex was
reported by Faulkner and coworkers in 2002. 3 Unfortunately, however, they obtained only lamellarin
13,20-disulfate (4) in low yield. Recently, we reported the first total synthesis of lamellarin ꢀ 20-sulfate
(1) from the differentially protected lamellarin ꢀ (5).4 The selective introduction of sulfate group at
MeO
MeO
R2O
OR1
20
lamellarin ꢀ 20-sulfate (1) (R1=SO3Na, R2=H)
lamellarin ꢀ 13-sulfate (2) (R1=H, R2=SO3Na)
lamellarin ꢀ (3) (R1=R2=H)
13
MeO
MeO
lamellarin ꢀ 13,20-disulfate (4) (R1=R2=SO3Na)
20O-benzyl-13O-isopropyllamellarin ꢀ (5) (R1=Bn, R2=i-Pr)
O
N
O

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HETEROCYCLES, Vol. 80, No. 2, 2010
20-OH was effected by
a
sequence involving selective debenzylation of 20-OBn,
2,2,2-trichloroethylsulfonation of the resulting 20-OH, deprotection of 13-Oi-Pr, and final reductive
cleavage of the 2,2,2-trichloroethyl ester moiety.5,6 For the structure-activity relationship studies
concerning integrase inhibition and anti-HIV activity, we needed to prepare lamellarin ꢀ 13-sulfate (2)
and 13,20-disulfate (4) also. It was revealed, however, the synthesis of 2 from 5 was difficult because
debenzylation at 20-OBn occurred simultaneously during deprotection at 13-Oi-Pr under the standard
BCl3 conditions. Thus, we designed a new lamellarin ꢀ derivative (6) in which 13-OH was protected by
a more labile methoxymethyl (MOM) group. In this communication, we report a divergent synthesis of
lamellarin ꢀ sulfate derivatives (1), (2), and (4) from the common intermediate (6) which in turn can be
obtained from 3,4-dihydroxypyrrole bistriflate (7) and arylboronic acids (8), (9) using the previously
established procedure developed in our laboratories (Scheme 1).4,5
TfO
MeO2C
OTf
CO2Me
MeO
MeO
MOMO
OBn
N
BnO
MeO
OMOM
MeO
+
+
1, 2, and 4
O
MeO
MeO
B(OH)2 MOMO
B(OH)2
N
8
9
O
OMe
7
OMe
6
Scheme 1
The synthesis of arylboronic acid (8) is shown in Scheme 2. Isovanillin (10) was benzylated with benzyl
bromide to give O-benzylisovanillin (11) in 86% yield.7 Baeyer-Villiger oxidation of 11 with
m-chloroperbenzoic acid (mCPBA) followed by methanolysis afforded the phenol (12) in 90% yield.
After MOM protection of the phenolic hydroxy group, the resulting 13 was regioselectively brominated
by N-bromosuccinimide (NBS) to give 14 in 97% yield. Bromine–lithium exchange of 14 with
tert-butyllithium followed by treatment with trimethyl borate afforded the desired arylboronic acid (8).
Another arylboronic acid (9) was prepared according to the procedure shown in Scheme 3. C-2-
RO
CHO
BnO
MeO
OR
BnO
MeO
OMOM
Br
BnO
MeO
OMOM
B(OH)2
(b)
(d)
(e)
MeO
(a)
10 (R=H)
11 (R=Bn)
12 (R=H)
13 (R=MOM)
14
8
(c)
Scheme 2. Reagents and conditions: (a) BnBr (1.1 equiv), K2CO3, acetone, reflux, 4.5 h (86%); (b) (1)
mCPBA (1.5 equiv), CH2Cl2, 0 °C, 3 h, (2) K2CO3, MeOH, rt, 1.5 h (90%); (c) MOM-Cl (1.5
equiv), i-Pr2NEt, CH2Cl2, 0 °C, 1 h then rt, 48 h (87%); (d) NBS (1.0 equiv), DMF, 0 °C, 1 h
(97%); (e) (1) tert-BuLi (2.1 equiv), THF, –78 °C, 1 h, (2) B(OMe)3 (1.5 equiv), –78 °C, 1 h
then rt, 1 h (99%).

HETEROCYCLES, Vol. 80, No. 2, 2010
843
selective bromine–lithium exchange of commercially available 2,4-dibromoanisole (15) followed by
boration and oxidation gave the phenol (16) in 78% yield.8 After MOM protection of the phenolic
hydroxy group, the resulting 17 was converted into the arylboronic acid (9) via bromine–lithium
exchange with tert-butyllithium followed by treatment with trimethyl borate.
MeO
Br
MeO
RO
MeO
(a)
(c)
Br
Br
16 (R=H)
17 (R=MOM)
MOMO
B(OH)2
15
9
(b)
Scheme 3. Reagents and conditions: (a) (1) n-BuLi (1.1 equiv), THF, –78 °C, 1 h, (2) B(OMe)3 (1.5
equiv), –78 °C, 1 h then rt, 1 h, (3) AcOH, H2O2, rt, 16 h (78%); (b) MOM-Cl (1.5 equiv),
K2CO3, acetone, 0 °C, 1 h then reflux, 19 h (96%); (c) (1) tert-BuLi (2.1 equiv), THF, –78 °C,
1 h, (2) B(OMe)3 (1.5 equiv), –78 °C, 1 h then rt, 1 h (72%).
The synthesis of lamellarin ꢀ 13-sulfate (3) was shown in Scheme 4. Suzuki-Miyaura coupling of the
MeO
MeO
MeO
MeO
MOMO
OBn
OBn
OBn
TfO
MeO2C
OTf
CO2Me
TfO
MeO2C
TfO
MeO2C
OMOM
O
O
(a)
(b)
(c)
RO2C
CO2Me
N
N
N
N
O
O
OMe
OMe
OMe
OMe
20 (R=Me)
21 (R=H)
7
18
19
OMe
OMe
OMe
MeO
MOMO
OMe
(d)
MeO
OBn
MeO
MeO
MeO
MeO
R2O
MeO
MeO
OBn
OR1
MOMO
MeO
O
(e)
(f)
(g)
O
O
N
O
N
N
O
O
MeO
6 (R1=Bn, R2=MOM)
24 (R1=Bn, R2=H)
25 (R1=Bn, R2=SO3CH2CCl3)
26 (R1=H, R2=SO3CH2CCl3)
2 (R1=H, R2=SO3Na)
23
(h)
(i)
OMe
(j)
22
OMe
(k)
Scheme 4. Reagents and conditions: (a) 8 (1.2 equiv), Pd(PPh3)4 (2 mol%), Na2CO3, water, THF, reflux,
3 h (74%); (b) (1) concd HCl, MeOH, reflux, 1 h, (2) p-TsOH, CH2Cl2, reflux, 2 h (93%); (c)
9 (2.0 equiv), Pd(PPh3)4 (8 mol%), Na2CO3, water, THF, reflux, 8 h (95%); (d) (1) 40%
aqueous KOH, EtOH, reflux, 2 h, (2) PPTS, CH2Cl2, reflux, 24 h (61%); (e) Cu2O (1.0 equiv),
quinoline, 220 °C, 10 min (83%); (f) PIFA (1.2 equiv), BF3·OEt2, CH2Cl2, –40 °C, 1.5 h
(62%); (g) DDQ (1.0 equiv), CH2Cl2, reflux, 30 h (87%); (h) concd HCl, MeOH-CH2Cl2 (1:2),
45 °C, 2 h (99%); (i) CCl3CH2OSO2Cl (2.0 equiv), Et3N, DMAP, CH2Cl2, rt, 5 h (89%); (j) H2,
10% Pd-C, EtOAc, rt, 4 h (61%); (k) (1) Zn powder (3.0 equiv), HCO2NH4 (6.0 equiv),
THF-MeOH (1:1), rt, 2 h, (2) Amberlite IRC-50 (Na+ form), MeOH, (3) Sephadex LH-20,
MeOH–CH2Cl2 (1:1) (61%).

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HETEROCYCLES, Vol. 80, No. 2, 2010
bistriflate (7) with 1.2 equiv of an arylboronic acid (8) under the standard conditions [Pd(PPh3)4 (2 mol%),
Na2CO3, water, THF, reflux, 3 h]9 gave the mono-arylated pyrrole (18) in 74% yield. Compound (18)
was converted into the lactone (19) by treatment with hydrochloric acid in methanol followed by
acid-catalyzed lactonization in 93% yield. The second cross-coupling of 19 with an arylboronic acid (9)
(2.0 equiv) using 8 mol% of Pd(PPh3)4 afforded 20 in 95% yield. Compound (20) was converted into
the acid (21) by alkaline hydrolysis followed by acid-catalyzed relactonization in 61% yield.
Decarboxylation of 21 in hot quinoline in the presence of copper(I) oxide produced 22.10 Intramolecular
oxidative biaryl coupling of 22 under Kita’s conditions11 using phenyliodine bis(trifluoroacetate)
(PIFA)-boron trifluoride etherate afforded the cyclized product (23) in 62% yield. Treatment of 23 with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in refluxing dichloromethane produced the common
intermediate (6). Deprotection of the MOM group by treatment with hydrochloric acid in methanol
afforded 24, which was reacted with 2,2,2-trichloroethyl chlorosulfate in dichloromethane to give the
mixed sulfate (25) in 89% yield.6 Hydrogenolysis of 25 over palladium on charcoal for 4 h at room
temperature afforded debenzylated 26 in 61% yield.
Final reductive deprotection of the
2,2,2-trichloroethyl ester with Zn/HCO2NH4 followed by ion exchange over Amberlite IRC-50 (Na+ form)
and Sephadex purification produced lamellarin ꢀ 13-sulfate (2)12 in 61% yield.
The syntheses of lamellarin ꢀ 20-sulfate (1) and lamellarin ꢀ 13,20-disulfate (4) are shown in Scheme 5.
Compound (6) was debenzylated by hydrogenolysis over palladium on charcoal to give 27 in 99% yield.
2,2,2-Trichloroethylsulfonation of 27 in a similar manner as described above provided 28 in 69% yield.
Selective removal of MOM protecting group provided 29 in 81% yield. Treatment of 29 with
Zn/HCO2NH4 followed by ion exchange over Amberlite IRC-50 (Na+ form) and Sephadex purification
produced lamellarin ꢀ 20-sulfate (1)13 in 85% yield. Deprotection of MOM group from 27 with
MeO
MeO
MeO
MOMO
MeO
R2O
MeO
MeO
OH
OR1
(a)
(b)
6
O
O
MeO
MeO
N
N
O
O
28 (R1=SO3CH2CCl3, R2=MOM)
29 (R1=SO3CH2CCl3, R2=H)
1 (R1=SO3Na, R2=H)
27
3
(c)
(d)
(c)
(e)
4
Scheme 5. Reagents and conditions: (a) H2, 10% Pd-C, EtOAc, rt, 2 h (99%); (b) CCl3CH2OSO2Cl (2.0
equiv), Et3N, DMAP, CH2Cl2, rt, 2.5 h (69%); (c) concd HCl, MeOH-CH2Cl2 (1:2), 45 °C, 5 h
(29, 81%; 3, 99%); (d) (1) Zn powder (3.0 equiv), HCO2NH4 (6.0 equiv), THF-MeOH (1:1),
rt, 4 h, (2) Amberlite IRC-50 (Na+ form), MeOH, (3) Sephadex LH-20, MeOH–CH2Cl2 (1:1)
(85%); (e) (1) pyridine-SO3, DMF-pyridine (4:1), 65 °C, 2 h, (2) Amberlite IRC-50 (Na+
form), MeOH, (3) Sephadex LH-20, MeOH–CH2Cl2 (1:1) (69%).

HETEROCYCLES, Vol. 80, No. 2, 2010
845
hydrochloric acid in methanol produced lamellarin ꢀ (3) in 99% yield. Treatment of 3 with
pyridine-SO3 complex in DMF-pyridine followed by ion exchange over Amberlite IRC-50 (Na+ form)
and Sephadex purification afforded lamellarin ꢀ 13,20-disulfate (4)14 in 69% yield. The spectroscopic
data of 1 and 4 are identical with those previously reported.3,4
In conclusion, we have succeeded in a divergent synthesis of lamellarin ꢀ 20-sulfate (1), 13-sulfate (2),
and 13,20-disulfate (4) using 6 as a common intermediate. The synthesis of the other lamellarin sulfate
derivatives and their structure-activity relationship studies are in progress.
ACKNOWLEDGEMENTS
The authors wish to thank the president’s discretionary fund of Nagasaki University and the Naito
Foundation for financial support.
REFERENCES AND NOTES
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7698; (b) H. Tohma, H. Morioka, S. Takizawa, M. Arisawa, and Y. Kita, Tetrahedron, 2001, 57,
345; (c) H. Hamamoto, G. Anilkumar, H. Tohma, and Y. Kita, Chem. Eur. J., 2002, 8, 5377.
12. Lamellarin ꢀ 13-sulfate (2). Mp 265-280 °C (dec.) (sealed capillary); IR (KBr): 3422, 1684, 1432,
1
1267, 1049 cm–1; H NMR (400 MHz, 8 mg of 2 in 0.7 mL of DMSO-d6): ꢀ 3.31 (s, 3H), 3.37 (s,
3H), 3.85 (s, 3H), 3.87 (s, 3H), 6.39 (s, 1H), 6.46 (s, 1H), 7.07 (s, 1H), 7.16 (dd, J= 2.0 and 8.3 Hz,
1H), 7.19 (d, J= 7.3 Hz, 1H), 7.26 (d, J= 8.3 Hz, 1H), 7.36 (s, 1H), 7.71 (d, J= 2.0 Hz, 1H), 9.03 (d,
13
J= 7.3 Hz, 1H); C NMR (100 MHz, 8 mg of 2 in 0.7 mL of DMSO-d6): ꢀ 54.4, 54.5, 55.5, 56.2,
103.2, 103.8, 104.9, 105.5, 107.9, 109.3, 111.4, 113.9, 118.2, 122.2, 123.3, 124.2, 126.0, 127.2,
130.9, 133.5, 143.8, 147.2, 148.4, 148.8, 149.7, 150.3, 154.9. HRFABMS m/z. Calcd for
C29H22NNa2O11S [(M+Na)+]: 638.0709. Found: 638.0662.
13. Lamellarin ꢀ 20-sulfate (1). Mp 258-268 °C (dec.) (sealed capillary) [lit.4, mp 263-269 °C (dec.)
(sealed capillary)]; IR (KBr): 3422, 1698, 1485, 1418, 1273, 1047 cm–1; 1H NMR (400 MHz, 17 mg
of 1 in 0.7 mL of DMSO-d6): ꢀ 3.34 (s, 3H), 3.37 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 6.82 (s, 1H),
6.86 (dd, J= 1.9 and 8.2 Hz, 1H), 7.02 (d, J= 1.9 Hz, 1H), 7.16 (d, J= 8.2 Hz, 1H), 7.18 (s, 1H), 7.26
(d, J= 7.4 Hz, 1H), 7.34 (s, 1H), 7.57 (s, 1H), 9.02 (d, J= 7.4 Hz, 1H); 13C NMR (100 MHz, 17 mg of
1 in 0.7 mL of DMSO-d6): ꢀ 54.4, 55.0, 55.5, 55.9, 104.7, 105.8, 106.9, 108.0, 108.7, 111.4, 111.5,
112.8, 113.4, 118.2 (118.16), 118.2 (118.24), 120.7, 122.0, 124.2, 127.0, 127.9, 133.4, 143.2, 145.1,
146.6, 148.3, 148.8, 149.0, 149.8, 154.1. HRFABMS m/z. Calcd for C29H22NNa2O11S [(M+Na)+]:
638.0709. Found: 638.0750.
14. Lamellarin ꢀ 13,20-disulfate (4). Mp 205-210 °C (dec.) (sealed capillary) [lit.3, mp > 260 °C
1
(chars)]; IR (KBr): 1699, 1486, 1419, 1272, 1050 cm–1; H NMR (400 MHz, DMSO-d6): ꢀ 3.37 (s,
3H), 3.39 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.73 (s, 1H), 7.12 (s, 1H), 7.21 (dd, J= 2.1 and 8.3 Hz,
1H), 7.29 (d, J= 8.3 Hz, 1H), 7.34 (d, J= 7.4 Hz, 1H), 7.42 (s, 1H), 7.58 (s, 1H), 7.75 (d, J= 2.1 Hz,
1H), 9.08 (d, J= 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): ꢀ 54.5, 55.0, 55.6, 56.2, 104.8, 105.6,
107.0, 108.1, 108.6, 111.0, 111.5, 112.9, 114.0, 118.3, 122.0, 123.1, 124.2, 125.9, 126.3, 128.2,
133.6, 143.1, 143.9, 145.0, 146.7, 149.1, 150.0, 150.6, 154.2. HRFABMS m/z. Calcd for
C29H21NNa3O14S2 [(M+Na)+]: 740.0097. Found: 740.0145.