Total synthesis of (±)-erythravine based on ring closing dienyne metathesis

Article abstract of DOI:10.1016/j.tetlet.2003.09.059

The first total synthesis of (±)-erythravine was achieved in thirteen steps from 3,4-dimethoxyphenethylamine using ring closing dienyne metathesis as the key step.

Full text of DOI:10.1016/j.tetlet.2003.09.059

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8047–8049
Total synthesis of ( )-erythravine based on ring closing
dienyne metathesisꢀ
Hironori Fukumoto, Tomoyuki Esumi, Jun Ishihara and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
Received 25 August 2003; revised 5 September 2003; accepted 10 September 2003
Abstract—The first total synthesis of ( )-erythravine was achieved in thirteen steps from 3,4-dimethoxyphenethylamine using ring
closing dienyne metathesis as the key step.
© 2003 Elsevier Ltd. All rights reserved.
Dienoid-type erythrinan alkaloids 1 comprise a major
group of the Erythrina family of natural products.
These compounds have received considerable attention
over the past few decades due to their various intrigu-
ing biological activity and unique erythrinane skeleton.1
Although a wide variety of methods have already been
developed for the synthesis of this family of alkaloids,1,2
we were interested in a new approach which relies on
ring closing metathesis (RCM) of dienyne 2 on the
basis of the Grubbs’ protocol (Scheme 1).3,4
bromide, 11 yielded dienyne 12 as a 1:1 epimeric mix-
ture. For the next RCM reaction, acetate 13 and TES–
ether 14 were also prepared each as a 1:1 epimeric
mixture from 12.
The crucial tandem RCM process was examined using
Grubbs’ catalysts 1510 and 1611 under various condi-
tions. When alcohol 12 was treated with 10–20 mol% of
either Grubbs’ catalyst in CH2Cl2 or toluene, no reac-
tion occurred at room temperature and only partial
decomposition of 12 was observed at elevated tempera-
ture. On the other hand, upon treatment of acetate 13
We postulated that the initial RCM reaction would
lead to preferential formation of complex 3 producing
1, rather than 4 giving 5, due to the difference in the
steric hindrance of two olefinic double bonds. Recently,
Mori et al. reported the synthesis of ( )-erythrocarine
based on the same strategy.5 Their report prompted us
to disclose herein the first total synthesis6 of ( )-ery-
thravine which we have independently achieved.7
3,4-Dimethoxyphenethylamine (6) was first converted
to compound 7, which was then reacted with diethyl
propiolate in boiling trifluoroacetic acid to give diester
9 via Pictet–Spengler type reaction8 of 8. Reduction of
9 with LiAlH4 followed by selective silylation gave
TBDPS–ether 10. Swern oxidation of 10 and reaction
of the resulting aldehyde with Bestmann’s reagent9
afforded enyne 11. Upon sequential desilylation, Swern
oxidation, and Grignard reaction using vinylmagnesium
Keywords: ring closing dienyne metathesis; erythrina alkaloid; ery-
thravine; total synthesis.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.059
* Corresponding author. E-mail: susumi@net.nagasaki-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.059

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H. Fukumoto et al. / Tetrahedron Letters 44 (2003) 8047–8049
Scheme 2. Reagents and conditions: (i) Boc2O, CH2Cl2; (ii) NaH, CH2ꢀCHCH2Br, THF, reflux; (iii) EtO2CCꢁCCO2Et, CF3CO2H,
reflux; (iv) LiAlH4, THF; (v) t-BuPh2SiCl, Et3N–DMAP (cat.), CH2Cl2; (vi) (COCl)2, DMSO, CH2Cl2 at −78°C then Et3N, 0°C;
(vii) (MeO)2P(O)C(N2)COMe, K2CO3, MeOH; (viii) (n-Bu)4NF, THF; (ix) (COCl)2, DMSO, CH2Cl2, at −78°C then Et3N, 0°C;
(x) CH2ꢀCHMgBr, THF; (xi) Ac2O, Et3N–DMAP (cat.), CH2Cl2; (xii) Et3SiCl, Et3N–DMAP (cat.), CH2Cl2; (xiii) 15 (10 mol%),
CH2Cl2 (0.04 M), reflux; (xiv) K2CO3, MeOH.
with 10 mol% of 15 in CH2Cl2 (0.04 M) at reflux, the
reaction completed after 8 h and tetracyclic compounds
17 and 18 were obtained in a ratio of 63:37 in 78% yield.
In this particular case, the reaction turned out to be very
sluggish at room temperature, possibly because of the
coordination of the free tertiary amine to the ruthenium
catalyst.12,13 After separation of 17 and 18, H–H COSY
and NOE experiments allowed us to determine their
stereostructures unambiguously. Similarly, reaction of 14
with 15 gave 19 and 20 in a ratio of 27:73 in 63% yield.
We were pleased to find that the tetetracyclic compounds
corresponding to 5 were not produced at all in these
reactions. It is therefore apparent that the RCM reac-
tions of 13 and 14 initially occurred between the N-allyl
group and the acetylene (Scheme 2).
References
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Sano, T. In The Alkaloids; Cordell, G. A., Ed.; Academic
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2. For the synthetic methodologies developed recently, see:
(a) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J.
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Interestingly, in each reaction, the two epimeric products
were not equally produced even though a 1:1 epimeric
mixture was used as the starting material. In addition,
in the reaction of 13, a-isomer 17 was preferentially
formed, while b-isomer 20 was favored in the reaction of
14. These results may have arisen from the difference
between the epimers in the rate of cyclization or the rate
of decomposition. The steric and electronic nature of the
C3-substituent is thought to affect these rates. Finally,
treatment of 17 with K2CO3 in methanol furnished
( )-erythravine. The synthetic substance exhibited spec-
tral properties14 in accord with those reported15 for
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thesized by methanolysis of 18, quantitatively.
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In conclusion, we have achieved a concise thirteen-step
synthesis of ( )-erythravine from 3,4-dimethoxyphene-
thylamine based on tandem RCM reaction of a dienyne
for the first time. The synthetic method used is of general
value in approaches to related erythrina alkaloids.

H. Fukumoto et al. / Tetrahedron Letters 44 (2003) 8047–8049
8049
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Hz, 1H), 5.75 (brs, 1H), 4.50–4.49 (m, 1H), 3.85 (s, 3H),
3.75 (s, 3H), 3.69 (dd, J=3.0, 14.5 Hz, 1H), 3.57 (d,
J=14.5 Hz, 1H), 3.51–3.46 (m, 1H), 3.02–2.92 (m, 2H),
2.65–2.59 (m, 1H), 2.56 (dd, J=5.5, 11.5 Hz, 1H), 1.82
(dd, J=10.5, 11.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) l 147.8, 147.3, 141.8, 134.3, 130.4, 126.0, 124.9,
122.7, 111.5, 109.2, 67.8, 67.3, 56.5, 55.8, 55.8, 45.3,
43.5, 23.8; HRMS (EI) calcd for C18H21NO3: 299.1517,
found: 299.1521.
13. In this regard, Mori et al. observed that the RCM
reaction of the corresponding hydrochloride successfully
occurred at room temperature; see Ref. 5.
14. 1H NMR (500 MHz, CDCl3) l 6.82 (s, 1H), 6.62 (s,
1H), 6.55 (dd, J=2.0, 10.0 Hz, 1H), 5.97 (d, J=10.0
15. Millington, D. S.; Steinman, D. H.; Rinehert, K. L., Jr.
J. Am. Chem. Soc. 1974, 96, 1909–1917.