Concerning directed oxidation and transacylation during a general approach to hydroxylated lactams

Article abstract of DOI:10.1016/j.tetlet.2009.03.084

A variant of Knight's route to d-mannolactam, exploring the stereoselectivity of directed oxidation conditions, reveals a tendency for hydroxylated N-tosyl lactams to rearrange to γ-lactones. An attempted directed dihydroxylation in this series is shown t

Full text of DOI:10.1016/j.tetlet.2009.03.084

Tetrahedron Letters 50 (2009) 3516–3518
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Tetrahedron Letters
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Concerning directed oxidation and transacylation during a general approach
to hydroxylated lactams
*
Jeremy Robertson , Emilia Abdulmalek
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A variant of Knight’s route to
D-mannolactam, exploring the stereoselectivity of directed oxidation con-
Received 15 January 2009
Revised 20 February 2009
Accepted 5 March 2009
Available online 16 March 2009
ditions, reveals a tendency for hydroxylated N-tosyl lactams to rearrange to
directed dihydroxylation in this series is shown to result in unexpectedly high anti-selectivity.
c
-lactones. An attempted
Ó 2009 Elsevier Ltd. All rights reserved.
In studies directed towards the total synthesis of naturally
occurring iminosugars, including nagstatin1 (Scheme 1), and their
analogues we have assessed a variety of synthetic routes to sugar
lactam intermediates of general structure 1.2 Of the 16 stereoiso-
mers of lactam 1, 11 are described in the literature,3 the vast
majority of their syntheses originating with naturally occurring
hexoses.4 Our efforts have focused on de novo approaches that
could give access to all stereoisomers including those not readily
available from carbohydrate sources. One variant employed
Knight’s decarboxylative carbonylation of N-sulfonyl vinyl oxazo-
lidinones 35 and elaboration of the derived d-lactam 2 by sequen-
tial epoxidation and dihydroxylation. This general route is very
CO2H
N
O
O
O
AcHN
HO
HO
HO
N
NH
NTs
O
NTs
R
OH OH
OH OH
OH
nagstatin
1
2
3
Scheme 1.
asymmetrically, in principle the same overall result could be
achieved from 4 using tandem aziridination and hydrolysis with
a chiral Rh(II)-catalyst.12
Carbamate 4 (Scheme 2) was prepared from divinyl alcohol
using the standard procedure13 and subsequent TA gave oxazolid-
inone 5 (3.8:1 trans/cis ratio) in 65% unoptimised yield.14 The pro-
duction of diastereomers in this reaction is of no consequence for
similar to Knight’s synthesis of D
-mannolactam.6
Our work differs from the published route in two key respects.
First, bearing in mind application to nagstatin, our interest was in
effecting hydroxy-directed epoxidation and dihydroxylation to
generate the 2S,3S,4S,5R-isomer4 (i.e., all syn) of lactam 1. Second,
our work was carried out on the N-tosyl derivative 2 rather than on
the free N–H compound. As will become evident, these two varia-
tions led to interesting outcomes that are reported here.
O
O
OCONH2
O
(iii),(iv)
(v)
(i)
O
NH
O
NH
NTs
Enantiomerically enriched oxazolidinones of general structure 3
(R = CH2OH, CH2OR0 and N-H/acyl variants) have been prepared
from carbohydrate precursors,7 vinyl epoxyalcohols generated by
Sharpless asymmetric epoxidation of dienyl alcohols8 and, most
frequently, from N,O-diprotected serine methyl ester.9 Since the
key aspect for us was to assess relative stereocontrol in elaborating
lactam 2, we were content to have access to ( )-trans-3
(R = CH2OH) provided that the route was significantly shorter than
the existing enantioselective routes and had the potential to be
rendered asymmetric with suitable reagent development. Our
solution was to effect tethered aminohydroxylation10 (TA) of pen-
tadienylcarbamate 4 (Scheme 2) which is a new substrate for this
reaction.11 Although the TA reaction has not yet been achieved
OR
4
RO
trans-5
RO
R = H
R = TBS trans-6
cis-5
cis-6
7, R = TBS
2, R = H
(ii)
O
O
H
O
O
O
O
NTs
NTs
H
O
H
(vi)
(vii)
H
NHTs
H
NHTs
O
O
OH
OH OH
H
8
9
10a
10b, trace
Scheme 2. Reagents and conditions: (i) K2OsO2(OH)4, t-BuOCl, NaOH, i-Pr2NEt, aq.
i-PrOH (65%); (ii) TBSCl, imidazole, DMF (86%); (iii) NaH, TsCl, THF (81%); (iv)
Pd2dba3, PPh3, CO, THF (62%); (v) H2SiF6, aq. CH3CN; (vi) MCPBA, CH2Cl2 (99%, used
crude); (vii) DBU, CH2Cl2 (26%). [Full and dashed arrows in 10a,b indicate,
respectively, an NOE correlation or a lack thereof.]
* Corresponding author. Tel.: +44 1865 275660.
E-mail address: jeremy.robertson@chem.ox.ac.uk (J. Robertson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.084

J. Robertson, E. Abdulmalek / Tetrahedron Letters 50 (2009) 3516–3518
3517
the subsequent chemistry but, in preparation for a potentially
O
O
O
Me
Me
Me
O
asymmetric variant, it is worth noting that this ratio is enhanced
to roughly 8:1 by Pd(0)-mediated equilibration of the O-silylated
diastereomers 6.15 Alternatively, trans-5 was obtained in pure form
by recrystallisation from ethyl acetate. Following N-tosylation,
application of Knight’s published protocol afforded lactam 7 in
62% yield on a 1.5 g scale.
O
N
NTs
NTs
NTs
(i)
(ii)
O
Os
N
O
O
O
Me
OTBS
OH OTBS
12
OH OTBS
13
11
(iii)
(iv)
(v)
Epoxidation of this b,c-unsaturated lactam is known to follow
steric control to give the anti-product6 (11, Scheme 4) but the via-
bility of effecting a hydroxy-directed epoxidation was examined. In
comparison with allylic alcohols, the directing effect of homoallylic
hydroxy groups is not as reliable16 although related precedent ex-
ists in the synthesis of cyclophellitol.17 In the event, epoxidation of
lactam 2 (obtained after silyl deprotection of 7) with the usual hy-
droxy-directable reagents18 gave little or none of the syn-epoxide;
for example, with MCPBA in dichloromethane an almost quantita-
tive yield of the anti-epoxide 8 resulted, the stereochemistry being
secured on the basis of subsequent products. For example, treat-
ment of this epoxide with DBU resulted in the production of bicy-
clic lactone 10a along with a small quantity of diastereomer 10b
(presumably originating from syn-8 impurity in the sample of
epoxide 8 in a proportion probably magnified by the low mass
recovery in this reaction). The structure of these products was de-
duced from the lack of alkene proton resonances in the 1H NMR
spectrum and by a strong IR absorption (1785 cmꢀ1) characteristic
O
Me
O
O
Me
HO
HO
O
Os
O
HO
HO
O
N
N
(v)
O
O
O
Me
Me
TBSO
NHTs
NHTs
NHTs
HO
TBSO
14
15
16
Scheme 4. Reagents and conditions: (i) DBU, CH2Cl2 (68%); (ii) OsO4, TMEDA,
CH2Cl2 (93%); (iii) concd HCl, MeOH (71% from 12); (iv) Na2SO3, aq acetone (40%);
(v) H2S (g), THF (63% from 15, 82% from 13).
of a c-lactone. The stereochemistry was supported by the NOE cor-
relations indicated.
Clearly, after epoxide-opening (?9) intramolecular transacyla-
tion and 1,4-O-addition followed but the timing of these two
events (pathway a or b, Scheme 3) is open to question, at least in
the formation of major isomer 10a. Some insight into this process
came from examination of molecular models19 that showed the
CH2OH group to prefer a pseudoaxial orientation, minimising
1,2-interaction with the N-Ts substituent.20 This, in turn, places
the 2°-OH in a pseudoaxial environment and many low-lying con-
formations were found (e.g., Fig. 1) in which the hydroxy lone pairs
are well disposed to initiate interaction with the lactam carbonyl
[\(OꢁꢁꢁC@O) ca. 140° and an OꢁꢁꢁC distance ca. 3.5 Å]. In support
of this, in the 1H NMR spectrum of silyl derivative 12 (Scheme 4)
the CH(OH)–CH(CH2OTBS) coupling constant is ca. 1.5 Hz consis-
tent with an average di-pseudoequatorial relative disposition of
these protons. These observations support the possibility that
pathway b operates in the production of lactone 10a; isomer 10b
must be formed by this pathway. Although conjugate O-cyclisation
has been observed in related systems, in those examples the lac-
tams were N-unsubstituted (or merely alkylated) and therefore
resistant towards attack by oxygen nucleophiles.21
Figure 1. Representative low-lying conformation of intermediate 9.19
single diastereomer in 93% yield. Although this osmate was a solid
we were unable to obtain a crystal of suitable quality for X-ray dif-
fraction and the stereochemistry was secured retrospectively from
subsequent products (see below). Various products were generated
from osmate 13 depending on the conditions employed to release
the diol functionality. For example, stirring this intermediate with
concd. HCl in methanol gave lactone 14 but less strongly acidic
conditions (aq Na2SO3) merely effected ring interchange to give
lactone 15. Treatment of this lactone with H2S, which is successful
in cleaving osmate esters in fragile systems,23 gave the free diol 16
in reasonable yield. Application of these mild conditions to the
cleavage of the osmate in lactam 13 also resulted in lactone forma-
tion. This sulfonamido lactone 16 was highly crystalline and the
structure, along with those of the preceding intermediates, was se-
cured by X-ray crystallography (Fig. 2).24
This ‘failure’ of the directed dihydroxylation of substrate 12 is,
presumably, a consequence of the preferred conformations of this
lactam (cf. 9, Fig. 1) which are dominated by those bearing a di-
pseudoaxial disposition of CH2OTBS and OH. In the context of
epoxidation in cyclohexenols, Whitham demonstrated that in-
creased rate and stereoselectivity were associated largely with
the presence of a pseudoequatorial hydroxy group.25 Furthermore,
Donohoe has shown that, of the diastereomers of 5-tert-butylcyclo-
hex-2-enol, only the cis-isomer provides good selectivity.26 The
very high anti-selectivity observed for the dihydroxylation of lac-
Under the same conditions, silyl ether 11 (Scheme 4) behaved
as expected and
a,b-unsaturated lactam 12 was obtained, as re-
ported.6 Application of Donohoe’s conditions for directed dihydr-
oxylation22 to lactam 12 produced osmate ester 13, isolated as a
O
O
O
[a]
1,4-
addn.
BAc2-
type
NTs
NTs
O
O
O
NHTs
OH OH
OH
9
10a
O
O
[b]
BAc2-
type
1,4-
addn.
NHTs
HO
Scheme 3. Plausible pathways for the formation of bicyclic lactone 10a in the DBU-
mediated epoxide opening of lactam 8.

3518
J. Robertson, E. Abdulmalek / Tetrahedron Letters 50 (2009) 3516–3518
4. For example: Nishimura, Y.; Adachi, H.; Satoh, T.; Shitara, E.; Nakamura, H.;
Kojima, F.; Takeuchi, T. J. Org. Chem. 2000, 65, 4871–4882.
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Armour, D. R.; Hollinshead, D. M.; Jaxa-Chamiec, A. A. J. Am. Chem. Soc. 2000,
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8. Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574–8583.
9. For example: Ibuka, T.; Suzuki, K.; Habashita, H.; Otaka, A.; Tamamura, H.;
Mimura, N.; Miwa, Y.; Taga, T.; Fujii, N. J. Chem. Soc., Chem. Commun. 1994,
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2001, 2078–2079; (b) Donohoe, T. J.; Cowley, A.; Johnson, P. D.; Keenan, M. J.
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Keenan, M.; Pye, R. J. Org. Lett. 2004, 6, 2583–2585; (e) Donohoe, T. J.; Chughtai,
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11. Kostiuk, S.L. Part II Thesis, Oxford, 2006.
12. Application of the Du Bois conditions (Espino, C.G.; Du Bois, J. Angew. Chem. Int.
Ed. 2001,40, 598–600) to carbamate 4 resulted in a 46% yield of the O-Ac
derivative of oxazolidinone 5 as a 1:1 mixture of diastereomers (Robertson, J.;
Unsworth, W. P., unpublished results).
13. Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521–5524.
14. Relative stereochemistry was assigned on the basis of NOE experiments
conducted on the derived acetate esters.
15. Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481–2484. We also found this
isomerisation procedure to be applicable to the unprotected alcohol 5 and,
following chromatography,
a 96:4 ratio of trans-5:cis-5 was obtained in
essentially quantitative yield.11
16. Henbest, H. B.; Nicholls, B. J. Chem. Soc. 1957, 4608–4612.
17. (a) Aceña, J. L.; De Alba, E.; Arjona, O.; Plumet, J. Tetrahedron Lett. 1996, 37,
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3364.
18. E.g. VO(acac)2, t-BuOOH Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136–6137.
Figure 2. ORTEP representation of lactone 16.24
tam 12 mirrors our recent results with butenolide spiroacetals27
and forms part of a broader trend.28
The pronounced tendency for d-lactams in this series to rear-
range to c-lactones by transacylation warrants comment because
19. A semi-empirical (PM3) conformational search was performed in Spartan using
the findboats keyword. SPARTAN’06; Wavefunction. Irvine, CA: Shao, Y.; Molnar, L.
F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gilbert, A. T. B.;
Slipchenko, L. V.; Levchenko, S. V.; O’Neill, D. P.; DiStasio Jr., R. A.; Lochan, R. C.;
Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.;
Chien, S. H.; Sodt, A.; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.; Korambath, P.
P.; Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.; Doerksen, R.
J.; Dreuw, A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.; Gwaltney, S. R.; Heyden,
A.; Hirata, S.; Hsu, C.-P.; Kedziora, G.; Khalliulin, R. Z.; Klunzinger, P.; Lee, A. M.;
Lee, M. S.; Liang, W. Z.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E.I.; Pieniazek, P.
A.; Rhee, Y. M.; Ritchie, J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.; Subotnik, J.
E.; Woodcock III, H. L.; Zhang, W.; Bell, A. T.; Chakraborty, A. K.; Chipman, D.
M.; Keil, F. J.; Warshel, A.; Hehre, W. J.; Schaefer, H. F.; Kong, J.; Krylov, A. I.; Gill,
P. M. W.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2006, 8, 3172–3191.
20. A similar conformational search performed on the N–H analogue revealed no
significant preference for a pseudoaxial CH2OH.
this is not generally a favourable process. Indeed, the reverse trans-
formation is a well-known method for the production of sugar lac-
tams from carbohydrate lactones (of various ring sizes).29 There is,
however, limited precedent for this reaction when the lactam is
destabilised by further N-acylation (e.g., by Boc)30 and there is a
single example of this ring contraction in an N-sulfonyl substrate
where it occurs as a side reaction within a study on the total syn-
thesis of xestocyclamine A.31 Further work would be necessary to
establish the generality of this reaction and its utility in the synthe-
sis of naturally occurring lactones from, for example, pyridine
derivatives.
21. Altenbach, H.-J.; Himmeldirk, K. Tetrahedron: Asymmetry 1995, 6, 1077–1080.
see also Ref. 6.
22. (a) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J. Tetrahedron Lett.
1997, 38, 5027–5030; (b) Donohoe, T. J. Synlett 2002, 1223–1232.
23. For example: Tius, M. A.; Drake, D. J. Tetrahedron 1996, 52, 14651–14660.
24. Crystal data for 16: C19H31NO7SSi, M = 445.61, colourless thin straw,
monoclinic, a = 6.3423(1), b = 18.3958(3), c = 20.0446(3) Å, V = 2308.69(6) Å3,
T = 150 K, space group P21/c, Z = 4, 8457 reflections measured, 4997
independent all of which were used for refinement (Rint = 0.072), final
wR = 0.1699. CCDC 721043 contains the full crystallographic data for this
compound; this can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
25. Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc. (B) 1970, 1374–
1381.
Acknowledgements
We thank Universiti Putra Malaysia for a studentship (E.A.). We
also thank Sarah Kostiuk and Andrew Tyrrell, respectively, for pre-
liminary experiments and for obtaining the crystal structure. We
also acknowledge the Oxford Chemical Crystallography Service
for use of instrumentation, and Dr. Amber Thompson for invaluable
assistance. Finally, we are very grateful to Dr. Kirill Tchabanenko
for his assistance with the carbonylation reactions.
26. Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell,
M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946–7956.
27. Robertson, J.; Naud, S. Org. Lett. 2008, 10, 5445–5448.
References and notes
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29. (a) Hanessian, S.; Haskell, T. H. J. Heterocycl. Chem. 1964, 1, 55–56; (b)
Hanessian, S.; Haskell, T. H. J. Heterocycl. Chem. 1964, 1, 57–58; (c) Weidmann,
H.; Fauland, E. Liebigs Ann. Chem. 1964, 679, 192–194.
30. (a) Yamauchi, C.; Kuriyama, M.; Shimazawa, R.; Morimoto, T.; Kakiuchi, K.;
Shirai, R. Tetrahedron 2008, 64, 3133–3140; (b) Dinsmore, A.; Doyle, P. M.;
Steger, M.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 2002, 613–621; (c) Coe, D.;
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Hamada, M.; Takeuchi, T. J. Antibiot. 1992, 45, 1404–1408; (b) Aoyama, T.;
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2. (a) Tchabanenko, K. DPhil Thesis, Oxford, 1998.; (b) Abdulmalek, E. DPhil
Thesis, Oxford, 2007.
3. According to an exact structure search of the Chemical Abstracts database
(SciFinder, Jan 2009). The (carbohydrate numbering) 2,3,4,5-R,R,R,S-, R,S,S,S-,
S,R,R,S-, S,R,S,S-, and S,S,S,S- diastereomers do not appear in the hitset.
31. Yun, H.; Gagnon, A.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 5311–5315.