(1′S,6′S,8′S,9′R)-9′-Bromo-12′-oxa­spiro­[1,3-dioxolane-2,4′-tricyclo­[6.3.1.01,6]dodeca­ne]

Goverdhan Mehta; Tabrez Babu Khan

doi:10.1107/S1600536812029777

. 2012 Jul 10;68(Pt 8):o2411–o2412. doi: 10.1107/S1600536812029777

(1′S,6′S,8′S,9′R)-9′-Bromo-12′-oxaspiro[1,3-dioxolane-2,4′-tricyclo[6.3.1.0^1,6]dodecane]

Goverdhan Mehta ^a,^b,^*, Tabrez Babu Khan ^a,^b

PMCID: PMC3414332 PMID: 22904865

Abstract

In an endeavor directed towards the construction of the oxabicyclic[3.2.1]octane segment present in the bioactive natural products of cortistatins and icetexanes genre, the title compound, C₁₃H₁₉BrO₃, was synthesized from (4aR,9aS)-1,3,4,4a,5,6,9,9a-octahydrospiro[benzo[7]annulene-2,2′-[1,3]dioxolane]-4a-ol via a transannular bromo-etherification protocol. The six-membered ring adopts a twist-boat conformation, while the fused cycloheptane ring adopts a chair conformation. The crystal packing is effected through two distinct intermolecular C—H⋯O hydrogen-bond patterns and molecules are arranged to define an interesting motif along the b axis.

Related literature

For the isolation and biological activity of cortistatins, see: Aoki et al. (2006 ▶, 2007 ▶); Watanabe et al. (2007 ▶); Zhao (2010 ▶) and for icetexanes, see: Esquivel et al. (1995 ▶); Uchiyama et al. (2005 ▶). For synthetic approaches towards the construction of the oxabicyclic core of cortistatins, see: Zhao (2010 ▶); Hardin Narayan et al. (2010 ▶) and references cited therein. For their use in the treatment of blindness, see: Czako et al. (2009 ▶). For the construction of relevant 6/7 fused-ring systems involving ring-closing metathesis, see: Mehta & Likhite (2008 ▶, 2009 ▶). For an example of the exploitation of transannular bromoetherification towards natural products synthesis, see: Mehta & Sen (2010 ▶); Mehta & Yaragorla (2011 ▶).

Experimental

Crystal data

C₁₃H₁₉BrO₃
M _r = 303.19
Monoclinic,
a = 11.0159 (3) Å
b = 12.6619 (3) Å
c = 10.2763 (2) Å
β = 117.044 (1)°
V = 1276.63 (5) Å³
Z = 4
Mo Kα radiation
μ = 3.21 mm⁻¹
T = 296 K
0.30 × 0.20 × 0.15 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.446, T _max = 0.644
11338 measured reflections
2368 independent reflections
1859 reflections with I > 2σ(I)
R _int = 0.027

Refinement

R[F ² > 2σ(F ²)] = 0.030
wR(F ²) = 0.076
S = 1.02
2368 reflections
154 parameters
?
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.32 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812029777/ds2204sup1.cif

e-68-o2411-sup1.cif^{(16.7KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812029777/ds2204Isup2.hkl

e-68-o2411-Isup2.hkl^{(116.4KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812029777/ds2204Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C11—H11⋯O2ⁱ	0.98	2.53	3.445 (3)	156
C1—H1⋯O1ⁱⁱ	0.98	2.57	3.471 (3)	153

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

TBK thanks the University Grants Commission, India for the award of Dr Kothari post-doctoral fellowship. We thank Mr Saikat Sen for his help in determining the X-ray crystal structure at the CCD facility of the Indian Institute of Science (IISc), Bangalore. GM acknowledges the research support from Eli Lilly and Jubilant-Bhartia Foundations.

supplementary crystallographic information

Comment

The oxabicyclic[3,2,1]octane scaffold manifest itself in a variety of terpenoids class of natural products viz. icetexanes (Fig. 1; Esquivel et al., 1995 & Uchiyama et al., 2005) and cortistatin family (Fig. 1; Aoki et al., 2006, 2007 & Watanabe et al., 2007). In particular, cortistatin A and its structural siblings isolated in trace amounts by Kobayashi & coworkers from an Indonesian marine sponge corticium simplex were shown to possess novel architecture and exhibited potent and promising anti-angiogenic activity (Zhao, 2010) and were effective in treating blindness (Czako et al., 2009), thereby triggering interest to devise tactics for their total synthesis and diversity creation. These attributes of cortistatins encouraged us to devise a strategy to gain rapid access to the oxatricyclic ABC core present in cortistatins.

Several synthetic approaches to cortistatins have been reported utilizing ring-expansion approach, oxidative dearomatization, electrocyclization, 1,3-dipolar cycloaddition/electrocyclization cascade, transannular [4 + 3] cycloaddition, classical Michael/aldol condensation cascade cyclization as the key strategic steps to access the oxatricyclic segment (Hardin Narayan et al., 2010). However, the present strategy employs a stepwise transannular bromoetherification sequence (Mehta & Sen, 2010; Mehta & Yaragorla, 2011) on a readily accessible bicyclic compound obtained via RCM (Fig. 2; Mehta & Likhite, 2008, 2009).

A two step transannular bromoetherification protocol on 7 furnished the title compound 3 (Fig. 2) as the major product corresponding to the oxatricyclic core present in icetexanes along with a minor regioisomeric compound 4 representing the oxatricyclic segment present in cortistatins.

The title compound 3 was crystallized from ethylacetate-hexane(1:1) and the structure was solved and refined in monoclinic P2₁/c space group with one molecule of 3 in the asymmetric unit. An ORTEP diagram of 3 drawn at 30% ellipsoidal probability is depicted in Fig 3. From the packing diagram it can be seen that the centrosymmetric molecules are connected by weak C11–H11···O2 (2.53 Å, 156°) hydrogen bonds forming a dimeric motif and these dimeric units are further connected by C1–H1···O1 (2.57 Å, 153°)) hydrogen bonds, three dimensionally (Fig. 4).These two hydrogen bond patterns link the molecules to define an interesting motif along the b axis.

Experimental

The synthesis of the title compound 3 as depicted in Fig. 2 emanates from the known 7-(prop-2-en-1-yl)-1,4-dioxaspiro[4.5]decan-8-one 5 through addition of butenylmagnesium bromide (1.5 equiv.) in THF at r.t. to furnish the desired RCM precursor 6 in decent yield. Exposure of 6 to Grubbs-1s t generation catalyst (10 mol%) in benzene at r.t. gave the bicyclic compound 7 in good yield. Finally, the stepwise transannular bromotherification on 7 was executed via bromination with pyH⁺Br₃^- (1.2 equiv.) in DCM at 0 °C followed by etherification in the presence of 10 M aq. NaOH in THF at 60 °C for 4 h to deliver 3, mp. 78–80 °C, as a colorless crystalline compound in 51% yield.