Total synthesis of dictyodendrillin-B

Article abstract of DOI:10.1055/s-1998-1723

Dictyodendrillin-B (1), an oxygenated sesquiterpene of marine origin, as well as its methoxyacetal 2 have been prepared by a concise route (6 steps, 43% overall yield).

Full text of DOI:10.1055/s-1998-1723

6
82
LETTERS
SYNLETT
Total Synthesis of Dictyodendrillin-B
K. Gerlach, H. M. R. Hoffmann*
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; e-mail: hoffmann@mbox.oci.uni-hannover.de
Received 19 February 1998
Abstract: Dictyodendrillin-B (1), an oxygenated sesquiterpene of
marine origin, as well as its methoxyacetal 2 have been prepared by a
concise route (6 steps, 43% overall yield).
attempted one-step conversion of isomeric acetal esters E-4 and Z-4 into
the target lactone using acidic tetrahydrofuran led to decomposition.
Unsaturated E-configurated acetal ester E-4 was also hydrolyzed5 and
cyclized under photoisomerization of the C2-C3 double bond (5 → 1).
Benzophenone is the sensitizer of choice for this process, giving the title
sesquiterpene 1 in 100% yield.
1
Recently, Capon and his coworkers have isolated and identified the title
molecule, an oxygenated sesquiterpene, from the marine sponge
Dictyodendrilla collected in Port Phillip Bay, Victoria, Australia. The
extract of this sponge inhibited the growth of the bacterium Escherichia
coli. It is of interest to note that several years preceding the report of
Finally, our approach to the western half of dictyodendrillin-B can be
applied directly to other terpenoid 5-hydroxyfuranones of current
6
7
interest, e.g. luffariellolide and manoalide which belongs to the class
of nonsteroidal anti-inflammatory drugs (NSAIDs) (Scheme 2).
2
Capon, the group of Katsumura and Isoe had actually prepared 4-
homogeranyl-5-hydroxyfuran-2(5H)-one 1 as well as its 3-homogeranyl
derivative as an inseparable mixture of regioisomers, at a time when it
was unknown that 1 is a natural product.
We here report a flexible synthesis of the title molecule (Scheme 1).
Pyruvic aldehyde dimethyl acetal was converted into the
cyclohexylimine and deprotonated to the azaenolate, which was
alkylated cleanly with geranyl bromide, giving ketoacetal 3 in excellent
yield (77 % over 3 steps). Peterson olefination provided an E/Z mixture
3
of unsaturated acetal esters E-4 and Z-4, which were separable by
chromatography. However, the formation of E/Z isomers at this stage is
not
a disadvantage, since either isomer can be converted into
dictyodendrillin-B.
Thus, saponification Z-4 and acid-catalyzed lactonization furnished the
desired natural product 1 and also the previously unknown methoxy
4
acetal 2. Hydrolysis of methoxyacetal 2, which is formed as a
byproduct in the cyclization of Z-4, also afforded hemiacetal 1. The
Scheme 2

June 1998
SYNLETT
683
The approach offers an alternative to using 4-vinylfuran-2(5H)-ones and
etheral layers were dried (MgSO ) and evaporated. The residue
4
4
-formylfuran-2(5H)-ones as building blocks, which are tetronic acid
was purified by column chromatography (silica gel, gradient PE/E
20:1 → 3:1) to afford the desired product dictyodendrillin-B 1 as
colourless liquid (80 mg, 49%) as well as its methoxy derivative 2
8
derivatives useful in the synthesis of heteroprostanoids.
(
69 mg, 40%, slightly yellow liquid). Method B: A solution of
References and Notes
trans formyl acid 5 (58 mg, 0.236 mmol, 0.01 M in anhydrous
(
(
(
1) Tran, N. H.; Hooper, J. N. A.; Capon, R. J. Aust. J. Chem. 1995,
8, 1757.
2) Katsumura, S.; Hori, K.; Fujiwara, S.; Isoe, S. Tetrahedron Lett.
985, 26, 4625.
benzene) and benzophenone (42 mg, 1.0 eq) in a two-necked flask
4
(
Duran) was degassed for 20 min by bubbling nitrogen through the
mixture. Irradiation with a high pressure mercury lamp (HPK 125
W/L, Phillips, cooling finger made from quartz) for 45 min at 0 - 5
1
°
C furnished dictyodendrillin-B 1 in quantitative yield after
3) To a 0.5 molar solution of LDA in THF (1.3 eq) was added a
solution of methyl (trimethylsilyl)acetate (1.41 mL, 1.3 eq) in
THF (4 mL) dropwise over 15 min at −78 °C. After stirring for 1 h
a solution of keto acetal 3 (1.68 g, 6.6 mmol, 0.5 M in THF) was
added dropwise over 1 h. The reaction mixture was then allowed
to warm to r.t. overnight. After addition of water the mixture was
extracted three times with diethyl ether. The combined organic
layers were dried over MgSO4 and concentrated in vacuo. MPL
Chromatography on silica gel (PE/E 40:1) afforded 3-
dimethoxymethyl-7,11-dimethyldodeca-2Z,6E,10E-trienoic acid
methyl ester Z-4 (698 mg, 34%) and its 2E-isomer E-4 (879 mg,
column chromatography (silica gel, CHCl3).
Data for 2: IR (neat): ν = 2916, 1796, 1768, 1648, 1444, 1116,
−
1 1
9
1
2
2
1
60, 896 cm ; H NMR (400 MHz, CDCl ): δ = 1.60 (s, 3H-15),
3
.62 (s, 3H-14), 1.68 (s, 3H-16), 1.96 - 2.04 (m, 2H-11), 2.03 -
.12 (m, 2H-10), 2.26 - 2.35 (m, 2H-7), 2.34 - 2.40 (m, 1H-6α),
.42 - 2.54 (m, 1H-6β), 3.56 (s, 3H-OMe), 5.04 - 5.14 (m, 2H-8,
H-12), 5.64 (s, 1H-1), 5.87 (d, J = 0.92 Hz, 1H-4); 13C NMR
(
100 MHz, CDCl ): δ = 16.2 (CH , C-15), 17.7 (CH , C-14), 25.1
3 3 3
(
CH , C-7), 25.7 (CH , C-16), 26.5 (CH , C-11), 27.8 (CH , C-6),
2 3 2 2
3
9.6 (CH , C-10), 56.8 (CH , OMe), 104.4 (CH, C-1), 118.3 (CH,
2 3
C-4), 122.0 (CH, C-12), 124.0 (C-8), 131.6 (C, C-13), 137.3 (C,
4
1
3%) as slightly yellow liquids. Z-4, IR (neat): ν = 2928, 1720,
652, 1436, 1140, 1104, 1072 cm−
1
1
C-9), 167.4 (C, C-5), 170.7 (C, C-3); MS (r.t.): m/z (%): 265 (2)
;
H NMR (400 MHz,
+
+
[
M +1], 264 (8) [M ], 233 (6), 232 (28), 221 (18), 196 (25), 189
CDCl ): δ = 1.60 (s, 3H-7-Me), 1.61 (s, 3H-11-Me), 1.67 (s, 3H-
3
(
31), 181 (10), 168 (17), 165 (26), 164 (47), 163 (22), 153 (36),
1
2
2), 1.95 - 2.01 (m, 2H-9), 2.03 - 2.10 (m, 2H-8), 2.16 - 2.23 (m,
H-5), 2.27 - 2.32 (m, 2H-4), 3.42 (s, 6H-OMe), 3.71 (s, 3H-
151 (64), 137 (39), 135 (27), 128 (81), 119 (67), 107 (33), 105
(
27), 96 (100), 93 (40), 91 (41). HRMS calcd for C16H24O3:
CO Me), 5.06 - 5.15 (m, 2H-6, 1H-10), 5.81 (d, J = 0.56 Hz, 1H-
2
1
3
264.1712, found 264.1725.
Data for 1: IR (neat): ν = 3356 bs, 2964, 2920, 2856, 1740, 1648,
1
1
1
-
CH(OMe) ), 5.96 (d, J = 0.73 Hz, 1H-2); C NMR (100 MHz,
2
CDCl ): δ = 15.9 (CH , 7-Me), 17.5 (CH , 11-Me), 25.5 (CH , C-
3
3
3
3
−
1
448, 1136, 948 cm ; IR (CHCl ): ν = 3588, 2916, 1764, 1648,
1
2), 26.3 (CH , C-5), 26.6 (CH , C-9), 30.2 (CH , C-4), 39.6
3
2
2
2
−
1 1
444, 1104 cm ; H NMR (400 MHz, CDCl ): δ = 1.60 (s, 3H-
(
CH , C-8), 51.1 (CH , OMe), 55.5 (CH , CO Me), 101.0 (CH,
3
2
3
3
2
5), 1.62 (s, 3H-14), 1.68 (s, 3H-16), 1.96 - 2.03 (m, 2H-11), 2.03
2.11 (m, 2H-10), 2.28 - 2.36 (m, 2H-7), 2.36 - 2.47 (m, 1H-6α),
CH(OMe) ), 117.9 (CH, C-2), 123.2 (CH, C-10), 124.2 (CH, C-
2
6
1
), 131.1 (C, C-11), 135.8 (C, C-7), 157.5 (C, C-3), 166.2 (C, C-
); MS (r.t.): m/z (%): 280 (3), 279 (12) [M −OMe], 246 (21), 231
+
2.47 - 2.60 (m, 1H-6β), 5.04 - 5.14 (m, 2H-8, 1H-12), 5.84 (s, 1H-
), 6.03 (s, 1H-4); 13C NMR (100 MHz, CDCl ): δ = 16.1 (CH ,
1
(15), 209 (20), 203 (16), 187 (19), 177 (26), 173 (16), 149 (31),
3
3
C-15), 17.7 (CH , C-14), 25.1 (CH , C-7), 25.7 (CH , C-16), 26.5
147 (12), 145 (23), 143 (29), 142 (32), 135 (34), 127 (41), 119
3
2
3
(
CH , C-11), 27.8 (CH , C-6), 39.6 (CH , C-10), 99.4 (CH, C-1),
2 2 2
(20), 117 (31), 110 (14), 105 (15), 99 (15), 93 (17), 91 (18), 81
1
17.4 (CH, C-4), 122.1 (CH, C-12), 124.0 (C-8), 131.7 (C, C-13),
(
1
25), 75 (73), 72 (16), 69 (100). E-4, IR (neat): ν = 2928, 1724,
656, 1436, 1232, 1196, 1164, 1136, 1100, 1056 cm− ; H NMR
1
1
137.3 (C, C-9), 170.0 (C, C-5), 172.2 (C, C-3); MS (r.t.): m/z (%):
+
+
251 (3) [M +1], 250 (6) [M ], 233 (6), 232 (18), 217 (8), 207 (20),
(400 MHz, CDCl ): δ = 1.60 (s, 3H-7-Me), 1.62 (s, 3H-11-Me),
3
1
89 (26), 179 (14), 164 (37), 163 (18), 153 (20), 137 (41), 135
1
-
.68 (s, 3H-12), 1.94 - 2.01 (m, 2H-9), 2.02 - 2.11 (m, 2H-8), 2.16
2.24 (m, 2H-5), 2.60 (m, 2H-4), 3.29 (s, 6 H, OMe), 3.72 (s, 3 H,
(
(
50), 123 (26), 121 (25), 119 (25), 113 (100), 93 (40), 91 (42), 81
42), 79 (36), 77 (28). HRMS calcd for C15H22O : 250.1580,
CO Me), 4.73 (d, J = 0.91 Hz, 1 H, CH(OMe) ), 5.09 (tq, J = 7,
3
2
2
found 250.1569.
1
.3 Hz, 1H-10), 5.19 (tq, J = 7.4, 1.1 Hz, 1H-6), 6.05 (s, 1H-2);
1
3
C NMR (100 MHz, CDCl ): δ = 15.8 (CH , 7-Me), 17.5 (CH ,
3
3
3
(5) Analogous treatment of acetal ester E-4 (200 mg, 0.65 mmol) and
purification by column chromatography on silica gel (PE/E 5:1)
gave 3-formyl-7,11-dimethyldodeca-2E,6E,10E-trienoic acid 5 as
yellow oil (125 mg, 77%). IR (neat): ν = 3270, 2924, 1700, 1640,
11-Me), 25.5 (CH , C-12), 26.6 (CH , C-5), 27.3 (CH , C-9), 28.5
3 2 2
(CH , C-4), 39.6 (CH , C-8), 51.0 (CH , OMe), 53.0 (CH ,
2 2 3 3
CO Me), 103.6 (CH, CH(OMe) ), 118.0 (CH, C-2), 123.5 (CH,
C-10), 124.3 (CH, C-6), 131.1 (C, C-11), 135.7 (C, C-7), 156.1
2
2
−1
1
1
3
2
2
1
444, 1252, 1128 cm ; H NMR (400 MHz, CDCl ): δ = 1.57 (s,
3
(
[
(
C, C-3), 166.4 (C, C-1); MS (r.t.): m/z (%): 280 (6), 279 (21)
M −OMe], 246 (13), 235 (16), 209 (17), 203 (16), 187 (11), 177
28), 173 (14), 149 (31), 145 (26), 143 (27), 142 (29), 135 (27),
H-7-Me), 1.59 (s, 3H-11-Me), 1.67 (s, 3H-12), 1.93 - 2.00 (m,
H-9), 2.01 - 2.09 (m, 2H-8), 2.15 (m, 2H-5), 2.77 (t, J = 7.6 Hz,
H-4), 5.07 (tq, J = 6.9, 1.3 Hz, 1H-10), 5.15 (tq, J = 7.3, 1.1 Hz,
+
127 (34), 119 (19), 117 (34), 109 (18), 91 (22), 81 (27), 75 (61),
H-6), 6.50 (s, 1H-2), 9.56 (s, 1H-CHO), 11.62 (bs, 1H-CO H);
2
+
69 (100). HRMS calcd for C17H26O3 (M −MeOH): 278.1889,
13
C NMR (100 MHz, CDCl ): δ = 15.88 (CH , 7-Me), 17.66
3
3
found 278.1882.
(
CH , 11-Me), 25.06 (CH , C-5), 25.68 (CH , C-12), 26.66 (CH ,
3 2 3 2
(
4) Dictyodendrillin-B (1) and 4-Homogeranyl-5-methoxyfuran-
C-9), 27.18 (CH , C-4), 39.65 (CH , C-8), 122.64 (CH, C-10),
2 2
2
(5H)-one (2). Method A: Acetal ester Z-4 (200 mg, 0.65 mmol)
was dissolved in THF (5 ml) and treated with 2N NaOH (1.62 ml,
.5 eq). The mixture was heated at reflux for 1 d. After cooling to
r.t. the solution was acidified by addition of half concentrated HCl
0.6 ml) and then vigorously stirred at 60 °C for 4 h. The mixture
was cooled and extracted three times with diethyl ether. The
124.25 (CH, C-6), 131.40 (C, C-11), 134.24 (CH, C-2), 134.24 (C,
C-7), 156.11 (C, C-3), 170.95 (C, CO H), 194.17 (CH, CHO); MS
(70 °C): m/z (%): 251 (3) [M +1], 250 (10) [M ], 232 (19), 217
(12), 207 (45), 189 (49), 178 (23), 163 (70), 145 (20), 137 (27),
136 (46), 135 (100), 125 (22), 123 (42), 121 (35), 119 (27), 109
(23), 107 (89), 105 (34), 95 (38), 93 (54), 91 (68), 81 (68), 79
2
+
+
2
(

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LETTERS
SYNLETT
(
2
55), 77 (36). HRMS calcd for C15H22O : 250.1558, found
50.1569.
1988, 29, 1173; Bury, P.; Hareau, G.; Kocienski, P. J.; Dhanak, D.
Tetrahedron 1994, 50, 8793; Pommier, A.; Kocienski, P. J. J.
Chem. Soc., Chem. Commun. 1997, 1139; Coombs, J.; Hoffmann,
H. M. R. Synthesis 1998, in press.
3
(
(
6) Albizati, K. F.; Holman, T.; Faulkner, D. J.; Glaser, K. B.; Jacobs,
R. S. Experientia 1987, 43, 949.
7) de Silva, E. D.; Scheuer, P. J. Tetrahedron Lett. 1980, 21, 1611.
Total syntheses: Garst, M. E.; Tallman, E. A.; Bonfiglio, J. N.;
Harcourt, D.; Ljungwe, E. B.; Tran, A. Tetrahedron Lett. 1986, 27,
(8) Lattmann, E.; Coombs, J.; Hoffmann, H. M. R. Synthesis 1996,
171; Hoffmann, H. M. R.; Gerlach, K.; Lattmann, E. Synthesis
1996, 164; Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996,
155.
4533; Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett.