Enantioselective total synthesis of (R)-(-)-complanine

Article abstract of DOI:10.3762/bjoc.8.192

A route is described for the enantioselective synthesis of (R)-(-)-complanine, a marine natural product isolated from Eurythoe complanata, and known to be a causative agent in inflammation. An organocatalytic, asymmetric oxyamination of a homoconjugated all-Z-dienal intermediate provides versatile and efficient access to the natural product.

Full text of DOI:10.3762/bjoc.8.192

Enantioselective total synthesis of
(R)-(−)-complanine
Krystal A. D. Kamanos and Jonathan M. Withey*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1695–1699.
Department of Physical Sciences, Grant MacEwan University, 10700
104 Ave, Edmonton, T5J 4S2, Canada
doi:10.3762/bjoc.8.192
Received: 16 July 2012
Email:
Accepted: 30 August 2012
Published: 04 October 2012
Jonathan M. Withey* - witheyj@macewan.ca
* Corresponding author
Keywords:
Associate Editor: P. R. Hanson
© 2012 Kamanos and Withey; licensee Beilstein-Institut.
complanine; enantioselective synthesis; marine fireworm; nitrosoaldol;
organocatalysis
License and terms: see end of document.
Abstract
A route is described for the enantioselective synthesis of (R)-(−)-complanine, a marine natural product isolated from Eurythoe
complanata, and known to be a causative agent in inflammation. An organocatalytic, asymmetric oxyamination of a homoconju-
gated all-Z-dienal intermediate provides versatile and efficient access to the natural product.
Introduction
The marine fireworm Eurythoe complanata resides in the alcohol N-acylated with a γ-aminobutyric acid (GABA) deriva-
shallow water and sands of temperate and sub-tropical regions. tive. Complanine is structurally related to the obscuraminols,
Its small setae cause skin inflammation upon contact, the isolated from another marine source, the ascidian Pseudodis-
causative agent having been identified as complanine. This toma obscurum [2]. Unlike complanine, however, these
novel amphipathic substance was first isolated from Eurythoe substances are simple amino alcohols that do not possess any
complanata in 2008, by Nakamura and Uemura [1]. Compla- other chemical functionalities. Synthetic studies, also conducted
nine induces inflammation by activating PKC (protein kinase C) by Nakamura and Uemura, established the absolute structure
in the presence of Ca2+ and TPA (12-O-tetradecanoylphorbol and configuration as (R)-(−)-complanine (Figure 1), showing it
13-acetate). PKC plays an important role in inflammation, to be related to other natural products that possess the vicinal
namely through control of signal transduction cascades, and the
biological activity of complanine may be understood in terms of
controlling these cascades.
From a structural perspective, complanine contains a novel
trimethylammonium cationic group and can be characterized as
Figure 1: Structure of (R)-(−)-complanine.
possessing a homoconjugated all-Z-diene moiety and an amino
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Beilstein J. Org. Chem. 2012, 8, 1695–1699.
Scheme 1: Retrosynthetic analysis of (R)-(−)-complanine.
amino alcohol moiety. Using a chiral-synthon approach, tion or multiple alkylation. Of the several methods reported, a
(R)-(−)-complanine was synthesized in a sequence of nine linear modification of the cesium carbonate-promoted coupling devel-
steps, beginning with (R)-malic acid [3].
oped by Caruso and Spinella provided the most efficient condi-
tions [4]. Thus, commercially available and unprotected
As part of our research endeavours directed towards the 5-hexyn-1-ol underwent smooth coupling with 1-bromopent-2-
organocatalytic synthesis of 1,2-amino alcohols, we have devel- yne in N,N-dimethylformamide, in the presence of stoichio-
oped a new asymmetric strategy leading to (R)-(−)-complanine. metric amounts of cesium carbonate, copper iodide and tetra-
This approach utilizes an asymmetric organocatalytic butylammonium iodide. The resulting skipped diyne 2 was
O-nitrosoaldol reaction as the source of chirality, with accom- selectively reduced to homoconjugated all-Z-diene 1, with
panying amination of the aldehyde functional group resulting in subsequent Swern oxidation affording aldehyde 3, in 86% yield
a concise and efficient synthesis.
from 2, as a key intermediate in the total synthesis.
Results and Discussion
With 3 in hand, attention was then turned to its conversion to
Herein we report the concise and efficient synthesis of amino alcohol 4. It was envisioned that such conversion could
(R)-(−)-complanine, via a highly effective organocatalytic be effected in a one-pot reaction by employing lithium
O-nitrosoaldol as the key step. A retrosynthetic analysis for aluminium hydride reduction of an aldoximine [5], formed in
complanine is depicted in Scheme 1.
situ by condensation of a suitably oxygenated aldehyde 5 with
hydroxylamine hydrochloride (Scheme 3).
The synthesis was initiated by preparation of homoconjugated
all-Z-diene 1 (Scheme 2). Sequential olefin preparation by using Although a number of acyloxylations have been reported, the
Wittig chemistry, or selective polyyne reduction represent two direct catalytic asymmetric acyloxylation of aldehydes has only
traditional methods for the preparation of homoconjugated all- been recently realized [6,7]. Thus, the asymmetric benzoylation
Z-polyenes. In the latter, metal-mediated coupling of 1-alkynes of aldehydes, according to the method of Tomkinson [7], was
and propargylic halides is generally employed, with copper (I) attempted. Utilizing benzoyl peroxide in the presence of
alkynides being the least prone to isomerization, polymeriza- MacMillan imidazolidinone (5R)-2,2,3-trimethyl-5-benzyl-4-
Scheme 2: Reagents and conditions: (a) Cs2CO3, CuI, TBAI, DMF, rt, 24 h, 91%; (b) H2 (1 atm), Lindlar catalyst, EtOAc, pyridine, rt, 24 h; (c) DMSO,
(COCl)2, DCM, −78 °C, then; 1, −78 °C, 45 min, then, Et3N, 0 °C, 1.5 h, 86% from 2.
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Scheme 3: Direct approach to amino alcohol 4.
imidazolidinone [8] with 4-nitrobenzoic acid as cocatalyst, all (R)-(−)-complanine [3]. Thus, the conversion of 8 to the corres-
efforts to effect benzoylation of 3, yielding 5, were unsuc- ponding amino alcohol was readily effected by azide formation
cessful, and this route was ultimately abandoned as attention and subsequent reduction. In an analogous fashion, the acti-
turned to more conventional α-oxygenation strategies and a vated ester of 4-(trimethylammonio)butanoate (synthesized
stepwise approach to 4.
from γ-aminobutyric acid [11]) underwent reaction with amino
alcohol 4 to furnish (R)-(−)-complanine in 62% yield.
The reaction of aldehydes with nitrosobenzene in the presence
of proline-derived secondary amine catalysts represents the The isolated, synthetic complanine was identical in all its spec-
current benchmark in organocatalytic α-oxygenation strategies tral data to the previously reported natural material [3], with an
[9]. A known drawback of this approach is the instability of the optical rotation in reasonable agreement ([α]D22 −12.1 (c 0.85,
oxyaminated products, presumably owing to N–O bond lability. H2O), lit. −9.9 (c 0.12, H2O)).
Recent reports suggest that this O-nitrosoaldol reaction
proceeds much more cleanly with 2-nitrosotoluene than with Conclusion
nitrosobenzene, probably owing to the suppression of N–O An efficient and enantioselective route to (R)-(−)-complanine
bond cleavage [10]. Thus, treatment of aldehyde 3 with was developed, by using an organocatalytic α-oxygenation
2-nitrosotoluene in the presence of L-proline as catalyst, strategy. This flexible approach also permits ready access to the
resulted in clean α-oxygenation (Scheme 4). Attempts to effect (S)-enantiomer of the natural product and offers an alternate
the direct conversion of 7 to amino alcohol 4, by using the route to the synthesis of recently isolated neocomplanines A
aldoximine approach described above (Scheme 3), yielded a and B [12], along with the obscuraminols [2]. Such synthetic
complex mixture of products. However, 6 was readily isolated studies are currently underway in our laboratory.
as oxyaminated alcohol 7, following in situ reduction with
sodium borohydride. Subsequent copper-mediated N–O bond Experimental
cleavage gave chiral diol 8 in 97% ee (determined by HPLC Undeca-5,8-diyn-1-ol (2): To a suspension of anyhydrous
analysis using a chiral stationary phase). Diol 8 had identical Cs2CO3 (9.19 g, 28.2 mmol), TBAI (10.39 g, 28.2 mmol) and
spectroscopic properties compared to those reported by Naka- CuI (5.37 g, 28.2 mmol) in anhydrous DMF (60 mL) was added
mura and Uemura and intercepted their synthesis of 5-hexyn-1-ol (3.11 mL, 28.2 mmol). Following stirring at rt for
Scheme 4: Reagents and conditions: (a) 2-Nitrosotoluene, L-proline (10 mol %), CHCl3, 0 °C, 3 h; (b) NaBH4, EtOH, 0 °C, 30 min, 78% from 3; (c)
Cu(OAc)2, EtOH, rt, 16 h, 72%; (d) MsCl, pyridine, CH2Cl2, 0 °C, 3 h; (e) NaN3, DMF, 80 °C, 16 h, 84% from 8; (f) PPh3, THF, H2O, rt, 12 h, 88%; (g)
N-[4-(trimethylammonio)butyryloxy]succinimide iodide, MeOH, rt, 16 h, 62%.
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Beilstein J. Org. Chem. 2012, 8, 1695–1699.
20 min, 1-bromopent-2-yne (2.88 mL, 28.2 mmol) was added undeca-5,8-dienal (3) as a colorless oil (3.08 g, 86% from 2): IR
dropwise. The reaction mixture was stirred for an additional νmax (thin film)/cm−1 3036, 2940, 2860, 2748, 1719, 1644,
24 h at rt before addition of NH4Cl (aq, sat, 100 mL) and 1455, 1207, 921, 875, 841, 698; 1H NMR (400 MHz, CDCl3) δ
extraction of the aqueous phase with Et2O (3 × 100 mL). The 0.97 (3H, t, J = 7.7 Hz, C11H3), 1.71 (2H, quintet, J = 7.7 Hz,
organic layer was dried (MgSO4), filtered and concentrated in C3H2), 2.01–2.17 (4H, m, C4H2 and C10H2), 2.44 (2H, td, J =
vacuo. Purification by flash column chromatography (silica gel, 7.9 Hz, 2.1, C2H2), 2.77 (2H, t, J = 5.6 Hz, C7H2), 5.24–5.45
hexane/ethyl acetate, 9:1) gave undeca-5,8-diyn-1-ol (2) as a (4H, m, C5H, C6H, C8H and C9H), 9.77 (1H, t, J = 2.1 Hz,
colorless oil (4.21 g, 91%): IR νmax (thin film)/cm−1 3328, CHO); 13C NMR (100 MHz, CDCl3) δ 14.1 (C11), 20.6 (C10),
3019, 2941, 2244, 1447, 1048, 976, 788, 698; 1H NMR 22.0 (C3), 25.6 (C7), 26.5 (C4), 43.3 (C2), 124.1, 124.9, 129.6
(400 MHz, CDCl3) δ 1.12 (3H, m, C11H3), 1.51–1.68 (4H, m, and 132.1 (C5, C6, C8 and C9), 201.2 (CHO); HRMS–ESI
C2H2 and C3H2), 2.20 (2H, m, C10H2), 3.12 (2H, m, C7H2), [M + H]+ calcd for C11H19O, 167.1436; found, 167.1432.
3.63 (2H, m, C1H2); 13C NMR (100 MHz, CDCl3) δ 5.6 (C7),
9.6 (C10), 12.4 (C11), 18.5 (C4), 25.0 and 32.0 (C2 and C3), (2R,5Z,8Z)-2-(N-o-Tolylaminooxy)-undeca-5,8-dien-1-ol (7):
62.0 (C1), 74.4, 75.7, 79.2 and 82.1 (C5, C6, C8 and C9); To a solution of 2-nitrosotoluene (403 mg, 3.33 mmol) and
HRMS–ESI [M + H]+ calcd for C11H17O, 165.1279; found, L-proline (115 mg, 1.00 mmol) in CHCl3 (20 mL) at 0 °C was
165.1282.
added a solution of (5Z,8Z)-undeca-5,8-dienal (3, 1.66 g,
10.0 mmol) in CHCl3 (20 mL). Following stirring at 0 °C for
(5Z,8Z)-Undeca-5,8-dien-1-ol (1): To a solution of undeca-5,8- 3 h, a solution of NaBH4 (570 mg, 15.0 mmol) in EtOH
diyn-1-ol (2, 4.01 g, 24.4 mmol) in ethyl acetate/pyridine (9:1, (30 mL) was added and the reaction mixture was stirred for an
50 mL) was added Lindlar’s catalyst (1.51 g). The mixture was additional 30 min at 0 °C. NaHCO3 (aq, sat, 100 mL) was
stirred at rt under a hydrogen atmosphere for 24 h. The reaction added and the reaction mixture was warmed to rt. The aqueous
mixture was filtered through a pad of celite and concentrated in phase was extracted with CHCl3 (3 × 50 mL) and the combined
vacuo to yield (5Z,8Z)-undeca-5,8-dien-1-ol (1, 4.26 g) of suffi- organic layers were dried (MgSO4), filtered and concentrated in
cient purity to be used directly in the next step. Purification of vacuo. Purification by flash column chromatography (silica gel,
an analytical sample by flash column chromatography (silica hexane/ethyl acetate, 10:1→4:1) gave (2R,5Z,8Z)-2-(N-o-toly-
gel, hexane/ethyl acetate, 9:1) gave (5Z,8Z)-undeca-5,8-dien-1- laminooxy)-undeca-5,8-dien-1-ol (7) as a colorless oil (752 mg,
ol (1) as a colorless oil: IR νmax (thin film)/cm−1 3281, 3022, 78%): [α]D22 −37.1 (c 1.00, CHCl3); IR νmax (thin film)/cm−1
2934, 2865, 1646, 1457, 1052, 1021, 928, 768, 694; 1H NMR 3280, 3031, 2941, 2865, 1641, 1606, 1586, 1487, 1449, 1308,
(400 MHz, CDCl3) δ 0.97 (3H, t, J = 7.6 Hz, C11H3), 1.44 (2H, 1247, 1133, 1097, 1072, 1032, 1008, 926, 888, 839, 798, 748,
m, C3H2), 1.58 (2H, m, C2H2), 2.09 (4H, m, C2H2 and C3H2), 705; 1H NMR (400 MHz, CDCl3) δ 0.96 (3H, t, J = 7.8 Hz,
2.78 (2H, m, C7H2), 3.65 (2H, t, J = 6.9 Hz, C1H2), 5.28–5.44 C11H3), 1.56 (2H, m, C3H2), 2.04 (2H, m, C4H2), 2.12 (3H, s,
(4H, m, C5H, C6H, C8H and C9H); 13C NMR (100 MHz, ArCH3), 2.21 (2H, m, C10H2), 2.79 (2H, m, C7H2), 3.76 (1H,
CDCl3) δ 14.3 (C11), 20.5 (C10), 25.6 and 25.8 (C3 and C7), dd, J = 14.2, 8.6 Hz, C1HA), 3.85 (1H, dd, J = 14.2, 4.1 Hz,
26.9 (C4), 32.4 (C2), 62.9 (C1), 127.3, 128.5, 129.6 and 131.9 C1HB), 3.96 (1H, m, C2H), 5.26–5.48 (4H, m, C5H, C6H, C8H
(C5, C6, C8 and C9); HRMS–ESI [M + H]+ calcd for C11H21O, and C9H), 6.89 (1H, t, J = 7.3 Hz, ArH), 7.05 (1H, d, J =
169.1592; found, 169.1593.
7.4 Hz, ArH), 7.18 (1H, t, J = 7.1 Hz, ArH), 7.23 (1H, d, J =
7.3 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ 14.2 (C11), 17.6
(5Z,8Z)-Undeca-5,8-dienal (3): A solution of DMSO (ArCH3), 20.1 (C10), 22.3 (C4), 24.8 (C7), 31.6 C3, 66.2 (C1),
(4.76 mL, 67.0 mmol) in CH2Cl2 (50 mL) was added dropwise 78.8 (C2), 114.6, 122.0, 123.6, 126.8, 130.3 and 145.9 (Ar);
to a solution of oxalyl chloride (2.83 mL, 33.5 mmol) in HRMS–ESI [M + H]+ calcd for C18H28NO2, 290.2120; found,
CH2Cl2 at −78 °C. Following stirring for 20 min, a solution of 290.2122.
(5Z,8Z)-undeca-5,8-dien-1-ol (1, 3.76 g, 22.3 mmol) in CH2Cl2
(50 mL) was added dropwise to the reaction mixture. After stir- (2R,5Z,8Z)-Undeca-5,8-diene-1,2-diol (8): To a solution of
ring for an additional 45 min at −78 °C, Et3N (18.7 mL, (2R,5Z,8Z)-2-(N-o-tolylaminooxy)-undeca-5,8-dien-1-ol (7,
134 mmol) was added dropwise, and the reaction mixture was 627 mg, 2.16 mmol) in EtOH (30 mL) was added Cu(OAc)2
warmed to 0 °C, whereat it was stirred for 1.5 h. Water (400 mg, 2.20 mmol) and the reaction mixture was stirred at rt
(100 mL) was added and the reaction mixture was warmed to rt. for 16 h. NH4Cl (aq, sat, 50 mL) was added and the aqueous
The aqueous phase was extracted with CH2Cl2 (3 × 50 mL) and phase was extracted with EtOAc (3 × 30 mL). The combined
the combined organic layers were dried (MgSO4), filtered and organic layers were dried (MgSO4), filtered and concentrated in
concentrated in vacuo. Purification by flash column chromatog- vacuo. Purification by flash column chromatography (silica gel,
raphy (silica gel, hexane/ethyl acetate, 20:1) gave (5Z,8Z)- hexane/ethyl acetate, 4:1) gave (2R,5Z,8Z)-undeca-5,8-diene-
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Beilstein J. Org. Chem. 2012, 8, 1695–1699.
1,2-diol (8) as a colorless oil (286 mg, 72%): [α]D22 −2.3 (c
0.90, CHCl3), lit. −2.0 (c 0.40, CHCl3); IR νmax (thin film)/
cm−1 3256, 3035, 2938, 2871, 1639, 1486, 1449, 1107, 1052,
1032, 1008, 786, 738, 702; 1H NMR (400 MHz, CDCl3) δ 0.97
(3H, t, J = 7.7 Hz, C11H3), 1.50 (2H, m, C3H2), 2.07 (2H, m,
C4H2), 2.20 (2H, m, C10H2), 2.80 (2H, t, J = 5.3 Hz, C7H2),
3.45 (1H, dd, J = 13.9, 8.1 Hz, C1HA), 3.63 (1H, dd, J = 13.9,
4.2 Hz, C1HB), 3.72 (1H, m, C2H), 5.27–5.44 (4H, m, C5H,
C6H, C8H and C9H); 13C NMR (100 MHz, CDCl3) δ 14.3
(C11), 20.6 (C10), 23.3 (C4), 25.5 (C7), 32.9 (C3), 66.8 (C1),
71.8 (C2), 127.1, 129.1 and 132.0 (C5H, C6H, C8H and C9H);
HRMS–ESI [M + H]+ calcd for C11H21O2, 185.1542; found,
185.1539. Enantiomeric excess was determined by HPLC
analysis (Chiralcel OD-H, hexane/2-propanol 95:5, 1.0 mL
min−1): tR 14.7 min (minor), 15.4 (major).
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Acknowledgements
We thank the Grant MacEwan University Undergraduate
Student Research Initiative for funding (K. A. D. K).
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