A new nucleophilic addition/ring-closure sequence. Enantioselective synthesis of 3-deoxy-8-oxatropanes

Article abstract of DOI:10.1021/ol036404o

(Equation presented) A study of new nucleophilic addition/ring-closure (NARC) sequences has resulted in the development of a stereoselective synthetic route to 3-deoxy-8-oxatropanes. The new sequences consisted of either a syn or anti aldol addition, empl

Full text of DOI:10.1021/ol036404o

ORGANIC
LETTERS
2004
Vol. 6, No. 6
893-895
A New Nucleophilic Addition/
Ring-Closure Sequence.
Enantioselective Synthesis of
3-Deoxy-8-oxatropanes
Giang Nguyen, Patrick Perlmutter,* Mark L. Rose, and Filisaty Vounatsos
School of Chemistry, Monash UniVersity, PO Box 23, Victoria 3800, Australia
patrick.perlmutter@sci.monash.edu.au
Received December 10, 2003
ABSTRACT
A study of new nucleophilic addition/ring-closure (NARC) sequences has resulted in the development of a stereoselective synthetic route to
3-deoxy-8-oxatropanes. The new sequences consisted of either a syn or anti aldol addition, employing an ω-alkenoyl sultam, followed by
two-step bicyclic ring construction involving, consecutively, ring-closing metathesis and intramolecular oxymercuration.
As part of a program directed toward the synthesis and
evaluation of new tropane analogues, we required ready
access to useful quantities of enantiomerically pure stereo-
isomers of the previously unreported 8-oxatropanes 1 (Figure
1).1 We envisaged that these might be available from new
lecular oxymercuration). As shown in Figure 1, two pathways
(a and b) were available depending upon the locus of the
alkene.
In previous work, we have demonstrated that the sequence
of a nucleophilic addition followed by one or more ring
closures (the NARC sequence) provides rapid access to
enantiomerically pure mono- and bicyclic structures. Such
sequences include asymmetric aldol addition followed by,
e.g., (a) an intramolecular 5-exo-oxymercuration4 (monocy-
clic products), (b) ring-closing metathesis5 (monocyclic
products), or (c) an intramolecular Wacker-type reaction
(bicyclic products).6
We began this study by selecting pathway a for the
synthesis of the exo isomer 2 (Scheme 1). At the outset of
(1) For reports on the synthesis and biological activity of 8-oxatropanes,
see: (a) Meltzer, P. C.; Blundell, P.; Yong, Y. F.; Chen, Z.; George, C.;
Gonzalez, M. D.; Madras, B. K. J. Med. Chem. 2000, 43, 2982. (b)
Kozikowsky, A. P.; Simoni, D.; Roberti, M.; Rondanin, R.; Wang, S.; Du,
P.; Johnson, K. M. Bioorg. Med. Chem. Lett. 1999, 9, 1831. (c) Eiden, F.;
Kainz, A.; Gebhard, R. Arch. Pharm. 1992, 325, 77.
Figure 1. Proposed retrosyntheses of 8-oxatropane 1.
(2) Perlmutter, P. In Topics in Current Chemistry; Metz, P., Ed.;
Springer: Heidelberg, 1997; Vol. 190, p 87.
(3) For elegant examples of the application of aldol/RCM sequences to
synthesis, see: Crimmins, M. T.; Tabet, E. A. J. Org. Chem. 2001, 66,
4012 and references therein.
(4) Bratt, K.; Garavelas, A.; Perlmutter, P., Westman, G. J. Org. Chem.
1996, 61, 2109.
nucleophilic addition/ring-closure (NARC) sequences2 involv-
ing stereoselective aldol addition followed by two-step bi-
cyclic ring construction (ring-closing metathesis (RCM) of
the resulting diene3 with, as the final closure, an intramo-
(5) Perlmutter, P.; Rose, M. L. J. Carbohydr. Chem. 2002, 21, 1.
10.1021/ol036404o CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004

Scheme 1. Synthesis of 2 via Pathway aa
Scheme 2. Synthesis of ent-2 via Pathway ba
a Reagents and conditions: (i) (a) Et2BOTf (2.0 equiv), (iPr)2NEt
(2.2 equiv), CH2Cl2, -78 °C, (b) OHCCH2CHdCH2; (ii) RuCl2-
(CHPh)(PCy3)2, CH2Cl2; (iii) (a) Hg(OCOCF3)2, CH3CN, (b) satd
aq NaCl; (iv) Bu3SnH, AIBN; (v) LiOH, H2O2.
a Reagents and conditions: (i) (a) Et2BOTf (2.0 equiv), (iPr)2NEt
(2.2 equiv), CH2Cl2, -78 °C, (b) OHCCH2CH2CHdCHPh; (ii)
RuCl2(CHPh)(PCy3)2, CH2Cl2; (iii) (a) Hg(OCOCF3)2, CH3CN, (b)
satd aq NaCl; (iv) Bu3SnH, AIBN; (v) LiOH, H2O2.
Treatment of 11 with Hg(II)(OCOCF3)2 in acetonitrile14
gave 12 as a single regioisomer in quantitative yield. Reduc-
tive demercuration and hydrolysis then gave enantiomerically
pure ent-2.
With pathway b established as the preferred route, it was
next employed in the synthesis of 17, one of the enantiomers
of the “endo” isomer of 1 (Scheme 3). To prepare 17, the
this work, it was not clear what levels of regioselectivity
could be obtained in the proposed intramolecular oxymer-
curations involved in either of the pathways outlined in
Figure 1.7 It appeared plausible that there may be some
preference for closure onto C4 of cycloheptene 5 as this
would minimize any steric interaction between the nucleo-
philic alcohol and the adjacent acyl sultam. Thus, 5 was
prepared in good yield employing a sequence of syn-aldol8
and ring-closing metathesis (RCM) reactions.
Scheme 3. Synthesis of 17 via Pathway ba
Intramolecular oxymercuration of 5,9,10 with either
Hg(II)(OAc)2 or Hg(II)(OCOCF3)2, gave predominantly the
product from closure onto C4 (a 4:1 ratio of, respectively, 6
and 7, Scheme 1). Chloromercurial 6 could be recrystallized
pure in 60% yield (its structure is shown in Figure 2).
a Reagents and conditions: (i) (a) Et2BOTf (2.0 equiv), (iPr)2Net
(1.9 equiv), CH2Cl2, -78 °C, (b) OHCCH2CHdCH2; (ii) RuCl2-
(CHPh)(PCy3)2, CH2Cl2; (iii) (a) Hg(OCOCF3)2, CH2Cl2, (b) satd
aq NaCl; (iv) Bu3SnH, AIBN; (v) LiOH, H2O2.
C1-epimer of 11 (i.e., 15) was required. As shown in Scheme
3, this necessitated employing an anti-aldol addition in the
first step. Although a number of anti-aldol protocols are
Figure 2. X-ray crystal structure of chloromercurial 6.
(6) (a) Fallon, G. D.; Jones, E. D.; Perlmutter, P.; Selajarern, W.
Tetrahedron Lett. 1999, 40, 7435. (b) Perlmutter, P.; Selajarern, W. Aust.
J. Chem. 2000, 53, 349.
(7) There have been very few reports on intramolecular oxymercurations
which produce oxygen-bridged bicyclic products. See: Foehlisch, B.;
Joachimi, R. Chem. Ber. 1987, 120, 1951.
(8) “Xc” in Schemes 1 and 4 is used to represent the (-)-enantiomer of
Oppolzer’s camphor-derived sultam auxiliary. “Yc” in Schemes 2 and 3
represents the (+)-enantiomer. See ref 12 for more details on the preparation
and use of these auxiliaries.
(9) For reviews on electrophilic cyclisations, see: (a) Robin, S.; Rousseau,
G. Tetrahedron 1998, 54, 13681. (b) Rousseau, G.; Homsi, F. Chem. Soc.
ReV. 1997, 26, 453. (c) Harmange, J. C.; Figadere, B. Tetrahedron:
Asymmetry 1993, 4, 1711.
Reductive demercuration11 followed by hydrolysis12 then
provided enantiomerically pure 2.
Although the chemistry outlined in Scheme 1 provides a
practical route to 2, the approach was not completely
regioselective. Hence, pathway b was next explored in a
synthesis of the enantiomer of 2. The synthesis of the next
intramolecular oxymercuration candidate, the new cyclo-
heptene 11 (employing Crimmins’ method for preparing
3-butenal13), proceeded in good overall yield (Scheme 2).
894
Org. Lett., Vol. 6, No. 6, 2004

available,15 we had noted that the stereoselectivity of aldol
additions to 3-butenal was very sensitive to the Lewis acid/
Lewis base ratio.16 By slightly reducing the amount of base
present (from 2.2 to 1.9 equiv relative to the acylsultam)
while maintaining the diethylboron triflate at 2.0 equiv, we
were able to obtain the anti-aldol adduct 14 exclusively and
in good yield. Intramolecular oxymercuration of the corre-
sponding RCM product 15 was also found to be completely
regioselective providing 16 in quantitative yield. Reductive
demercuration and hydrolysis then gave enantiomerically
pure 17.
Scheme 4. Regioselective Oxymercuration of Cycloheptene 20a
Although we only have very limited evidence at this stage,
it appears that, for pathway b, if one considers only exo-
modes of closure in forming bridged products, the 6-exo-
mode is, not surprisingly, highly favored over the 4-exo-
mode. Further support for this came from oxymercuration
of 20 which gave, exclusively, regioisomer 21 (Scheme 4).
a Reagents and conditions: (i) (a) Et2BOTf (2.0 equiv), (iPr)2NEt
(2.2 equiv), CH2Cl2, -78 °C, (b) OHC(CH2)3CHdCH2; (ii)
RuCl2(CHPh)(PCy3)2, CH2Cl2; (iii) (a) Hg(OAc)2, CH2Cl2, (b) satd
aq NaCl.
In summary, we have developed a new NARC sequence
which involves stepwise bicyclic ring construction via ring-
closing metathesis and intramolecular oxymercuration. Em-
ploying these methods, each of the stereoisomers of oxa-
tropane 1 is now readily available.
(10) For a recent review on, specifically, electrophile-induced endo-
cyclizations, see: Knight, D. W. Prog. Heterocycl. Chem. 2002, 14, 19.
(11) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
(12) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem.
Soc. 1990, 112, 2767.
(13) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675.
(14) 11 failed to react with Hg(II)(OAc)2. For some of the benefits of
employing acetonitrile in oxymercurations as solvent, see: Garavelas, A.;
Mavropoulos, I.; Perlmutter, P.; Westman, G. Tetrahedron Lett. 1995, 36,
463.
Acknowledgment. We thank the Australian Research
Council for financial support and Dr. Gary D. Fallon for
determining the crystal structure of 6.
(15) See: Ghosh, A. K.; Kim, J.-H. Org. Lett. 2003, 5, 1063 and
references therein.
Supporting Information Available: Full details of
experimental procedures and spectroscopic and analytical
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) For a recent example of the use of Lewis acid promoted anti-aldol
reactions, see: Fraser, B.; Perlmutter, P. J. Chem. Soc., Perkin Trans. 1
2002, 2896 and references therein. See also: (a) Heathcock, H. C.;
Raimundo, B. C. Synth. Lett. 1995, 12, 1213. (b) Heathcock, H. C.; Walker,
M. A. J. Org. Chem. 1991, 56, 5747. (c) Heathcock, H. C.; Hansen, M.
M.; Danda, H. J. Org. Chem. 1990, 55, 173.
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