Stereoselective reductions of N-Boc-hexahydro-1H-indolin-5(6H)-ones

Article abstract of DOI:10.1016/j.tetlet.2007.01.078

We report the divergent effects of a 3a-methyl and 3a-phenyl substituent on the chemoselectivity and stereoselectivity of reduction of the enamide moiety of N-Boc-hexahydro-1H-indolin-5(6H)-ones. Under ionic reduction conditions (triethylsilane/trifluoroacetic acid) the enamide group of 3a-methyl-N-Boc-hexahydro-1H-indolin-5(6H)-one was reduced to afford exclusively a cis ring-fused product. For the 3a-phenyl substituted analogue more forcing conditions (sodium cyanoborohydride at pH 2-2.5) were required and resulted in the selective reduction of the enamide group to give a trans ring-fused product as well as reduction of the ketone group.

Full text of DOI:10.1016/j.tetlet.2007.01.078

Tetrahedron Letters 48 (2007) 1939–1943
Stereoselective reductions
of N-Boc-hexahydro-1H-indolin-5(6H)-ones
Michael A. Brodney,a Marcus L. Cole,b, Jamie A. Freemont,c Stella Kyi,c Peter C. Junk,b
Albert Padwa,d Andrew G. Richesc and John H. Ryanc,*
aPfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
bSchool of Chemistry, Monash University, PO Box 23, Vic. 3800, Australia
cCSIRO Molecular and Health Technologies, Bag 10, Clayton South, Vic. 3169, Australia
dDepartment of Chemistry, Emory University, Atlanta 30322, Georgia
Received 10 November 2006; revised 8 January 2007; accepted 17 January 2007
Available online 19 January 2007
Abstract—We report the divergent effects of a 3a-methyl and 3a-phenyl substituent on the chemoselectivity and stereoselectivity of
reduction of the enamide moiety of N-Boc-hexahydro-1H-indolin-5(6H)-ones. Under ionic reduction conditions (triethylsilane/tri-
fluoroacetic acid) the enamide group of 3a-methyl-N-Boc-hexahydro-1H-indolin-5(6H)-one was reduced to afford exclusively a cis
ring-fused product. For the 3a-phenyl substituted analogue more forcing conditions (sodium cyanoborohydride at pH 2–2.5) were
required and resulted in the selective reduction of the enamide group to give a trans ring-fused product as well as reduction of the
ketone group.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The 3a-substituted hydroindole skeleton 1 is a key sub-
unit of the Sceletium alkaloids,1 crinine-type Amaryllid-
R
aceae alkaloids2 (R = Ar) and the alkaloid dendrobine
H
(R = Me).1 In the last few years Padwa et al. have estab-
N
R'
lished that the intramolecular Diels–Alder cyclization of
alkenyl-substituted 2-amidofuran derivatives 2 (IM-
1, 3a-substituted hydroindole ring system
R = Ar, Me
DAF) is a convenient method for assembling 3a-substi-
tuted hexahydroindolin-5-one species 3 (Scheme 1).3–7
In order to apply the IMDAF products to the synthesis
of 3a-substituted hydroindoles and analogues, the selec-
tive reduction of the enamine moiety is required. For the
majority of natural product systems there is a cis-rela-
tionship between the 3a-substituent and the ring-junc-
tion proton. Herein we describe a study involving an
improved preparation of 3a-methyl- and 3a-phenyl-
hexahydroindolin-5-one and exploration of stereoselec-
tivity in the reductions of these molecules.
O
O
IMDAF
R
Δ
N
R
R'
N
R'
2
3
Scheme 1.
3a-Methyl-hexahydroindolin-5-one
4
was prepared
using the protocol reported by Padwa et al.5 with opti-
mization at each step to ensure that the process was
amenable to larger scale operations (Scheme 2). Furoic
acid was converted to the Boc-protected aminofuran 5
using diphenylphosphorazidate in refluxing tert-buta-
nol.3,8,9 We improved the procedure3 for the formation
of 5 by employment of a stoichiometric amount of
Keywords: Hydroindole; Intramolecular Diels–Alder cyclization;
Furan; Stereoselective; Enamide reduction.
*
Corresponding author. Tel.: +61 3 9545 2541; fax: +61 3 9545
2446; e-mail: jack.ryan@csiro.au
Present address: Department of Chemistry, University of Adelaide,
Adelaide, South Australia 5005, Australia.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.078

1940
M. A. Brodney et al. / Tetrahedron Letters 48 (2007) 1939–1943
O
NaOH, K2CO3,
MsO
BHT, Toluene
140 o
65%
nBu4N.HSO4
O
Boc
CH3
+
N
H
O
CH3
Toluene, 80 o
80%
C
CH3
N
C
Boc
N
5
6
Boc
7
4
Scheme 2.
phosphorazidate and use of an alkaline aqueous work-up,
rather than chromatography, to remove the diphenyl-
phosphate by-product. Alkylation of freshly prepared
carbamate 5 with crude mesylate 6,10 afforded the
alkenyl-substituted carbamate 7 in high yield after puri-
fication through a short column of silica.12 The intra-
molecular [4+2]-cycloaddition/rearrangement cascade
reaction of 7 was performed in toluene rather than the
relatively toxic benzene as first reported.5 It was found
that maintenance of the temperature at 140 ꢁC over 2
days in a sealed tube containing the antioxidant 2,6-di-
tert-butyl-4-methyl phenol (BHT) gave an optimal yield
of the known 3a-methyl-hexahydroindolin-5-one 4. At
higher temperatures (150 ꢁC and above) the reaction
was completed in a shorter time; however, the yield
of isolated product was lower due to the formation of
significant amounts of polymeric side products. For
reaction temperatures below 130 ꢁC, the cycloaddition
reaction was too sluggish to be practical. Using the
optimal conditions, over 70 g of ketoenamide 4 was
obtained in 48% overall yield from furoic acid.
for the intramolecular [4+2]-cycloaddition/rearrange-
ment cascade reaction of amidofuran 12a in toluene in-
volved heating crude amidofurans 12a/b and BHT in a
sealed tube at 140 ꢁC for 2 days. This procedure gave
a mixture of the hexahydroindolin-5-one 8 and unre-
acted alkene 12b. Ketoenamide 8 was isolated in 56%
yield after silica gel chromatography. This methodology
allowed for efficient production of over 30 g of the re-
quired phenyl-substituted ketoenamide 8 in 27% overall
yield from a-methylstyrene (9).
Chemo- and stereoselective reduction of the enamide
moiety of 4 was effected using triethylsilane in the pres-
ence of TFA16,17 to afford a high yield of ketone 13 as a
single product (Scheme 4). Interestingly, the order of
addition of the reagents was crucial for the success of
this reaction. When triethylsilane was added to the sub-
strate prior to the TFA good reproducible yields of 13
resulted. In contrast, when TFA was added before tri-
ethylsilane rapid degradation of the starting material
3a-Phenyl-hexahydroindolin-5-one 8 was prepared from
a-methylstyrene (9) (Scheme 3).13 Styrene 9 was con-
densed with formaldehyde and acetic anhydride14 to
give acetate 10a (as a ca. 5:1 mixture with isomer
10b).15 Acetate hydrolysis followed by mesylation under
standard conditions gave mesylates 11a/b. N-Alkylation
of furanyl carbamate 5 with mesylates 11a/b afforded
excellent yields of the styrenyl-substituted amidofurans
12a/b. As with the methyl analogue, optimal conditions
O
O
1) Et
2) CF3CO2H
3SiH, CH2Cl2
CH3
CH3
80%
H
N
N
Boc
Boc
13
4
Scheme 4.
AcO
MsO
1) NaOH, MeOH
2) MsCl, Et3N
CH2Cl2
Δ
1) (CH2O)n, AcOH,
Ph
Ph
Ph
CH3
10a
+
11a
Δ
2) Ac2O,
+
0 to 25 oC
79%
AcO
MsO
62%
Ph
10b
9
11b
O
Boc
O
N
H
O
5
N
N
Ph
Ph
Boc
12a
BHT, Toluene
NaOH, K2CO3
Ph
+
140 oC
56%
nBu4N.HSO4
O
N
Toluene, 80o
97%
C
Boc
8
Boc
12b
Scheme 3.

M. A. Brodney et al. / Tetrahedron Letters 48 (2007) 1939–1943
1941
was observed resulting in the formation of an intractable
material. Neither 4 nor 13 were recovered when the
residue was treated with di-tert-butyl-dicarbonate in
the presence of base indicating that the degradation
did not simply involve TFA-promoted loss of the Boc
group.4
ratio), which were separated by chromatography. Crys-
tals of minor trifluoroacetamide 15b suitable for X-ray
analysis were obtained. The resultant crystal structure
determination of 15b clearly shows a cis-relationship
between the ring-junction substituents (Fig. 1),19 and
therefore confirms the cis ring-fusion stereochemistry
of precursor ketone 13.
Ketone 13 was initially assigned cis ring fusion stereo-
chemistry based on NMR NOE studies. As the cis-stereo-
selectivity of the triethylsilane/TFA reduction of the
methyl analogue 4 did not correspond to the previous
report of trans-stereoselectivity for an aryl-substituted
analogue,6 we sought to confirm the NOE stereochemi-
cal assignment by the X-ray structure determination of
13 or a derivative. While the low melting ketone 13
proved unsuitable for such analysis, a crystalline deriva-
tive of 13 was obtained (Scheme 5). Thus, reductive
methylamination of 13 using the procedure of Bhatta-
charyya and co-workers18 gave a 3:2 mixture of diaste-
reomeric methylamines, 14a and b, obtained as an oil
in 92% yield. Methylamines 14 were converted to the
corresponding trifluoroacetamides 15a and b (ca. 3:2
In contrast to the methyl-substituted analogue, at-
tempted selective enamide reduction of 8 with triethyl-
silane and TFA gave poor results. On a single occasion
an enamide reduction product 16 (ring-fusion stereo-
chemistry not determined) was isolated in 18% yield
(Scheme 6); however, this result could not be repeated.
We suspect that a side reaction, involving acid-
promoted cleavage of the Boc-group occurs to give 17
(and/or the imine tautomer), predominates over the
required enamide reduction. Consistent with this suspi-
cion was the observation that subjection of the crude
product, from an attempted triethylsilane/TFA reduc-
tion of 8, to trifluoroacetic anhydride in the presence
of base produced a trifluoroacylated derivative of 17.
Alternative methods for the stereoselective reduction of
enamide 8 were explored. Treatment with sodium boro-
hydride in methanol or ethanol or with Raney Nickel
resulted in reduction of the ketone and not the enamide.
The use of sodium cyanoborohydride in acetic acid20
resulted in competitive enamide and ketone reductions
and a mixture of all four possible diastereoisomers 18
was obtained. In this case, little selectivity was observed,
for instance, major isomer 18a represented only 40% of
the mixture of products 18, as assessed by HPLC analy-
sis. The reduction of 8 with sodium cyanoborohydride
in acidic aqueous methanol21 was explored and the ste-
reoselectivity of the reduction under these conditions
1. CH3NH2.HCl
Ti(OiPr)4
H3C
H
O
N
Et3N, EtOH
2. NaBH4
CH3
CH3
H
H
92%
N
N
Boc
Boc
13
14a/b
TFAA, Et3N
O
O
N
H3C
H3C
N
CF3
CF3
CH3
O
O
O
1) Et3SiH
CH2Cl2
+
CH3
Ph
Ph
+
Ph
2) TFA
H
H
H
N
N
N
N
TFA.HN
17
Boc
Boc
Boc
Boc
8
16
15b (33%)
15a (49%)
Scheme 5.
Scheme 6.
Figure 1. ORTEP diagram of trifluoroacetamide 15b, illustrating the cis relationship between the ring-junction proton H6 and methyl C9 substituent.

1942
M. A. Brodney et al. / Tetrahedron Letters 48 (2007) 1939–1943
silane/TFA reduction (so-called ionic reduction condi-
O
OH
N
OH
NaCNBH3
pH 2.0-2.5
tions) afforded cis-product 13. For enamide 8, the bulk-
ier phenyl substituent hinders reduction from the same
face of the molecule as the phenyl group. This results
in negligible reduction of the enamide under ionic
hydrogenation conditions. Under more forcing condi-
tions (i.e., sodium cyanoborohydride at pH 2–2.5) ena-
mide and ketone reductions both occur, but from the
concave face of the molecule to give the trans ring-fused
product 18a.
Ph
Ph
Ph
+
aq. MeOH
rt
H
H
N
N
Boc
Boc
Boc
18a (62 - 75%)
18b-d
8
Scheme 7.
was significantly improved (Scheme 7). The effect of pH
on conversion rate and stereoselectivity was studied with
the optimal conditions for the formation of the major
isomer 18a being pH 2–2.5 (the pH was controlled by
addition of 2 M HCl) at room temperature. Attempts
to further improve the stereoselectivity by lowering the
temperature to 0 ꢁC resulted in unacceptably low con-
version rates. Under the optimal conditions, HPLC
analysis indicated that the major isomer 18a represented
80% of the product mixture and could be isolated in 75%
yield after chromatography on silica. A larger scale
preparation yielded 20 g of analytically pure 18a in
62% yield after chromatography and recrystallization.
In summary, the synthesis of hexahydroindolin-5-ones
via IMDAF chemistry has been developed so as to be
amenable for large-scale chemistry. Our preliminary
results for the reduction of the hexahydroindolin-5-ones
show that the ring-junction substituent plays an impor-
tant role in the reduction of the enamide moiety. The
smaller methyl substituent favours formation of the cis
ring-fused product, whereas the larger phenyl substitu-
ent results in favoured reduction to the trans ring-fused
product.
Acknowledgements
The stereochemistry of major alcohol 18a was unequiv-
ocally determined by single crystal X-ray structure
analysis (Fig. 2). The crystal structure clearly shows a
trans-relationship between the ring-junction phenyl
and hydrogen groups and a cis-relationship between
the phenyl group and the alcohol group.19
This work was funded by Pfizer Global Research and
Development. The authors thank Dr. Roger Mulder
for assistance with collection and analysis of NMR data.
Supplementary data
We have found that the ring-junction substituent in 4
(methyl) or 8 (phenyl) has a marked effect on the ena-
mide reactivity and the stereoselectivity of the reduction
of the enamide moiety in N-Boc-hexahydroindolin-5-
ones. The molecular models of compounds 4 and 8 indi-
cate that they are bowl-shaped with the 3a-substituent
situated on the convex side of the hexahydroindolinone
framework. The shape of the molecule would favour
reduction of the enamide from the same face of the mole-
cule as the substituent. Thus for enamide 4, triethyl-
Experimental procedures and analytical data for all new
compounds. X-ray experimental procedures for com-
pounds 15b and 18a. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.078.
References and notes
1. Jeffs, P. W. In The Alkaloids; Rodrigo, R. G. A., Ed.;
Academic Press: New York, 1981; Vol. 19, pp 1–80.
2. Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 30, pp 251–356.
3. Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J.
Org. Chem. 1997, 62, 4088–4096.
4. Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem.
1998, 63, 5304–5305.
5. Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J.
Org. Chem. 1999, 64, 4617–4626.
6. Padwa, A.; Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu, T.
J. Org. Chem. 2001, 66, 3119–3128.
7. Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasak-
hon, P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69,
3735–3745.
8. Shioiri, T.; Ninomiya, K.; Yamada, S.-I. J. Am. Chem.
Soc. 1972, 94, 6203–6205.
9. Alternatively 5 can be obtained by the reaction of 2-furoyl
chloride with sodium azide in tert-butanol at reflux:
Padwa, A.; Brodney, M. A.; Lynch, S. M. Org. Synth.
2002, 78, 202–211. Despite the expense, we preferred the
phosphorylazidate method for larger scale preparations
(>0.1 mol) due to the consistently higher yields and purity
of 5 obtained.
Figure 2. ORTEP diagram of alcohol 18a, illustrating the trans
relationship of the ring-junction proton H6 and phenyl substituent.

M. A. Brodney et al. / Tetrahedron Letters 48 (2007) 1939–1943
1943
˚
˚
10. Mesylate 6 was prepared from 3-methyl-3-buten-1-ol
using standard procedures. The original procedure for
the preparation of 75 involved the conversion of 6 into the
corresponding bromide11 for N-alkylation of 5. The
alkylating agent 6 was found to be sufficiently reactive
for N-alkylation of 5.
11. Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M.
A.; Blackwell, C. M.; Anderson, L. G. J. Am. Chem. Soc.
1992, 114, 7375–7387.
12. Chromatographic purification of intermediate 7 facilitated
the purification of 4 after the IMDAF reaction.
13. An alternative approach utilizing a-(bromoethyl)styrene
was considered, involving acylation of benzene with 3-
bromopropionyl chloride followed by methylenation of
the aryl ketone product with Tebbe’s reagent.6 The current
route was chosen on the basis that it would be less
expensive and more amenable to larger scale production.
14. Maercker, A.; Weber, K. Liebigs Ann. Chem. 1972, 756,
20–32.
15. No attempt was made to remove the isomeric impurity 10b
at this stage as impurities derived from 10b were readily
removed after the intramolecular [4+2]-cycloaddition/
rearrangement step.
16. Miller, R. A.; Humphrey, G. R.; Thompson, A. S.
Tetrahedron Lett. 1995, 36, 7949–7952.
17. Cannon, J. G.; Kirschbaum, K. S. Synthesis 1993, 1151–
1154.
18. Neidigh, K. A.; Avery, M. A.; Williamson, J. S.;
Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1998,
2527–2531.
c = 14.080(3) A, a = 106.72(3), b = 95.73(3), c = 92.22(3)ꢁ,
3
3
V = 941.5(3) A , Z = 2, Dc = 1.285 g/cm , F0 0 0 = 388,
˚
Nonius Kappa CCD, MoKa radiation, k = 0.71073 A,
T = 123(2) K, 2hmax = 55.5ꢁ, 12,716 reflections collected,
4393 unique (Rint = 0.0968). Final GooF = 1.035,
R1 = 0.0601, wR2 = 0.1432, R indices based on 2499
reflections with I > 2sigma(I) (refinement on F2), 231
parameters, 0 restraints. Lp and absorption corrections
applied, l = 0.107 mmÀ1. Crystal data for major alcohol
18a: C19H27NO3, M = 317.42, colourless flat extended
plates, 0.20 · 0.20 · 0.10 mm, monoclinic, space group
P21/c (No. 14), a = 16.434(3), b = 6.2497(12), c =
3
˚
˚
17.761(4) A, b = 112.36(3)ꢁ, V = 1687.1(6) A , Z = 4,
Dc = 1.250 g/cm3, F0 0 0 = 688, Nonius Kappa CCD,
˚
MoKa radiation, k = 0.71073 A, T = 123(2) K, 2hmax
55.7ꢁ, 15,631 reflections collected, 3969 unique (Rint
=
=
0.0841). Final GooF = 1.017, R1 = 0.0457, wR2 = 0.1008,
R indices based on 2472 reflections with I > 2sigma(I)
(refinement on F2), 212 parameters, 0 restraints. Lp and
absorption corrections applied, l = 0.084 mmÀ1. Crystal-
lographic data (excluding structure factors) for the struc-
tures reported in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publications Nos. CCDC-626810 for compound 15b
and CCDC-626809 for compound 18a. Copies of the
data can be obtained free of charge on application to
the CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK {fax: (+44) 1223 336 033; email: deposit@ccdc.cam.
ac.uk}.
20. Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.;
Stercho, Y. P. J. Org. Chem. 1983, 48, 3412–3422.
21. Guarna, A.; Occhiato, E. G.; Machetti, F.; Scarpi, D.
J. Org. Chem. 1998, 63, 4111–4115.
19. Crystal data for minor trifluoroacetamide 15b: C17H27-
F3N2O3, M = 364.41, 0.20 · 0.10 · 0.10 mm, triclinic,
space group P-1 (No. 2), a = 6.3551(13), b = 11.069(2),