Convolutamydine A: the first authenticated absolute configuration and enantioselective synthesis

Article abstract of DOI:10.1016/j.tetasy.2006.11.021

The absolute configuration of (+)-convolutamydine A 1 isolated from Amathia convoluta has been unambiguously established as (R) by enantioselective synthesis, based on chiral auxiliary-directed π-face discrimination in an allyl metal addition to (1R,2S,5R)-8-phenylmenthyl ester 7. For an independent and unequivocal proof, the absolute stereochemistry of synthetic precursor 11 en route to 1 was determined by X-ray crystallography.

Full text of DOI:10.1016/j.tetasy.2006.11.021

Tetrahedron: Asymmetry 17 (2006) 3070–3074
Convolutamydine A: the first authenticated absolute
configuration and enantioselective synthesis
Giancarlo Cravotto,a Giovanni B. Giovenzana,b Giovanni Palmisano,c,* Andrea Penoni,c
Tullio Pilati,d Massimo Sistic and Federica Stazic
aDipartimento di Scienza e Tecnologia del Farmaco, Via Giuria 9, 10125 Torino, Italy
bDISCAFF and DFB Center, Via Bovio 6, 28100 Novara, Italy
cDipartimento di Scienze Chimiche e Ambientali, Via Valleggio 11, 22100 Como, Italy
dCNR—Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy
Received 3 November 2006; accepted 14 November 2006
Abstract—The absolute configuration of (+)-convolutamydine A 1 isolated from Amathia convoluta has been unambiguously established
as (R) by enantioselective synthesis, based on chiral auxiliary-directed p-face discrimination in an allyl metal addition to (1R,2S,5R)-8-
phenylmenthyl ester 7. For an independent and unequivocal proof, the absolute stereochemistry of synthetic precursor 11 en route to 1
was determined by X-ray crystallography.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
volutamydine A 1, one of the simplest members of the
oxindole subfamily, exhibited a potent inhibitory activity
on the differentiation of HL-60 human promyelocytic leu-
kaemia cells @ 12.5–25 lg/mL. Its structure was deduced
from spectroscopic data and confirmed by synthesis,
although its absolute configuration remained unknown.
The discovery of this unique structure has spurred the
development of several synthetic routes, recently crowned
by the synthesis of ( )-convolutamydines A and C 1 and
3, respectively, via Rh(II)-promoted cyclization of diazo-
amides,4 Claisen rearrangement of 2-allyloxy indolin-3-
ones5 and aldol condensation of 4,6-dibromoisatin with
acetone.6 Within this context, Tomasini et al. recently re-
ported an interesting dipeptide-catalyzed enantioselective
aldol reaction with isatins.7 While the present manuscript
was in preparation, Kobayashi reported the first enantio-
selective synthesis of convolutamydines B and E (2 and 5,
respectively) via a vinylogous Mukaiyama aldol reaction;
the absolute configuration of natural compound 2 was
assigned as (R) by its chiroptical properties.8 Previously,
Aimi9 had tried to predict the absolute configuration of
convolutamydines A–D 1–4 by comparing their CD spec-
tra in the 225–250 nm range with the corresponding CD
spectra of 3(R)–3-hydroxy-L-tryptophan. Because the
absolute configurations of convolutamydines have been
inferred by empirical CD methods, the need was felt for an
independent, unequivocal verification of these assignments.
The rapidly growing domain of natural products isolated
from marine organisms has caused widespread interest
because of their intriguing structural features and bio-
activities.1 Recently, a number of oxindole alkaloids, for
example, convolutamydines A–E 1–5 along with some dis-
tantly related metabolites (e.g., bryostatins), have been iso-
lated by Pettit from the bryozoan Amathia convoluta
Lamarck, collected off the Northeastern Gulf of Mexico
(Fig. 1).2,3
These compounds share an unprecedented structural
feature, viz. the 4,6-dibromo-3-hydroxyindoline motif that
bears a quaternary stereocentre at C-3. Interestingly, con-
Br
1
2
3
4
5
R = CH2COCH3 (A)
OH
R = CH2CH2Cl
R = CH3
R = CH=CH2
(B)
(C)
(D)
R
Br
N
O
R = CH2CH2OH (E)
H
Figure 1.
*
Corresponding author. Tel.: +39 031 2386234; fax: +39 031 2386449;
e-mail: giovanni.palmisano@uninsubria.it
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.11.021

G. Cravotto et al. / Tetrahedron: Asymmetry 17 (2006) 3070–3074
3071
Herein, we report the first enantioselective synthesis of (+)-
convolutamydine A 1 and the X-ray diffraction analysis of
a strictly related compound, thus providing unambiguous
proof of the previous configurational assignment.
8-phenylmenthyl chloroformate12 (1.1 equiv) in the pres-
ence of DMAP (0.22 equiv) in MeCN at 40 ꢁC for 3 h
could achieve conversion of 8 to 710,13 (through the inter-
mediacy of a mixed carboxylic-carbonic anhydride),14
albeit in modest yields (22%).15
2. Results and discussion
As the esterification approach did not appear viable, we
turned to the regioselective base-catalyzed ring opening
(BAC2 mechanism) of N-BOC protected lactams (e.g., isa-
tins16 and pyroglutamates17) successfully employed by
several authors, and decided to react 618 per se with (ꢀ)-
8-phenylmenthol according to the protocol developed by
Schoenfelder and Mann.19
Our approach to the synthesis of (+)-1 involved enantio-
controlled access to alcohol A, which was to be unmasked
and oxidized (Wacker) (Scheme 1). The homoallylic alco-
hol functionality (viz. the latent 2-oxopropyl moiety in 1)
was to be installed in A by the addition to B of an allyl
anion after ring opening of an N-EWG-substituted 4,6-di-
bromoisatin C in the presence of an enantiopure alcohol as
a chiral auxiliary. For the sake of expediency, we opted for
N-BOC-4,6-dibromoisatin 610 as the starting material;
(ꢀ)-(1R,2S,5R)-8-phenylmenthol was chosen with the in-
tent of favourably influencing the chiral-auxiliary-directed
p-face discrimination in the subsequent addition step (see
Scheme 2).11
In our initial experiments, we added tetrabutylammonium
cyanide or KCN, together with the chiral auxiliary, to a
solution of 6 in dry THF at room temperature (24 h).
Under these conditions, we detected the formation of 7, but
the yield was less than 10%. The use of other bases (e.g.,
K2CO3, K3PO4 and Cs2CO320) as catalysts for the ring
opening reaction did not significantly improve yields. These
results were attributed to the poor nucleophilicity of the
hydroxyl group in the chiral auxiliary. Accordingly, we
resorted to using the preformed alkoxide of (ꢀ)-8-
phenylmenthol as nucleophile. After screening many
combinations of bases [n-BuLi, NaH/15-crown-5, potas-
sium bis(trimethylsilyl)amide (KHMDS), t-BuOK, CsOH,
phosphazene base (BEMP)21] and solvents, we found that
the most successful procedure was the formation of potas-
Our initial efforts on the preparation of isatinic ester 7 from
6 proved less straightforward than expected. The use of
coupling reagents proved critical for achieving esterifica-
tion with (ꢀ)-8-phenylmenthol of isatinic acid 8, obtained
by hydrolysis of 6 with LiOH in THF–MeOH–H2O, 3:1:1
[rt, 1 h, followed by acidification with AcOH]. After an
extensive screening of coupling conditions, we found that
Br
Br
O
Br
HO
O
COOXc*
COOXc*
(R)-1
Br
NH
EWG
Br
NH
Br
N
O
EWG
EWG
A
B
Scheme 1.
Br
Br
HO
Br
O
O
O
O
O
a)
d)
O
O
Br
N
Br
NH
Br
NH
BOC
7
BOC
BOC
6
9
b)
c)
e)
Br
O
Br
COOH
HO
f)
Br
NH
BOC
(R)-1
Br
N
H
O
8
10
Scheme 2. Reagents and conditions: (a) (ꢀ)-8-phenylmenthol, KH, 18-crown-6, THF, rt; (b) LiOH, THF–MeOH–H2O, rt; then AcOH; (c) (ꢀ)-8-
phenylmenthyl chloroformate, MeCN, DMAP, 40 ꢁC; (d) In, allyl bromide, KI, DMF, rt; (e) TFA, CH2Cl2, rt or 6 M HCl, DME, reflux; (f) O2, CuCl2,
PdCl2 (cat.), MeCN–H2O, 40 ꢁC.

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G. Cravotto et al. / Tetrahedron: Asymmetry 17 (2006) 3070–3074
sium (ꢀ)-8-phenylmenthoxide with KH in THF.22 Gratify-
ingly, isatinic ester 7 was obtained in 65% yield by treating
(ꢀ)-8-phenylmenthol with a suspension of oil-free KH
(2.1 equiv) in the presence of 18-crown-6 (5 mol %), and
subsequently adding the resulting product to a 0.2 M solu-
tion of 6 (1.1 equiv) in THF at rt. The desired functionali-
zation of ester 7 was then achieved by a carbonyl allylation
reaction. Several methods currently exist to obtain homo-
allylic alcohols by allylmetal addition reactions to a carbonyl
group.23 We opted for indium-mediated allylation because
the procedure is simple, the reaction conditions are mild,
the product yields were high and the metal to be employed
was not toxic.24 Thus, the reaction in DMF of 7 with (allyl)3-
In2Br3 [generated in situ by In metal (99.99%, 100 mesh,
2 equiv) and allyl bromide(3 equiv)] in the presence of KI
(3.1 equiv) at rt for 45 min, followed by quenching with
aq NH4Cl, afforded alcohol 910 (55% yield) essentially as
a single diastereomer, as indicated by its clean 1H and
13C NMR spectra.10 At this stage, we were unable to assign
the configuration at C(3) from the NMR data, while at-
tempts to obtain suitable crystals for X-ray analysis proved
fruitless. The amino functionality release required for c-lac-
tam formation with concomitant detachment of the chiral
inductor was achieved [TFA (5 equiv), CH2Cl2, rt, 12 h
or 6 M HCl, DME, reflux, 5 h25] to provide 1010 in nearly
quantitative yield and >95% ee (by chiral-HPLC26). In par-
ticular, this procedure allowed a 95% recovery of pure (ꢀ)-
8-phenylmenthol (97% ee), which could be reused offsetting
the expense met in employing it. Enantiopure 10 exhibited
a CD spectrum (MeOH) with a negative Cotton effect (CE)
in the long-wave region (285–245 nm, due to 1La/1Lb
transitions) and a positive CE in the short-wave region
However, as crystallographic evidence was lacking for
the absolute configuration of (+)-convolutamydine, we
decided to fill the gap by preparing crystalline derivatives.
The racemic lactam 1027 proved to be particularly suitable
for resolution by diastereomer formation with a resolving
agent.28 From the chemical and configurational points of
view, this convolutamydine precursor was completely sta-
ble in the conditions that were required for introducing
and cleaving off a chiral resolving agent (Fig. 2).
The resolving agent of choice was (S)–O-methyl mandelic
acid which, by coupling with rac-10 (DCC, DMAP,
MeCN, rt), gave esters 1110 and 1210 in 64% yield. These
were easily separated by standard silica flash chromatogra-
phy (separation factor a of 1.45 0.05). The high-Rf dia-
stereomer 11 was crystalline, and its single-crystal X-ray
study unequivocally established the absolute configuration
at C-3 as (S) (Fig. 3).29 Interestingly, the (S)-O-methyl
mandelate subunit was used as an internal standard for
the X-ray determination of absolute configuration; more-
over 11, containing two heavy atoms (Br), made it possible
to assess the absolute configuration by the Bijvoet method.
Thus, the absolute configuration of 11 was determined
independently by two crystallographic methods.
The CD spectrum of convolutamydine derived from the
high-Rf crystalline diastereomer 11 [by hydrolysis (LiOH,
THF–H2O 2:1, 0 ꢁC, 1 h), followed by Wacker oxidation
(vide supra)] was roughly enantiomeric [positive CE
(285–245 nm), negative CE (245–210 nm)] to that of the
natural product. By the sequence of reactions detailed
above, the low-Rf amorphous diastereomer 12 was con-
verted to a convolutamydine whose CD spectrum matched
that reported by Pettit.
1
(245–210 nm, due to Bb transitions); according to Aimi’s
estimation, this would unequivocally prove the
configuration.
R
As we also wished to evaluate the reactivity and diastereo-
facial selection capability for other commercially available
chiral auxiliaries [viz., (1S,2R,5S)-(+)-menthol, (1S)-endo-
O
S
OCH3
(ꢀ)-borneol,
(1R,2S)-trans-(ꢀ)-2-phenyl-1-cyclohexanol
Br
Br
O
OCH3
and (1S,2S,3S,5R)–(+)-isopinocampheol], we studied the
allylindation of the corresponding a-oxo esters carried
out in a similar way as the one just described. In all cases
the homoallylic alcohols were not isolated, but directly
converted to the c-lactam 10. Overall yields (from 6) fell
in the 35–56% range but selectivities were insignificant (ee
in the 4–26% range, by chiral HPLC).
O
O
S
R
S
O
Br
N
O
Br
N
H
H
12
11
Figure 2.
Finally, in order to convert the allyl group in 10 to the 2-
oxopropyl group, a Wacker reaction under ligandless aero-
bic conditions was employed using CuCl2 as a co-catalyst.
Thus, treatment of 10 (>95% ee) with PdCl2 (0.2 equiv) and
CuCl2 (3 equiv) in MeCN–H2O 3:1 in an oxygen atmo-
sphere (balloon) (40 ꢁC, 4 h) afforded virtually enantiopure
(+)-convolutamydine 110 (68% yield; >98% ee by chiral
26
HPLC26). Apart from the discrepancy between ½aꢁD
¼
þ27:4 (c 0.06, MeOH)2a and our specific rotation for (+)-
20
1, ½aꢁD ¼ þ48:2 (c 0.20, MeOH), H, 13C NMR and CD
spectra [negative CE (285-245 nm), positive CE (245–
210)] exactly matched those of the natural product, leading
us to assign the (R)-configuration to natural (+)-
convolutamydine.
1
Figure 3.

G. Cravotto et al. / Tetrahedron: Asymmetry 17 (2006) 3070–3074
3073
J = 7), 0.88 (3H, s). 13C NMR (100 MHz, DMSO-d6) 172.0
(CO), 152.9 (CO), 147.1 (C), 138.2 (C), 130.0 (CH), 128.2 (C),
128.0 (CH), 125.4 (CH), 125.2 (CH), 123.0 (C), 121.0 (CH2),
119.1 (CH), 116.5 (C), 80.0 (C), 78.5 (CH), 78.0 (C), 50.5
(CH), 43.0 (CH2), 39.4 (C) 38.7 (CH2), 34.5 (CH2), 30.6 (CH),
28.7 (CH3), 27.6 (CH2), 27.5 (CH3), 25.6 (CH3), 22.2 (CH3).
Compound 10, mp 221–223 ꢁC (MeOH); Rf 0.11 (hexane/t-
3. Conclusion
In conclusion, with the present results we achieved the first
enantioselective synthesis of natural convolutamydine A 1,
and established beyond any doubt that (+)-1 has an (R)-
configuration.
1
BuOMe, 3:2); H NMR (400 MHz, DMSO-d6) 10.62 (1H, br
s), 7.35 (1H, d, J = 1.5), 6.93 (1H, d, J = 1.5), 5.20 (1H, m),
4.97 (1H, dd, J = 17, 2), 4.90 (1H, dd, J = 10, 2), 3.02 (1H,
dd, J = 13, 7.5), 2.55 (1H, dd, J = 13, 7.5); 13C NMR
(100 MHz, DMSO-d6) 178.6 (C), 146.2 (C), 131.5 (CH), 129.1
(C), 128.0 (CH), 123.2 (C), 120.5 (C), 120.3 (CH2), 112.7
(CH), 77.8 (C), 41.0 (CH2). Compound 11, mp 192 ꢁC (dec)
(CH2Cl2/hexane); Rf 0.36 (PE/AcOEt, 4:1); 1H NMR
(400 MHz, CDCl3) 7.61 (1H, br s), ca. 7.50 (5H, m), 7.27
(1H, d, J = 1.5), 6.93 (1H, d, J = 1.5), 5.31 (1H, ddt, J = 17.1,
9.8, 7.2), 5.08 (1H, J = 17.1, 1.8, 1.1), 4.99 (1H, J = 9.8, 1.8,
1.1); 4.86 (1H, s), 3.33 (3H, s), 3.19 (1H, dd, J = 13.2, 7.2),
2.78 (1H, dd, J = 13.2, 7.2). Compound 12, colourless glass,
Acknowledgement
Financial support from Regione Piemonte (Ricerca
Scientifica Applicata 2004) is gratefully acknowledged.
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J = 2), 7.26 (6H, m), 5.11 (1H, d, J = 16), 5.10 (1H, d,
J = 11), 4.82 (1H, dd, J = 11, 4), 3.02 (1H, dd, J = 14, 6), 2.87
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29. Crystal data for compound 11: (C20H17Br2NO4) M = 495.17,
˚
monoclinic, P21, a = 9.814(2), b = 8.629(2), c = 12.602(3)ꢀA3,
3
˚
24. For reviews on indium-mediated reactions: (a) Cintas, P.
Synlett 1995, 1089; (b) Podlech, J.; Maier, Y. T. C. Synthesis
1996, 52, 5643; (c) Li, C. J. In Green Chemistry, Frontiers in
Benign Chemical Syntheses and Processes; Anastas, P.,
Williamson, T. C., Eds.; Oxford University Press: New York,
1998, Chapter 14; (d) Li, C. J.; Chan, T. K. Tetrahedron 1999,
55, 11149; (e) Araki, S.; Hirashita, T. Indium in Organic
Synthesis. In Main Group Metals in Organic Synthesis;
Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim,
2004; pp 323–386; (f) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B.
S. Tetrahedron 2004, 60, 1959.
25. Elliott, E. L.; Bushell, S. M.; Cavero, M.; Tolan, B.; Kelly, R.
T. Org. Lett. 2005, 6, 2449.
26. Pirkle (R,R)-WHELK-01 column: eluant: hexane/propan-2-
ol/diethylamine 20:5:0.1; flow: 1 mL/min.
27. For allylindation of isatins, see: (a) Nair, V.; Ros, S.; Jayan,
C. N.; Viji, S. Synthesis 2003, 2542; (b) Nair, V.; Ros, S.;
Jayan, C. N. Tetrahedron 2001, 57, 9453; (c) Nair, V.; Ros, S.;
Jayan, C. N. J. Chem. Res., Synop. 2001, 551; (d) Gong, J. H.;
Lee, K. Y.; Son, J. N.; Kim, J. N. Bull. Korean Chem. Soc.
b = 110.62(3)ꢁ, V = 998.8(4) A , Z = 2, Dc = 1.646 g cm
,
l(MoKa) = 4.083 cmꢀ1, F(000) = 492; T = 295(2) K; elon-
gated prism, 0.36 · 0.26 · 0.16 mm, Bruker P4 diffractometer;
4548 data collected, 3854 unique, Rint = 0.0155, 3134 with
I > r(I). Absorption corrections by w-scan (Ref. 30),
Tmin = 0.369, Tmax = 0.694. The structure was solved by
direct method (Ref. 31) and refined anisotropically by matrix
least-squares based on F2 (Ref. 32) (to give R1 = 0.0543,
wR2 = 0.1242) for 3134 observed reflections and 245 para-
meters. Supplementary crystallographic data were deposited
as CCDC 622273 with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
30. North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr., Sect. A 1968, 24, 351.
31. Burla, M. C.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.;
Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr.
2003, 36, 1103.
32. Sheldrick, G. M. SHELXL-97. Program for the Refinement of
Crystal Structures; University of Go¨ttingen, Go¨ttingen,
Germany, 1997.