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P. Bernhardt, S. E. O’Connor / Tetrahedron Letters 50 (2009) 7118–7120
(s, 3H), 3.67–3.57 (m, 2H), 3.50–3.41 (m, 2H), 2.03 (ddd, 1H, J = 4.1, 7.4, 13.8),
1.99–1.85 (m, 4H), 1.77 (ddd, 1H, J = 3.0, 6.6, 14.0), 1.20 (s, 9H), 1.19–1.13 (m,
6H); 13C NMR (125 MHz, CDCl3): d 152.8, 110.2, 101.4, 93.3, 75.8, 61.8, 58.9,
51.2, 38.9, 36.1, 30.9, 28.7, 25.0, 15.5. trans-12: 1H NMR (300 MHz, CDCl3): d
7.42–7.41 (m, 1H), 5.20 (dd, 1H, J = 2.4, 9.5), 4.55 (t, 1H, J = 5.5), 3.64 (s, 3H),
3.69–3.57 (m, 2H), 3.49–3.41 (m, 2H), 2.74–2.68 (m, 1H), 2.48 (ddd, 1H, J = 1.5,
5.6, 7.2), 1.98–1.85 (m, 2H), 1.49 (ddd, 1H, J = 5.7, 9.8, 14.2), 1.73–1.67 (m, 1H),
1.23 (s, 9H), 1.18–1.13 (m, 6H); 13C NMR (125 MHz, CDCl3): d 154.0, 109.3,
102.2, 93.1, 76.3, 62.4, 60.4, 51.2, 39.8, 32.7, 28.7, 26.9, 15.5; ESI-MS
(C17H31O6þ) calcd m/z 353.1935 [M+Na]+, obsd: m/z 353.1941 [M+Na]+. cis-
13: 1H NMR (400 MHz, CDCl3): d 7.42 (s, 1H), 5.23 (t, 1H, J = 2.8), 4.66 (dd, 1H,
J = 5.0, 7.2), 3.66 (s, 3H), 3.70–3.40 (m, 4H), 2.63 (ddd, 2H, J = 4.5, 7.2, 9.9), 2.05
(td, 1H, J = 2.8, 14.1), 2.00–1.20 (m, 13H), 1.18–1.13 (m, 6H); 13C NMR (75 MHz,
CDCl3): d 152.42, 110.53, 101.47, 96.34, 76.29, 61.82, 58.96, 51.27, 36.16, 33.45,
31.61, 29.88, 25.80, 24.61, 23.65, 23.62, 15.49; trans-13: 1H NMR (300 MHz,
CDCl3): d 7.42 (s, 1H), 5.11 (dd, 1H, J = 2.3, 9.3), 4.57 (t, 1H, J = 5.6), 3.66 (s, 3H),
3.70–3.40 (m, 4H), 2.72 (ddd, 1H, J = 3.2, 5.9, 12.6), 2.00–1.20 (m, 14H), 1.18–
1.13 (m, 6H); 13C NMR (125 MHz, CDCl3): d 153.69, 109.62, 101.96, 96.80,
77.64, 62.38, 60.15, 51.29, 38.68, 33.67, 31.94, 30.43, 26.65, 25.69, 24.32, 24.19,
15.56; ESI-MS (C19H32O6), calcd m/z 379.2097 [M+Na]+, obsd m/z 379.2097
[M+Na]+.
competent substrates. Surprisingly, both the 2,4-trans configura-
tion—found in the natural substrate secologanin—and the unnatu-
ral 2,4-cis configuration were accepted by strictosidine synthase.
For smaller aldehydes 14–16, the trans/cis selectivity was low
(de = 5–10%), whereas for 17 the selectivity for the trans configura-
tion was significantly higher >60% (Fig. 2B). Therefore, increased
acetal substituent size appears to be correlated with a substrate
preference for the natural trans stereochemistry.
We reported the successful synthesis of a series of des-vinyl
secologanin aglycones. For the first time, it is shown that strictos-
idine synthase accepts alternate stereoisomers. Notably, turnover
of ‘unnatural’ cis stereoisomers occurs when the acetal substituent
is small. This study demonstrates that a central alkaloid biosyn-
thetic enzyme can recognize a variety of stereoisomers.
Acknowledgment
10. cis-14: 1H NMR (CDCl3, 400 MHz): d 9.74 (t, 1H, J = 1.2), 7.50 (d, 1H, J = 0.5),
5.14 (t, 1H, J = 2.5), 3.78 (dq, 1H, J = 7.1, 9.5), 3.68 (s, 3H), 3.50 (dq, 1H, J = 7.1,
9.5), 3.11–3.05 (m, 1H), 2.99 (ddd, 1H, J = 1.3, 9.6, 17.7), 2.75 (ddd, 1H, J = 1.0,
3.4, 17.4), 2.00 (td, 1H, J = 2.2, 14.4), 1.89 (ddd, 1H, J = 2.8, 6.7, 14.4), 1.16 (t, 3H,
J = 7.1; 13C NMR (CDCl3, 100 MHz): d 202.43, 167.67, 153.10, 108.81, 97.96,
64.87, 51.46, 47.87, 30.06, 22.34, 15.29. trans-14: 1H NMR (CDCl3, 500 MHz): d
9.74 (t, 1H, J = 1.2), 7.49 (d, 1H, J = 1.1), 4.97 (dd, 1H, J = 2.4, 7.5), 3.90 (dq, 1H,
J = 7.1, 9.5), 3.68 (s, 3H), 3.58 (dq, 1H, J = 7.1, 9.5), 3.24–3.18 (m, 1H), 2.87 (ddd,
1H, J = 1.2, 4.2, 16.9), 2.38 (ddd, 1H, J = 2.2, 9.0, 16.9), 1.93 (ddd, 1H, J = 6.2, 7.3,
13.7), 1.77 (ddd, 1H, J = 2.4, 5.2, 13.9), 1.21 (t, 3H, J = 7.1); ESI-MS (C11H16O5),
m/z calcd m/z 251.0890 [M+Na]+, obsd m/z 251.0884 [M+Na]+. cis-15: 1H NMR
(500 MHz, CDCl3): d 9.75 (t, 1H, J = 1.3), 7.49 (d, 1H, J = 0.7), 5.11 (t, 1H, J = 2.5),
3.68 (s, 3H), 3.51 (dd, 1H, J = 6.7, 9.2), 3.21 (dd, 1H, J = 6.4, 9.2), 3.14–3.05 (m,
1H), 2.99 (ddd, 1H, J = 1.4, 9.6, 17.4), 2.80–2.70 (m, 1H), 2.03 (td, 1H, J = 2.1,
14.5), 1.93–1.84 (m, 1H), 1.80 (dd, 1H, J = 6.6, 13.4), 0.85 (d, 6H, J = 6.6); 13C
NMR (125 MHz, CDCl3): d 202.32, 167.65, 153.04, 108.84, 98.39, 76.26, 51.43,
48.00, 29.83, 28.58, 22.24, 19.46, 19.44. trans-15: 1H NMR (500 MHz, CDCl3): d
9.74 (t, 1H, J = 1.8), 7.49 (d, 1H, J = 1.1), 4.95 (dd, 1H, J = 2.4 7.2), 3.67 (s, 3H),
3.61 (dd, 1H, J = 6.6, 9.2), 2.27 (dd, 1H, J = 6.8, 9.2), 3.24–3.18 (m, 1H), 2.88
(ddd, 1H, J = 1.5, 4.2, 17.0), 2.38 (ddd, 1H, J = 2.1, 9.0, 17.0), 1.96 (td, 1H, J = 6.4,
13.7), 1.84 (td, 1H, J = 6.7, 13.4), 1.76 (ddd, 1H, J = 2.4, 5.5, 13.9), 0.88 (dd, 6H,
J = 3.4, 6.7); 13C NMR (125 MHz, CDCl3): d 201.28, 167.51, 154.15, 108.29,
98.17, 76.32, 51.45, 48.65, 32.49, 28.62, 23.79, 19.42, 19.38; ESI-MS
(C13H20O5þ), calcd m/z 279.1208 [M+Na]+, obsd m/z 279.1209 [M+Na]+. cis-
16: 1H NMR (500 MHz, CDCl3): d 9.74 (t, 1H, J = 1.3), 7.49 (d, 1H, J = 0.6), 5.38 (t,
1H, J = 2.8), 3.67 (s, 3H), 3.09 (qd, 1H, J = 4.4, 9.0), 2.99 (ddd, 1H, J = 1.4, 9.5,
17.7), 2.77 (ddd, 1H, J = 1.3, 4.0, 17.7), 1.87 (dd, 2H, J = 3.0, 4.4), 1.20 (s, 9H); 13C
NMR (125 MHz, CDCl3): d 202.6, 167.8, 153.6, 108.3, 92.9, 76.2, 51.4, 48.0, 31.4,
28.7, 22.8. trans-16: 1H NMR (500 MHz, CDCl3): d 9.74 (dd, 1H, J = 1.8, 2.2),
7.49 (d, 1H, J = 1.0), 5.20 (dd, 1H, J = 2.5, 7.8), 3.67 (s, 3H), 3.24–3.18 (m, 1H),
2.86 (ddd, 1H, J = 1.5, 5.4, 16.7), 2.38 (ddd, 1H, J = 2.3, 8.9, 16.7), 1.89 (ddd, 1H,
J = 5.9, 7.9, 13.8), 1.67 (ddd, 1H, J = 2.5, 3.7, 13.9), 1.24 (s, 9H); 13C NMR
(125 MHz, CDCl3): d 201.4, 167.6, 154.7, 101.7, 92.6, 76.5, 51.4, 49.0, 33.7, 28.7,
24.3; ESI-MS (C13H20O5), calcd m/z 279.1208 [M+Na]+, obsd m/z 279.1200
[M+Na]+. cis-17: 1H NMR (500 MHz, CDCl3): d 9.74 (t, 1H, J = 1.3), 7.49 (d, 1H,
J = 0.6), 5.27 (t, 1H, J = 2.6), 3.67 (s, 3H), 3.65–3.59 (m, 1H), 3.10–3.05 (m, 1H),
3.02 (ddd, 1H, J = 1.3, 9.6, 17.5), 2.78–2.72 (m, 1H), 1.97 (td, 1H, J = 2.3, 14.4),
1.88 (ddd, 1H, J = 2.8, 6.5, 14.4), 1.82–1.72 (m, 2H), 1.68–1.58 (m, 2H), 1.48–
1.41 (m, 1H), 1.40–1.13 (m, 5H); 13C NMR (125 MHz, CDCl3): d 202.53, 167.73,
153.26, 108.70, 96.10, 76.55, 51.40, 48.02, 33.45, 31.59, 30.43, 25.72, 23.91,
23.74, 22.45; trans-17: 1H NMR (500 MHz, CDCl3): d 9.74 (t, 1H, J = 1.8), 7.48
(d, 1H, J = 1.1), 5.10 (dd, 1H, J = 2.4, 7.5), 3.67 (s, 3H), 3.68–3.62 (m, 1H), 3.21
(td, 1H, J = 5.1, 14.6), 2.86 (ddd, 1H, J = 1.5, 4.2, 16.9), 2.38 (ddd, 1H, J = 2.2, 8.9,
16.9), 1.93 (ddd, 1H, J = 6.1, 7.4, 13.7), 1.89–1.82 (m, 2H), 1.74 (ddd, 1H, J = 2.4,
5.2, 13.9), 1.72–1.67 (m, 2H), 1.53–1.47 (m, 1H), 1.42–1.15 (m, 5H); 13C NMR
(125 MHz, CDCl3): d 201.36, 167.58, 154.37, 108.07, 96.15, 51.44, 48.80, 39.78,
33.61, 32.86, 32.03, 25.67, 24.26, 24.14, 24.00; ESI-MS (C15H22O5þ), calcd m/z
283.1545 [M+H]+, obsd m/z 283.1544 [M+H]+.
We acknowledge financial support from the NIH (GM074820).
References and notes
1. O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532–547.
2. Tietze, L. F.; Meier, H.; Nutt, H. Chem. Ber. 1989, 122, 643–650; Tietze, L. F.;
Meier, H.; Nutt, H. Liebigs Ann. Chem. 1990, 253–260; Tietze, L. F. Angew. Chem.
1983, 95, 840–853.
3. Maresh, J. J.; Giddings, L. A.; Friedrich, A.; Loris, E. A.; Panjikar, S.; Stöckigt, J.;
Peters, B.; O’Connor, S. E. J. Am. Chem. Soc. 2008, 130, 710–723.
4. McCoy, E. A.; Galan, M. C.; O’Connor, S. E. Bioorg. Med. Chem. Lett. 2006, 16,
2475–2478; Treimer, J. F.; Zenk, M. H. Eur. J. Biochem. 1979, 101, 225–233.
5. Loris, E. A.; Panjikar, S.; Ruppert, M.; Barleben, L.; Unger, M.; Schubel, H.;
Stöckigt, J. Chem. Biol. 2007, 14, 979–985.
6. Ma, X.; Panjikar, S.; Koepke, J.; Loris, E.; Stöckigt, J. Plant Cell 2006, 23, 532–547.
7. Galan, M. C.; O’Connor, S. E. Tetrahedron Lett. 2005, 47, 1563–1565.
8. The aldehyde was prepared by Dess–Martin periodinane mediated oxidation of
3,3-diethoxy-1-propanol. 1H NMR (300 MHz, CDCl3): d 9.72 (t, 1H, J = 2.3), 4.93
(t, 1H, J = 5.5), 3.65 (qd, 1H, J = 7.1, 9.3), 3.52 (qd, 1H, J = 7.1, 9.3), 2.70 (dd, 1H,
J = 2.3, 5.5), 1.78 (t, 1H, J = 7.1); 13C NMR (75 MHz, CDCl3): d 200.17, 98.85,
62.30, 48.22, 15.40.
9. cis-10: 1H NMR (600 MHz, CDCl3): d ppm 7.43 (s, 1H), 5.10–5.07 (m, 1H), 4.64
(dd, 1H, J = 5.1, 7.0), 3.93 (dq, 1H, J = 7.1, 14.3), 3.70–3.40 (m, 5H), 3.66 (s, 3H),
2.66–2.59 (m, 1H), 2.10–2.03 (m, 1H), 2.03–1.89 (m, 2H), 1.80 (ddd, 1H, J = 2.9),
1.21 (t, 3H, J = 7.1), 1.19–1.13 (m, 6H); 13C NMR (200 MHz, CDCl3): d ppm
168.01b, 167.85a, 153.44b, 152.25a, 110.63a, 109.80b, 101.70b, 101.52a,
98.44a,b, 65.30b, 64.74a, 62.41b, 61.78a, 59.85b, 59.25a, 51.32a,b, 51.30a,b,
38.53b, 36.15a, 31.46b, 29.60a, 26.60b, 24.54a, 15.52–15.29; trans-10: 1H NMR
(600 MHz, CDCl3): d ppm 7.43 (s, 1H), 4.97 (dd, 1H, J = 1.7, 9.1), 4.58 (t, 1H,
J = 5.7), 3.79 (dq, 1H, J = 7.1, 14.2), 3.70–3.40 (m, 5H), 3.66 (s, 3H), 2.75–2.70 (m,
1H), 2.10–2.03 (m, 1H), 2.03–1.89 (m, 2H), 1.72 (ddd, 1H, J = 5.9, 9.1, 14.3), 1.47
(ddd, 1H, J = 5.4, 9.8, 14.5, 1.21), 1.19–1.13 (m, 9H, b); ESI-MS(C15H26O6) m/z
calcd: 325.1622 [M+Na]+, found: 325.1623 [M+Na]+. cis-11: 1H NMR (300 MHz,
CDCl3): d 7.42 (s, 1H), 5.07 (t, 1H, J = 2.7), 4.65 (dd, 1H, J = 5.6, 6.6), 3.65 (s, 3H),
3.68–3.40 (m, 4H), 3.52 (dd, 1H, J = 6.5, 9.1), 3.19 (dd, 1H, J = 6.4, 9.1), 2.66–2.57
(m, 1H), 2.11 (td, 1H, J = 2.3, 14.2), 2.02–1.70 (m, 4H), 1.19–1.10 (m, 6H), 0.84
(dd, 6H, J = 1.4, 6.7); 13C NMR (125 MHz, CDCl3): d 167.99, 152.20, 110.60,
101.77, 98.81, 96.09, 61.93, 58.77, 51.28, 36.05, 29.11, 28.62, 24.29, 19.41,
15.47, 15.54; trans-11: 1H NMR (300 MHz, CDCl3): d 7.42 (s, 1H), 4.94 (dd, 1H,
J = 2.2, 9.0), 4.57 (t, 1H, J = 5.7), 3.65 (s, 3H), 3.68–3.40 (m, 5H), 3.25 (dd, 1H,
J = 6.9, 9.3), 2.72 (dq, 1H, J = 3.5, 6.4), 2.02–1.70 (m, 4H), 1.46 (ddd, 1H, J = 5.4,
9.7, 14.3), 1.19–1.10 (m, 6H), 0.87 (dd, 6H, J = 2.2, 6.7); 13C NMR (125 MHz,
CDCl3): d 167.84, 153.46, 109.78, 101.77, 98.81, 76.44, 62.33, þ59.97, 51.28,
38.46, 31.40, 26.35, 19.35, 15.54, 15.47. ESI-MS (C17H30O6
) calcd m/z
353.1940 [M+Na]+, obsd: m/z 353.1957 [M+Na]+. cis-12: 1H NMR (300 MHz,
CDCl3): d 7.42 (d, 1H, J = 0.8), 5.32 (t, 1H, J = 3.1), 4.64 (dd, 1H, J = 4.7, 7.4), 3.65