Dias and Salles
JOCArticle
The same sequence applied to spiroketal 22 provided
pteridic acid B (2) in 2.8% overall yield for the 13-step linear
sequence (Scheme 6). The spectroscopic and physical data
[1H and 13C NMR, IR, [R]D, Rf] were identical in all respects
with the published data for both natural and synthetic
pteridic acid B (see the Supporting Information for compar-
ison of natural and our synthetic pteridic acid B).1,2
separated, and the aqueous phase was washed with CH2Cl2
(3ꢀ10 mL). The combined organic phases were then dried
(Na2SO4) and concentrated in vacuo. Flash chromatography
(40% EtOAc/Hex) afforded spiroketals 21 (9 mg, 0.03 mmol,
40%) and 22 (9 g, 0.03 mmol, 40%) as colorless oils.
1
Spiroketal (21):. Rf 0.31 (40% EtOAc in hexane); H NMR
(500 MHz, C6D6) δ 5.62 (dd, J 10.2, 5.5 Hz, 1H), 5.33 (dd, J 10.2,
1.3 Hz, 1H), 3.85-3.90 (q, J 7.1 Hz, 1H þ dd, J 10.1, 2.2 Hz, 1H),
3.77 (dd, J 11.0, 4.8 Hz, 1H), 3.72 (dd, J 10.7, 7.8 Hz, 1H), 3.57
(dd, J 10.7, 3.8 Hz, 1H), 1.90-2.00 (m, 2H), 1.70-1.79 (m, 2H),
1.52-1.61 (m, 2H), 1.38 (d, J 6.8 Hz, 3H), 0.98 (d, J 6.7 Hz, 3H),
0.92 (d, J 6.9 Hz, 3H), 0.74 (t, J 7.4 Hz, 3H), 0.56 (d, J 6.9 Hz,
3H); 13C NMR (125 MHz, C6D6) δ 4.9, 11.8, 12.9, 13.0, 21.6,
26.4, 37.01, 37.02, 40.7, 41.0, 68.3, 71.7, 71.9, 77.1, 97.2, 128.3,
130.4; [R]23D þ2.8 (c 0.4, CH2Cl2); HRMS (ESI TOF-MS) calcd
for C17H31O4 299.2222, found 299.2192.
Conclusions
In summary, we have achieved the total synthesis of
pteridic acids A and B. Notable features of this approach
include convergence, a lithium enolate-mediated aldol reac-
tion to set up the desired C9 and C10 stereocenters, and a
spiroketalization reaction. This approach compares very
well with previously published routes and, in principle, is
readily applicable for the preparation of additional novel
structural analogues. Further optimization of the synthesis
as well as application of this strategy to the synthesis of
pteridic acid analogues is underway and the results will be
described in due course.19
1
Spiroketal (22):. Rf 0.20 (40% EtOAc in hexane); H NMR
(500 MHz, C6D6) δ 5.73 (ap t, J 11.6 Hz, 1H þ d, J 11.9 Hz, 1H),
3.96 (dq, J 9.8, 6.1 Hz, 1H), 3.72 (ap t, J 11.1, 10.8 Hz, 1H), 3.61
(dd, J 10.6, 6.8 Hz, 1H), 3.25 (dd, J 11.4, 4.7 Hz, 1H), 3.18 (dd, J
9.8, 2.0 Hz, 1H), 2.01-1.85 (m, 2H), 1.70-1.60 (m, 2H), 1.32-
1.17 (m, 2H), 1.12 (d, J 6.2 Hz, 3H), 1.02 (d, J 6.7 Hz, 3H), 0.91
(d, J 6.9 Hz, 3H), 0.76 (t, J 7.5 Hz, 3H), 0.56 (d, J 6.9 Hz, 3H); 13
C
NMR (125 MHz, C6D6) δ 5.0, 10.2, 11.9, 12.8, 19.5, 23.5, 36.85,
D
36.92, 41.0, 42.7, 68.4, 69.0, 73.7, 77.9, 98.6, 124.0, 133.7; [R]23
Experimental Section
-2.0 (c 0.3, CH2Cl2); HRMS (ESI TOF-MS) calcd for
C17H31O4 299.2222, found 299.2198.
(5R,6S,10S,11R,12S,13S,Z)-6-Ethyl-11-hydroxy-13-((S)-
1-(4-methoxybenzyloxy)propan-2-yl)-2,2,3,3,5,10,12,15,15,-
16,16-undecamethyl-4,14-dioxa-3,15-disilaheptadec-7-en-9-one
(19). To a solution of LHMDS (0.94 mL, 0.94 mmol, 1 M in
THF/ethylbenzene, 1.2 equiv) in THF (6.5 mL) at -78 °C was
added a solution of ethyl ketone 5 (0.221 g, 0.78 mmol) and
HMPA (0.42 mL, 2.37 mmol, 3 equiv) in THF (16 mL). The
reaction mixture was stirred at -78 °C for 2 h before a solution
of aldehyde 4 (0.296 g, 0.78 mmol, 1 equiv) in THF (2.9 mL)
was added dropwise. The solution was stirred at -78 °C for 2 h,
quenched with saturated NH4Cl (50 mL), and warmed to room
temperature. The aqueous layer was extracted with Et2O/
EtOAc (1:1, 3ꢀ15 mL), and the combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (10% hexanes/
EtOAc) to afford 0.293 g (0.44 mmol) of aldol 19 as a colorless
oil (56% yield), together with a second diastereoisomer tenta-
tively assigned as the corresponding syn aldol with Felkin
addition (0.073 g, 0.11 mmol, 14% yield). Aldol 19: Rf 0.45
(10% EtOAc in hexane); 1H NMR (250 MHz, CDCl3) δ 7.25
(br d, J 8.6 Hz, 2H), 6.86 (br d, J 8.7 Hz, 2H), 6.32 (br d, J 11.7
Hz, 1H), 6.14 (ap t, J 10.5 Hz, 1H), 4.41 (br s, 2H), 4,00 (dd,
J 7.2, 1.5 Hz, 1H), 3.82-3.92 (m, 2H), 3.80 (s, 3H), 3.58 (dd,
J 8.9, 4.3 Hz, 1H), 3.35-3.15 (m, 3H), 2.64 (qd, J 7.3, 1.6 Hz,
1H), 1.91-2.01 (m, 1H), 1.62-1.19 (m, 3H), 1.08 (d þ m, J 7.2
Hz, 3H þ 1H), 1.04 (d, J 6.3 Hz, 3H), 0.96 (d, J 6.8 Hz, 3H),
0.88 (s, 9H), 0.86 (s þ t, 12H), 0.77 (d, J 6.9 Hz, 3H), 0.07 (s,
3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (62.5
MHz, C6D6) δ -4.7, -4.1, -3.9, -3.7, 8.3, 9.8, 12.1, 14.7, 18.3,
18.8, 22.3, 25.0, 26.1, 26.5, 38.4, 39.3, 47.2, 47.8, 54.7, 70.6, 71.1,
72.5, 73.1, 73.3, 114.0, 129.4, 131.4, 151.0, 159.6, 207.6; IR νmax
(film) 3472, 3053, 2959, 2932, 2856, 1674, 1612, 1514, 1462, 1265,
1036, 837; [R]23D þ21.0 (c 1.4, CH2Cl2); HRMS (ESI TOF-MS)
calcd for C37H69O6Si2 665.4633, found 665.4546.
Ester 25. To a solution of triethyl 4-phosphonocrotonate
(31 mg; 0.123 mmol) in THF (0.5 mL) at -78 °C was added
LiHMDS (0.12 mL, 1 M in THF/ethylbenzene, 0.120 mmol)
and the resultant solution stirred for 10 min. A solution of
aldehyde 23 (0.050 mmol) in THF (0.25 mL) was then added
slowly and the reaction mixture allowed to warm to -25 °C and
stirred for 1.5 h. The reaction was then allowed to warm to rt and
quenched by the addition of saturated aqueous NH4Cl (1 mL).
The aqueous phase was extracted with Et2O (3ꢀ5 mL), and the
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (20% EtOAc/Hex) afforded
ester 25 (12 mg, 0.031 mmol, 60% for two steps) as a colorless
oil: Rf 0.30 (30% EtOAc/40-60 petroleum ether); 1H NMR
(400 MHz, C6D6) δ 7.53 (dd, J 15.4, 10.3 Hz, 1H), 6.06 (dd,
J 15.4, 7.5, 1H), 5.97 (dd, J 15.4, 10.4 Hz, 1H), 5.90 (d, J 15.6 Hz,
1H), 5.65 (ddd, J 10.3, 5.6, 1.1 Hz, 1H), 5.42 (dd, J 10.3, 0.8 Hz,
1H), 4.06 (q, J 7.0, 2H), 3.85 (br q, J 6.9, 1H), 3.78 (dt, J 10.9, 4.7,
1H), 3.66 (dd, J 9.8, 2.2 Hz, 1H), 2.38-2.27 (m, 1H), 1.79-1.72
(m, 1H), 1.61-1.53 (m, 1H), 1.39-1.27 (m, 3H), 1.21 (d, J 6.9
Hz, 3H), 1.01 (d, J 6.4 Hz, 3H), 0.99 (t, J 7.3 Hz, 3H), 0.93 (d, J
6.7 Hz, 3H), 0.77 (t, J 7.5 Hz, 3H), 0.71 (d, J 6.9 Hz, 3H); 13C
NMR (100 MHz, C6D6) δ 4.8, 11.9, 12.9, 14.4, 15.1, 23.1, 26.7,
36.8, 38.8, 40.7, 41.1, 59.9, 71.7, 72.2, 74.7, 97.0, 120.0, 127.3,
127.8-128.8 (obs), 129.6, 145.3, 148.7, 166.8; IR νmax (film)
3454, 2964, 2928, 1713, 1641, 1618, 1460, 1421, 1265, 1144, 1030,
1003; [R]23 þ20.5 (c 0.14, MeOH); HRMS (ESI TOF-MS)
D
calcd for C23H37O5 393.2641, found 393.2593.
Ester 27. To a solution of triethyl-4-phosphonocrotonate
(9.3 g, 0.037 mmol) in THF (0.3 mL) at -78 °C was added
LiHMDS (0.035 mL, 1 M in THF/ethylbenzene, 0.035 mmol)
and the resultant solution stirred for 10 min. A solution of
aldehyde 26 (0.015 mmol) in THF (0.1 mL) was then added
slowly and the reaction mixture allowed to warm to -25 °C and
stirred for 1.5 h. The reaction was then allowed to warm to rt and
quenched by the addition of saturated aqueous NH4Cl (0.5 mL).
The aqueous phase was extracted with Et2O (3ꢀ5 mL), and the
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (20% EtOAc/Hex) afforded
ester 27 (3,5 g; 0.009 mmol, 62% for two steps) as a colorless oil:
Spiroketals 21 and 22. To a solution of aldol 20 (42 mg,
0.08 mmol) in THF/H2O (10:1, 9.3 mL) in a polypropylene
vessel at 0 °C was added HF-pyridine (1.70 mL). After 8 h at rt,
the reaction mixture was partitioned between saturated aqueous
NaHCO3 (20 mL) and CH2Cl2 (10 mL). The phases were
(19) New compounds and the isolatable intermediates gave satisfactory
1H and 13C NMR, IR, HRMS, and analytical data. Yields refer to chroma-
tographically and spectroscopically homogeneous materials.
1
Rf 0.20 (30% EtOAc/40-60 petroleum ether); H NMR (400
MHz, C6D6) δ 7.54 (dd, J 15.4, 10.6 Hz, 1H), 6.05 (dd, J 15.4,
5588 J. Org. Chem. Vol. 74, No. 15, 2009