Semipinacol rearrangement of cis-fused β-lactam diols into keto-bridged bicyclic lactams

Article abstract of DOI:10.1021/ol300605y

The 6-azabicyclo[3.2.1]octane ring system, prevalent in a range of biologically active molecules, is prepared through a novel semipinacol rearrangement utilizing a cyclic phosphorane or sulfite intermediate. The rearrangement proceeds with exclusive N-acyl group migration of a β-lactam ring and results in carbonyl functionality at the 7- and bridging 8-position of the bicycle. Precursor ring-fused β-lactam diols are prepared through a sequence of 4-exo trig carbamoyl radical cyclization, regioselective dithiocarbamate group elimination, and dihydroxylation.

Full text of DOI:10.1021/ol300605y

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2234–2237
Semipinacol Rearrangement of Cis-Fused
β-Lactam Diols into Keto-Bridged Bicyclic
Lactams
Richard S. Grainger,*,† Marie Betou,† Louise Male,† Mateusz B. Pitak,‡ and
Simon J. Coles‡
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.,
and National Crystallography Service, School of Chemistry, University of Southampton,
Southampton SO17 1BJ, U.K.
r.s.grainger@bham.ac.uk
Received March 9, 2012
ABSTRACT
The 6-azabicyclo[3.2.1]octane ring system, prevalent in a range of biologically active molecules, is prepared through a novel semipinacol
rearrangement utilizing a cyclic phosphorane or sulfite intermediate. The rearrangement proceeds with exclusive N-acyl group migration of a
β-lactam ring and results in carbonyl functionality at the 7- and bridging 8-position of the bicycle. Precursor ring-fused β-lactam diols are prepared
through a sequence of 4-exo trig carbamoyl radical cyclization, regioselective dithiocarbamate group elimination, and dihydroxylation.
The 6-azabicyclo[3.2.1]octane ring system is found in a
wide variety of biologically active, natural1À8 and non-
natural products.9À11 We have targeted the 7,8-dioxo-6-
azabicyclo[3.2.1]octane core structure 1 as a potential
useful building block, particularly for the synthesis of
C-8 substituted variants.3À8 In this letter we report the
synthesis of 1 based on a novel semipinacol rearrangement
of a cis-fused β-lactam (Scheme 1).12,13
(6) Sarain A: Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.;
Garg, N. K.; Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.;
Ng, F. W.; Overman, L. E. J. Am. Chem. Soc. 2007, 129, 11987–12002.
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Dekhane, M. Org. Lett. 2010, 12, 2834–2837. (b) The first total synthesis
of peduncularine exploits a keto-bridged bicyclic lactam as a key
intermediate: Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am.
Chem. Soc. 1989, 111, 2588–2595.
† University of Birmingham.
‡ University of Southampton.
(8) Nominine: Peese, K. M.; Gin, D. Y. Chem.;Eur. J. 2008, 14,
1654–1665.
(1) Securinega alkaloids: Weinreb, S. Nat. Prod. Rep. 2009, 26, 758–
775.
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Ed. 2007, 46, 5377–5380.
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2008, 130, 13778–13789. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan,
R. R.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187–11194. (c)
Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2011, 133, 418–419.
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Nurimoto, S.; Hayashi, G. J. Med. Chem. 1977, 20, 221–228.
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Smith, D. F. J. Chem. Soc., Chem. Commun. 1990, 1412–1414.
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Nat. Prod. 2008, 71, 1663–1668. (b) Calyciphylline F: Saito, S.; Kubota,
T.; Kobayashi, J. Tetrahedron Lett. 2007, 48, 3809–3812. (c) Calyciphyl-
line D: Saito, S.; Kubota, T.; Fukushi, E.; Kawabata, J.; Zhang, H.;
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(12) For a review of the semipinacol rearrangement, see: Song, Z.-L.;
Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.
(13) A related rearrangement in the all carbocyclic [4.2.0]-ring system
is hampered by the instability of the bridged 1,3-dicarbonyl product:
Blanchard, A. N.; Burnell, D. J. Tetrahedron Lett. 2001, 42, 4779–4781.
r
10.1021/ol300605y
Published on Web 04/18/2012
2012 American Chemical Society

cis-Fused β-lactams 3 were prepared in four steps
(three purifications) from cyclohexenylbromide using
our previously reported carbamoyl radical cycliza-
tionÀdithiocarbamate group transfer methodology
(Scheme 3).18 Initial attempts to prepare a substrate
suitable for semipinacol rearrangement (Scheme 1,
LG = SC(S)NEt2) through deprotonation of the
β-lactam and oxidation of the resulting anion were un-
successful, but resulted in the discovery that 3 was prone to
dithiocarbamate group elimination using strong bases
such as LDA. Optimized conditions for regioselective
elimination were therefore determined, with the use of
1.1 equiv of both lithium hexamethyldisilazane and MeI
at À78 °C providing good to excellent yields of 4.19 The
MeI is presumed to activate the dithiocarbamate through
S-alkylation, producing a better leaving group.20 In the
absence of MeI, yields were routinely lower (ca. 50%).
Use of a large excess base is detrimental to the yield of 4 as
the double bond can be moved out of conjugation to give
5.21,22 Dihydroxylation of 4 gave the diol 6 as a single
stereoisomer. The stereochemistry of 6 was assigned based
on the unlikelihood of forming the alternative highly
strained trans-fused [4.2.0] bicyclic ring system and con-
firmed through X-ray analysis of the corresponding cyclic
sulfites (vide infra).
Scheme 1. Proposed Semipinacol Rearrangement and Represen-
tative Natural Products Containing 8-Functionalized
6-Azabicyclo[3.2.1]octane Ring Systems (LG = Leaving Group)
β-Lactams have previously been investigated as precur-
sors to five-membered nitrogen heterocycles,14 though
rarely through rearrangement with C2ÀC3 bond migra-
tion, and only for nonfused ring systems (Scheme 2).15À17
Notably in all cases only migration of the N-acyl carbon
occurs; compounds resulting from migration of the alter-
native C3ÀC4 bond of the β-lactam were not observed.
Scheme 3. Synthesis and Rearrangement of Cis-Fused β-Lac-
tam Diols
Scheme 2. Previous Examples of Ring Expansion of Mono- and
Spirocyclic β-Lactams with N-Acyl Group Migration15À17
(14) (a) For a review on the synthetic utility of β-lactams, see:
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
4437–4492. For more recent examples of ring expansion involving
N1ÀC4 bond migration, see: (b) Dekeukeleire, S.; D’hooghe, M.; De
Kimpe, N. J. Org. Chem. 2009, 74, 1644–1649. (c) Alcaide, B.; Almendros,
ꢀ
P.; Cabrero, G.; Callejo, R.; Ruiz, M. P.; Arno, M.; Domingo, L. R. Adv.
Synth. Catal. 2010, 352, 1688–1700 and references therein.
(15) Paquette, L. A.; Brand, S.; Behrens, S. C. J. Org. Chem. 1999, 64,
2010–2025.
(18) (a) Grainger, R. S.; Innocenti, P. Angew. Chem., Int. Ed. 2004,
43, 3445–3448. (b) Grainger, R. S.; Innocenti, P. Heteroatom. Chem.
2007, 18, 568–571.
(16) Williams, E. L. Synth. Commun. 1992, 22, 1017–1021.
(17) (a) Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. R. Adv.
Synth. Catal. 2010, 352, 621–626. (b) Alcaide, B.; Almendros, P.; Luna,
(19) CCDC 866295 (1b hydrate), CCDC 866296 (4b), CCDC 866297
(9b), CCDC 866298 (10b), and CCDC 869870 (13) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
ꢀ
A.; Cembellın, S.; Arno, M.; Domingo, L. R. Chem.;Eur. J. 2011, 17,
´
11559–11566.
Org. Lett., Vol. 14, No. 9, 2012
2235

A screen of standard conditions for the pinacol and
semipinacol rearrangement12 of diols and their deri-
vatives was complicated by unexpected difficulties in
selectively activating the secondary over the tertiary
alcohol in 6. Attention therefore turned to the use of
cyclic systems for diol activation. The simplest con-
ditions found involve treatment of 6 with a mixture of
Ph3P and C2Cl6 in refluxing acetonitrile, which pro-
vide the target bridged bicycle 1 in good to excellent
yield.23b,c Ph3PCl2, generated in situ, is presumed to
react with the diol to form a cyclic phosphorane 7.
There is a strong thermodynamic driving force for
rearrangement of 7, involving strain release through
ring expansion of the β-lactam and formation of strong
CdO and PdO bonds. Rearrangements through in situ
generated cyclic phosphoranes have rarely been ap-
plied in synthesis,23 and only to carbonÀhydrogen bond
migrations (Meinwald rearrangement). Hence this is
the first example where cyclic phosphoranes have been
applied to rearrangement with carbonÀcarbon bond
migration.
Two possible rearrangement pathways are available
for 7, with migration of bond i, in either a concerted or
stepwise process, leading to the keto-bridged bicylic lactam
1, or migration of bond ii, leading to the fused 2,3-
dioxopyrrolidine 8. We have only observed formation of
1, irrespective of the N-substituent, suggesting that the
preference for N-acyl group migration, as seen for mono-
and spirocyclic β-lactams (Scheme 2), is maintained in
fused ring systems. The formation of 1 rather than 8 was
initially deduced based on the 13C NMR spectrum of the
alcohol obtained upon L-selectride-mediated reduction of
the ketone and confirmed by X-ray analysis of the crystal-
lized ketone hydrate of 1b (see Supporting Information).19
A second related method, although requiring an
additional step, avoids the potential problem of re-
moval of triphenylphosphine oxide from the reaction
mixture. Diol 6 was transformed into a 1:1 mixture of
diastereomeric cyclic sulfites 9 and 10 (Scheme 4).
Thermolysis of the mixture of 9 and 10 in dipheny-
lether at 190 °C cleanly afforded 1 in excellent yield,
presumably through loss of SO2.24 The process
was again compatible with alkyl, benzyl, and aryl
N-substituents.
Figure 1. X-ray crystal structures of 9b (top) and 10b
(bottom). Selected bond lengths and torsion angles: 9b:
C2ÀC7 1.542(2) A, C2ÀC3 1.558(2) A, O2ÀC1ÀC2ÀC7
140.95(13)°, O2ÀC1ÀC2ÀC3 À117.46(14)°; 10b: C2ÀC7
1.5394(17) A, C2ÀC3 1.5617(17) A, O2ÀC1ÀC2ÀC7
147.23(11)°, O2ÀC1ÀC2ÀC3 À108.61(12)°.
(20) Hayashi, T.; Sakurai, A.; Oishi, T. Chem. Lett. 1977, 1483.
(21) The X-ray crystal structure19 of 4b suggests a degree of strain
about a nonplanar carbonÀcarbon double bond. See Supporting In-
formation for details.
Scheme 4. Thermal Rearrangement of Cyclic Sulfites
(22) We have previously shown that thermal elimination of dithio-
carbamate 3a gives the nonconjugated alkene 5a in 79% yield: Ahmed,
S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org.
Chem. 2008, 73, 8116–8119.
(23) (a) Applequist, D. E.; Gebauer, P. A.; Gwynn, D. E.; O’Con-
nor, L. H. J. Am. Chem. Soc. 1972, 94, 4272–4278. (b) Decamp, A. E.;
Mills, S. G.; Kawaguchi, A. T.; Desmond, R.; Reamer, R. A.;
DiMichele, L.; Volante, R. P. J. Org. Chem. 1991, 56, 3564–3571.
(c) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetra-
hedron Lett. 2000, 41, 1959–1962. (d) Defaut, B.; Parsons, T. B.;
Spencer, N.; Male, L.; Kariuki, B. M.; Grainger, R. S. Submitted for
publication.
(24) For semipinacol rearrangements of cyclic sulfites, see: (a)
Griffin, G. W.; Manmade, A. J. Org. Chem. 1972, 37, 2589–2600. (b)
Nemoto, H.; Miyata, J.; Hakamata, H.; Nagamochi, M.; Fukumoto, K.
Tetrahedron 1995, 51, 5511–5522.
2236
Org. Lett., Vol. 14, No. 9, 2012

The overall strategy is also applicable to the pre-
paration of a larger ring system. Radical cyclizationÀ
dithiocarbamate group transfer of amidocyclohep-
tene 11 gave a separable mixture of diastereoisomers
12 and 13 (Scheme 5), with the structure of the latter
proven by X-ray crystallography.19 Elimination of
the dithiocarbamate group in 12 proceeded without
incident to give the conjugated alkene 14 in excel-
lent yield.27 Surprisingly, 13 proved inert to the
combination of LHMDS and MeI but was success-
fully converted to 14 through thermal elimination.22
Dihydroxylation of 14, followed by semipinacol re-
arrangement, via the cyclic sulfite 16 or directly
through the phosphorane, gave the keto-bridged bi-
cyclic lactam 17 in excellent yield. The 7-azabicyclo-
[4.2.1]nonane ring system is found within members
of the Gelsemium alkaloids, such as gelsedine and
gelselegine.28
Scheme 5. Synthesis of the 8,9-Dioxo-7-azabicyclo-
[4.2.1]nonane Ring System
In summary, the semipinacol rearrangement of cis-fused
β-lactam diols can be readily achieved through the inter-
mediacy of a cyclic phosphorane or sulfite. Chemoselec-
tive N-acyl group migration leads to keto-bridged bi-
cyclic lactams in excellent yield. The presence of both an
amide and a ketone in the rearrangement products 1 makes
them potentially versatile intermediates for organic synth-
esis. Future work will concentrate on extension to more
highly substituted systems and their application in target
synthesis.
Careful chromatography allowed for separation of
the two cyclic sulfite diastereoisomers 9b and 10b, the
structures of which were confirmed by X-ray crystal-
lography (Figure 1).19,25 In both cases the C2ÀC7 bond
(the equivalent of bond i in phosphorane 7, Scheme 3) is
shorter than the C2ÀC3 bond (the equivalent of bond ii
in 7). However, as seen in the O2ÀC1ÀC2ÀC7 and the
O2ÀC1ÀC2ÀC3 torsion angles, the migrating C2ÀC7
bond is better aligned with the breaking C1ÀO2 bond
than the C2ÀC3 bond.26
(25) The sulfinyl stereocenter in sulfites 9 and 10 was assigned by 1H
NMR and confirmed though X-ray analysis of 9b and 10b.19 The
anisotropy of the sulfinyl group results in a downfield shift of the proton
adjacent to oxygen (C(10)ÀH in Figure 1) for 9 (5.25À5.41 ppm)
compared with 10 (4.91À5.04 ppm). For examples of the use of sulfinyl
group anisotropy for the assignment of stereochemistry, see: (a) Bed-
ford, S. T.; Grainger, R. S.; Steed, J. W.; Tisselli, P. Org. Biomol. Chem.
2005, 3, 404–406. (b) Tanaka, S.; Sugihara, Y.; Sakamoto, A.; Ishii, A.;
Nakayama, J. J. Am. Chem. Soc. 2003, 125, 9024–9025. (c) Aggarwal,
V. K.; Grainger, R. S.; Newton, G. K.; Spargo, P. L.; Hobson, A. D.;
Adams, H. Org. Biomol. Chem. 2003, 1, 1884–1893 and references
therein.
Acknowledgment. We thank the EPSRC for funding
(studentship to M.B., EP/G031371/1). The NMR
spectrometers used in this research were obtained
through Birmingham Science City: Innovative Uses
for Advanced Materials in the Modern World (West
Midlands Centre for Advanced Materials Project 2),
with support from Advantage West Midlands (AWM)
and part funded by the European Regional Devel-
opment Fund (ERDF). We thank the EPSRC UK
National Crystallographic Service at the University
of Southampton for the collection of crystallographic
data.
Supporting Information Available. Experimental pro-
cedures, analytic data, and copies of 1H and 13C NMR for
all new compounds. X-ray crystallographic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Qualitatively, 9b was found to rearrange faster and in higher
yield (45 min, 100% yield) than 10b (135 min, 87% yield).
(27) For an alternative approach to structures such as 14 based on
palladium catalyzed carbonylation of 2-bromoallylamines, see: Mori,
M.; Chiba, K.; Okita, M.; Kayo, I.; Ban, Y. Tetrahedron 1985, 41, 375–
385.
(28) van Henegouwen, W. G. B.; Fieseler, R. M.; Rutjes, F. P. J. T.;
Hiemstra, H. J. Org. Chem. 2000, 65, 8317–8325.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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