A general method for making bicyclic compounds with nitrogen at a bridgehead-application to the halichlorine spiro subunit

Article abstract of DOI:10.1039/b413481h

N-Protected β-amino aldehydes having the nitrogen in a ring are easily converted into Morita-Baylis-Hillman adducts; O-acetylation and N-deprotection result in spontaneous cyclization to bicyclic structures having nitrogen at a bridgehead. The Royal Socie

Full text of DOI:10.1039/b413481h

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A general method for making bicyclic compounds with nitrogen at a
bridgehead—application to the halichlorine spiro subunit{
Derrick L. J. Clive,* Maolin Yu and Zhiyong Li
Received (in Corvallis, OR, USA) 26th August 2004, Accepted 7th October 2004
First published as an Advance Article on the web 23rd December 2004
DOI: 10.1039/b413481h
stereoelectronic or reactivity factors intervene to direct cyclization
onto the CO2R group7 of 7 or to cause O A N acetyl transfer; in
the event, the desired ring closure (7 A 8) occurs smoothly.
The lactam 9,1 an intermediate in the preparation of 1, was
deprotected (Me3SiBr, 84%, 9 A 10) and oxidized (Swern, 85%) to
aldehyde 11. Wittig reaction with Ph3PLCH(OMe) and hydrolysis
(CSA, aqueous MeCN) of the intermediate enol ethers then gave
the expected aldehyde (11 A 12 A 13, 74% overall). When
aldehyde 138 was dissolved in methyl acrylate, condensation
occurred on addition of DABCO and Sc(OTf)3.9 Although the
resulting alcohols (14a, more polar) and 14b (less polar) could be
separated, it was more convenient to acetylate the mixture and
separate the corresponding acetates 15a (37% from 13) and 15b
(34%). When each of the acetates 15a and 15b was treated with
Me3OBF4 and then with aqueous Na2CO3, the lactam ring was
opened to amino esters 16a and 16b, respectively, and these
cyclized in situ to afford the desired bis-ester 3 (77% for 15a and
72% for 15b).10 Aldehyde 13 was recovered unchanged either after
exposure to DABCO in CH2Cl2 for 3 days, or when the MBH
condensation was worked up before completion. These observa-
tions show that epimerization by retro-Michael elimination and
re-addition does not occur.
N-Protected b-amino aldehydes having the nitrogen in a ring
are easily converted into Morita–Baylis–Hillman adducts;
O-acetylation and N-deprotection result in spontaneous cycli-
zation to bicyclic structures having nitrogen at a bridgehead.
A recent report from this laboratory1 described the preparation of
spiro amine 1, which was made during studies on the total
synthesis of the marine natural product halichlorine (2).2 An
obvious next step was to convert 1 into 3, and this has now been
achieved through the development of a new and general method
for making compounds that contain a bicyclic subunit with
nitrogen at a bridgehead. The approach (Scheme 1) is based on
sequential formation of Morita–Baylis–Hillman (MBH) alcohols
(4 A 5) and intramolecular SN29 displacement of the derived
acetates (6 A 7 A 8). In the present work we have made alcohols
of type 5 by MBH3 condensation (and used only acrylates), but the
same compounds should also be accessible by other3,4 methods.
While O-acetates of MBH alcohols are known to undergo
intermolecular SN29 displacement,3,5 the intramolecular 6-endo
pathway6 (Scheme 1, 7 A 8) requires that no competing
Scheme 2 Reagents and conditions: (i) Me3SiBr, CH2Cl2, 210 uC, 2 h,
84%; (ii) Swern oxidation, 85%; (iii) MeOCH2PPh3Cl, t-BuOK, THF, 0 uC,
2 h; (iv) camphorsulfonic acid, MeCN–water, 4 h, 74% over two steps; (v)
methyl acrylate, DABCO, Sc(OTf)3, 5 days; (vi) AcCl, pyridine, CH2Cl2,
0 uC, 1 h, 25 uC, 1 h, over two steps 37% of 15a, 34% of 15b; (vii)
Me3OBF4, CH2Cl2, 1.5 h; (viii) 20% aqueous Na2CO3, MeCN, 2 h, 77%
from 15a, 72% from 15b.
Scheme 1
{ Electronic supplementary information (ESI) available: characterization
data for compounds 3, 21, 26, 32 and 38. See http://www.rsc.org/suppdata/
cc/b4/b413481h/
*derrick.clive@ualberta.ca
906 | Chem. Commun., 2005, 906–908
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Scheme 3 Reagents and conditions: (i) References 10–12; (ii) methyl acrylate, DABCO, 3 days, 39% (19a), 34% (19b); (iii) AcCl, pyridine, CH2Cl2, 1 h,
89% (20a), 85% (20b); (iv) CF3CO2H, CH2Cl2, 1 h; aq Na2CO3, MeCN, 1 h, 77%; (v) (a) (Boc)2O, Et3N, CH2Cl2, 0 uC, 1 h, room temperature, 12 h, 87%;
(b) Dess–Martin periodinane, CH2Cl2, 1.5 h, 88%; (vi) as in (ii), 46% (less polar), 38% (more polar); (vii) as in (iii), 94% for 24a, 92% for 24b; (viii) as in (iv),
77%; (ix) (a) NaN3, aq H2SO4, 0 uC, 16 h, 74%; (b) LiAlH4, dioxane, reflux, 24 h, 80%; (x) (a) (Boc)2O, EtOAc, 16 h, 98%; (b) Swern, 2 h, 87%; (xi) as in
(ii), 5 days, 39% (less polar), 47% (more polar); (xii) as in (iii), 92% for 30a, 94% for 30b; (xiii) as in (iv) 90% (more polar), 87% (less polar); (xiv) (a) NaN3,
aq H2SO4, 0 uC, 16 h, 80%; (b) LiAlH4, THF, reflux, 24 h, 71%; (xv) (a) as in (x), 83%; (b) as in (x), 80%; (xvi) as in (ix) 49% (more polar 36a), 45% (less
polar 36b); (xvii) as in (iii), 78% for 37a,79% for 37b; (xviii) as in (iv), 84% for 37a, 93% for 37b.
The approach of Scheme 2 appears to be general, and we have
applied it to several other cases (Scheme 3).
and then into aldehyde 35. Our standard sequence (35 A 36a,b,
A 37a,b, A 38) then proceeded in the expected way.
In summary, synthetic work related to halichlorine has led to the
development of a method for generating bicyclic amines with
nitrogen at a bridgehead. The process occurs with preservation of
stereochemistry a to the nitrogen.
L-Proline (17) was converted by literature methods11–13 into
aldehyde 18, which underwent condensation with methyl acrylate,
affording a separable mixture of 19a (more polar, 39%) and 19b
(less polar, 34%). Acetylation produced the corresponding acetates
20a (89%) and 20b (85%). Finally, exposure of a mixture of both
acetates to CF3CO2H resulted in N-deprotection, at which point,
treatment with aqueous Na2CO3 caused spontaneous cyclization
to 21 (77% yield). HPLC analysis [Chiracel OD-H, 1% EtOH–
hexane] showed the material to have an enantiomeric purity of
99.8%, indicating that little, if any, racemization occurs in the
synthetic sequence.
All new compounds were fully characterized by spectroscopic
methods, including high resolution mass spectrometry. We thank
NSERC for financial support and C. Boucher [Boehringer
Ingelheim (Canada)] for ee measurements. M.Y. holds a Province
of Alberta Graduate Fellowship.
Derrick L. J. Clive,* Maolin Yu and Zhiyong Li
Chemistry Department, University of Alberta, Edmonton, Alberta,
Canada T6G 2G2. E-mail: derrick.clive@ualberta.ca;
Fax: 780-492-8231; Tel: 780-492-3251
In another series of experiments, commercial (2-hydroxy-
ethyl)piperidine (22) was converted by N-protection (Boc2O,
87%) and Dess–Martin oxidation (88%) into aldehyde 23, which
underwent efficient MBH condensation [23 A 24a (more polar,
38%) and 24b (less polar, 46%)]. Once again, acetylation (94% for
24a, 92% for 24b), N-deprotection (CF3CO2H), and treatment
with aqueous Na2CO3 resulted in ring closure, giving 26 (77%
from a mixture of both acetates).
Notes and references
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We also investigated two other ring sizes for the starting amine.
Keto ester 27 was converted by Schmidt reaction and LiAlH4
reduction into 28,14 which was protected on nitrogen [Boc2O,
98%], oxidized (Swern, 87%), and subjected to the MBH
condensation [29 A 30a (more polar, 47%) and 30b (less polar,
39%)]. Acetylation (92% for 31a, 94% for 31b) and N-deprotection
(CF3CO2H) and basification gave 32 (90% from 31a, 87% from
31b). Similarly, keto ester 33 was converted into amino alcohol 34
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908 | Chem. Commun., 2005, 906–908
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