Synthesis of the spiro fused β-lactone-γ-lactam segment of oxazolomycin

Article abstract of DOI:10.1016/j.tetlet.2006.06.117

An effective synthetic strategy for construction of the novel spiro-bicyclic β-lactone-γ-lactam system present in oxazolomycin has been demonstrated. The 3,4-disubstituted pyrrolidine ring system was constructed via an Evans aldol reaction. The spiro-β-la

Full text of DOI:10.1016/j.tetlet.2006.06.117

Tetrahedron Letters 47 (2006) 6031–6035
Synthesis of the spiro fused b-lactone-c-lactam segment
of oxazolomycin
Debendra K. Mohapatra,* Dhananjoy Mondal, Rajesh G. Gonnade,
Mukund S. Chorghade and Mukund K. Gurjar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 22 April 2006; revised 12 June 2006; accepted 22 June 2006
Abstract—An effective synthetic strategy for construction of the novel spiro-bicyclic b-lactone-c-lactam system present in oxazolo-
mycin has been demonstrated. The 3,4-disubstituted pyrrolidine ring system was constructed via an Evans aldol reaction. The spiro-
b-lactone ring was elaborated from a gem-hydroxymethyl moiety that was successfully installed by an aldol followed by a crossed
Cannizzaro reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxazolomycin (1) and neooxazolomycin (2) were iso-
lated from the strain of Streptomyces sp. KBFP-2025.1
These drew initial attention for their strong antibacterial
and anticancer activities.2 Later studies revealed their
exceptional ability to suppress replication of vaccinia,
herpes simplex virus type-1, and influenza A virus in
both human and chicken cells.3 Unique structural
features of oxazolomycin are a triene moiety (Z,Z,E)
attached to an oxazole ring, a diene system (E,E), and
a spiro-bicyclic b-lactone-c-lactam subunit (Fig. 1).
Their fascinating biology allied with their structural
complexity and novelty of the backbone has resulted
in several groups dedicating efforts toward the synthesis
of these molecules. Hitherto, the total synthesis of 1 has
not been accomplished. Most studies have focused on
the left and middle segments;4 a simple model of the
spiro-bicyclic system of 1 has been reported by Taylor
and Papillon.5 Additional research needs to be pursued
to install the requisite functionalities on the pyrrolidine
ring and modulate their behavior while forming the
spiro-bicyclic b-lactone-c-lactam system.
O
N
11'
10'
12'
Me
2'
O
O
1'
Me
6
OMe
4
O
12
7
HO
N
H
3
N
Me
HO
Me
Me
Me
OH
1
2
O
O
1
N
O
OH
Me
Me
Me
O
O
N
HO
N
H
Me
HO
Me
O
OH
Me
2
Figure 1. Oxazolomycin (1) and neooxazolomycin (2).
between B and C could be mediated by a Wittig reac-
tion. Subsequent Sharpless asymmetric dihydroxylation
with an appropriate chiral auxiliary would ensure instal-
lation of the two hydroxyl groups present at C-3 and C-
4 in oxazolomycin. Described in this article is a synthetic
strategy for segment C via successful adoption of an
Evans’ aldol reaction followed by further elaboration
to the 3,4-disubstituted-prolinol intermediate. In order
to construct the spiro-bicyclic b-lactone ring system,
we utilized an aldol reaction followed by a crossed
Oxazolomycin (1) can be envisioned as an assembly of
three intermediates A–C (Fig. 2) representing the left,
middle, and right segments. The critical coupling
Keywords: Garner’s aldehyde; Evans’ aldol reaction; Crossed
Cannizzaro reaction; Ruthenium tetroxide oxidation; Intramolecular
Mitsunobu reaction.
*
Corresponding author. Tel.: +91 20 25902627; fax: +91 20
25902629; e-mail: dk.mohapatra@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.117

6032
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 6031–6035
N
O
Me
O
Me
O
Me
O
O
HO
N
H
N Me
O
HO
Me
Me
O
Me
OH
N
Oxazolomycin (1)
O
O
HO
Me
Me
Me
N Me
O
O
+
+
NHPG
PPh3
HO
OH
OH
Me
Me
Left-hand segment (A)
Middle segment (B)
Right-hand segment (C)
Figure 2. Retrosynthesis of oxazolomycin (1).
Cannizzaro reaction to install the gem-hydroxymethyl
derivative. The b-lactone ring could be appropriately
derived from this (Scheme 1).
O
O
OHC
R
O
O
N
N
+
Bn
8a R = Boc
Our first concern was the Evans’ aldol6 reaction between
the (R)-oxazolidinone7 derivative (7) and (R)-Garner’s
aldehyde8 (8a) using Crimmins’ modified method.9 It
was reported that this aldol reaction with TiCl4 catalysis
ensures a higher diastereomeric excess. In our case, the
chirality present in both the substrates would have either
a complementary or an opposing effect on the course of
the aldol reaction. The reaction was carried out in the
presence of TiCl4 (1.0 equiv) and DIPEA (2.5 equiv) at
0 °C, to give syn-6a as the sole product (Scheme 2).
Much to our delight, 6a crystallized out in 82% yield
after column chromatography. Spectroscopic and
elemental data supported the structure of 6a;10 a single
crystal X-ray study (CCDC 603757)11 conclusively
proved the (Fig. 3) stereochemical assignments. Simi-
larly, the structure of 6b (CCDC 603758)11 was con-
firmed by single crystal X-ray crystallography (Fig. 4).
The aldol product 6a on reductive hydrolysis12 with
lithium borohydride generated the primary alcohol 9.
The protection and deprotection sequence, shown in
7
8b R = Cbz
a
O
O
OH
O
N
O
N
Me
Bn
R
6a R = Boc
6b R = Cbz
Scheme 2. Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2, 0 °C,
82%.
OBz
O
OBn
OH
OH
Me
O
Me
N
Boc
3
N
O
Boc
4
OH
Me
O
O
OBn
Figure 3. ORTEP diagram of 6a.
OH
O
+
N
O
N
N
Boc
Me
Bn
Boc
5
Scheme 3, furnished tosylate 12 via intermediates 10
and 11. Exposure of 12 to p-TSA-MeOH gave the
6a
OHC
O
O
appropriately substituted pyrrolidine derivative13
5
O
O
N
(Scheme 3) by deprotection of the isopropylidene group
followed by ring closure.
N
Boc
Bn
7
8a
We next turned our attention to introducing the
gem-hydroxymethyl group at C-2. We planned to use
an aldol reaction followed by a crossed Cannizzaro reac-
Scheme 1. Retrosynthetic analysis of spiro fused b-lactone-c-lactam
segment (3).

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 6031–6035
6033
OBn
OH
Me
OBn
OH
Me
a, b
c
N
N
OH
Boc
4
Boc
5
OBn
OBz
Me
Me
d
O
O
O
O
N
O
N
Boc
13
Boc
14
Scheme 4. Reagents and conditions: (a) IBX, DMSO, THF, rt; (b)
HCHO, 2 M NaOH, THF:H2O (7:1), rt (55%, two steps); (c) DMP,
p-TSA, rt, 85%; (d) RuCl3, NaIO4 (aq), EtOAc, rt, 82%.
OBz
OBz
OH
Me
O
Me
O
Figure 4. ORTEP diagram of 6b.
a
b
O
O
N
N
OH
O
O
OH
OH
Boc
15
Boc
14
a
c
b
d
O
N
HO
HO
O
O
O
OBz
OTBS
OBz
OTBS
Me
N
Boc
Me
O
N
Me
Me
O
Bn
d
c
Boc
6a
9
N
N
OH
OH
OBn
OBn
Boc
17
O
Boc
16
TBSO
TsO
O
N
Boc
Me
N
Me
OBz
OBz
Me
Me
Boc
e
OH
11
10
OBn
O
O
N
O
N
OH
OBn
OH
Me
Boc
18
Boc O
O
e
O
3
N
N
Boc
Me
Boc
5
Scheme 5. Reagents and conditions: (a) p-TSA, MeOH, rt, 86%; (b)
TBSCl, imidazole, CH2Cl2, rt, 82%; (c) RuCl3, NaIO4 (aq), EtOAc, rt,
86%; (d) AcOH, THF, H2O, rt, 77%; (e) TPP, DEAD, THF, ꢀ78 °C-
rt, 88%.
12
Scheme 3. Reagents and conditions: (a) LiCl, NaBH4, EtOH: THF
(2:1), rt, 75%; (b) (i) TBDMSCl, Et3N, DMAP (cat.), CH2Cl2, rt, 82%;
(ii) NaH, BnBr, DMF, 0 °C, 91%; (c) TBAF, THF, rt, 89%; (d) TsCl,
Et3N, CH2Cl2, rt, 97%; (e) p-TSA, MeOH, rt, 63%.
removed using aqueous acetic acid in THF to furnish
the hydroxy acid derivative25 18. This was finally lacton-
ized under Mitsunobu5,26 conditions (TPP and DEAD
at ꢀ78 °C-rt) to provide the spiro-bicyclic b-lactone-c-
lactam fragment 3. The characteristic IR absorption at
1841 cmꢀ1 for the carbonyl stretching frequency verified
tion14 at C-2. Prior to performing this key reaction,
compound 5 was first oxidized with IBX–DMSO–
THF15 and the corresponding aldehyde treated with
formaldehyde in the presence of 2 M NaOH solution
to furnish the gem-dihydroxymethyl derivative 4. The
structure of 416 was supported by spectroscopic and ele-
mental data. To secure the pyrrolidinone benzoate17
derivative 14, diol 4 was first protected as the isopropyl-
idene18 derivative 13, and subsequently oxidized selec-
tively with RuO4 as per the literature protocol.19 The
1H and 13C NMR, IR and elemental analysis confirmed
the structure of 1420 (Scheme 4).
Our next endeavor was to construct the b-lactone ring.
The isopropylidene group of 14 was cleaved and the
resulting gem-hydroxymethyl derivative 15 was selec-
tively protected with a TBS-group.21 The structure of
the mono-protected TBS-derivative22 16 was proposed
on the basis of steric hindrance of the adjacent b-OBz
group and substantiated by NOESY experiments. The
free b-hydroxymethyl group was oxidized with ruthe-
nium tetroxide to acid 17,23,24 and the TBS group was
Figure 5. ORTEP diagram of 3.

6034
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 6031–6035
formation of the b-lactone (Scheme 5). The 1H, 13C
NMR, and elemental analysis of 327 were in agreement
with the assigned structure. Unambiguous proof of the
stereochemistry was obtained from single crystal X-ray
crystallography (CCDC 603759) (Fig. 5).11
(dd, 1H, J = 9.7, 13.4 Hz), 3.15 (d, 1H, J = 5.2 Hz), 3.28
(dd, 1H, J = 3.4, 13.4 Hz), 3.60 (quintet, 1H, J= 6.8 Hz),
3.99 (dd, 2H, J = 5.2, 10.4 Hz), 4.07 (dd, 1H, J = 1.5,
9.2 Hz), 4.14 (dd, 1H, J = 2.5, 8.8 Hz), 4.24 (dd, 2H,
J = 7.4, 9.2 Hz), 4.74 (m, 1H), 7.24 (m, 5H); 13C NMR
(CDCl3, 50 MHz): d 12.7, 24.0, 26.8, 28.3, 38.2, 41.4, 55.4,
58.5, 66.2, 75.1, 81.0, 94.4, 127.2, 128.8, 129.4, 135.5,
153.2, 154.7, 175.2; Anal. Calcd for C24H34N2O7: C, 62.32;
H, 7.41; N, 6.06%; Found: C, 62.31; H, 7.49, N; 6.08%.
11. Crystallographic data for the structures in this letter have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
603757 for 6a, CCDC 603758 for 6b, and CCDC 603759
for 3. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK [fax: +44 0 1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk].
In conclusion, we have demonstrated a strategy to
install a spiro fused b-lactone-c-lactam ring possessing
3,4-substituted functional groups using an aldol reac-
tion, followed by a crossed Cannizzaro reaction. Ruthe-
nium tetroxide mediated oxidation on an already
installed pyrrolidine ring system led to improved yields
in c-lactam formation.
Acknowledgements
12. Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62,
7548–7549.
D.M. thanks CSIR, New Delhi, for financial support in
the form of a research fellowship. We thank Dr. Mohan
M. Bhadbhade and Dr. P. R. Rajmohanan for X-ray
crystallographic assistance and NMR data, respectively.
25
13. Analytical and spectral data of compound 5. ½aꢁD +31.4 (c
1
1.25, CHCl3); IR (CHCl3): 1684 cmꢀ1; H NMR (CDCl3,
200 MHz): d 1.01 (d, 3H, J = 6.8 Hz), 1.46 (s, 9H), 2.30
(quintet, 1H, J = 6.8 Hz), 2.92 (dd, 1H, J = 7.8, 10.7 Hz),
3.55 (dd, 1H, J = 7.8, 10.7 Hz), 3.60–3.80 (m, 2H), 3.92
(dt, 1H, J = 2.4, 11.7 Hz), 4.12 (m, 1H), 4.54 (d, 1H,
J = 11.5 Hz), 4.61 (d, 1H, J = 11.5 Hz), 7.34 (s, 5H); 13C
NMR (CDCl3, 50 MHz): d 15.6, 28.3, 36.2, 50.8, 60.4,
63.4, 72.5, 80.1, 83.8, 127.7, 127.8, 128.4, 137.4, 156.4;
Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36%;
Found: C, 67.26; H, 8.53; N, 4.36%.
References and notes
1. (a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura,
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Nakano, F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26,
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2. Kawazu, K.; Kanzaki, H.; Kawabata, G.; Kawai, S.;
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1992, 36, 166–172.
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J. Org. Chem. 1979, 44, 1301–1309; (b) Shimida, K.;
Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
4048–4049.
15. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019–8022.
25
16. Analytical and spectral data of compound 4. ½aꢁD +15.0 (c
1.0, CHCl3); IR (CHCl3): 1665, 3436 cmꢀ1
;
1H
4. (a) Kende, A. S.; Kawamura, K.; Orwat, M. J. Tetra-
hedron Lett. 1989, 30, 5821–5824; (b) Kende, A. S.;
Kawamura, K.; DeVita, R. J. J. Am. Chem. Soc. 1990,
NMR (CDCl3, 200 MHz): d 1.08 (d, 3H, J = 6.4 Hz),
1.46 (s, 9H), 2.22–2.44 (m, 1H), 2.80 (t, 1H, J = 10.6 Hz),
3.45 (d, 1H, J = 9.2 Hz), 3.64 (dd, 1H, J = 8.9, 10.6 Hz),
3.77 (d, 1H, J = 11.8 Hz), 3.85–4.10 (m, 3H), 4.71 (s, 2H),
7.34 (br s, 5H); 13C NMR (CDCl3, 100 MHz): d 16.0, 28.3,
36.0, 51.5, 62.5, 65.6, 68.9, 74.5, 80.5, 88.7, 127.9, 128.1,
128.5, 137.5, 155.8; Anal. Calcd for C19H29NO5: C, 64.93;
H, 8.32; N, 3.99%; Found: C, 64.76; H, 8.37; N, 4.12%.
17. (a) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling,
J. D. Angew. Chem., Int. Ed. 2004, 43, 2293–2296; (b)
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3837.
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112, 4072–4074; (c) Henaff, N.; Whiting, A. Org. Lett.
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G.; Moloney, M. G.; Trippier, P. C. Org. Biomol. Chem.
2003, 1, 3726–3737.
5. Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000, 2,
1987–1990.
6. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem.
Soc. 1981, 103, 2127–2129; (b) Evans, D. A.; McGee, L. R.
J. Am. Chem. Soc. 1981, 103, 2876–2878; (c) Evans, D. A.
Topics Stereochem. 1982, 13, 1; (d) Gage, J. R.; Evans, D.
A. Org. Syn. Coll. Vol. 1993, 8, 339; (e) Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1; (f) Palomo, C.;
Oiarbide, M.; Garcia, J. M. Chem. Eur. J. 2002, 8, 37–44;
(g) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc.
Rev. 2004, 33, 65–75.
20. Analytical and spectral data of compound 14. Mp 73.1 °C
7. (a) Ho, G. J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–
2273; (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
Rev. 1996, 96, 835–876.
25
(re-crystallized from ethyl acetate/hexane): ½aꢁD ꢀ33.0 (c
1.0, CHCl3); IR (CHCl3): 1725, 1743, 1783 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz): d 1.24 (s, 3H), 1.46 (d, 3H,
J = 7.8 Hz), 1.52 (s, 3H), 1.58 (s, 9H), 2.70 (dq, 1H, J =
4.0, 7.8, 11.5 Hz), 3.65 (d, 1H, J = 11.3 Hz), 4.11 (d, 1H,
J = 11.3 Hz), 4.64 (t, 2H, J = 11.3 Hz), 5.60 (d, 1H, J =
4.0 Hz), 7.45 (t, 2H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz),
8.06 (d, 2H, J = 7.5 Hz); 13C NMR (CDCl3, 100 MHz): d
15.3, 20.1, 27.2, 28.0, 43.7, 59.5, 61.9, 64.0, 75.2, 84.4, 98.8,
128.5, 129.6, 129.8, 133.3, 150.1, 165.5, 174.5; Anal. Calcd
for C22H29NO7: C, 62.99; H, 6.97; N, 3.34%; Found: C,
63.18; H, 6.98; N, 3.47%.
8. Liang, K.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin
Trans. 1 2001, 2136–2157, and references cited therein.
9. (a) Evans, D. A.; Reiger, D. L.; Bilodeau, M. T.; Urpi, F.
J. Am. Chem. Soc. 1991, 113, 1047–1049; (b) Crimmins,
M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894–902.
10. Analytical and spectral data of compound 6a. Mp 127–
25
128 °C; ½aꢁD ꢀ6.6 (c 1.0, CHCl3); IR (CHCl3): 1688,
1
1781 cmꢀ1; H NMR (CDCl3, 200 MHz): d 1.34 (d, 3H,
J = 6.8 Hz), 1.45 (s, 9H), 1.49 (s, 3H), 1.59 (s, 3H), 2.77

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 6031–6035
6035
21. Montembault, M.; Bourgougnon, N.; Lebreton, J. Tetra-
hedron Lett. 2002, 43, 8091–8094.
100 MHz): d ꢀ5.6, ꢀ5.5, 13.4, 18.1, 25.7, 27.9, 42.7, 61.2,
70.7, 74.1, 84.1, 128.5, 128.8, 129.7, 130.2, 133.5, 133.7,
149.2, 165.5, 172.9, 173.0; Anal. Calcd for C25H37NO8Si:
C, 59.15; H, 7.35; N, 2.76%; Found: C, 59.34; H, 7.24; N,
2.92%.
25
22. Analytical and spectral data of compound 16. ½aꢁD ꢀ14.3
(c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 0.04 (s,
3H), 0.09 (s, 3H), 0.88 (s, 9H), 1.32 (d, 3H, J = 7.3 Hz),
1.56 (s, 9H), 2.86–2.94 (m, 1H), 3.65 (d, 1H, J = 10.3 Hz),
3.90 (d, 1H, J = 11.8 Hz), 4.10 (d, 1H, J = 10.3 Hz), 4.13
(d, 1H, J = 11.8 Hz), 5.63 (d, 1H, J = 8.8 Hz), 7.47 (t, 2H,
J = 7.5 Hz), 7.60 (m, 1H), 8.04 (m, 2H); 13C NMR
(CDCl3, 100 MHz): d ꢀ5.6, ꢀ5.5, 13.9, 18.3, 25.8, 25.9,
26.2, 42.9, 61.1, 61.6, 69.6, 75.2, 83.7, 128.7, 129.4, 129.8,
151.3, 165.6, 173.3; Anal. Calcd for C25H39NO7Si: C,
60.82; H, 7.96; N, 2.84%; Found: C, 60.95; H, 7.87; N,
2.97%.
25. (a) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc.
1972, 94, 6190–6191; (b) Kawai, A.; Hara, O.; Hamada,
Y.; Shioiri, T. Tetrahedron Lett. 1988, 29, 6331–6334.
26. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Lall, M. S.;
Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J. Org.
Chem. 2002, 67, 1536–1547.
25
27. Analytical and spectral data of compound 3. ½aꢁD +35.0 (c
1.1, CHCl3); IR (CHCl3): 1720, 1728, 1794, 1841 cmꢀ1; 1H
NMR (CDCl3, 400 MHz): d 1.37 (d, 3H, J = 7.3 Hz), 1.58
(s, 9H), 2.99 (quintet, 1H, J = 7.3 Hz), 4.54 (d, 1H,
J = 5.4 Hz), 4.86 (d, 1H, J = 5.4 Hz), 5.63 (d, 1H,
J = 6.3 Hz), 7.48 (t, 2H, J = 7.5 Hz), 7.61 (m, 1H), 8.08
(m, 2H); 13C NMR (CDCl3, 100 MHz): d 13.4, 27.8, 43.0,
69.0, 74.4, 76.6, 86.4, 128.1, 128.5, 128.7, 130.1, 134.1,
148.3, 165.7, 165.9, 171.5; Anal. Calcd for C19H21NO7: C,
60.79; H, 5.64; N, 3.73%; Found: C, 60.84; H, 5.75; N,
3.92%.
23. Hodgson, D. M.; Hachisu, S.; Andrews, M. D. Org. Lett.
2005, 7, 815–817.
25
24. Analytical and spectral data of compound 17. ½aꢁD +9.1 (c
1
1.7, CHCl3); H NMR (CDCl3, 400 MHz): d 0.05 (s, 3H),
0.10 (s, 3H), 0.86 (s, 9H), 1.34 (d, 3H, J = 7.2 Hz), 1.50 (s,
9H), 2.93 (m, 1H), 4.06 (d, 1H, J = 10.6 Hz), 4.34 (d, 1H,
J = 10.6 Hz), 5.66 (d, 1H, J = 8.0 Hz), 7.37 (m, 2H), 7.48
(m, 1H), 7.97 (m, 2H), 8.37 (br s, 1H); 13C NMR (CDCl3,