Stereoselective synthesis of four possible isomers of streptopyrrolidine

Article abstract of DOI:10.3762/bjoc.7.6

The synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R, 5S)-streptopyrrolidine (3) and (4S,5S)-strepto- pyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reacti

Full text of DOI:10.3762/bjoc.7.6

Stereoselective synthesis of four possible isomers
of streptopyrrolidine
Debendra K. Mohapatra*, Barla Thirupathi, Pragna P. Das
and Jhillu S. Yadav*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 34–39.
Division of Organic Chemistry-I, Indian Institute of Chemical
Technology (CSIR), Hyderabad-500607, India, Tel/Fax:
0091-40-27193128
doi:10.3762/bjoc.7.6
Received: 01 September 2010
Accepted: 26 November 2010
Published: 10 January 2011
Email:
Debendra K. Mohapatra* - mohapatra@iict.res.in; Jhillu S. Yadav* -
yadavpub@iict.res.in
Associate Editor: J. Aubé
* Corresponding author
© 2011 Mohapatra et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aldol reaction; angiogenesis; cancer; Lewis acid mediated
lactamization; streptopyrrolidine
Abstract
The synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R,5S)-streptopyrrolidine (3) and (4S,5S)-strepto-
pyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reaction with the
trimethylsilyl enolate of ethyl acetate and Lewis acid mediated lactamization as the key reactions in ≈42% yield over six steps
starting from D-phenylalanine and L-phenylalanine, respectively. The absolute configuration of the natural product was shown to
be (4S,5S) by comparing its spectral and analytical data with the reported values.
Introduction
Cancer is at present the second most common cause of death, [2], as well as the potential for treating a broad spectrum of
after cardiovascular diseases, and will become the primary tumor types, arthritis, and psoriasis [3-8]. For this reason,
cause in the next 10 to 20 years [1]. Traditional cancer thera- angiogenesis inhibition has become an active area of pharma-
pies make use of chemotherapy at the maximum tolerated dose. ceutical research, and over 40 such agents are currently under-
This approach has generally considerable associated toxicity, going clinical trials [9]. In particular, efforts have been focused
often with limited success. Therefore, more universal, more on small-molecules based on inhibitors isolated from natural
effective, and less toxic therapeutic agents are desirable. products that can block tumor angiogenesis [10,11].
Recently, inhibition of angiogenesis has been considered as a
desirable pathway for preventing tumor growth and metastasis, Recently, streptopyrrolidine (Figure 1), was isolated as an
primarily because of the low potential for toxicity or resistance angiogenesis inhibitor from the fermentation broth of a marine
34

Beilstein J. Org. Chem. 2011, 7, 34–39.
Streptomyces sp. found in deep sea sediments [12]. The system three steps by a known protocol [26,27]. The aldehyde was
is present in many biologically active compounds [13-21] and it treated with the lithium enolate of ethyl acetate [28,29] at −78
could act as a versatile intermediate for the synthesis of a wide °C according to a modification of the procedure of Steulmann
range of γ-amino acids as well as pyrrolidines [22,23]. The and Klostermeyer [30] to afford two diastereomers 8a and 8b in
interesting chemical structure and potent anti-angiogenic a 3:2 ratio (as determined by NMR) (Scheme 2).
activity at non-toxic threshold doses of streptopyrrolidine
attracted our attention for developing a concise and efficient
protocol for its synthesis in sizable amounts for further bio-
logical studies. To date, three syntheses [15,24,25] of (4S,5S)-
streptopyrrolidine have been described, two of which [15,24]
were reported only as a synthetic intermediate prior to its isola-
tion from the natural source.
Scheme 2: Reagents and conditions: (a) LDA, EtOAc, THF, −78 °C,
4 h, 80% (8a:8b = 3:2); (b) BF3·OEt2, (1-ethoxyvinyloxy)trimethyl-
silane, CH2Cl2, −78 °C, 2 h, 85% (exclusively 8b); (c) SnCl4,
(1-ethoxyvinyloxy)trimethylsilane, CH2Cl2, −78 °C, 2 h, 70% (8a:8b =
3:7); (d) LDA, EtOAc, ZnBr2, −78 °C, 1 h, 82%, (8a:8b = 95:5).
Diastereomers 8a and 8b were easily separated by standard
column chromatography on silica gel. The pioneering work on
catalytic aldol reactions recently reported by Shibasaki [31]
prompted us to investigate whether the ketene silyl acetal could
be utilized for the aldol reaction in the presence of different
Lewis acids to obtain a better selectivity particularly for (R)-
Figure 1: Structures of (4R,5R)-streptopyrrolidine (1), (4S,5R)-strepto-
pyrrolidine (2) (4R,5S)-streptopyrrolidine (3) and (4S,5S)-strepto-
pyrrolidine (4).
Results and Discussion
In this paper, we report the syntheses of (4R,5R)-strepto- tert-butyl (1-oxo-3-phenylpropan-2-yl)carbamate (6). To our
pyrrolidine (1), (4S,5R)-streptopyrrolidine (2), (4R,5S)-strepto- surprise, when the reaction was carried out with the ketene silyl
pyrrolidine (3) and (4S,5S)-streptopyrrolidine (4) in a concise acetate at −78 °C, of the five Lewis acids investigated (SnCl4,
and highly efficient manner via a highly stereoselective aldol BF3·OEt2, ZnI2, TiCl4, EtOAc/LDA/ZnBr2) BF3·OEt2 gave
type reaction and Lewis acid mediated lactamization as the key excellent selectivity (exclusively 8b) (Table 1).
reactions. A retrosynthetic analysis for streptopyrrolidine is
depicted in Scheme 1.
Following a modification of the Mosher method [32,33], the
newly created stereogenic center in compound 8b bearing the
The synthesis was initiated from D-phenylalanine (7) which hydroxyl group was assigned. The syntheses of both the (S)-
was converted to N-Boc-D-phenylalaninal (6) in 76% yield in and (R)-MTPA ester of 8b were achieved using MTPA acid
with DCC as the coupling reagent. The chemical shifts of both
the (S)- and (R)-MTPA esters of 8b were assigned by 1H NMR.
From the equation given in Figure 2, the Δδ values were calcu-
lated for as many protons as possible. The carbon chain bearing
protons showing Δδ negative values should be placed on the left
hand side of the model (Figure 2) whilst that where Δδ has posi-
tive values should be placed on the right hand side. From this
the center was found to have the S-configuration which thus
establishes the absolute stereochemistry of 8a. With the
absolute stereochemistry of both the isomers known, we were
interested to develop a protocol to have control over the selec-
Scheme 1: Retrosynthetic analysis.
tivity to obtain exclusively 8a. Stereoselective addition of the
35

Beilstein J. Org. Chem. 2011, 7, 34–39.
Table 1: Addition reaction under different conditions to obtain 8a and 8b.
Entry
Reagent
Additive (Lewis Acid)
Time (h)
Yielda (%)
8a:8b
1
2
3
4
5
ketene silyl acetate
ketene silyl acetate
ketene silyl acetate
ketene silyl acetate
EtOAC/LDA
SnCl4
BF3·OEt2
TiCl4
2
2
70
85
42
59
82
30:70
0:100
35:65
80:20
95:05
10
12
1
ZnI2
ZnBr2
aisolated yield.
zinc enolate [34] of ethyl acetate to N-Boc-phenylalaninal (6) of 1-hydroxy-7-azabenzotriazole (HOAt) gave the best result
resulted in 8a as a 95:5 mixture of diastereomers (as deter- [36], i.e., 82% yield over the two steps. The spectral and analyt-
mined by HPLC), which were easily separated by silica gel ical data {[α]D25 +40.5 (c 1.8, MeOH); lit. [15,25] [α]D25 −43.5
column chromatography. The stereochemical outcome in both (c 1.0, MeOH) for its enantiomer} of compound 1 [6] were in
the cases was explained by Crams’ rule, i.e., for a non-chela- good agreement with the reported values for its enantiomer
tion model, the (R)-aldehyde would give rise to the (3S,4R) except the sign of the specific rotation, which confirmed the
isomer. Alternatively, in a chelation model, the metal imposes a absolute configuration of the natural product as (4S,5S). To
syn relationship between the formyl and neighboring nitrogen confirm further the absolute stereochemistry of natural strepto-
functionality which would lead to the (3R,4R) isomer [35].
pyrrolidine, (4R,5S)-streptopyrrolidine (3) and (4S,5S)-strepto-
pyrrolidine (4) were prepared starting from L-phenylalanine.
The spectral and analytical data of (4S,5S)-streptopyrrolidine
were in good agreement with natural streptopyrrolidine.
Figure 2: Δδ = (δS−δR) × 103 for (S)- and (R)-MTPA esters of com-
pound 8b.
Deprotection of the Boc-group with TFA and CH2Cl2 was fol-
lowed by evaporation and treatment of the crude product under
different reaction conditions for lactamization (Table 2 is for
lactamization of 8a, almost similar yields were obtained for 8b),
afforded (4R,5R)-streptopyrrolidine (1) and (4S,5R)-strepto-
pyrrolidine (2) in good to excellent overall yield (Scheme 3).
From all of the conditions investigated, Zr(OtBu)4 in presence
Scheme 3: Reagents and conditions: (a) (1) TFA, CH2Cl2, rt, 4 h;
(2) Zr(OtBu)4, HOAt, toluene, 60 °C, 12 h, 82% over two steps.
Table 2: Lactamization under different reaction conditions to obtain 1 and 2.
Entry
Reagent
Additive/ Solvent
Temp. (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
Py
Et3N
none/CH2Cl2
none/CH2Cl2
none/toluene
none/toluene
HOAt/toluene
HOAt/toluene
50
50
12
12
6
41
46
55
58
42
82
Py
100
100
60
Et3N
6
KOtBu
Zr(OtBu)4
6
60
6
ayield over two steps.
36

Beilstein J. Org. Chem. 2011, 7, 34–39.
Conclusion
Na2CO3, extracted with ethyl acetate (3 × 25 mL). The
In conclusion, the total synthesis of all four possible isomers of combined organic layers were washed with brine, dried over
streptopyrrolidine (1–4) has been achieved in ≈42% yield over Na2SO4 and concentrated under reduced pressure to give a pale
6 steps starting from either D- or L-phenylalanine which further yellow liquid. The crude product was purified by silica gel
confirmed the absolute configuration of natural strepto- column chromatography with ethyl acetate and hexane (1:3) as
pyrrolidine. Our protocol is highly flexible for the synthesis of eluent to yield 8b as a colorless viscous liquid as the sole pro-
all four possible isomers of streptopyrrolidine compared to duct (0.115 g, 85%).
previous reports.
A stirred solution of LDA (4.9 mL, 2 N, 9.8 mmol) in anhy-
Experimental
General information
drous THF (10 mL) was cooled to −78 °C under nitrogen
atmosphere. Ethyl acetate (1.05 mL, 9.8 mmol) was then added
All reactions were carried out under an inert atmosphere, unless followed by a 0 °C solution of anhydrous ZnBr2 (2.17 g, 9.8
otherwise stated. Solvents were dried and purified by standard mmol) in anhydrous THF (5 mL). A −78 °C solution of N-Boc-
methods prior to use. The progress of all reactions was moni- protected aldehyde 6 (0.35 g, 1.41 mmol) in anhydrous THF (4
tored by TLC using glass plates pre-coated with silica gel 60 mL) was added and the mixture stirred at −78 °C for 30 min
F254 with a thickness of 0.5 mm. Column chromatography was then allowed to warm to room temperature. The reaction mix-
performed on silica gel (60 mesh) with ethyl acetate and hexane ture was stirred at room temperature for 10 h. After completion
the eluent. Optical rotations were measured with a Perkin Elmer of the reaction (as determined by TLC), saturated NH4Cl/acetic
P241 polarimeter and a JASCO DIP-360 digital polarimeter at acid (9:1) (20 mL) was added to the reaction mixture which was
25 °C. IR spectra were recorded on a Perkin-Elmer FT-IR spec- then extracted with ethyl acetate (3 × 30 mL). The combined
trometer. 1H and 13C NMR spectra were recorded on a Variant organic layers were washed with brine (2 × 50 mL), dried over
Gemini 200 MHz, Bruker Avance 300 MHz, or Varian Inova Na2SO4, concentrated under reduced pressure, and the crude
500 MHz spectrometer with TMS as an internal standard in product purified by silica gel column chromatography to give
CDCl3, CD3OD etc. Mass spectra were recorded on a Micro- 8a (0.378 g, 82%) as a colorless viscous liquid. Analytical and
mass VG-7070H for EI.
spectral data of 8a: [α]D25 +34.9 (c 1.2, MeOH); IR (KBr):
3553, 3496, 3376, 2979, 2934, 1727, 1683 cm−1; 1H NMR (300
(3R,4R)-Ethyl-4-(tert-butoxycarbonylamino)-3-hydroxy-5- MHz, CDCl3): 7.28–7.20 (m, 5H, ArH), 5.07 (d, J = 9.6 Hz,
phenylpentanoate (8a) and (3S,4R)-ethyl-4-(tert-butoxycar- 1H, NH), 4.16–4.09 (q, J = 6.9, 14.1 Hz, 2H, OCH2CH3), 3.98
bonylamino)-3-hydroxy-5-phenylpentanoate (8b): To a (d, J = 9.6 Hz, 1H, CHOH), 3.74 (q, J = 8.1, 16.2 Hz, 1H,
stirred solution of the aldehyde 6 (0.2 g, 0.8 mmol) in CH2Cl2 CHNH), 2.91 (d, J = 7.5 Hz, 2H, PhCH2), 2.59 (dd, J = 10.1,
(5 mL) under a nitrogen atmosphere and cooled to −78 °C, was 16.8 Hz, 1H, CH'2COO), 2.38 (dd, J = 2.3, 16.9 Hz, 1H,
added 1 M solution of SnCl4 in CH2Cl2 (0.1 mL, 0.81 mmol). CH2COO), 1.41 (s, 9H, t-Bu), 1.23 (t, J = 6.9 Hz, 3H,
After 10 min, (1-ethoxyvinyloxy)trimethylsilane (0.26 g, 1.6 OCH2CH3); 13C NMR (75 MHz, CDCl3): 173.4, 155.8, 138.1,
mmol) was added at the same temperature. The reaction mix- 129.3, 128.4, 126.3, 79.3, 67.0, 60.7, 55.3, 38.5, 29.6, 28.3,
ture was stirred for 1 h at −78 °C. After completion of the reac- 14.0; ESI-MS: m/z = 338 [M + H]+; ESI-HRMS: Calcd. for
tion (as determined by TLC), the reaction mixture was C18H27NNaO5, 360.1781; found: 360.1789. Analytical and
quenched with 1 N KOH (3 mL). The reaction mixture was spectral data of 8b: [α]D25 +11.6 (c 0.6, MeOH); IR (KBr):
extracted with ethyl acetate (3 × 25 mL). The combined organic 3354, 2982, 2936, 1735, 1684 cm−1; 1H NMR (300 MHz,
layers were washed with brine, dried over Na2SO4 and concen- CDCl3) 7.31–7.20 (m, 5H, ArH), 4.61 (d, J = 8.4 Hz, 1H, NH),
trated under reduced pressure to obtain pale yellow liquid which 4.20–4.13 (q, J = 7.1, 14.1 Hz, 2H, OCH2CH3), 3.99–3.86 (m,
on purification by silica gel column chromatography afforded 2H, CHOH, CHNH), 2.96 (dd, J = 3.8, 13.7 Hz, 1H, PhCH'2),
8a and 8b in a ratio of 3:7 (0.19 g, 70%) as colorless viscous 2.82 (m, 1H, PhCH2), 2.64–2.45 (m, 2H, CH2COO), 1.34 (s,
liquid.
9H, t-Bu), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3); 13C NMR (75
MHz, CDCl3): 172.9, 155.7, 137.6, 129.4, 128.4, 126.4, 79.6,
To a stirred solution of the aldehyde 6 (0.1 g, 0.4 mmol) in 70.1, 60.8, 55.1, 38.2, 35.8, 28.2, 14.1; ESI-MS: m/z = 360 [M
CH2Cl2 (5 mL) under a nitrogen atmosphere and cooled to −78 + Na]+; ESI-HRMS: Calcd. for C18H27NNaO5, 360.1781;
°C, was added BF3·OEt2 (0.03 g, 0.2 mmol). After 30 min, found: 360.1794.
(1-ethoxy vinyloxy)trimethylsilane (0.26 g, 1.6 mmol) was
added at the same temperature. The reaction mixture was stirred (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine
for 1 h at −78 °C when TLC showed completion of the reaction. (2), (4R,5S)-streptopyrrolidine (3), (4S,5S)-strepto-
The reaction mixture was quenched with saturated aqueous pyrrolidine (4): A solution of TFA/H2O (2.8 mL, 0.28 mL)
37

Beilstein J. Org. Chem. 2011, 7, 34–39.
was added to 8a or 8b (200 mg, 0.59 mmol) and the resulting DMSO-d6): 174.9, 138.6, 129.2, 128.2, 126.8, 66.9, 60.1, 40.8,
mixture stirred at room temperature for 3 h. After completion of 34.5; ESI-HRMS: Calcd. for C11H14NO2, 192.1019; found:
the reaction (as determined by TLC), the solvent was evapo- 192.1026.
rated under reduced pressure and the resulting reddish oil
dissolved in ethyl acetate (10 mL). The organic phase was
Supporting Information
washed with NaHCO3, dried over Na2SO4 and concentrated
under reduced pressure. The red oil so obtained was dissolved
Supporting Information features 1H and 13C NMR spectra
in toluene. Zr(OtBu)4 (22 mg, 0.059 mmol) followed by HOAt
of all intermediates.
(160 mg, 0.11 mmol) were added and the reaction mixture
Supporting Information File 1
allowed to stir at 60 °C for 12 h. After completion of the reac-
tion (as determined by TLC), the toluene was evaporated under
reduced pressure. Water was added and the reaction mixture
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure to give a brown liquid which on purification by silica
1H and 13C NMR spectra of all intermediates.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-6-S1.pdf]
gel column chromatography furnished 1 (98 mg, 82%) as a Acknowledgements
white sticky solid. Analytical and spectral data of 1: [α]D25 B.T. and P.P.D. thank UGC and CSIR, New Delhi, India, res-
+40.5 (c 1.8, MeOH); IR (KBr): 3452, 3234, 2924, 1690 cm−1; pectively, for the financial assistance in the form of fellowships.
1H NMR (500 MHz, DMSO-d6): 7.51 (s, 1H, NH), 7.27 (m,
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