Dimerization of lithiated terminal aziridines

Article abstract of DOI:10.1002/anie.200503303

Let's get together: Dimerization of enantiopure terminal aziridines by lithiation gives efficiently N-protected 2-ene-1,4-diamines with complete selectivity for the E olefin (see scheme). The usefulness of the method was demonstrated in a concise synthesis of (R,S,S,R)-2,5-diamino-1,6-diphenylhexane- 3,4-diol, the core unit of many extremely potent HIV protease inhibitors and also asymmetric catalysts. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200503303

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Chemie
method for the preparation of symmetric 2-ene-1,4-diols 2
(X = O) from terminal epoxides.[2] Although a useful entry to
this valuable class of compounds, this method unfortunately
displayed only a 2:1 selectivity in favor of the E isomer of the
newly formed alkene when using epoxides with primary (R =
C5H11) or secondary (R = cyclohexyl) alkyl substituents (62%
and 77% yield of 2-ene-1,4-diol olefin isomer mixtures,
respectively).
Following on from this, we considered the possibility that
lithiated terminal aziridines 1 (X = NPG, PG = protecting
group)[3] might undergo similar dimerization, thus leading to
synthetically useful (protected) 2-ene-1,4-diamines 2 (X =
NPG).[4] At the outset of our studies we were not aware of
any examples of such dimerizations in the literature,[5] and it
was not known whether the method would yield dimer
compounds in useful efficiencies or whether other pathways
such as formation of 2H-azirines 3[6] (Scheme 1) would be
favored. Although certain lithiated aziridines fused to 5- to 8-
membered rings undergo carbenoid transformations,[7] for-
mation of 2H-azirines in these cases would be significantly
disfavored because of additional ring strain. There is little
precedent for lithiated aziridines having carbenoid reactivity
when the aziridine is not fused to a second ring.[7b]
One additional variable for aziridines (relative to epox-
ides) is the choice of the protecting/activating group at the
aziridine nitrogen atom. In our initial studies we attempted to
dimerize alkyl substituted terminal aziridines bearing the
groups Boc (butyloxycarbonyl), tosyl, or Bus (tert-butylsul-
fonyl),[8] by using lithium 2,2,6,6-tetramethylpiperidide
(LTMP) as the base.[3] Upon treatment with this base, the
N-Boc- and N-tosyl-protected aziridines gave complex mix-
tures of products with no dimers observed, but the lithiated N-
Bus-protected aziridine 1a (X = NBus; R = C5H11) formed
and underwent dimerization in 90% yield to give the
protected 2-ene-1,4-diamine 2a (X = NBus; R = C5H11) as a
mixture of three discernible diastereoisomers.
There are only two possible isomers (alkene E and
Z isomers) that could arise upon dimerization of an enantio-
pure terminal aziridine, and so this method seems better
suited to enantiopure substrates. With this in mind, we
examined the scope of the dimerization reaction with a range
of enantiopure (99% ee) N-Bus-protected terminal aziri-
dines[9] (Table 1).
Synthetic Methods
DOI: 10.1002/anie.200503303
Dimerization of Lithiated Terminal Aziridines**
David M. Hodgson* and Steven M. Miles
It has been known for a long time that lithiated epoxides 1
(Scheme 1, X = O) can display carbenoid-type reactivity,
including dimerization.[1] Such dimerizations have been
developed recently by our research group as a synthetic
The enantiopure aziridines (entries 1–5) all dimerized in
high efficiency under the same straightforward reaction
conditions (aziridine 0.32 moldmÀ3 in THF/hexanes (2:3),
3 equiv LTMP, À788C to 08C, total reaction time 80 min; see
Experimental Section).[10] Crucially, all these reactions pro-
ceeded with complete E selectivity for the alkene bond
formed, with no traces of the Z alkene detectable in either
the crude or purified products. The E geometry of the alkene
was determined unambiguously in the case of 5b (single-
crystal X-ray structure, see Supporting Information), with the
other products 5a and 5c–e assigned as E isomers by analogy.
Other possible reaction pathways for the lithiated aziridines
such as azirine formation, reaction with excess LTMP to give
enamines/aldehydes,[11] or intramolecular cyclopropanation[12]
(entry 4) did not feature significantly. Even when aziridine 4a
was added to LTMP in THF at RT with no cooling, dimer 5a
Scheme 1. Possible reactions of lithiated epoxides or aziridines.
[*]Dr. D. M. Hodgson, Dr. S. M. Miles
Department of Chemistry
University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX13TA (UK)
Fax: (+44)186-528-5002
E-mail: david.hodgson@chem.ox.ac.uk
[**]We thank the EPSRC for a Research Grant (GR/S46789/01), the
EPSRC National Mass Spectrometry Service Centre for providing
mass spectra, Dr. A. Cowley for X-ray crystallographic analyses, and
P. Humphreys for preliminary observations and samples of
aziridines 4d and 4g.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Dimerization of lithiated N-Bus aziridines.
Entry
Aziridine 4
Yield of dimer 5 [%]
1
2
3
4
5
6
7
(R)-4a
(S)-4b
(R)-4c
(R)-4d
(R)-4e
4 f
97
Scheme 3. DMP323 and its derivation from a 1,4-diamine-2,3-diol
unit.[13b]
97
81
received considerable attention in recent years as peptidomi-
metic HIV protease inhibitors.[13] A common structural
feature of these inhibitors is a 1,4-diamine-2,3-diol unit with
R,S,S,R configuration, often with flanking (1,4-) benzyl
groups.
We decided to see if our new methodology could be
applied in a concise synthesis of such a desirable structural
motif, starting with the benzyl-substituted aziridine (R)-4h
(Scheme 4). We found that treatment of aziridine 4h[9] with
LTMP gave the N-Bus-protected 2-ene-1,4-diamine 5h in
88
70
86[a]
41[b]
4g
[a]Mixture of olefin isomers obtained (ratio 93:7). [b]Reaction quenched
after 10 min at À788C and yielded a mixture of olefin isomers (ratio
57:43). Cy=cyclohexyl.
was isolated in 84% yield and as a single alkene
isomer after reaction for 30 minutes, thus dem-
onstrating the inherent robustness and selectivity
of the method. Enantiomeric aziridine (S)-4a
also underwent dimerization in 97% yield
(entry 1), thus showing the methodology to be
equally applicable to the preparation of either
enantiomeric series of dimers 5. The reaction was
also efficient for an achiral 2,2-disubstituted
aziridine 4 f and to a lesser extent with the
nonsubstituted aziridine 4g (entries 6 and 7,
respectively). In both these latter cases hetero-
chiral as well as homochiral dimerization path-
ways are possible, and the products were isolated
as mixtures of E and Z isomers.
Scheme 4. Applications of the dimerization methodology. Reagents and conditions:
a) LTMP (3 equiv), THF/hexanes, À788C to 08C, 80 min; b) OsO4 (2.5 mol%), NMO
(1.4 equiv), THF/H2O, RT, 2 days; c) F3CSO3H (0.1n in CH2Cl2), anisole, 08C to RT,
16 h; d) H2 (1 atm), Pd on C (5 mol%), EtOH, RT, 24 h.
Formation of the E isomer from enantiopure
substrates is consistent with an inital trans-lithiation of the
aziridine at the terminal position,[3] followed by reaction of
one lithiated aziridine as a nucleophile with a second acting as
an electrophile, and finally syn elimination.[2] One possible
reason for the superior alkene stereoselectivity seen with
aziridines relative to their epoxide counterparts may be a
further disfavoring of the anti-elimination pathway as a result
of steric hindrance between the N-Bus groups (Scheme 2).
1,4-Diamine derivatives, especially cyclic ureas such as the
parent DuPont Merck compound DMP323 (Scheme 3), have
91% yield and with complete E selectivity. Importantly,
potential side products arising from benzylic deprotonation
rather than deprotonation at the aziridine were not observed
to any significant extent.[14] Simple treatment of alkene 5h
with OsO4/NMO (N-methylmorpholine-N-oxide) yielded the
R,S,S,R diol 6 with high diastereoselectivity (ca. 7:1) over the
R,R,R,R diol (83% yield for 6).[15] The R,S,S,R configuration
of 6 (and also indirectly the E geometry of 5h prior to syn-
dihydroxylation) was confirmed by X-ray crystallographic
analysis (see Supporting Information).
Removal of the N-Bus group[8a] of diol (R,S,S,R)-6 gave
the free diaminodiol (R,S,S,R)-7 in 99% yield; this is a core
C2-symmetric unit of a number of extremely potent HIV
protease inhibitors. (R,S,S,R)-7 has been prepared in a
previous HIV protease inhibitor study[16] and has also found
use as a ligand or ligand precursor in various enantioselective
transformations.[17] The efficiency of deprotection to give the
functionalized diaminodiol (R,S,S,R)-7 is of particular note.
Benzyl aziridine (S)-4h was also prepared and dimerized
(94% yield), thus demonstrating that the opposite enantio-
meric series can also be accessed.[18] Finally, hydrogenation of
Scheme 2. Possible elimination pathways in dimer formation.
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Chemie
Aggarwal, E. Alonso, M. Ferrara, S. E. Spey, J. Org. Chem. 2002,
the alkene bond in the dimeric compound (R,R)-5h was also
achieved under mild conditions (1 atm H2, 5 mol% Pd on C,
RT) to give the saturated analogue 8 in 99% yield. This result
further highlights the utility of the dimerization methodology,
and demonstrates efficient access to saturated protected
enantiopure C2-symmetric 1,4-diamines.
67, 2335 – 2344; c) R. Luisi, V. Capriati, S. Florio, R. Ranaldo,
Tetrahedron Lett. 2003, 44, 2677 – 2681; d) R. Luisi, V. Capriati,
S. Florio, P. Di Cunto, B. Musio, Tetrahedron 2005, 61, 3251 –
3260.
[7] a) P. Müller, P. Nury, Helv. Chim. Acta 2004, 87, 227 – 239;
ˇ
b) D. M. Hodgson, B. Stefane, T. J. Miles, J. Witherington, Chem.
In summary, we have developed a dimerization pathway
of terminal aziridines by lithiation to give N-protected 2-ene-
1,4-diamines with complete E-olefin selectivity when starting
with enantiopure substrates. The dimerization proved highly
efficient for a range of alkyl-substituted and functionalized
aziridines, by using the same straightforward reaction con-
ditions in each case. The usefulness of the method was
demonstrated by the efficient and selective synthesis of
diaminodiol (R,S,S,R)-7, the core unit of a number of
extremely potent HIV protease inhibitors.
Commun. 2004, 2234 – 2235; c) C. M. Rosser, S. C. Coote, J. P.
Kirby, P. OꢀBrien, D. Caine, Org. Lett. 2004, 6, 4817 – 4819.
[8] a) P. Sun, S. M. Weinreb, M. Shang, J. Org. Chem. 1997, 62,
8604 – 8608; b) A. V. Gontcharov, H. Liu, K. B. Sharpless, Org.
Lett. 1999, 1, 783 – 786.
[9] Enantiopure aziridines were prepared in a straightforward
manner and in excellent yield from the corresponding epoxides
of opposite configuration (available commercially or according
to: S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B.
Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 1307 – 1315) using the following sequence:
a) tBuSO2NH2, BnEt3NCl, K2CO3; b) (MeSO2)2O, 4-dimethyla-
minopyridine, pyridine; c) K2CO3 (see Ref. [3] and also: D. M.
Hodgson, M. J. Fleming, S. J. Stanway, Org. Lett. 2005, 7, 3295 –
3298).
Experimental Section
Representative procedure for dimerization of terminal aziridine 4:
nBuLi (1.6m in hexanes, 1.88 mL, 3.0 mmol) was added dropwise to a
solution of 2,2,6,6-tetramethylpiperidine (0.51 mL, 3.0 mmol) in THF
(0.4 mL) at À788C. The mixture was warmed to 08C over 15 min,
then cooled to À788C before dropwise addition of the aziridine 4
(1.0 mmol) in THF (0.8 mL). The mixture was stirred at À788C for
20 min, then at 08C for 1 h, before the addition of MeOH (0.8 mL),
saturated aqueous NH4Cl (8 mL), and Et2O (16 mL). The layers were
separated, and the aqueous phase was extracted with Et2O (16 mL).
The combined organic phase was dried (MgSO4) and concentrated
under reduced pressure. Flash chromatography of the residue (SiO2,
petroleum ether/diethyl ether) gave the protected 2-ene-1,4-diamine
5.
[10] In studies with substrate 4a, the use of fewer equivalents of
LTMP or extended reaction times at À788C led to incomplete
reaction.
[11] D. M. Hodgson, C. D. Bray, N. D. Kindon, J. Am. Chem. Soc.
2004, 126, 6870 – 6781.
[12] a) D. M. Hodgson, Y. K. Chung, J.-M. Paris, J. Am. Chem. Soc.
2004, 126, 8664 – 8665; b) D. M. Hodgson, Y. K. Chung, J.-M.
Paris, Synthesis 2005, 2264 – 2266.
[13] a) P. Y. S. Lam, P. K. Jadhav, C. J. Eyermann, C. N. Hodge, Y. Ru,
L. T. Bacheler, J. L. Meek, M. J. Otto, M. M. Rayner, Y. N.
Wong, C.-H. Chang, P. C. Weber, D. A. Jackson, T. R. Sharpe, S.
Erickson-Viitanen, Science 1994, 263, 380 – 384; b) M. E. Pierce,
G. D. Harris, Q. Islam, L. A. Radesca, L. Storace, R. E.
Waltermire, E. Wat, P. K. Jadhav, G. C. Emmet, J. Org. Chem.
1996, 61, 444 – 450; c) D. A. Nugiel, K. Jacobs, T. Worley, M.
Patel, R. F. Kaltenbach III, D. T. Meyer, P. K. Jadhav, G. V.
De Lucca, T. E. Smyser, R. M. Klabe, L. T. Bacheler, M. M.
Rayner, S. P. Seitz, J. Med. Chem. 1996, 39, 2156 – 2169;
d) P. Y. S. Lam, Y. Ru, P. K. Jadhav, P. E. Aldrich, G. V. DeLucca,
C. J. Eyermann, C.-H. Chang, G. Emmett, E. R. Holler, W. F.
Daneker, L. Li, P. N. Confalone, R. J. McHugh, Q. Han, R. Li,
J. A. Markwalder, S. P. Seitz, T. R. Sharpe, L. T. Bacheler, M. M.
Rayner, R. M. Klabe, L. Shum, D. L. Winslow, D. M. Korn-
hauser, D. A. Jackson, S. Erickson-Viitanen, C. N. Hodge, J.
Med. Chem. 1996, 39, 3514 – 3525; e) A. M. Davis, S. J. Teague,
G. J. Kleywegt, Angew. Chem. 2003, 115, 2822 – 2841; Angew.
Chem. Int. Ed. 2003, 42, 2718 – 2736; f) W. A. Loughlin, J. D. A.
Tyndall, M. P. Glenn, D. P. Fairlie, Chem. Rev. 2004, 104, 6085 –
6117.
Received: September 16, 2005
Published online: December 27, 2005
Keywords: aziridines · lithiation · small ring systems ·
.
synthetic methods
[1] a) K. L. Dhawan, B. D. Gowland, T. Durst, J. Org. Chem. 1980,
45, 922 – 924; b) P. Lohse, H. Loner, P. Acklin, F. Sternfeld, A.
Pfaltz, Tetrahedron Lett. 1991, 32, 615 – 618; c) for a review, see:
D. M. Hodgson, C. D. Bray in Aziridines and Epoxides in
Organic Synthesis (Ed.: A. K. Yudin), Wiley-VCH, Weinheim,
2006, pp. 143 – 184.
[2] D. M. Hodgson, C. D. Bray, N. D. Kindon, Org. Lett. 2005, 7,
2305 – 2308.
[14] Conversely, when 2,3-epoxypropylbenzene was subjected to
dimerization conditions (see Experimental Section) the major
product was cinnamyl alcohol (arising from benzylic deproto-
nation and eliminative rearrangement), and no significant 2-ene-
1,4-diol was observed.
[15] Similar dihydroxylation of the analogous N-Boc-protected 2-
ene-1,4-diamine displayed poor diastereoselectivity (2:3) and
favored the opposite (less desirable for HIV protease inhibition)
diastereoisomer to that seen in our case, see: a) A. V. R. Rao,
M. K. Gurjar, S. Pal, R. J. Pariza, M. S. Chorghade, Tetrahedron
Lett. 1995, 36, 2505 – 2508; b) M. K. Gurjar, S. Pal, A. V. R. Rao,
R. J. Pariza, M. S. Chorghade, Tetrahedron 1997, 53, 4769 – 4778.
[16] A. Dondoni, D. Perrone, M. Rinaldi, J. Org. Chem. 1998, 63,
9252 – 9264.
[3] The electrophile trapping of lithiated terminal aziridines has
been developed recently, see: D. M. Hodgson, P. G. Humphreys,
J. G. Ward, Org. Lett. 2005, 7, 1153 – 1156.
[4] For a review of the utility of diamine derivatives in asymmetric
catalysis, see: F. Fache, E. Schulz, M. L. Tommasino, M. Lemaire,
Chem. Rev. 2000, 100, 2159 – 2231; for the utility of 1,4-diamine
derivatives as HIV protease inhibitors, see Ref. [13].
[5] Dimerization of a lithiated methylene aziridine to give a
cyclopentene has been reported, see: H. Quast, C. A. W.
VØlez, Angew. Chem. 1974, 86, 380 – 381; Angew. Chem. Int.
Ed. Engl. 1974, 13, 342 – 343; dimerization of N-unprotected
aziridines under Lewis acid catalysis to give aminoaziridines is
known, see: A. Caiazzo, S. Dalili, A. K. Yudin, Synlett 2003,
2198 – 2202.
[6] a) F. A. Davis, H. Liu, C.-H. Liang, G. V. Reddy, Y. Zhang, T.
Fang, D. D. Titus, J. Org. Chem. 1999, 64, 8929 – 8935; b) V. K.
[17] a) A. Zhang, Y. Feng, B. Jiang, Tetrahedron: Asymmetry 2000,
11, 3123 – 3130; b) J. Zhao, X. Bao, X. Liu, B. Wan, X. Han, C.
Angew. Chem. Int. Ed. 2006, 45, 935 –938
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Communications
Yang, J. Hang, B. Jiang, Tetrahedron: Asymmetry 2000, 11, 3351 –
3359; c) B. Jiang, Y. Feng, J.-F. Hang, Tetrahedron: Asymmetry
2001, 12, 2323 – 2329.
[18] Derivatization of (S,R,R,S)-7 has been used to produce arrays of
HIV protease inhibitors for biological evaluation and has
yielded a number of highly active compounds, see: a) D. J.
Kempf, L. Codacovi, X. C. Wang, W. E. Kohlbrenner, N. E.
Wideburg, A. Saldivar, S. Vasavanonda, K. C. Marsh, P. Bryant,
H. L. Sham, B. E. Green, D. A. Betebenner, J. Erickson, D. W.
Norbeck, J. Med. Chem. 1993, 36, 320 – 330; b) K.-H. Budt, A.
Peyman, J. Hansen, J. Knolle, C. Meichsner, A. Paessens, D.
Ruppert, B. Stowasser, Bioorg. Med. Chem. 1995, 3, 559 – 571;
c) S. F. Martin, G. O. Dorsey, T. Gane, M. C. Hillier, H. Kessler,
M. Baur, B. Mathꢁ, J. Med. Chem. 1998, 41, 1581 – 1597.
938
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