Confirmation of the absolute configuration of (-)-aurantioclavine

Article abstract of DOI:10.1016/j.tetlet.2010.11.074

We confirm our previous assignment of the absolute configuration of (-)-aurantioclavine as 7R by crystallographically characterizing an advanced 3-bromoindole intermediate reported in our previous synthesis. This analysis also provides additional support

Full text of DOI:10.1016/j.tetlet.2010.11.074

Tetrahedron Letters 52 (2011) 2152–2154
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Confirmation of the absolute configuration of (À)-aurantioclavine
Douglas C. Behenna a, Shyam Krishnan b, Brian M. Stoltz a,
⇑
a California Institute of Technology, Division of Chemistry and Chemical Engineering, Mail Code 101-20, Pasadena, CA 91125, USA
b HHMI Institute, University of California, San Francisco, Genentech Hall, 600 16th St, MC 2280, San Francisco, CA 94158, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 18 November 2010
We confirm our previous assignment of the absolute configuration of (À)-aurantioclavine as 7R by crys-
tallographically characterizing an advanced 3-bromoindole intermediate reported in our previous syn-
thesis. This analysis also provides additional support for our model of enantioinduction in the
palladium(II)-catalyzed oxidative kinetic resolution of secondary alcohols.
Dedicated to Professor Harry H. Wasserman
on behalf of his 90th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aurantioclavine
Absolute configuration
Oxidative kinetic resolution
Indole alkaloid
Azepinoindole
As part of a research program in oxidative catalysis, we have
developed a palladium(II)-catalyzed oxidative kinetic resolution
(OKR) of secondary alcohols.1 To demonstrate the utility of this
methodology, we have carried out several natural product synthe-
ses that rely on OKR to induce asymmetry.2 Specifically, we com-
pleted the first enantioselective synthesis of (À)-aurantioclavine
(1), which allowed the assignment of the absolute configuration
of the natural product as 7R (Scheme 1).2c Aurantioclavine was a
focal point of our interest in the calycanthaceous alkaloids (e.g.,
communesin A (2))3 and allowed us to demonstrate the utility of
the enantioenriched secondary alcohols produced from our OKR
reaction as precursors to enantioenriched amines. However, a re-
cent personal communication from Professor Jia called into ques-
tion our stereochemical assignment.4 This coupled with our
recent experience with an attempted SN2 reaction that proceeded
with retention of configuration5 prompted us to reinvestigate our
assignment.
Our synthesis of the ergot natural product (À)-aurantioclavine
(1) employed an OKR of racemic diol 3, which produced enantioen-
riched diol (À)-3 and ketone 4 (Scheme 2). Incorporation of the re-
quired nitrogen atom was achieved by treating diol (À)-3 with
hydrazoic acid under low temperature Mitsunobu conditions to
give the displacement product, azide 5, which was expected to
be of inverted configuration. A sequence of azide reduction, nosyl
protection, and bromination provided bromoindole 7. Elaboration
of the indole 3-position and dehydration provided alcohol 9 under-
went smooth cyclization to form indoleazepine 10.6 Deprotection
O
H
N
N
H
N
O
Proposed
Biosynthesis
NH
N
H
N
H
(–)-Aurantioclavine (1)
Communesin A (2)
Scheme 1. Alkaloid natural products of interest.
of bis-sulfonamide 10 afforded (À)-aurantioclavine, which
matched the optical rotation of the natural material in both sign
and magnitude.7
It should be noted that the assignment of the absolute configu-
ration of diol (À)-3 in our previous paper was based entirely on the
extrapolation of our model for enantioinduction in the OKR reac-
tion and our extensive experience with such secondary benzylic
alcohol substrates.8 No definitive proof of the absolute configura-
tion of diol (À)-3 was obtained at that time. While this was a rea-
sonable course of action given the complete agreement between
the experimental data from other substrates of known absolute
configuration and our model, we chose to reexamine the route.
In scrutinizing our synthesis, we judged that the two most
probable, albeit unlikely, opportunities for an unanticipated
stereochemical outcome were the OKR and Mitsunobu steps
(Scheme 3). In one scenario (path A), alcohol 3 might act as an
anomalous substrate, such that under the OKR conditions the (S)-
enantiomer is oxidized more rapidly. Alternatively, we considered
the possibility that during the Mitsunobu reaction the pendant
⇑
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 395 8436.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.074

D. C. Behenna et al. / Tetrahedron Letters 52 (2011) 2152–2154
2153
N
N
OH
OH
O
HO
HO
HO
Pd
(S)
(10 mol%)
Cl
Cl
+
(–)-sparteine (40 mol%)
MS3Å, O2 (1 atm), t-BuOH
40 → 70 °C, 98 h
N
N
N
Ts
Ts
Ts
( )-3
(–)-3
4
96% ee
51% yield
(59.2% conversion)
37% yield
OH
N3
NHNs
HO
HO
HO
1. H2, cat Pd/C
HCl/MeOH, 23 °C
HN3, PBu3, DIAD
PyHBr3
2. o-NsCl, Et3N, CH2Cl2
0 → 23 °C
PhMe, –78 → –20 °C
CH2Cl2, 0 → 23 °C
N
N
N
Ts
Ts
Ts
(80% yield)
(72% yield)
(92% yield)
(–)-3
5
6
1.
, Pd(PPh3)4
SnBu3
OH
NHNs
Br
NHNs
NHNs
HO
1. 9-BBN,THF, 23 °C
PPh3, DIAD
PhMe, 100 °C
2. H2O2, NaOH
THF/EtOH/H2O
0 → 23 °C
2. POCl3, pyr, 0 → 23 °C
PhMe, 0 → 23 °C
N
N
N
(71% yield)
68 : 32 mixture of olefins from
dehydration favoring 8
(97% yield)
Ts
Ts
Ts
(48% yield)
9
7
8
Ns
N
H
N
(R)
1. PhSH, K2CO3, DMF, 23 °C
2. TBAF,THF, 70 °C
N
H
N
Ts
(36% yield)
10
(–)-1
Scheme 2. Synthesis of (À)-aurantioclavine.
Path A
OKR
conditions
OH
OH
O
HO
HO
HO
(R)
+
N
Ts
N
N
Ts
Ts
( )-3
(+)-3
4
Not observed
Path B
OH
N3
Mitsunobu
HO
HO
conditions
OH
H
N
N
N
Ts
Ts
Not observed
H
Ns
(R)
Br
(–)-3
(–)-5
PPh3
N
O
Ts
O
HO
7
N
N
Ts
Ts
11
12
Scheme 3. Potential pathways for unanticipated stereochemical outcomes in the
functionalization of diol 3.
tertiary alcohol could displace an activated intermediate to form
oxetane 12, which could be opened by the azide nucleophile and
give the product with an overall retention of configuration (path
Figure 1. ORTEP representation of compound 7.

2154
D. C. Behenna et al. / Tetrahedron Letters 52 (2011) 2152–2154
B).5,9 While it seemed possible, a priori, that later steps in the syn-
thesis might erode the enantiomeric excess of advanced intermedi-
ates, no step subsequent to the azide displacement appeared
capable of completely inverting the stereocenter.
by quoting the deposition number (772069). Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.074.
In order to address these possibilities, we initiated efforts to ob-
tain definitive evidence regarding the absolute configuration gen-
erated by our synthesis. Fortunately, intermediate bromide 7
proved to be crystalline and provided crystals of sufficient quality
for single crystal X-ray diffraction studies. Calculation of the Flack
parameter10 clearly indicated that the absolute stereochemistry of
the C(7) stereocenter is R (Fig. 1).
This structural data reaffirms our assertion that the natural
product (À)-aurantioclavine (1) is of the (7R)-configuration and
provides further support for our model of asymmetric induction
in the OKR reaction.
References and notes
1. (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726; (b)
Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5, 835–837; (c)
Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 42, 353–357; (d) Ebner,
D. C.; Novák, Z.; Stoltz, B. M. Synlett 2006, 3533–3539; (e) Ebner, D. C.; Trend, R.
M.; Genet, C.; McGrath, M. J.; O’Brien, P.; Stoltz, B. M. Angew. Chem., Int. Ed.
2008, 47, 6367–6370.
2. (a) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–
11753; (b) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem. 2007, 72, 7352–
7358; (c) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.; Tambar, U.
K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754.
3. May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262–5271.
4. (a) For an account describing the Jia group’s difficulties assigning the
configuration of clavicipitic acid derivatives, see: Xu, Z.; Hu, W.; Liu, Q.;
Zhang, L.; Jia, Y. J. Org. Chem. 2010, 75, 7626–7635; (b) Xu, Z.; Li, Q.; Zhang, L.;
Jia, Y. J. Org. Chem. 2010, 75, 6316.
Acknowledgments
5. Baumgartner, C.; Ma, S.; Liu, Q.; Stoltz, B. M. Org. Biomol. Chem. 2010, 8, 2915–
2917.
6. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–6374.
7. Kozlovskii, A. G.; Soloveva, T. F.; Sakharovskii, V. G.; Adanin, V. M. Dokl. Akad.
Nauk. SSSR 1981, 260, 230–233.
8. (a) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 15957–15966; (b)
Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2004,
126, 7967–7974; (c) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
4482–4483.
9. (a) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591–4593;
(b) Dai, P.; Dussault, P. H. Org. Lett. 2005, 7, 4333–4335.
This publication is based on work supported by Award No. KUS-
11-006-02, made by King Abdullah University of Science and Tech-
nology (KAUST). Financial support from Caltech, Amgen, and the
California TRDRP (postdoctoral fellowship to S.K.) is also gratefully
acknowledged. The Bruker KAPPA APEXII X-ray diffractometer
used in this study was purchased via an NSF CRIF:MU award to Cal-
tech, CHE-0639094.
10. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876–881.
Supplementary data
Crystallographic data for compound 7 can be obtained from this
journal or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK