Formal total synthesis of (±)-conduramine E utilising the Bryce-Smith-Gilbert photoamination reaction

Article abstract of DOI:10.1055/s-0029-1219526

Utilising a Bryce-Smith-Gilbert photoamination of benzene as a key step, a synthesis of (±)-conduramine E was carried out. A highly regioselective dihydroxylation of a cyclic diene was effected utilising Sharpless AD-mix-β. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219526

LETTER
517
Formal Total Synthesis of ( )-Conduramine E Utilising the
Bryce-Smith–Gilbert Photoamination Reaction
Total
S
ynthesis of
a
(
)-Condur
v
amine
E
id Chappell, Michael G. B. Drew, Shane Gibson, Laurence M. Harwood, Andrew T. Russell*
Department of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 6AD, UK
Fax +44(118)3786331; E-mail: a.t.russell@reading.ac.uk
Received 17 December 2009
Dedicated to Prof. Gerry Pattenden in celebration of his 70th birthday
of protonation, 4 would be expected to rearrange to the
thermodynamically more stable formamide 6 with subse-
quent cyclization to afford 7.6 Overall, this transformation
achieves the same stereochemical outcome as a Wood-
ward–Prevost dihydroxylation.7 Hydrolysis of the for-
mate 5 afforded an amino alcohol that was directly
protected with triphosgene to give the desired urethane 2
in an overall, purified yield of 86% from 1.
Abstract: Utilising a Bryce-Smith–Gilbert photoamination of ben-
zene as a key step, a synthesis of ( )-conduramine E was carried
out. A highly regioselective dihydroxylation of a cyclic diene was
effected utilising Sharpless AD-mix-b.
Key words: Bryce-Smith–Gilbert photoamination, ( )-condur-
amine E, diastereocontrolled synthesis
Treatment of 2 with DBU effected elimination of HBr to
afford diene 8 in 90% yield (Scheme 4). At this stage, syn-
thesis of conduramine E required a regio- and stereoselec-
tive dihydroxylation to give 9. Treatment of 8 under
modified Van Rheenen conditions resulted in dihydroxy-
lation exclusively on the exo face with a 4:1 mixture of re-
gioisomers (9/10) in 55% combined yield.8 Sharpless
asymmetric dihydroxylation reagents are usually ineffec-
tive at kinetic resolution but can be regioselective in diene
dihydroxylation.9 Indeed, when we treated 8 with AD-
mix-b for five hours between 0 °C and –5 °C, 9 was ob-
tained as a single regio- and stereoisomer in 76% yield.10
The shape of the bicyclic ring system makes the exo stereo-
selectivity unsurprising but the high regioselectivity is
more difficult to rationalise. Unfortunately, kinetic reso-
lution was ineffective with only 18% ee being achieved at
40% conversion with AD-mix-b.
We have recently reported on the use of formamide 1, pre-
pared via Bryce-Smith–Gilbert photoamination of ben-
zene, as a precursor for the enantioselective synthesis of
(–)-fortamine.1,2 The synthetic potential of this crystalline
compound has now been further realized, forming the
foundation for a synthesis of ( )-conduramine E
(Scheme 1).3
NtBuCHO
NH2
HO
HO
ref. 1
1
OH
conduramine E
Scheme 1 Proposed synthesis of conduramine E
Thus, beginning from formamide 1,1 bromonium ion in-
duced cyclisation was investigated to install the relative
stereochemistry between the adjacent carbon–nitrogen
and carbon–oxygen bonds required for conduramine E.
However, contrary to expectation, treatment of 1 with two
equivalents of N-bromosuccinimide (NBS) delivered a
49% yield of oxazolidinone 2, presumably via hydration
of the intermediate 3 and oxidation of 4 (Scheme 2).
O
NtBu
NtBu
O
O
(i)
Br
1
2
NBS
NBS
In an effort to improve the yield of this conversion we ex-
amined a two-step procedure (Scheme 3). Initial treat-
ment of 1 with polymer-supported Br3– afforded formate
5, presumably again via 4.4 It is proposed that the acidic
nature of this reagent is sufficient to cause N-protonation
of 4, driving its ring opening to give 5. It is noteworthy
that, in the presence of 2,6-lutidene, amidinium ion 7 was
isolated, presumably via 6. The structure of 7 was con-
firmed by X-ray crystallographic analysis.5 In the absence
HO
O
NtBu
NtBu
O
H2O
Br
Br
3
4
Scheme 2 Oxidative cyclisation of 1. Reagents and conditions: (i)
NBS (2 equiv), CH2Cl2, 0 °C (49%).
SYNLETT 2010, No. 4, pp 0517–0520
0
1.
0
3.
2
0
1
0
Advanced online publication: 11.02.2010
DOI: 10.1055/s-0029-1219526; Art ID: D36909ST
© Georg Thieme Verlag Stuttgart · New York

518
D. Chappell et al.
LETTER
Ph
Ph
O
O
O
O
(i)
HO
OH
13
12
Scheme 5 Takano’s desymmetrisation of 12. Reagents and conditi-
ons: AD-mix-b, MeSO2NH2, t-BuOH–H2O (1:1, 85%).
To examine the effect of the cinchona alkaloid ligand on
the outcome of the dihydroxylation of 8, its reaction with
AD-mix-a was carried out but the same product (9) was
obtained (68% yield). Thus, as suggested by the reaction
under Van Rheenen conditions, the selectivity is innate to
the structure of 8. Calculating the transition state energies
in the exo approach of OsO4–NH3, as a model, to either
double bond of 8 showed that leading to 9 to be 0.9 kcal
mol–1 lower in energy than that leading to 10 (Figure 1).
Whilst no firm conclusions can be made on the basis of
this small difference in energies, it is consistent with the
observed ratio of products obtained in the room-tempera-
ture Van Rheenen dihydroxylation.12
Scheme 3 Optimised synthesis of 2. Reagents and conditions: (i)
–
polymer-supported Br3 , CH2Cl2, r.t.; (ii) 1 M HCl–MeOH; (iii) tri-
phosgene, pyridine, CH2Cl2, (86% from 1); (iv) polymer-supported
–
Br3 , 2,6-lutidene, CH2Cl2, r.t. (68%).
O
O
O
O
Nt-Bu
Nt-Bu
(i)
Figure 1 Calculated transition-state models leading to 9 and 10
(Gaussian 03); DFT used with B3LYP. LANL2DZ basis set for Os,
6-31+G* for other atoms.
Br
2
8
(ii)
Deprotection of 9 was effected by refluxing with TFA to
afford 11 in 76% yield,13,14 which has been previously re-
ported by Prinzbach et al. as an intermediate in their syn-
thesis of (–)-conduramine E.3a For completeness, utilising
known conditions, 11 was hydrolysed with Ba(OH)2 to
give conduramine E then converted into its tetraacetyl de-
O
O
O
O
O
O
NH
OH
NtBu
NtBu
OH
OH
(iii)
+
1
rivative and its H NMR spectrum found to be in accord
HO
HO
with data reported by Chida et al.3b
OH
11
9
10
In conclusion, we have further demonstrated the synthetic
utility of crystalline formamide 1, obtained by photoami-
nation of benzene, as a precursor for the regio- and diaste-
reocontrolled synthesis of natural products possessing
polyhydroxylation.
Scheme
4
Regio- and stereoselective dihydroxylation of 8.
Reagents and conditions: (i) DBU (1.6 equiv), toluene, r.t. (90%); (ii)
AD-mix-b, MeSO2NH2, t-BuOH–H2O (1:1) (76%) (9/10 = 100:0) or
K2OsO4·2H2O, NMO, H2O–acetone–t-BuOH (1.0:0.75:1.0) (55%, 9/
10 = 4:1); (iii) TFA, reflux (76%).
Acknowledgment
During a study directed toward the synthesis of (+)-con-
duritol E, the meso-diene 12 was effectively desymme-
trised to give 13 (85% ee) by treatment with AD-mix-b
whilst, as expected, AD-mix-a afforded its enantiomer
(Scheme 5).9,11
We wish to recognize financial support from Reading Endowment
Trust Fund (S.G. and D.C.), the University of Reading Chemical
Analysis Facility for access to spectroscopic equipment, and the
University of Reading and EPSRC for funds for the Oxford Diffrac-
tion Gemini X-ray diffractometer.
Synlett 2010, No. 4, 517–520 © Thieme Stuttgart · New York

LETTER
Total Synthesis of ( )-Conduramine E
519
which they were attached. An absorption correction was
applied using ABSPACK.17 The structure was refined on F2
using Shelxl97 [2] to R1 = 0.0903, wR2 = 0.1744 for 872
reflections with I > 2s(I). Details of the structure have been
deposited at the Cambridge Crystallographic Data Centre as
CCDC 752251.
References and Notes
(1) (a) Gibson, S. PhD Thesis; University of Reading: UK,
2004. (b) Synthesis of 1
A solution of N-tert-butylcyclohexa-2,5-dienylamine
contaminated with N-tert-butylcyclohexa-2,4-dienylamine
(2.5 g, 16.5 mmol)2b and Et3N (4.65 mL, 33.4 mmol, 2 equiv)
in dry Et2O (375 mL) was stirred under argon at 0 °C before
formic acetic anhydride (1.75 mL, 19.8 mmol, 1.2 equiv)
was added slowly, and the resulting yellow solution left
stirring for 4 h whilst allowing to warm to r.t. The reaction
was quenched with H2O and the layers separated. The
aqueous layer was extracted with Et2O (3 × 150 mL), the
combined organic extracts dried over MgSO4, and the
solvent removed in vacuo. The resultant amber oil was
purified via flash column chromatography (Florisil®,
gradient; hexane–EtOAc = 19:1 to 2:1) to give N-tert-butyl-
N-cyclohexa-2,5-dienylformamide (1) as a colourless
crystalline solid (1.83g, ca. 62%); mp 44–47 °C; Rf = 0.11
(SiO2, hexane–EtOAc = 7:3). IR (thin film): nmax = 3030,
2972, 2814, 1668 (C=O stretch), 1220. 1H NMR (250 MHz,
CDCl3): d = 1.42 [9 H, s, C(CH3)3, rotamer A], 1.48 [9 H, s,
C(CH3)3, rot. B], 2.64–2.69 [2 H, m, H(4), rot. A and B],
4.56–4.63 [1 H, m, H(1), rot. A], 4.80–4.95 [1 H, m, H(1),
rot. B], 5.57–5.91 [4 H, m, 2 × CH=CH, rot. A and B], 8.16
[1 H, s, C(O)H, rot. B], 8.51 [1 H, s, C(O)H, rot. A], [rot. A/
rot. B = 2:1]. 13C NMR (63 MHz, CDCl3): d = 25.95, 26.39
[CH2, C(4), rots. A and B], 29.33 [CH3, C(CH3)3, rot. B],
29.71 [CH3, C(CH3)3, rot. A], 48.07, 49.02 [CH, C(1), rot. A
and B], 56.96, 57.24 [C, C(CH3)3, rot. A and B], 126.28,
126.41, 126.93, 127.86 [CH, C(2,3,5,6), rot. A and B],
162.72 [C, C(O)H, rot. A], 165.89 [C, C(O)H, rot. B].
HRMS (CI): m/z calcd for C11H17NO [M+]: 179.1310; found:
179.1310. Anal. Calcd (%) for (CHN): C, 73.70; H, 9.56; N,
7.81. Found: C, 73.46; H, 9.68; N, 7.67.
(6) (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21,
4233. (b) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc.
1981, 103, 2876. (c) Phillips, A. P.; Baltzly, R. J. Am. Chem.
Soc. 1947, 69, 200.
(7) Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958,
80, 209.
(8) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(10) Procedure
AD-mix-b [K3Fe(CN)6 (0.35 g, 1.08 mmol, 3 equiv), K2CO3
(0.16 g, 1.08 mmol, 3 equiv), (DHQD)2PHAL (2.5 mol%)
and K2OsO4·2H2O (2.5 mol%)] were dissolved in t-BuOH–
H2O (1:1; 20 mL) and stirred for 5 min before addition of
MeSO2NH2 (29 mg, 0.36 mmol, 1 equiv). The solution was
cooled to 0 °C before addition of ( )-(3aS,7aR)-3-(tert-
butyl)-3,3a,7a-trihydrobenzoxazol-2-one (8, 70 mg, 0.36
mmol) in t-BuOH (1 mL). The reaction was left stirring for
5 h between 0 °C and –5 °C. The reaction was diluted with
MeOH and evaporated to dryness in vacuo. The residue was
dissolved in CHCl3–MeOH (9:1) and filtered through a plug
of Celite® upon silica gel. The filtrate was concentrated in
vacuo to give the crude diol which was purified by flash
chromatography (SiO2, CHCl3–MeOH = 9:1) to yield ( )-
(3aS,6S,7S,7aS)-3-(tert-butyl)-6,7-dihydroxy-3,6,7,3a,7a-
pentahydrobenzoxazol-2-one (9) as a colourless oil that
solidified on standing (63 mg, 76%); mp 63–65 °C; Rf = 0.17
(SiO2, CHCl3–MeOH = 19:1). IR (CHCl3): nmax 3441 (OH
stretch), 1728 (C=O stretch) cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.37 [9 H, s, -C(CH3)3], 3.10 (1 H, br s, OH),
3.54 (1 H, d, J = 7 Hz, OH), 4.24–4.27 [2 H, m, H(3a,7)],
4.37–4.40 [1 H, m, H(6)], 4.56–4.61 [1 H, m H(7a)], 5.75 [2
H, br s, H(4,5)]. 13C NMR (63 MHz, CDCl3): d = 28.79 [-
C(CH3)3], 52.52 [CH, C(3a)], 54.37 [C, C(CH3)3], 64.25
[CH, C(6)], 67.51 [CH, C(7)], 73.47 [CH, C(7a)], 124.87
[CH, C(4)], 131.60 [CH, C(5)], 156.43 (C, C=O). MS (CI):
m/z (%) = 228 (37) [MH+]. HRMS: m/z calcd for C11H18NO4:
228.1236; found: 228.1242.
(2) (a) Bellas, M.; Bryce-Smith, D.; Gilbert, A. J. Chem. Soc.,
Chem. Commun. 1967, 862. (b) Bellas, M.; Bryce-Smith,
D.; Clarke, M. T.; Gilbert, A.; Klunkin, G.; Krestonosich, S.;
Manning, C.; Wilson, S. J. Chem. Soc., Perkin Trans. 1
1977, 2571. See also: (c) Yasuda, M.; Yamashita, T.;
Matsumoto, T.; Shima, K.; Pac, C. J. Org. Chem. 1985, 50,
3667. (d) Yasuda, M.; Yamashita, T.; Shima, K.; Pac, C.
J. Org. Chem. 1987, 52, 753. (e) Yasuda, M.; Matsuzaki,
Y.; Shima, K.; Pac, C. J. Chem. Soc., Perkin Trans. 2 1988,
745.
(3) For previous syntheses of conduramine E, see:
(a) Spielvogel, D.; Kammerer, J.; Keller, M.; Prinzbach, H.
Tetrahedron Lett. 2000, 41, 7863. (b) Chida, N.; Sakata, N.;
Murai, K.; Tobe, T.; Nagase, T.; Ogawa, S. Bull. Chem. Soc.
Jpn. 1998, 71, 259. (c) Trost, B. M.; Pulley, S. R.
(11) Takano, S.; Yoshimitsu, T.; Ogasawara, K. J. Org. Chem.
1994, 59, 54.
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Tetrahedron Lett. 1995, 36, 8737.
(4) Amberlite® IRA-900 Br3– form, purchased from Fluka.
(5) Crystal Data
C11H20BrNO3, M = 294.19, monoclinic, Z = 4, spacegroup
P21/a, a = 11.297 (14) Å, b = 9.511 (11) Å, c = 13.553 (14)
Å, b = 106.50 (1)°, U = 1396 (3) Å3. 2765 data were
collected with MoKa radiation at 150 K using the Oxford
Diffraction X-Calibur CCD System. The crystal was
positioned at 50 mm from the CCD. 321 frames were
measured with a counting time of 10 s. Data analysis was
carried out with the CrysAlis program.15 The structure was
solved using direct methods with the Shelxs97 program.16
The nonhydrogen atoms were refined with anisotropic
thermal parameters. The hydrogen atoms bonded to carbon
were included in geometric positions and given thermal
parameters equivalent to 1.2 times those of the atom to
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520
D. Chappell et al.
LETTER
(15) CrysAlis; Oxford Diffraction Ltd.: Abingdon UK, 2006.
(16) Sheldrick, G. M. Acta Crystallogr., Sect. A: Fundam.
Crystallogr. 2008, 64, 112; Shelxs97 and Shelxl97,
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision C.02; Gaussian, Inc.: Wallingford USA, 2004.
(13) Knapp, S.; Patel, D. V. J. Org. Chem. 1984, 49, 5072.
(14) The structure of 11 was confirmed by X-ray crystallography.
Programs for Crystallographic Solution and Refinement.
(17) ABSPACK; Oxford Diffraction Ltd.: Oxford UK, 2005.
Synlett 2010, No. 4, 517–520 © Thieme Stuttgart · New York