Unexpected cis selectivity in the Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.tetlet.2009.03.121

Whilst cis:trans selectivity of about 4:1 can be obtained from Pictet-Spengler reactions between tryptophan methyl esters and aldehydes using conditions of kinetic control, much higher cis selectivity (>95:5) can be obtained when both the tryptophan deriv

Full text of DOI:10.1016/j.tetlet.2009.03.121

Tetrahedron Letters 50 (2009) 3645–3647
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected cis selectivity in the Pictet–Spengler reaction
*
Patrick D. Bailey , Mark A. Beard, Theresa R. Phillips
Research Institute for the Environment, Physical Sciences and Applied Mathematics, Keele University, Keele, Staffordshire ST5 5BG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Whilst cis:trans selectivity of about 4:1 can be obtained from Pictet–Spengler reactions between trypto-
phan methyl esters and aldehydes using conditions of kinetic control, much higher cis selectivity (>95:5)
can be obtained when both the tryptophan derivative and the aldehyde possess a suitable p-system; pre-
Received 16 January 2009
Revised 5 March 2009
Accepted 16 March 2009
Available online 21 March 2009
liminary results on the scope and limitations of this exceptional stereocontrol are presented in this Letter.
Ó 2009 Elsevier Ltd. All rights reserved.
The Pictet–Spengler reaction is a key step in the total synthesis
of a large number of indole alkaloids, as exemplified by syntheses
of ajmalicine (1),1 raumacline (2),2 spirotryprostatin A (3)3 and
ajmaline (4).4
Epimeric with respect to
D
-stereochemistry
stereochemistry of natural products
CO2Me
HN
CO2Me
R CHO
1
N
N
Bn
N
H
Bn
H
R
5
6
H
OH
H
N
H
H
H
O
Scheme 1. Trans control with N-benzyl derivatives.
Me
NH
N
H
Me
H
H
MeO2C
Et
ajmalicine (1)
raumacline (2)
from L-tryptophan, the 1-substituent is always required to be cis
relative to the carboxylic acid derivative of the tryptophan.
For many indole alkaloids, the carboxylic group is absent in the
final natural product (e.g., ajmalicine 1), although tryptophan is the
biosynthetic building block, and can be used in total syntheses if
the carboxy group is removed after the Pictet–Spengler reaction.7
O
O
H
HN
HO
N
H
MeO
O
N
H
Me
Me
Et
OH
Me
For bridged indole alkaloids such as ajmaline, the
a-carboxy group
spirotryprostatin A (3)
ajmaline (4)
can be incorporated into the target molecule. In either case, cis-
selective Pictet–Spengler reactions are required if
to be used as the starting material.
L-tryptophan is
The indolic Pictet–Spengler reaction involves the formation of
an imine between a tryptamine derivative and an aldehyde, which
can then undergo acid-catalysed cyclisation to generate a new
piperidine ring.5
We have studied the mechanism of the Pictet–Spengler reaction,
and used this to develop a cis-selective procedure that involved
kinetically controlled conditions (Scheme 2);8 in contrast, the origi-
nal5 or improved9 procedures used until the 1980s gave poor stereo-
control (mainly trans, and with problems of racemisation).
Using our conditions of kinetic control, we recently completed a
total synthesis of the alkaloid (–)-raumacline.2a Notable in our ap-
proach was an early Pictet–Spengler reaction in which complete
cis-stereocontrol was observed (Scheme 3); as far as we are aware,
only one other cis-specific Pictet–Spengler reaction had been
reported.10
However, in 2004, we reported that tryptophan allyl esters could
be reacted with benzaldehyde, to give >95:5 cis:trans selectivity;
this unexpected result turned out to be quite general, such that aryl
aldehydes can be reacted with tryptophan allyl ester to give the cis-
1,3-disubstituted tetrahydro-b-carbolines (Scheme 4).11
If the tryptamine derivative contains an
a-substituent (e.g.,
tryptophan esters), then diastereoisomers can be generated. In
the case of N-benzyl tryptophan derivatives, Cook ascertained that
the trans isomer is the sole product;6 his group have used this in
their synthesis of bridged indole alkaloids such as ajmaline,4
although this necessitates starting from non-DNA-encoded
tophan, and epimerisation of the -centre during the formation of
the bridged ring system (Scheme 1).
D-tryp-
a
It is worth noting that the tetrahydro-b-carboline moiety is the
commonest sub-structure amongst indole alkaloids and, if derived
* Corresponding author. Tel.: +44 1782 734583; fax: +44 1782 734593.
E-mail address: p.bailey@natsci.keele.ac.uk (P.D. Bailey).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.121

3646
P. D. Bailey et al. / Tetrahedron Letters 50 (2009) 3645–3647
Table 1
L
-stereochemistry
CO2Me
NH2
Results from the kinetically controlled Pictet–Spengler reaction using a range of
tryptophan esters14
N
H
Entry
X in 15
R in aldehyde
Yield (%)
Cis:trans ratio
18
–CO2Me
–CO2Me
–CO2Me
–CO2Me
–CO2iPr
–CO2iPr
–CO2iPr
–CO2iPr
–CO2Allyl
–CO2Allyl
–CO2Allyl
–CO2Allyl
–CO2Bn
–CO2Bn
–CO2Bn
–CO2Bn
–Ph
74
71
72
75
>95
>95
>95
>95
57
39
52
67
74
81
72
77
4.6:1
2.5:1
4.0:1
4.9:1
7.3:1
3.5:1
2.7:1
2.7:1
>20:1
3.0:1
2.0:1
3.5:1
4.7:1
3.3:1
2.3:1
3.1:1
R-CHO/ RT/ H+
OR
R-CHO/ PhH/
reflux/ cat. H+
7
28
–Cyclohexyl
–(CH2)2Ph
–(CH2)2CH3
–Ph
–Cyclohexyl
–(CH2)2Ph
–(CH2)2CH3
–Ph
–Cyclohexyl
–(CH2)2Ph
–(CH2)2CH3
–Ph
–Cyclohexyl
–(CH2)2Ph
–(CH2)3CH3
R-CHO (-H2O)
38
then
excess H+/ low T
48
513
613
713
813
911
1011
1111
1211
13
CO2Me
NH
CO2Me
Correct
NH
N
H
N
stereochemistry
for natural
H
8
9
R
R
Cis/trans mixture
Racemisation can occur
Mainly cis (typically
products
4:1 cis:trans)
Optically pure
14
15
16
Scheme 2. Stereocontrol in the Pictet–Spengler reaction.
X
X
CHO
R CHO
NH2
NH
N
Kinetically controlled
Pictet-Spengler reaction
N
H
11
t
CN
CN
H
OSiPh2Bu
R
15
16
NH2
NH
N
H
N
H
Pre-f orm imine, then
excess TFA at –35 ºC
12
10
Scheme 5. Scope of selectivity (Tables 1 and 2).
OSiPh2But
cis only
these reactions (entry 9) did not reduce the cis selectivity, despite
the fact that one might have expected the -additives to interfere
with any -stacking interactions.
Scheme 3. Cis selectivity with homologous nitrile 14.
p
p
Thirdly, we have carried out further Pictet–Spengler reactions
with the homologous nitrile 10, and have extended the range of
aldehydes that react with high cis selectivity. Our starting point
was the reaction of 10 with Ph2ButSiO–(CH2)2–CHO (11), which
forms >95% of the cis adduct (Scheme 3);2a when repeated using
tryptophan methyl ester (Table 2, entry 2), this reaction gave a
O
O
Ar CHO
O
O
NH2
NH
N
H
N
H
1) Pre-form imines
2) Excess H+/ low T
Ar
14
13
> 95% cis
3:1 cis:trans ratio of products, confirming the need for a
in the ester. Demonstration that the aldehyde must also possess
-group came from the use of the TBDMS-protected aldehyde
p-group
Scheme 4. Cis selectivity with tryptophan allyl esters.
a
p
At that time, no other types of aldehyde or tryptophan deriva-
tives were found to give high cis selectivity. However, we report
in this Letter a much wider range of other tryptophan derivative/
aldehyde combinations that also give outstanding cis selectivity
of >95:5. Although we are not yet able to provide either a definitive
explanation, or a definitive ‘rule’ for this stereocontrol, our results
provide strong guidelines for those wishing to access cis-tetrahy-
dro-b-carbolines using the Pictet–Spengler reaction.
Firstly, we report the use of benzyl esters in place of allyl esters,
for which we hoped that the aryl group would have the same effect
as the ethylene moiety. Tryptophan benzyl ester is surprisingly dif-
ficult to be prepared,12 but did provide some improvement in cis
selectivity with benzaldehyde, although all other aldehydes
showed only modest selectivity (see Table 1, entries 13–16). The
use of benzyl esters can be useful for aldehydes with sensitive side
chains because (unlike allyl) the benzyl group can be removed un-
der mild hydrogenation conditions.
(entry 3), which reverted to the normal selectivity in the Pictet–
Spengler reaction. However, most intriguingly, we found that the
high cis selectivity was retained when 10 was reacted with alkyl
aldehydes possessing phenyl group(s) at a range of positions, sub-
stantially increasing the scope of this highly cis-selective reaction.
In summary, Table 1 demonstrates the yield and modest cis
selectivity that can be obtained using a range of tryptophan esters
in the kinetically controlled Pictet–Spengler reaction; the excellent
cis control using tryptophan allyl ester with aryl aldehydes is also
highlighted. However, the excellent cis control possible using the
homologous nitrile 10 with a wide range of aldehydes possessing
a phenyl group in the side chain is extraordinary; we are still prob-
Table 2
Pictet–Spengler reactions with nitrile 1015
Secondly, these results with the benzyl ester allowed us to com-
plete a useful matrix of results using four tryptophan esters and
four archetypical aldehydes (Scheme 5), as summarised in Table
1, which also provides a reminder that the use of isopropyl esters
(in ethanol-free chloroform) ensures the highest yield of the Pic-
tet–Spengler product13 (but with varying stereocontrol).
From Table 1, it is clear that both the ester and the aldehyde
must contain an appropriate p-moiety (in addition to the C@O p-
bond) in order for high cis selectivity to be observed. However,
the addition of 10 equiv of toluene, anisole or nitrobenzene to
Entry
X in 15
R in aldehyde
Yield %
Cis:trans ratio
1
2
3
4
5
6
7
8
9
–CH2CN
–CO2Me
–CH2CN
–CO2allyl
–CH2CN
–CH2CN
–CH2CN
–CH2CN
–CH2CN
–CH2CN
–(CH2)2OSiButPh2
–(CH2)2OSiButPh2
–(CH2)2OSiButMe2
–(CH2)2OSiButPh2
–CH2OSiButPh2
–(CH2)3OSiButPh2
–(CH2)6OSiButPh2
–(CH2)7OSiButPh2
–(CH2)2Ph
59
82
51
58
70
58
53
56
41
64
>20:1
3.0:1
3.6:1
2.5:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10
–(CH2)2OBn

P. D. Bailey et al. / Tetrahedron Letters 50 (2009) 3645–3647
3647
residue was subjected to column chromatography eluting with 10% MeOH/
CH2Cl2 to give the TFA salt of the title compound (0.765 g). This was
partitioned between CH2Cl2 (20 mL) and sat. aqueous NaHCO3 (20 mL), and
the aqueous phase was extracted with further CH2Cl2 (4 ꢀ 20 mL). The
combined organics were dried over MgSO4 and were reduced in vacuo to
give the title compound as a colourless foam (0.523 g, 88%). [For alternative
one-step syntheses, see (a) Wilchek, M.; Patchornik, A. J. Org. Chem., 1963, 28,
1874; (b) Stocking, E. M.; Sanz-Cervera, J. F.; Unkefer, C. J.; Williams, R. M.
ing the reasons for this. Furthermore, this chemistry is being
exploited in the total synthesis of indole alkaloids.
Acknowledgement
We thank the EPSRC for funding.
References and notes
Tetrahedron, 2001, 57, 5303. Ref. (b) also includes 1H/13C data for the 1-13
C
derivative of Trp–OBn.]
13. Bailey, P. D.; Moore, M. H.; Morgan, K. M.; Smith, D. I.; Vernon, J. M. Tetrahedron
Lett. 1994, 35, 3587.
1. (a) Massiot, G.; Mulamba, T. Chem. Commun. 1983, 1147; (b) Massiot, G.;
Mulamba, T. Chem. Commun. 1984, 715.
14. General method for the entries given in Table 1. L-Tryptophan allyl ester
(150 mg, 0.613 mmol) was dissolved in DCM (5 mL) with 3 Å molecular sieves
(15 mg/mmol of ester) under argon. The solution was cooled to 0 °C, and the
appropriate aldehyde (1 mmol) was added. After 30 min, the solution was
allowed to warm to room temperature and was stirred overnight. A small
aliquot was then removed, the solvents were evaporated off and the remaining
solid was analysed by NMR spectroscopy confirming complete formation of the
imine. The solution was then cooled to 0 °C, TFA (2 equiv) was added, and the
reaction mixture was stirred at this temperature for 3–8 h. The reaction
mixture was quenched with satd aq NaHCO3 (12 mL) and was warmed to room
temperature. The phases were separated and the combined organic solutions
were washed with brine, dried over MgSO4 and reduced in vacuo. The products
were purified by column chromatography leading to isolation of the
tetrahydro-b-carboline. Table 1, entry 9: 57% yield. Rf 0.22 (2% Et2O/CH2Cl2).
2. (a) Bailey, P. D.; Clingan, P. D.; Mills, T. J.; Price, R. A.; Pritchard, R. G. Chem.
Commun. 2003, 2800; (b) Bailey, P. D.; Beard, M. A.; Dang, H. P. T.; Phillips, T. R.;
Price, R. A.; Whittaker, J. H. Tetrahedron Lett. 2008, 49, 2150.
3. (a) Edmondson, S. D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1138; (b)
Edmondson, S. D.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem.
Soc. 1999, 121, 2147.
4. (a) Li, J.; Cook, J. M. J. Org. Chem. 1998, 63, 4166; (b) Li, J.; Wang, T.; Yu, P.;
Peterson, A.; Weber, R.; Soerens, D.; Grubisha, D.; Bennett, D.; Cook, J. M. J. Am.
Chem. Soc. 1999, 121, 6998.
5. Pictet, A.; Spengler, T. Berichte 1911, 44, 2030.
6. Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org. Chem. 1981, 46, 164.
7. The CO2H group can be removed via conversion to the nitrile followed by
a-
reduction with NaBH4 (Ref. 1), or using a radical reduction route—for example:
Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79.
8. Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.; Morgan, K. M.; Palmer, S. J.; Prince,
S. N.; Reynolds, C. D.; Wood, S. D. J. Chem. Soc., Perkin Trans. 1 1993, 431.
9. Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.;
Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem. 1979, 44, 535.
10. See reference 1; this neatly exploited both cis and trans selective Pictet-
Spengler reactions to access both antipodes; the cis-tetrahydro-b-carboline
[from tryptophanamide and (PhS)2C(CO2Me)-(CH2)2CHO] was diastereo-
merically pure within the NMR detection limits. Using chiral aldehydes
IR mmax (neat) 3652, 3052, 2990, 2307, 1732, 1266 cmꢁ1. ½a D23
ꢁ 13 (c 1.09,
ꢂ
CH2Cl2). 1H NMR (CDCl3, 400 MHz) d 2.28 (1H, br s, NH), 2.93 (1H, ddd, J = 15.0,
11.4, 2.5 Hz, ArCHH), 3.15 (1H, ddd, J = 15.0, 4.2, 1.8 Hz, ArCHH), 3.87 (1H, dd,
J = 11.1, 7.7 Hz, ArCH2CH), 4.55–4.66 (2H, m, OCH2CH = CH2), 5.10 (1H, s,
ArCHNH), 5.19 (1H, dd, J = 10.4, 1.4 Hz, OCH2CH = CHH), 5.28 (1H, dd, J = 17.2,
1.4 Hz, OCH2CH=CHH), 5.81–5.86 (1H, m, OCH2CH=CH2), 7.05–7.45 (10H, m,
ArH and indole NH) ppm. 13C NMR (CDCl3, 100 MHz) 26.2, 57.3, 59.1, 66.2,
109.2, 111.4, 118.6, 119.3, 120.0, 122.3, 127.5, 128.7, 128.9, 129.0, 129.1, 129.6,
132.2, 135.1, 136.6, 141.2, 172.4 ppm. HRMS (ES+): Calcd for C21H21N2O2
[M+H]+: 333.1604. Found: 333.1617 (100%), 334.1642 (10%).
(Z-protected
a-aminoaldehydes) with Trp-OMe, cis specific reactions have
15. General method for the entries given in Table 2. The amino-nitrile (150 mg,
0.684 mmol) was dissolved in CH2Cl2 (5 mL) with 3 Å molecular sieves (15 mg/
mmol of amino-nitrile) under N2. The solution was cooled to 0 °C, and the
appropriate aldehyde (0.855 mmol) in CH2Cl2 (2.5 mL) was added. After
30 min, the solution was allowed to warm to room temperature and was
been reported for matched substrates (Pulka, K.; Kulis, P.; Tymecka, D.; Lukasz,
F., Wilczek, M.; Kozminski, W.; Misicka, A. Tetrahedron 2008, 64, 1506. Aqueous
Pictet-Spengler reactions show typical cis selectivity of about 4:1, although a
9:1 cis:trans ratio was reported for Trp-OMe with 2-hydroxybenzaldehyde
(Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Tetrahedron Lett. 2007, 48, 1379).
11. Alberch, L.; Bailey, P. D.; Clingan, P. D.; Mills, T. J.; Price, R. A.; Pritchard, R. G.
Eur. J. Org. Chem. 2004, 1887.
stirred overnight.
A small aliquot was then removed, the solvents were
evaporated off and the remaining solid was analysed by NMR spectroscopy
confirming complete formation of the imine. The mixture was then cooled to
ꢁ78 °C before the addition of TFA (2 equiv). The reaction mixture was stirred at
ꢁ78 °C for 3 h, 0 °C for 1 h and room temperature for 2 h (except entry 3, which
was run at ꢁ35 °C until the reaction was complete by TLC). The resulting red
mixture was filtered and the molecular sieves were washed thoroughly with
CH2Cl2 (25 mL) before the addition of sat. aqueous NaHCO3 (15 mL). The phases
were separated and the combined organic solutions were washed with satd aq
NaHCO3 (15 mL) and brine (15 mL), dried over MgSO4 and reduced in vacuo.
The products were purified by column chromatography leading to isolation of
the tetrahydro-b-carboline. Data for Table 2, entry 1: 59% yield. Rf 0.38 (10%
12. N-a-Boc-L-tryptophan benzyl ester: Prepared by analogy with the literature
method of MacLeod, A.M.; Merchant, K. J.; Brookfield, F.; Kelleher, F.;
Stevenson, G.; Owens, A. P.; Swain, C. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.;
Strader, C. D.; MacIntyre, D. E.; Metzger, J. M.; Ball, R. G.; Baker, R. J. Med. Chem.
1994, 37, 1269. N-a-Boc-L-tryptophan (1.34 g, 4.4 mmol) was dissolved in
MeOH (18 mL) and water (10 mL). Caesium carbonate (0.716 g, 2.2 mmol,
0.5 equiv) in water (2 mL) was added and the solution was stirred for 20 min.
The solvent was removed in vacuo, and the residue was azeotroped with
anhydrous DMF (2 ꢀ 18 mL). Benzyl bromide (0.752 g, 4.4 mmol, 1.0 equiv)
was added to a solution of the caesium salt in DMF (18 mL) and the reaction
mixture was stirred for 16 h. The solvent was removed in vacuo and the
residue was partitioned between EtOAc and water. The organic phase was
washed with brine, dried over MgSO4 and reduced in vacuo to give a white
solid, which was recrystallised from EtOAc/ petroleum ether to give the title
compound (1.46 g, 84%). (See Crosignani, S.; White, P. D.; Steinauer, R.; Linclau,
Et2O/CH2Cl2). IR m .
max (neat) 3362, 3071, 2930, 2250, 1428, 1112 cmꢁ1 1H NMR
(CDCl3, 500 MHz) d 1.06 (9H, s, C(CH3)3), 1.46 (1H, br s, NH), 1.76 (1H, ddt,
J = 14.8, 4.1, 3.7 Hz, CHHCH2OSi), 2.07–2.13 (1H, m, CHHCH2OSi), 2.43–2.47
(1H, m, ArCHH), 2.49 (2H, dd, J = 6.8, 2.5 Hz, CHHCN), 2.84 (1H, ddd, J = 15.0,
4.0, 1.9 Hz, ArCHH), 3.15–3.21 (1H, m, CHCH2CN), 3.85–3.87 (2H, m,
CH2CH2OSi), 4.19–4.22 (1H, m, ArCH), 6.98–7.04 (3H, m, ArH), 7.26–7.38 (7H,
m, ArH), 7.57–7.61 (4H, m, ArH), 8.86 (1H, br s, indole NH) ppm. 13C NMR
(CDCl3, 125 MHz) d 19.5, 25.0, 27.1, 28.5, 37.7, 51.3, 53.7, 62.9, 111.1, 117.9,
118.0, 119.4, 121.6, 123.6, 127.3, 128.0, 128.1, 130.1, 130.2, 135.5, 135.6 ppm.
HRMS (ES+): Calcd for C31H35N3OSi [M+H]+: 494.6223. Found: 494.6217 (100%).
B. Org. Lett., 2003, 5, 853 for an alternative preparation and 1H/13C data).
Tryptophan benzyl ester: N- -Boc- -tryptophan benzyl ester (0.795 g, 2.2 mmol)
L-
a
L
was dissolved in CH2Cl2 (18 mL) at 0 °C. To this were added MeOH (0.9 mL) and
trifluoroacetic acid (9 mL) and the solution was stirred at 0 °C for 1 h. Volatiles
were removed in vacuo and were triturated three times with CH2Cl2. The