Total synthesis of (±)-flustramines A and C, (±)-flustramide A, and (-)- and (+)-debromoflustramines A

Article abstract of DOI:10.1021/jo800984a

(Chemical Equation Presented) Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Clai

Full text of DOI:10.1021/jo800984a

Total Synthesis of (()-Flustramines A and C, (()-Flustramide A,
and (-)- and (+)-Debromoflustramines A
Tomomi Kawasaki,* Masashi Shinada, Mayu Ohzono, Atsuyo Ogawa, Romi Terashima, and
Masanori Sakamoto
Meiji Pharmaceutical UniVersity, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
kawasaki@my-pharm.ac.jp
ReceiVed May 7, 2008
Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids
and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-
isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (()-Flustramine C (5) was
synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (()-Flustramine A
(1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a.
(()-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers
of19weresynthesizedthroughopticalresolutionof(()-carboxylicacid17busing(R)-4-phenyloxazolidin-2-one.
Introduction
C (4), and (ii) pyrroloindoline containing a 3a-prenyl group,
e.g., flustramines B (7) and E (8). Flustramines A (1) and B
(7), isolated from F. foliacea, were the first members of the
family to be identified.1 These compounds exhibit both skeletal
and smooth muscle relaxant activities.9 Recently, flustramine
A (1) was demonstrated to have blocking activity on a voltage-
activated potassium channel.10 Flustramine D (2) and dihydro-
flustramine C (3) show antibacterial activities.6,11 The unique
structural array and the interesting biological activities displayed
by these alkaloids make them and the related compounds
attractive synthetic targets.12 Recently, we have developed
our synthetic methodology using the domino olefination-
isomerization-Claisen rearrangement (OIC) and reductive
cyclization (RC) for construction of the 3a-allylpyrrolo[2,3-b]-
indoline architecture including the related alkaloids of flustra-
mines.13 In the present paper, we describe the total synthesis
of (()-flustramines A (1) and C (5), (()-flustramide A (6), and
(()-debromoflustramine A (19) as an efficient approach to F.
The flustramines and flustramides, isolated from the marine
invertebrate Bryozoa Flusta foliacea, are a small family of
brominated hexahydropyrrolo[2,3-b]indole alkaloids bearing
isoprenyl substituents at various positions.1–8 These alkaloids
are classified into two structural categories (Figure 1): (i)
pyrroloindole having a 1,1-dimethylallyl (reverse prenyl) group
at the 3a-position, e.g., flustramines A (1), C (5), D (2),
flustramide A (6), isoflustramine D (3), and dihydroflustramine
(1) Flustramines A and B: (a) Carle´, J. S.; Christophersen, C. J. Am. Chem.
Soc. 1979, 101, 4012–4013. (b) Carle´, J. S.; Christophersen, C. J. Org. Chem.
1980, 45, 1586–1589.
(2) Flustramine C: Carle´, J. S.; Christophersen, C. J. Org. Chem. 1981, 46,
3440–3443.
(3) Flustramide A: Wulff, P.; Carle´, J. S.; Christophersen, C. Comp. Biochem.
Physiol. 1982, 71B, 523–524.
(4) Dihydroflustramine C: Wright, J. L. C. J. Nat. Prod. 1984, 47, 893–895.
(5) Flustramide B: Keil, P.; Nielsen, E. G.; Anthoni, U.; Christophersen, C.
Acta Chem. Scand. B 1986, 40, 555–558.
(6) Flustramine D: Laycock, M. V.; Wright, J. A.; Patil, A. D. Can. J. Chem.
1986, 64, 1312–1316.
(7) Flustramine E and debromoflustramine B: Holsy, P. B.; Anthoni, U.;
Christophersen, C.; Nielsen, P. H. J. Nat. Prod. 1994, 57, 997–1000.
(8) For a review, see:(a) Christophersen, C. Acta Chem. Scand. B 1985, 39,
517–529. (b) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletiesr, S. W. Ed.; Pergamon Press:
New York, 1999; Vol. 13, pp 163-236. (c) Morales-Rios, M. S.; Suarez-Castillo,
O. R. Nat. Prod. Commun. 2008, 3, 629–642.
(9) Sjoeblom, T.; Bohlin, L.; Christophersen, C. Acta Pharm. Suec. 1983,
20, 415–418.
(10) Peters, L.; Ko¨nig, G. M.; Terlau, H.; Wright, A. D. J. Nat. Prod. 2002,
65, 1633–1637.
(11) (a) Dix, A. V.; Meseck, C. M.; Lowe, A. J.; Mitchell, M. O. Bioorg.
Med. Chem. Lett. 2006, 16, 2522–2524. (b) Hodgson, J. W.; Mitchell, M. O.;
Thomas, M. L.; Waters, K. F. Bioorg. Med. Chem. Lett. 1995, 5, 2527–2528.
10.1021/jo800984a CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5959–5964 5959

Kawasaki et al.
the presence of t-BuOK at -78 °C, followed by warming to
room temperature, Horner-Wadsworth-Emmons olefination of
10, isomerization, Claisen rearrangement of 12, and deacety-
lation took place continuously to produce 3-cyanomethyl-3-(2-
methyl-3-buten-2-yl)indolin-2-one (13a) in 90% yield. On
treatment of 13a with Red-Al reduction at 0 °C, followed by
warming to room temperature, selective reduction of the nitrile
group with subsequent cyclization gave pyrroloindole 14 in 89%
yield.15 Methylation of 14 afforded (()-flustramine C (5) in
38% yield together with its isomer 15 (29%). A comparison of
the spectroscopic data of synthetic (()-5 with that reported for
the natural2,10 and synthetic products12c,e revealed that they were
identical except for the optical activity.
Next, we synthesized (()-flustramine A (1) and (()-flustra-
mide A (6) from the nitrile 13a as shown in Scheme 2.
N-Alkylation of 13a with prenyl bromide in the presence of
NaH followed by selective hydrolysis of 16a with NaOH in
boiling MeOH gave the corresponding carboxylic acid 17a in
excellent yield. Consecutive treatment of 17a with pentafluo-
rophenol and EDC and with methylamine facilitated condensa-
tion to yield N-methylamide 18a (93%). On treatment of the
amide 18a with alane-N,N-dimethylethylamine complex at -15
°C for 5 min, chemoselective reduction of the lactam carbonyl
group of 18a proceeded smoothly without reduction of the side
chain amide or debromination, and successive cyclization
produced (()-flustramide A (6) in 92% yield. Furthermore,
according to Morales-R´ıos’s procedure,12j reduction of 6 with
the alane complex at room temperature afforded (()-flustramine
A (1, 90%). The spectral properties of our synthetic compounds
1 and 6 are identical to those reported for the natural and
synthetic products flustramine A1,12e,j and flustramide A,3,12j
respectively, except for the optical activity.
FIGURE 1. Flustramines and flustramide.
SCHEME 1. Synthesis of (()-Flustramine C (5)
Using this procedure (Scheme 2), debromoflustramine A (19)
was prepared from 13b,13b which was readily obtained by
domino OIC reactions of debromo derivative of 9. The similar
three-step transformation of 13b to 18b was smoothly carried
(12) (a) Cardoso, A. S. P.; Marques, M. M. B.; Srinivasan, N.; Prabhakar,
S.; Lobo, A. M. Tetrahedron 2007, 63, 10211–10225. (b) Miyamoto, H.; Okawa,
Y.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2007, 48, 1805–808. (c) Lindel,
T.; Bra¨uchle, L.; Golz, G.; Bo¨hrer, P. Org. Lett. 2007, 9, 283–286. (d) Andrew,
V. D.; Meseck, C. M.; Lowe, A. J.; Mitchell, M. O. Bioorg. Med. Chem. Lett.
2006, 16, 2522–2524. (e) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677–680.
(f) Morales-R´ıos, M. S.; Rivera-Becerril, E.; Joseph-Nathan, P. Tetrahedron
Asymm. 2005, 16, 2493–2499. (g) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao,
W.-J.; MacMillan, D. W. C. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5482–
5487. (h) Tan, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801–1803. (i)
Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; Joseph-Nathan, P. Tetrahedron 2002,
58, 1479–1484. (j) Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; Trujillo-Serrato,
J. J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186–1192. (k) Cardoso, A. S. P.;
Srinivasan, N.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 2001, 42, 6663–
6666. (l) Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; Joseph-Nathan, P. J. Org.
Chem. 1999, 64, 1086–1087. (m) Somei, M.; Yamada, F.; Izumi, T.; Nakajou,
M. Heterocycles 1997, 45, 2327–2330. (n) Jensen, J.; Anthoni, U.; Christo-
phersen, C.; Nielsen, P. H. Acta Chem. Scand. 1995, 49, 68–71. (o) Bruncko,
M.; Crich, D.; Samy, R. J. Org. Chem. 1994, 59, 5543–5549. (p) Takase, S.;
Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5879–5886. (q) Takase,
S.; Uchida, I.; Tanaka, H.; Aoki, H. Heterocycles 1984, 22, 2491–2494. (r)
Muhtusubramanian, P.; Carle´, J. S.; Christophersen, C. Acta Chem. Scand. B
1983, 37, 803–807. (s) Hino, T.; Tanaka, T.; Matsuki, K.; Nakagawa, M. Chem.
Pharm. Bull. 1983, 31, 1806–1808.
foliacea alkaloids. Furthermore, we performed synthesis of (-)-
19 and (+)-19 through optical resolution of (()-carboxylic acid
17b by coupling with (R)-4-phenyloxazolidin-2-one.
(13) (a) Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A.
Chem. Commun. 2006, 420, 422. (b) Kawasaki, T.; Ogawa, A.; Terashima, R.;
Saheki, T.; Ban, N.; Sekiguchi, H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem.
2005, 70, 2957–2966. (c) Kawasaki, T.; Ogawa, A.; Terashima, R.; Sekiguchi,
H.; Sakamoto, M. Tetrahedron Lett. 2003, 44, 1591–1593. (d) Kawasaki, T.;
Terashima, R.; Sakaguchi, K.; Sekiguchi, H.; Sakamoto, M. Tetrahedron Lett.
1996, 37, 7525–7528.
Results and Discussion
Initially the synthesis of flustramine C (5) was performed as
illustrated in Scheme 1. Bromination of 6-bromoindolin-3-one
(9)14 at the C2 site and successive substitution with prenyl
alcohol in the presence of MS 4A were carried out to give
2-prenyloxyindolin-3-one 10 in 89% yield over two steps. When
10 was allowed to react with cyanomethylphosphonate 11 in
(14) Holt, S. J.; Kellie, A. E.; O’Sullivan, D. G.; Sadler, P. W. J. Chem.
Soc. 1958, 1271, 1223.
(15) The regiochemistry of 14 was confirmed by comparing its chemical
shifts (δ 3.77 and 3.87) of C2-methylene proton signals with that of flustramine
C (5) (δ 3.39 and 3.94) and its regioisomer 15 (δ 3.80 and 3.99).
5960 J. Org. Chem. Vol. 73, No. 15, 2008

Total Synthesis of (()-Flustramines A and C
SCHEME 2. Synthesis of (()-Flustramide A (1),
Flustramine A (6), and Debromo Derivative 19
SCHEME 3. Synthesis of (-)- and (+)-Debromoflustramine
A (19)
out in 90% overall yield. Reductive cyclization of 18b with
LiAlH4 instead of alane directly afforded debromoflustramine
A (19)12j in a moderate yield.
variety of pyrrolo[2,3-b]indole alkaloids containing a reversed
prenyl group at the 3a position. The optical resolution of (()-
carboxylic acid 17b was employed in preparation of optically
active debromoflustramine A 19. Further applications of this
methodology to the synthesis of other related alkaloids are now
underway.
Finally, in order to obtain optically active 19, we performed
optical resolution of (()-carboxylic acid 17b (Scheme 3). Thus,
successive treatment of 17b with pentafluorophenol and EDC
and with the lithium salt of (R)-4-phenyloxazolidin-2-one
furnished N-acyloxazolidin-2-ones 20 (40%) and 21 (46%).16
Hydrolysis of 20 and 21 with 30% aq H2O2 and LiOH afforded
(-)-17b and (+)-17b, each in 72% yield, respectively. Con-
densation of (-)-17b with methylamine using EDC and LiAlH4
reduction of (-)-18b to (-)-19 were accomplished in the same
way as for the racemic version. (+)-19 also was obtained from
(+)-17b. The stereochemistry of (-)-19 was elucidated by
comparing with the specific rotation of the known pyrrolo[2,3-
b]indoline compounds, e.g., (-)-flustramines1–8 and (-)-phy-
sostigmine.17
In conclusion, we have accomplished the concise total
synthesis of four marine indole alkaloids including (()-
flustramines A (1) and C (5), (()-flustramide A (6), and (()-
debromoflustramineA19viadominoolefination-isomerization-
Claisen rearrangement (OIC) and reductive cyclization (RC) as
key steps. This approach provides a potentially wide route to a
Experimental Section
1-Acetyl-6-bromoindolin-3-one (9)14 and 3-(2-methylbut-3-en-
2-yl)-3-cyanomethylindolin-2-one (13b)13b were prepared according
to the reported procedures.
1-Acetyl-6-bromo-2-(3-methylbut-2-en-1-yloxy)indolin-3-one (10).
To a solution of 9 (1.10 g, 4.33 mmol) in dry dichloromethane (20
mL) was added a dichloromethane solution of bromine (1.0 M,
7.36 mL, 7.36 mmol) at 0 °C. After 1.5 h at the same temperature,
the reaction mixture was diluted with dichloromethane, washed with
satd NaHCO3 and with brine, dried over MgSO4, and concentrated
under reduced pressure. The obtained residue (1.39 g) as 2-bro-
moindolin-3-one was used without further purification in the next
reaction. A suspension of the residue, 3-methylbut-2-enol (850 µL,
d ) 0.85, 8.34 mmol), and MS 4A (0.8 g) in dry acetonitrile (10
mL) was stirred at room temperature under nitrogen atmosphere.
After 3 days, the reaction mixture was diluted with Et2O and filtered
through Celite. The filtrate was washed with 5% NH4OH and brine,
dried over MgSO4, and concentrated under reduced pressure. The
obtained residue was chromatographed by silica gel column with
AcOEt-hexane (1:2) as an eluent to give 10 (1.30 g, 89%) as a
(16) The stereochemistries of 20 and 21 were tentatively assigned by their
transformation to (-)-19 and (+)-19, respectively.
(17) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992, 114,
5566–5572.
1
viscous oil: IR (CHCl3) 1732, 1694, 1599, 1426 cm-1; H NMR
J. Org. Chem. Vol. 73, No. 15, 2008 5961

Kawasaki et al.
(CDCl3, 300 MHz) δ 1.59 (3H, s), 1.69 (3H, s), 2.35 (3H, s), 4.08
(1H, dd, J ) 11.0, 7.4 Hz), 4.18 (1H, dd, J ) 11.0, 7.4 Hz), 5.18
(1H, s), 5.29 (1H, tt, J ) 7.4, 1.4 Hz), 7.33 (1H, dd, J ) 8.2, 1.8
Hz), 7.54 (1H, d, J ) 8.2 Hz), 8.72 (1H, d, J ) 1.8 Hz); MS m/z
339 (M + 2, 1), 337 (M+, 1), 271 (13), 269 (14), 255 (50), 253
(51), 228 (94), 226 (100), 213 (15), 211 (16), 69 (48), 43 (47);
HRMS (EI) m/z calcd for C15H16NO3Br 337.0314, found 337.0315.
2-[6-Bromo-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl]aceto-
nitrile (13a). A solution of diethyl cyanomethylphosphonate (11)
(1.55 mL, d ) 1.13, 9.7 mmol) in dry DMF (8 mL) was added to
a suspension of potassium tert-butoxide (1.03 g, 8.9 mmol) in dry
DMF (12 mL) at 0 °C. After being stirred at the same temperature
for 1 h, the mixture was cooled to -78 °C. A solution of 10 (0.99
g, 2.97 mmol) in dry DMF (10 mL) was gradually added to the
mixture at -78 °C. After TLC showed that 10 was consumed (ca.
0.5 h), the reaction mixture was warmed slowly to room temper-
ature, stirred at the same temperature for 0.5 h, quenched by10%
aq HCl at 0 °C, and extracted with Et2O. The extract was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The obtained residue was chromatographed by silica gel
column with AcOEt-hexane (1:1.5) as an eluent to give 13a (0.84
g, 90%) as colorless crystals: mp 156-157 °C (AcOEt-hexane);
33), 251 (99), 249 (100), 210 (4), 208 (5), 170 (42), 138 (11), 129
(13), 69 (5); HRMS (EI) m/z calcd for C16H19N2Br: 318.0732, found
318.0730.
1
15: IR (CHCl3) 1669, 1601, 1366 cm-1; H NMR (CDCl3, 270
MHz) δ 0.93 (3 H, s), 0.97 (3 H, s), 2.03 (1 H, dt, J ) 12.7, 9.0
Hz), 2.41 (1 H, dd, J ) 12.7, 5.4 Hz), 3.12 (3 H, s), 3.80 (1 H, dd,
J ) 14.0, 9.0 Hz), 3.99 (1 H, ddd, J ) 14.0, 9.0, 5.4 Hz), 4.96 (1
H, d, J ) 17.5 Hz), 5.00 (1 H, d, J ) 10.9 Hz), 5.93 (1 H, dd, J
) 17.5, 10.9 Hz), 6.79 (1 H, d, J ) 1.7 Hz), 6.93 (1 H, dd, J ) 7.9
Hz), 6.97 (1 H, dd, J ) 7.9, 1.7 Hz); MS m/z 320 (M + 2, 15),
318 (M+, 13), 251 (98), 249 (100), 224 (4), 222 (5), 170 (19), 143
(7), 129 (5), 69 (4); HRMS (EI) m/z calcd for C16H19N2Br 318.0732,
found 318.0736.
2-[6-Bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]acetonitrile (16a). A solution of 13a (400 mg, 1.25
mmol) in dry DMF (8 mL) was added to a suspension of NaH
(60% in mineral oil, 60 mg, 1.50 mmol) in DMF (4 mL) at 0 °C
under nitrogen atmosphere. After the mixture was stirred at the
same temperature for 0.5 h, 4-bromo-2-methyl-2-butene (173 µL,
d ) 1.29, 1.50 mmol) was added under the same conditions. After
0.5 h, the reaction mixture was quenched with water and extracted
with Et2O. The extract was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography with AcOEt-hexane (1:3)
as an eluent to give 16a (463 mg, 95%) as a viscous oil: IR (CHCl3)
2255, 1713, 1603, 1487 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.94
(3H, s), 1.05 (3H, s), 1.66 (3H, s), 1.76 (3H, s), 2.75 (1H, d, J )
16.3 Hz), 2.90 (1H, d, J ) 16.3 Hz), 4.12 (1H, dd, J ) 15.4, 6.8
Hz), 4.36 (1H, dd, J ) 15.4, 6.4 Hz), 4.99 (1H, dd, J ) 17.4, 0.9
Hz), 5.04 (1H, m), 5.12 (1H, dd, J ) 10.6, 0.9 Hz), 5.92 (1H, dd,
J ) 17.4, 10.6 Hz), 6.91 (1H, d, J ) 1.7 Hz), 7.07 (1H, d, J ) 8.0
Hz), 7.14(1H, dd, J ) 8.0, 1.7 Hz); 13C NMR (100 MHz, CDCl3)
δ 18.3, 21.5, 21.97, 21.99, 25.7, 38.4, 41.8, 54.5, 112.3, 115.3,
116.3, 117.3, 122.8, 124.8, 126.4, 126.6, 137.4, 141.5, 144.9, 175.3;
MS m/z 388 (M + 2, 9), 386 (M+, 10), 320 (76), 318 (76), 264
(61), 262 (62), 251 (8), 249 (8), 225 (5), 223 (5), 69 (100), 41
(34); HRMS (EI) m/z calcd for C20H23BrN2O 386.0994, found
386.0993.
2-[6-Bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]acetic Acid (17a). A solution of 16a (210 mg, 0.54
mmol) and 35% aq NaOH (1.6 mL) in MeOH (10 mL) was heated
under reflux for 45 h. After evaporation in vacuo, the residue was
acidified with 10% HCl and extracted with AcOEt. The extract was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure to afford 17a (205 mg, 93%) as a solid: mp
123-126 °C; IR (CHCl3) 3200, 1712, 1601, 1487 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.92 (3H, s), 1.05 (3H, s), 1.71 (3H, s), 1.80
(3H, s), 2.79 (1H, d, J ) 16.4 Hz), 3.11 (1H, d, J ) 16.4 Hz), 4.14
(1H, dd, J ) 15.6, 6.4 Hz), 4.35 (1H, dd, J ) 15.6, 6.4 Hz), 4.98
(1H, dd, J ) 17.4, 0.9 Hz), 5.04 (1H, t, J ) 6.4 Hz), 5.10 (1H, dd,
J ) 10.8, 0.9 Hz), 5.91 (1H, dd, J ) 17.4, 10.8 Hz), 6.86 (1H, d,
J ) 1.7 Hz), 6.94 (1H, d, J ) 8.1 Hz), 7.09 (1H, dd, J ) 8.1, 1.7
Hz); 13C NMR (CDCl3, 100 MHz) δ 18.3, 21.7, 21.8, 25.7, 36.6,
38.2, 41.8, 54.0, 111.5, 114.4, 117.7, 121.6, 123.8, 125.6, 128.2,
136.4, 142.2, 145.6, 175.3, 177.3; MS m/z 407 (M + 2, 13), 405
(M+, 14), 339 (98), 337 (100), 293 (14), 291 (13), 283 (62), 281
(64), 238 (27), 236 (28), 69 (90), 41 (54); HRMS (EI) m/z calcd
for C20H24BrNO3 405.0940, found 405.0932.
1
IR (CHCl3) 3430, 2255, 1612, 1481 cm-1; H NMR (CDCl3, 300
MHz) δ 1.07 (3H, s), 1.16 (3H, s), 2.84 (1H, d, J ) 16.5 Hz), 3.00
(1H, d, J ) 16.5 Hz), 5.10 (1H, d, J ) 17.4, 0.9 Hz), 5.23 (1H, dd,
J ) 10.8, 0.9 Hz), 6.02 (1H, dd, J ) 17.4, 10.8 Hz), 7.10 (1H, d,
J ) 1.7 Hz), 7.14 (1H, d, J ) 8.2 Hz), 7.22 (1H, dd, J ) 8.2, 1.7
Hz), 8.21 (1H, brs); MS m/z 320 (M + 2, 2), 318 (M+, 3), 252
(64), 250 (67), 225 (18), 223 (19), 69 (100), 41 (23); HRMS (EI)
m/z calcd for C15H15N2OBr 318.0368, found 318.0364. Anal. Calcd
for C15H15N2OBr: C, 56.44; H, 4.74; N, 8.78. Found: C, 56.38; H,
4.72; N, 8.72.
6-Bromo-1,2,3,3a-tetrahydro-3a-(2-methylbut-3-en-2-yl)pyrro-
lo[2,3-b]indole (14). To a solution of 13a (29 mg, 0.09 mmol) in
toluene (2 mL) was added Red-Al (65% toluene solution, 136 µL,
0.45 mmol) at 0 °C. After being stirred at room temperature for
14 h, the reaction mixture was treated with 5% aq NaOH (3 mL)
and extracted with diethyl ether. The extract was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography with
CHCl3-MeOH (30:1) as an eluent to give 14 (25 mg, 89%) as
pale yellow crystals: mp 169-171 °C (C6H6); IR (CHCl3) 1719,
1680, 1635, 1605, 1586 cm-1; 1H NMR (CDCl3, 270 MHz) δ 0.95
(3 H, s), 1.00 (3 H, s), 2.06 (1 H, dt, J ) 12.9, 9.2 Hz), 2.40 (1 H,
dd, J ) 12.9, 5.2 Hz), 3.31 (1 H, brs), 3.77 (1 H, dd, J ) 12.2, 9.2
Hz), 3.87 (1 H, ddd, J ) 12.2, 9.2, 5.6 Hz), 5.01 (1 H, d, J ) 17.1
Hz), 5.04 (1 H, d, J ) 10.9 Hz), 6.01 (1 H, dd, J ) 17.1, 10.9 Hz),
6.93 (1 H, d, J ) 7.9 Hz), 6.97 (1 H, dd, J ) 7.9, 1.3 Hz), 7.04 (1
H, d, J ) 1.3 Hz); MS m/z 306 (M + 2, 31), 304 (M+, 33), 237
(99), 235 (100), 210 (8), 208 (9), 156 (34), 129 (18), 69 (7); HRMS
(EI) m/z calcd for C15H17N2Br 304.0575, found 304.0574.
Flustramine C (5). A suspension of 14 (10 mg, 0.033 mmol),
methyl iodide (1.0 M acetone solution, 266 µL, 0.266 mmol), and
Na2CO3 in acetone (1 mL) was heated at 55 °C for 7 h. The reaction
mixture was filtered through Celite and concentrated under reduced
pressure. The residue was purified by preparative TLC on silica
gel with CHCl3-MeOH (50:1) as an eluent to give flustramine C
(5, 4.0 mg, 38%) and 6-bromo-2,3,3a,8-tetrahydro-8-methyl-3a-
(2-methylbut-3-en-2-yl)pyrrolo[2,3-b]indole (15, 3.0 mg, 29%) as
viscous oils.
2-[6-Bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]-N-methylacetamide (18a). A solution of 17a (186
mg, 0.46 mmol), pentafluorophenol (253 mg, 1.37 mmol), triethyl-
amine (127 mL, d ) 0.73, 0.92 mmol), and N-ethyl-N′-(3-
dimethylaminopropyl)carbodiimide (EDC) HCl salt (132 mg, 0.69
mmol) in THF (6.5 mL) was kept at room temperature for 1.5 h.
Gaseous methylamine was passed through the reaction mixture at
room temperature. After acidification with 10% HCl, the resulted
mixture was extracted with diethyl ether. The extract was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
1
5: IR (CHCl3) 1636, 1586, 1565, 1426, 1416 cm-1; H NMR
(CDCl3, 270 MHz) δ 0.89 (3 H, s), 0.99 (3 H, s), 2.06 (1 H, ddd,
J ) 8.9, 9.9, 12.9 Hz), 2.35 (1 H, dd, J ) 6.6, 12.9 Hz), 3.02 (3 H,
s,), 3.39 (1 H, t, J ) 9.9 Hz), 3.94 (1 H, ddd, J ) 6.6, 8.9, 9.9 Hz),
5.04 (1 H, d, J ) 17.2 Hz), 5.06 (1 H, d, J ) 10.9 Hz), 6.01 (1 H,
dd, J ) 17.2, 10.9 Hz), 6.910 (1 H, d, J ) 7.9 Hz), 6.912 (1 H, d,
J ) 7.9 Hz), 7.21 (1 H, s); 13C NMR (CDCl3, 67.8 MHz) δ 21.6,
22.8, 27.9, 33.2, 42.9, 59.7, 65.7, 113.6, 119.1, 121.9, 122.0, 124.3,
137.6, 143.4, 163.5, 188.1; MS m/z 320 (M + 2, 32), 318 (M+,
5962 J. Org. Chem. Vol. 73, No. 15, 2008

Total Synthesis of (()-Flustramines A and C
tography with AcOEt as an eluent to give 18a (179 mg, 93%) as
crystals: mp 78-83 °C (AcOEt-hexane); IR (CHCl3) 3463, 1698,
1603, 1525, 1487 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.95 (3H,
s), 1.08 (3H, s), 1.73 (3H, s), 1.83 (3H, s), 2.50 (3H, d, J ) 4.9
Hz), 2.65 (1H, d, J ) 14.0 Hz), 3.00 (1H, d, J ) 14.0 Hz), 4.21
(1H, dd, J ) 15.8, 6.6 Hz), 4.40 (1H, dd, J ) 15.8, 6.6 Hz), 4.98
(1H, dd, J ) 17.4, 1.1 Hz), 5.07-5.09 (1H, m), 5.10 (1H, dd, J )
10.8, 1.1 Hz,), 5.44 (1H, br), 5.96 (1H, dd, J ) 17.4, 10.8 Hz),
6.89 (1H, d, J ) 1.7 Hz), 7.04 (1H, d, J ) 8.1 Hz), 7.11 (1H, dd,
J ) 8.1, 1.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 18.3, 21.7, 22.1,
25.7, 26.1, 38.2, 38.6, 41.9, 55.4, 111.5, 114.0, 117.9, 121.5, 123.8,
126.1, 128.4, 136.4, 142.5, 145.2, 169.4, 178.0; MS m/z 420 (M +
2, 10), 418 (M+, 10), 352 (99), 350 (100), 294 (29), 292 (23), 238
(52), 236 (53), 225 (21), 223 (20), 69 (39), 41 (16); HRMS (EI)
m/z calcd for C21H27BrN2O2 418.1256, found 418.1257. Anal. Calcd
for C21H27BrN2O2: C, 60.15; H, 6.49; N, 6.68. Found: C, 60.34;
H, 6.72; N, 6.41.
Flustramide A (6). To a solution of 18a (50 mg, 0.12 mmol) in
THF (5 mL) was added AlH3 ·EtMe2N (0.5 M toluene solution,
1.2 mL, 0.60 mmol) at -15 °C. After 5 min, the reaction mixture
was treated with THF-water (1:1, 10 mL) at the same temperature
and stirred at room temperature for 15 min. The mixture was filtered
through Celite. The filtrate was concentrated under reduced pressure
to give a residue, which was diluted with AcOEt. The organic
solution was washed with satd aq Na2CO3 and brine, dried over
MgSO4, and concentrated under reduced pressure. The obtained
residue was purified by column chromatography on silica gel with
AcOEt-hexane (1:1) as an eluent to give flustramide A (6, 44.3
mg, 92%) as a viscous oil: IR (CHCl3) 1682, 1593, 1491 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 0.94 (3H, s), 1.03 (3H, s), 1.75 (3H,
s), 1.77 (3H, s), 2.54 (1H, d, J ) 17.4 Hz), 2.84 (1H, d, J ) 17.4
Hz), 2.85 (1H, s), 3.93 (2H, d, J ) 6.6 Hz), 4.83 (1H, s), 5.05 (1H,
dd, J ) 17.4, 1.1 Hz), 5.17 (1H, dd, J ) 10.8, 1.1 Hz) 5.26 (1H,
t, J ) 6.6, Hz), 5.78 (1H, dd, J ) 17.4, 10.8 Hz), 6.56 (1H, d, J )
1.7 Hz), 6.81 (1H, dd, J ) 7.9, 1.7 Hz), 6.92 (1H, d, J ) 7.9 Hz);
13C NMR (CDCl3, 100 MHz) δ 18.3, 22.0, 22.7, 25.8, 28.1, 39.5,
41.3, 46.4, 55.5, 85.9, 110.9, 114.5, 120.3, 120.6, 122.4, 126.1,
131.6, 135.6, 143.1, 150.9, 172.4; MS m/z 404 (M + 2, 37), 402
(M+, 37), 335 (44), 333 (45), 267 (94), 265 (97), 210 (20), 208
(20), 69 (100); HRMS (EI) m/z calcd for C21H27BrN2O 402.1307,
found 402.1301.
dry DMF (10 mL) was added to a suspension of NaH (60% in
mineral oil, 0.20 mg, 4.99 mmol) in DMF (8 mL) at 0 °C under
nitrogen atmosphere. After the mixture was stirred at the same
temperature for 0.5 h, 4-bromo-2-methyl-2-butene (575 µL, d )
1.29, 4.99 mmol) was added under the same conditions. After 1.5 h,
the reaction mixture was quenched with 10% HCl and extracted
with AcOEt. The extract was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography with AcOEt-hexane (1:3)
as an eluent to give 16b (1.25 g, 98%) as colorless powder: mp
109 °C (AcOEt-hexane); IR (CHCl3) 2251, 1707, 1612, 1489
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.04 (s, 3H), 1.13 (s, 3H),
1.72 (s, 3H), 1.83 (s, 3H), 2.84 (d, 1H, J ) 16.4 Hz), 2.97 (d, 1H,
J ) 16.4 Hz), 4,23 (dd, 1H, J ) 15.6, 6.6 Hz), 4.46 (dd, 1H, J )
15.6, 6.6 Hz), 5.07 (dd, 1H, J ) 17.4, 1.1 Hz), 5.12 (m, 1H), 5.18
(dd, 1H, J ) 10.8, 1.1 Hz), 6.07 (dd, 1H, J ) 17.4, 10.8 Hz), 6.84
(d, 1H, J ) 7.5 Hz), 7.07 (t, 1H, J ) 7.5 Hz), 7.25-7.34 (m, 2H);
MS m/z 308 (M+, 8), 240 (60), 184 (100), 171 (11), 145 (10), 128
(7), 69 (36), 41 (15); HRMS (EI) m/z calcd for C20H24N2O
308.1889, found 308.1893. Anal. Calcd for C20H24N2O: C, 77.89;
H, 7.84; N, 9.08. Found: C, 78.00; H, 8.07; N, 8.83.
2-[1-(3-Methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindo-
lin-3-yl]acetic Acid (17b). A solution of 16b (6.51 g, 21.1 mmol)
and 35% aq NaOH (48.2 mL) in MeOH (75 mL) was heated under
reflux for 15 h. After evaporation in vacuo, the residue was acidified
with 10% HCl and extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure to afford 17b (6.60 g, 96%) as a colorless powder: mp
83-86 °C (AcOEt); IR (CHCl3) 3100, 1713, 1610, 1489, 1468
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.95 (s, 3H), 1.06 (s, 3H),
1.70 (s, 3H), 1.80 (s, 3H), 2.81 (d, 1H, J ) 16.2 Hz), 3.11 (d, 1H,
J ) 16.2 Hz), 4.18 (dd, 1H, J ) 15.6, 6.4 Hz), 4.39 (dd, 1H, J )
15.6, 6.4 Hz), 4.98 (dd, 1H, J ) 17.4, 1.3 Hz), 5.08 (m, 1H), 5.08
(dd, 1H, J ) 10.8, 1.3 Hz), 5.97 (dd, 1H, J ) 17.4, 10.8 Hz), 6.72
(d, 1H, J ) 7.5 Hz), 6.92 (t, 1H, J ) 7.5 Hz), 7.07 (d, 1H, J ) 7.5
Hz), 7.20 (1H, t, J ) 7.5 Hz); 13C NMR (CDCl3, 100 MHz) δ
18.3, 21.8, 21.9, 25.7, 36.8, 38.2, 41.9, 54.3, 108.2, 114.0, 118.4,
121.0, 124.6, 128.0, 129.1, 135.8, 142.7, 144.3, 174.4, 177.5; MS
m/z 327 (M+, 16), 259 (100), 213 (18), 203 (91), 158 (43), 145
(32), 128 (8), 117 (9), 69 (29), 41 (16); HRMS (EI) m/z calcd for
C20H25NO3 327.1834, found 327.1834.
Flustramine A (1). To a solution of 6 (35 mg, 0.087 mmol) in
THF (7 mL) was added AlH3 ·EtMe2N (0.5 M toluene solution,
0.26 mL, 0.13 mmol) at room temperature. The reaction mixture
was stirred at the same temperature for 5 min, treated with
THF-H2O (1:1, 10 mL), and filtered through Celite. The filtrate
was evaporated to give a residue, which was basified with satd aq
NaHCO3 and extracted with AcOEt. The organic layer was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography with AcOEt-hexane (3:2) as an eluent to give flustramine
A (1, 30.3 mg, 90%) as a viscous oil: IR (CHCl3) 2968, 2930,
2857, 1591, 1489 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.95 (3H,
s), 1.00 (3H, s), 1.72 (3H, s), 1.73 (1H, ddd, J 11.8, 5.3 and 2.6
Hz), 1.75 (3H, s), 2.23 (1H, ddd, J 11.8, 9.7 and 6.8 Hz), 2.42
(3H, s), 2.43 (1H, ddd, J 9.9, 9.7 and 5.3 Hz), 2.65 (1H, ddd, J
9.9, 6.8 and 2.6 Hz), 3.82 (1H, dd, J 16.7 and 6.3 Hz), 3.84 (1H,
dd, J 16.7 and 5.8 Hz), 4.34 (1H, s), 4.98 (1H, d, J 17.4 Hz), 5.06
(1H, d, J 10.8 Hz), 5.22 (1H, dd, 6.3 and 5.8 Hz), 5.94 (1H, dd, J
17.4 and 10.8 Hz), 6.47 (1H, d, J 1.5 Hz), 6.68 (1H, dd, J 7.8 and
1.5 Hz), 6.90 (1H, d, J 7.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
18.1, 22.5, 23.5, 25.6, 34.5, 37.8, 41.3, 45.9, 53.1, 63.4, 89.3, 109.3,
113.0, 119.1, 120.9, 121.7, 125.8, 132.5, 134.6, 144.9, 153.6; MS
m/z 390 (M + 2, 22), 388 (M+, 22), 321 (96), 319 (98), 290 (12),
288 (11), 278 (12), 276 (13), 253 (94), 251 (100), 210 (19), 172
(16), 171 (14), 69 (35); HRMS (EI) m/z calcd for C21H29BrN2
388.1514, found 388.1518.
2-[1-(3-Methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindo-
lin-3-yl]-N-methylacetamide (18b). A solution of 17b (290 mg, 0.89
mmol), pentafluorophenol (325 mg, 1.77 mmol), triethylamine (238
mL, d ) 0.73, 1.77 mmol), and N-ethyl-N′-(3-dimethylaminopro-
pyl)carbodiimide (EDC) HCl salt (253 mg, 1.33 mmol) in THF
(10 mL) was kept at room temperature for 2 h. Gaseous methyl-
amine was passed through the reaction mixture at room temperature.
After acidification with 20% HCl, the resulted mixture was extracted
with diethyl ether. The extract was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with AcOEt as an
eluent to give 18b (295 mg, 98%) as colorless crystals: mp 150-154
°C (AcOEt-hexane); IR (CHCl3) 3462, 1688, 1611, 1528, 1489,
1
1468 cm-1; H NMR (CDCl3, 300 MHz) δ 0.99 (s, 3H), 1.09 (s,
3H), 1.71 (s, 3H), 1.83 (s, 3H), 2.47 (d, 3H, J ) 4.7 Hz), 2.68 (d,
1H, J ) 13.9 Hz), 3.00 (d, 1H, J ) 13.9 Hz), 4.27 (dd, 1H, J )
15.6, 6.9 Hz), 4.39 (dd, 1H, J ) 15.6, 6.1 Hz), 4.99 (dd, 1H, J )
17.4, 1.3 Hz), 5.09 (m, 1H), 5.09 (dd, 1H, J ) 10.8, 1.3 Hz), 5.37
(1H, br), 6.02 (dd, 1H, J ) 17.4, 10.8 Hz), 6.76 (d, 1H, J ) 7.5
Hz), 7.00 (t, 1H, J ) 7.5 Hz), 7.19-7.26 (m, 2H); MS m/z 340
(M+, 17), 272 (100), 213 (26), 158 (67), 145 (23), 69 (15), 41 (9);
HRMS (EI) m/z calcd for C21H28N2O2 340.2151, found 340.2152.
Anal. Calcd for C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found:
C, 74.06; H, 8.43; N, 8.12. (-)-(3R)-18b: [R]23 ) -41.3 (c )
D
0.77, CHCl3). (+)-(3S)-18b: [R]23 ) +41.7 (c ) 0.24, CHCl3).
D
1-Methyl-3a-(2-methylbut-3-en-2-yl)-8-(3-methylbut-2-enyl)-
1,2,3,3a-tetrahydropyrrolo[2,3-b]indole (19, Debromoflustramine
A). To a solution of 18b (100 mg, 0.29 mmol) in THF (10 mL)
2-[1-(3-Methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindo-
lin-3-yl]acetonitrile (16b). A solution of 13b (1.00 g, 4.2 mmol) in
J. Org. Chem. Vol. 73, No. 15, 2008 5963

Kawasaki et al.
was added LiAlH4 (1 M THF solution, 2.93 mL, 2.93 mmol) at
room temperature. After being refluxed for 4 h, the reaction mixture
was treated with THF-water (1:1, 10 mL). The resulting mixture
was filtered through Celite. The filtrate was concentrated under
reduced pressure to give a residue, which was diluted with AcOEt.
The organic solution was washed with satd aq NaHCO3 and brine,
dried over MgSO4, and concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica
gel with AcOEt-hexane (1:1) as an eluent to give 19 (53 mg, 58%)
(CDCl3, 100 MHz) δ 18.2, 21.7, 22.3, 25.6, 37.6, 38.2, 42.1, 54.7,
57.2, 69.9, 108.1, 114.1, 118.5, 120.8, 124.1, 125.4 (2C), 127.8,
128.3, 128.9 (2C), 129.9, 135.6, 138.2, 142.6, 144.5, 153.7, 169.1,
177.6; MS m/z 472 (M+, 7), 404 (100), 241 (30), 213 (15), 185
(25), 172 (43), 158 (15), 145 (17), 69 (16); HRMS (EI) m/z calcd
for C29H32N2O4 472.2362, found 472.2366.
21: viscous oil; [R]16D ) -90.4 (c ) 3.74, CHCl3); IR (CHCl3)
1781, 1705, 1611, 1535, 1518 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.04 (3H, s), 1.11 (3H, s), 1.62 (3H, d, J ) 1.1 Hz), 1.74 (3H,
d, J ) 1.1 Hz), 3.30 (1H, d, J ) 16.3 Hz), 3.99 (1H, dd, J ) 8.8,
3.7 Hz), 4.06 (1H, dd, J ) 15.6, 6.1 Hz), 4.29 (1H, d, J ) 16.3
Hz), 4.36 (1H, dd, J ) 15.6, 6.1 Hz), 4.48 (1H, t, J ) 8.8 Hz),
4.96-5.04 (1H, m), 5.02 (1H, dd, J ) 17.4, 1.1 Hz), 5.09 (1H, dd,
J ) 10.8, 1.1 Hz), 5.15 (1H, dd, J ) 8.8, 3.7 Hz), 6.07 (1H, dd, J
) 17.4, 10.8 Hz), 6.58 (1H, d, J ) 7.5 Hz), 6.63-6.69 (2H, m),
6.89 (1H, td, J ) 7.5, 1.1 Hz), 7.05-7.20 (4H, m), 7.23 (1H, td, J
) 7.5, 0.9 Hz); 13C NMR (CDCl3, 100 MHz) δ 18.2, 21.7, 22.4,
25.6, 37.0, 38.1, 42.0, 54.9, 57.3, 69.8, 108.1, 114.0, 118.7, 120.8,
124.4, 124.8 (2C), 127.7, 127.8, 128.6 (2C), 129.3, 135.2, 138.1,
142.7, 144.3, 153.6, 169.1, 177.7; MS m/z 472 (M+, 7), 404 (100),
241 (30), 213 (15), 185 (25), 172 (43), 158 (15), 145 (17), 69 (16);
HRMS (EI) m/z calcd for C29H32N2O4 472.2362, found 472.2361.
(-)-(3R)- and (+)-(3S)-2-[1-(3-Methylbut-2-enyl)-3-(2-methyl-
but-3-en-2-yl)-2-oxoindolin-3-yl]acetic Acid (17b). A solution of 20
(500 mg, 1.05 mmol), 30% H2O2 (424 mL, 4.23 mmol), and
LiOH·H2O (88 mg, 2.10 mmol) in THF-H2O (15 mL, 2:1) was
stirred at 0 °C for 12 h. After treatment with Na2SO3, the reaction
mixture was washed with diethyl ether, acidified with 20% HCl
(pH 1-2), and extracted with diethyl ether. The extract was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography with AcOEt-hexane (1:1) as eluent to give (-)-(R)-17b
(251 mg, 72%). In the same way, (+)-(S)-17b (250 mg, 72%) was
obtained from 21 (500 mg, 1.05 mmol). (-)-(3R)-17b: [R]23D -79.2
(c ) 0.98, CHCl3); (+)-(3S)-17b: [R]23D +76.0 (c ) 1.82, CHCl3).
1
as a viscous oil: IR (CHCl3) 2934, 1599, 1489, 1462 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.95 (s, 3H), 1.03 (s, 3H), 1.71 (s,
3H), 1.73 (s, 3H), 1.78 (ddd, 1H, J ) 11.9, 5.5, 2.7 Hz), 2.24 (ddd,
1H, J ) 11.9, 9.7, 6.6 Hz), 2.42 (ddd, 1H, J ) 9.7, 9.0, 5.5 Hz),
2.43 (s, 3H), 2.64 (ddd, 1H, J ) 9.0, 6.6, 2.7 Hz), 3.84 (dd, 1H, J
) 16.0, 7.4 Hz), 3.88 (dd, 1H, J ) 16.0, 6.0 Hz), 4.32 (s, 1H),
4.99 (dd, 1H, J ) 17.3, 1.4 Hz), 5.06 (d, 1H, J ) 10.8, 1.4 Hz),
5.26 (m, 1H), 5.98 (dd, 1H, J ) 17.3, 10.8 Hz), 6.39 (d, 1H, J )
7.9 Hz), 6.59 (td, 1H, J ) 7.4, 1.3 Hz), 7.04 (td, 1H, J ) 7.5, 1.3
Hz), 7.07 (dd, 1H, J ) 7.4, 1.3 Hz); 13C NMR (CDCl3, 100 MHz)
δ 18.1, 22.8, 23.7, 25.7, 34.8, 37.7, 41.5, 46.5, 53.3, 63.7, 89.0,
106.4, 112.5, 116.4, 121.7, 124.6, 127.5, 133.2, 133.6, 145.2, 152.2;
MS m/z 310 (M+, 28), 241 (100), 210 (12), 198 (18), 173 (88),
130 (26), 69 (12); HRMS (EI) m/z calcd for C21H30N2 310.2409,
found 310.2415. (-)-(3aR)-19: [R]23D ) -132.6 (c ) 0.89, CHCl3).
(+)-(3aS)-19: [R]23 ) +137.4 (c ) 1.55, CHCl3).
D
(3′′R,4R)- and (3′′S,4R)-3-{2′-[1′′-(3-Methylbut-2-enyl)-3′′-(2-
methylbut-3-en-2-yl)-2′′-oxoindolin-3′′-yl]acetyl}-4-phenyloxazoli-
din-2-one (20 and 21). A solution of 17b (2.00 g, 6.10 mmol),
pentafluorophenol (2.24 g, 12.2 mmol), triethylamine (1.69 mL, d
) 0.73, 12.2 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)car-
bodiimide (EDC) HCl salt (1.74 g, 9.15 mmol) in THF (60 mL)
was kept at room temperature for 1.5 h. After concentration of the
reaction mixture under reduced pressure, an AcOEt solution of the
residue was washed with satd Na2CO3 and with brine, dried over
MgSO4, and concentrated under reduced pressure. To a solution
of the residue in THF (70 mL) was added a solution of lithium salt
generated from (R)-4-phenyloxazolidin-2-one (1.99 g, 12.2 mmol)
and n-buthyllithium (1.58 mmol/mL, 8.5 mL, 13.4 mmol) in THF
(70 mL) at 0 °C. After 10 min, the resulting mixture was
concentrated and extracted with diethyl ether. After neutralization
with 1 N HCl, the extract was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with AcOEt-hexane
(1:3) as an eluent to give 20 (1.15 g, 40%) and 21 (1.33 g, 46%).
Acknowledgment. This research was supported by Special
Coordination Funds for promoting Science and Technology of
the Science and Technology Agency of the Japanese Govern-
ment. We wish to thank Professor C. Christophersen (University
of Copenhagen, Denmark) for providing spectral data of natural
flustramine C. We are also grateful to N. Eguchi, T. Koseki,
and S. Kubota of the Analytical Center at our university for
microanalysis and mass spectra measurements and NOE
experiments.
20: mp 143-147 °C (ACOEt-hexane); [R]16 ) -155.8 (c )
D
1.23, CHCl3); IR (CHCl3) 1781, 1709, 1611, 1536, 1518 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 1.02 (3H, s), 1.11 (3H, s), 1.65 (3H, d,
J ) 1.5 Hz), 1.74 (3H, d, J ) 0.9 Hz), 3.44 (1H, d, J ) 17.1 Hz),
4.11 (1H, dd, J ) 8.8, 3.7 Hz), 4.12 (1H, dd, J ) 15.6, 6.6 Hz),
4.14 (1H, d, J ) 17.1 Hz), 4.36 (1H, dd, J ) 15.6, 6.6 Hz), 4.45
(1H, t, J ) 8.8 Hz), 5.03 (1H, dd, J ) 8.8, 3.7 Hz), 5.00-5.07
(1H, m), 5.03 (1H, dd, J ) 17.4, 1.1 Hz), 5.11 (1H, dd, J ) 10.8,
1.1 Hz), 6.01 (1H, dd, J ) 17.4, 10.8 Hz), 6.74 (1H, d, J ) 7.9
Hz), 6.95 (1H, td, J ) 7.9, 1.1 Hz), 7.08-7.30 (7H, m); 13C NMR
1
Supporting Information Available: H NMR spectra of
synthetic flustramines A (1) and C (5), flustramide A (6),
debromoflustramine A (19), and all synthetic intermediates 10,
13-18, 20, and 21. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO800984A
5964 J. Org. Chem. Vol. 73, No. 15, 2008