Total syntheses of proposed (±)-trichodermatides B and C

Article abstract of DOI:10.1016/j.tetlet.2013.07.137

Total syntheses of putative (±)-trichodermatides B and C are described. These efficient syntheses feature the oxa-[3+3] annulation strategy, leading to B and C along with their respective C2-epimers. However, these synthetic samples are spectroscopically

Full text of DOI:10.1016/j.tetlet.2013.07.137

Tetrahedron Letters 54 (2013) 5567–5572
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Tetrahedron Letters
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Total syntheses of proposed ( )-trichodermatides B and C
a,
b,
Qian Li a, Yan-Shuang Xu a, Gregory A. Ellis b, Timothy S. Bugni b, , Yu Tang , Richard P. Hsung
⇑
⇑
⇑
a School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery and High-Efficiency, Tianjin University, Tianjin 300072, PR China
b Division of Pharmaceutical Sciences, Department of Chemistry, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Total syntheses of putative ( )-trichodermatides B and C are described. These efficient syntheses feature
the oxa-[3+3] annulation strategy, leading to B and C along with their respective C2-epimers. However,
these synthetic samples are spectroscopically very different from the natural products. DFT calculations
of C13 chemical shifts are conducted and the predicted values are in good agreement with those of syn-
thetic samples, thereby questioning the accuracy of structural assignments of trichodermatides B and C.
Published by Elsevier Ltd.
Received 2 July 2013
Revised 19 July 2013
Accepted 25 July 2013
Available online 2 August 2013
Keywords:
Trichodermatides
oxa-[3+3] Annulation
Biosynthesis
Davis’ oxaziridine
Electrocyclic ring-opening
DFT calculations
In 2008, Pei and co-workers1 reported the isolation of four new
natural products, trichodermatides A–D (Fig. 1), from the marine-
derived fungus Trichoderma reesei, which is a source of natural
products known to possess a vast array of rich bioactivities.2 While
trichodermatide A signifies an unprecedented pentacyclic manifold
for a polyketide and was the subject of a recent elegant total syn-
thesis by Hiroya,3 trichodermatide B–D are structural relatives of
known polyketide metabolites such as the koninginin family found
from the culture of Trichoderma koningii.4,5 The key differences be-
tween trichodermatides and koninginins are the position of the hy-
droxyl group, and the oxidation state on the C9-side aliphatic chain.
We are interested in pursuing total syntheses of these novel nat-
ural products because of their activities against A375-S2 human
melanoma cell line1 as well as agricultural significance of this entire
structural array,4,5 and because of the potential to apply an oxa-[3+3]
annulation strategy in these syntheses.6,7 Our oxa-[3+3] annulation
represents a biomimetic approach,8,9 that has proven to be a power-
ful tandem strategy10 for natural product synthesis.11 More impor-
tantly, while authors illustrated a possible biosynthetic pathway
for trichodermatide A, we envisioned an alternative biosynthetic
pathway that would involve intermediates related to trichoderma-
tide B and/or C because trichodermatide A essentially represents a
an unexpected outcome during this pursuit. That is we are unable
to match them spectroscopically with the reported data.1 We wish
to communicate here this unexpected encounter.
Our general synthetic strategy for approaching trichodermatide
B and C is shown in Scheme 1. Both B and C can be envisioned from
the common intermediate 1, derived from the oxa-[3+3] annula-
tion of aldehyde 2 with 1,3-cyclohexanedione 3. We recognized
that while the same annulation with diketone 5 may lead to a more
convergent route, lack of regioselectivity could lead to a trouble-
some mixture of regioisomers 4 and 40.12 While perhaps more con-
servative, the use of 1,3-cyclohexanedione 3 would present no
such regiochemical issue. It is also noteworthy that to quickly as-
sess the feasibility of our plan, we first pursued racemic syntheses.
Enal 8 could be readily constructed in 6 steps from propargyl
alcohol and heptanal (Scheme 2).13 With enal 8 in hand, total syn-
thesis of trichodermatide B could be accomplished. As shown in
Scheme 3,
L-proline promoted oxa-[3+3] annulation of enal 8 with
1,3-cyclohexanedione 3 was carried out in high yield.12 Subse-
quent standard hydrogenation and
a-hydroxylation using Davis’
oxaziridine would afford alcohol 11.14 A sequence of standard pro-
tection, desilylation, Dess–Martin periodinane oxidation, and
deacetylation would give trichodermatide B [putative—vide infra]
and its C2-epimer as a 2:1 isomeric mixture.
union of
a-hydroxy-1,3-cyclohexanedione with a derivative of
trichodermatide B or C [highlighted in red]. Consequently, we first
targeted syntheses of trichodermatide B and/or C, but encountered
Total synthesis of trichodermatide C took two different ap-
proaches. The most direct one would involve oxa-[3+3] annulation
of dienal 13 (Scheme 4). Intriguingly, using either the piperidine/
Ac2O or the L
-proline protocol12 led to only the Knoevenagel con-
⇑
Corresponding authors.
E-mail addresses: tbugni@pharmacy.wisc.edu (T.S. Bugni), yutang@tju.edu.cn
densation product 15. It is possible that the desired annulation
product 14 was initially formed, but the ring-opened form is
(Y. Tang), rhsung@wisc.edu (R.P. Hsung).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.07.137

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Q. Li et al. / Tetrahedron Letters 54 (2013) 5567–5572
Scheme 3. Total syntheses of trichodermatide B and its C2-epimer.
Figure 1. Trichodermatides A–D.
Scheme 1. General retrosynthetic strategy.
Scheme 4. An attempt on oxa-[3+3] annulation using Dienal 13.
favored due to the extended conjugation. It is noteworthy that this
is the first reported attempt of an oxa-[3+3] annulation using
dienal.6
Ultimately, total synthesis of trichodermatide C was accom-
plished using the common intermediate 10 used for the synthesis
of trichodermatide B via a sequence of desilylation, Martin’s sulfu-
rane promoted elimination, and a-hydroxylation via Davis’ oxazir-
idine (Scheme 5). Again, trichodermatide C [putative—vide infra]
and its C2-epimer were obtained as an inseparable isomeric mix-
ture with a ratio of 1:1.
Unfortunately, neither the synthetic trichodermatide B nor C
matched the reported 1H and 13C NMR chemical shifts for the
natural products (see Figs. 2 and 3). Although we were unable to
separate the C2-epimer from B [or C2-epimer from C], we could
Scheme 5. Total syntheses of trichodermatide C and its C2-epimer.
clearly distinguish key downfield proton resonances in B [or C]
from its C2-epimer via COSY. In addition, in each case of B and C,
there are a significant number of non-overlapping and resolved
C13 resonances for the C2,9-trans and C2,9-cis diastereomers. Con-
sequently, a seemingly undesirable stereorandom total synthesis
of B [or C] turned into an opportunity that allowed us to compare
both B and its C2-epimer with the corresponding natural product.
Scheme 2. Synthesis of the key enal 8.

Q. Li et al. / Tetrahedron Letters 54 (2013) 5567–5572
5569
Figure 2. 1H NMR comparison: synthetic and reported chemical shifts.
Figure 3. 13C NMR comparison: synthetic and reported chemical shifts.
Our inability to match them suggests that the possible mis-assign-
ment is not in the relative stereochemistry at C2 and C9 of the
putative trichodermatide B and C.
To provide better assurance of the integrity of our syntheses, we
pursued DFT calculations to predict C13 chemical shifts for the
synthesized structures. For the low energy conformer of each struc-
ture,16,17 geometry optimization and NMR calculations [B3LYP/6-
31G(d,p)]18 were performed with GAUSSIAN 09.19 The predicted values
are in very good agreement with those recorded for the synthetic
samples and not those for the isolated samples, thereby suggesting
possible erroneous assignments in the original isolation paper (see
Fig. 4 for partial listings].15 When comparing the synthetic values
with the isolated values in regard to difference from the calculated
values, most of the largest deviations were in the area of C5–C9
(Fig. 4; respective C2-epimers excluded for clarity). Most impor-
tantly, for each structure, we used the DP4 probability method20 to
check which data set would most closely match the calculated val-
ues. Consequently, by using the DP4 probability method, we ob-
served a 100.0% probability for matching the calculated values
with those reported here for our synthetic samples, and a 0.0% prob-
ability for matching with those reported by Pei and co-workers.
Overall, spectroscopic comparisons between our synthetic
samples and the isolated ones reveal the major differenced residue
at C4 and C7–C9 for trichodermatide B and its C2-epimer, and
C7–C9 for trichodermatide C and its C2-epimer. These differences
imply a possible skeleton difference in the structural assignment.
Attempts were made but failed to reassign the isolated structures
based on available data.
Figure 4. 13C NMR comparison: synthetic and DFT calculated shifts.
reported natural products. DFT calculations of C13 chemical shifts
were conducted and predicted values are in good agreement with
those of the synthetic samples, thereby questioning the accuracy of
structural assignments of trichodermatide B and C.
Acknowledgments
We have described here total syntheses of proposed ( )-tricho-
dermatides B and C. These total syntheses are efficient and feature
the oxa-[3+3] annulation strategy, leading to trichodermatide B
and C along with their respective C2-epimers. However, the syn-
thetic samples are spectroscopically very different from the
Y.T. thanks Natural Science Foundation of China for generous
funding [Nos. 21172169 and 21172168]. T.S.B. thanks NIH
[GM104192] for generous funding. R.P.H. thanks University of

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Q. Li et al. / Tetrahedron Letters 54 (2013) 5567–5572
(60 mL) was added solid TBAF (3.80 g, 14.6 mmol, 1.2 equiv). The resulting
mixture was stirred for 12 h at rt before it was quenched with H2O. The
aqueous layer was extracted with equal volume of EtOAc three times. The
combined organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude residue was purified using flash silica gel column
chromatography (Gradient eluent: 0–50% EtOAc in petroleum ether) to
afford the desired diol 7 as colorless oil (1.09 g, 52%). Rf = 0.16 [50% EtOAc in
petroleum ether]; 1H NMR (600 MHz, CDCl3) d 0.88 (t, 3H, J = 6.2 Hz), 1.24–1.37
(m, 8H), 1.49–1.54 (m, 2H), 4.13 (m, 1H), 4.16 (d, 1H, J = 5.2), 5.74 (dd, 1H,
J = 6.3, 15.4 Hz), 5.83 (dt, 1H, J = 5.1, 15.4 Hz); 13C NMR (150 MHz, CDCl3) d
14.0, 22.5, 25.3, 29.2, 31.7, 37.1, 62.7, 72.2, 129.6, 134.5; IR (KBr) cmꢀ1 3270 br
s, 2921s, 2856s, 1463m, 1327m, 1083s, 1007s, 908m; mass spectrum (ESI): m/e
(% relative intensity) 194.8 (100) (M+Na)+.
Wisconsin-Madison Vilas Associate for a faculty award. Service
from The Instrumentation Center at School of Pharmaceutical Sci-
ence and Technology of Tianjin University is greatly appreciated.
References and notes
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To a solution of diol 7 (300.0 mg, 1.70 mmol) in CH2C12 (20 mL) was added
MnO2 (3.80 g, 43.6 mmol) at rt. The resulting mixture was stirred for 20 h
before being filtered. After filtration, the excess solvent was removed in vacuo.
The crude yellow residue was purified using flash silica gel column
chromatography (Gradient eluent: 10–50% EtOAc in petroleum ether) to
afford the desired trans-enal (86.0 mg, 71%, based on recovered start material)
as pale yellow oil. Rf = 0.72 [50% EtOAc in petroleum ether]; 1H NMR (600 MHz,
DMSO-d6) d 0.91 (t, 3H, J = 6.0 Hz), 1.29–1.33 (m, 6H), 1.36–1.41 (m, 2H), 1.47–
1.50 (m, 1H), 1.53–1.57 (m, 1H), 4.29–4.30 (m, 1H), 5.19 (br s, 1H), 6.20 (dd, 1H,
J = 8.0, 15.4 Hz), 7.07 (dd, 1H, J = 4.2, 15.4 Hz), 9.58 (d, 1H, J = 8.0 Hz); 13C NMR
(150 MHz, DMSO-d6) d 13.8, 22.0, 24.7, 28.6, 31.2, 35.9, 69.2 (d), 129.5 (d),
162.2, 194.2 (d); IR (KBr) cmꢀ1 3456 br s, 2929s, 2857s, 2732w, 1690s, 1642m,
1466m, 1126w; mass spectrum (ESI): m/e (% relative intensity) 171.0 (100)
(M+H)+; m/e calcd for C10H18O2Na+ (M+Na)+ 193.1199, found 193.1199.
To a solution of the above trans-enal (400.0 mg, 2.35 mmol) in CH2Cl2 (15 mL)
were added imidazole (320 mg, 4.7 mmol) and TBDPSCl (0.79 mL, 3.0 mmol) at
0 °C. After stirring at rt for 6 h, the reaction mixture was quenched with H2O
and the mixture was concentrated under reduced pressure. The aqueous
fraction was extracted with equal volume of CH2Cl2 three times. The combined
organic phases were washed with sat aq NaCl, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel
flash column chromatography (Gradient eluent: 0–10% EtOAc in petroleum
ether) to provide the desired enal 8 (0.58 g) in 61% yield. Rf = 0.76 [20% EtOAc
in petroleum ether]; 1H NMR (600 MHz, CDCl3) d 0.84 (t, 3H, J = 7.3 Hz), 1.08 (s,
9H), 1.13–1.15 (m, 5H), 1.20–1.24 (m, 2H), 1.25–1.28 (m, 1H), 1.45–1.55 (m,
2H), 4.44–4.47 (m, 1H), 6.15 (ddd, 1H, J = 1.4, 8.0, 15.6 Hz), 6.68 (dd, 1H, J = 5.2,
15.6 Hz), 7.33–7.44 (m, 6H), 7.60 (dd, 2H, J = 1.3, 8.0 Hz), 7.66 (dd, 2H, J = 1.3,
8.0 Hz), 9.45 (d, 1H, J = 8.0 Hz); 13C NMR (150 MHz, CDCl3) d 14.0, 19.3, 22.5,
24.0, 27.0, 29.1, 31.5, 36.7, 72.5, 127.6, 129.9, 130.9, 133.5 (d), 135.8 (d), 159.2,
193.5; IR (KBr) cmꢀ1 3736s, 2933m, 2340w, 1697m, 1518m, 692s; m/e calcd
for C26H37O2Si+ (M+H)+ 409.2557, found 409.2554.
3. Shigehisa, H.; Suwa, Y.; Furiya, N.; Nakaya, Y.; Fukushima, M.; Ichihashi, Y.;
Hiroya, K. Angew. Chem., Int. Ed. 2013, 125, 3734.
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Jacyno, J. M.; Phillips, R. S.; Von Tersch, R. L.; Cole, P. D.; Montemurro, N. Agric.
Biol. Chem. 1991, 55, 243; For koninginin B: (c) Culter, H. G.; Himmelsbach, D.
S.; Yagen, B.; Arrendale, R. F.; Jacyno, J. M.; Cole, P. D.; Cox, R. H. J. Agric. Food
Chem. 1991, 39, 977; For koninginin E: (d) Parker, S. R.; Culter, H. G.; Schreiner,
P. R. Biosci. Biotechnol. Biochem. 1995, 59, 1747.
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Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23; (e) Hsung, R. P.;
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Org. Lett. 2012, 14, 5530; (c) dos Samntos, W. H.; da Silva-Filho, L. C. Synthesis
2012, 3361; (d) Lee, Y. R.; Pandit, R. P. Synthesis 2012, 2910; (e) Parker, K. A.;
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Marquez, R. Nat. Prod. Rept. 2008, 25, 254.
To a solution of enal 8 (325.0 mg, 0.80 mmol) in THF (8 mL) were added L-
9. Also see: see: (a) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730; (b)
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proline (46.0 mg, 0.40 mmol) and 1,3-cyclohexanedione (98.0 mg, 0.87 mmol).
The vessel was sealed under nitrogen and placed in a 65 °C oil bath for 3 h.
After TLC analysis indicated complete consumption of the starting materials,
the excess solvent was removed in vacuo. The crude residue was purified using
flash silica gel column chromatography (Gradient eluent: 0–20% EtOAc in
petroleum ether) to afford the desired oxa-[3+3] annulation product
9
11. For recent applications of oxa-[3+3] annulations in natural product syntheses,
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(324.0 mg, 80%) as colorless oil. Characterized as an inseparable mixture of
two diastereomers: Rf = 0.50 [20% EtOAc in petroleum ether]; 1H NMR
(600 MHz, CDCl3) diastereomer-I: d 0.83 (t, 3H, J = 7.1 Hz), 1.03 (s, 9H), 1.05–
1.14 (m, 7H), 1.40–1.46 (m, 1H), 1.52–1.58 (m, 1H), 1.98–2.04 (m, 1H), 1.77–
1.91 (m, 3H), 2.22–2.36 (m, 3H), 3.81–3.85 (m, 1H), 4.81 (dd, 1H, J = 2.4,
4.9 Hz), 5.30 (dd, 1H, J = 2.4, 10.2 Hz), 6.53 (dd, 1H, J = 2.0, 10.2 Hz), 7.29–7.44
(m, 6H), 7.64–7.70 (m, 4H); resolved proton resonances for diastereomer-II: d
1.17–1.22 (m, 7H), 2.09–2.15 (m, 1H), 4.91 (m, 1H), 5.33 (dd, 1H, J = 3.1,
10.2 Hz), 6.50 (dd, 1H, J = 1.3, 10.2 Hz); 13C NMR (100 MHz, CDCl3)
diastereomer-I: d 14.0, 19.47, 20.4, 22.5, 25.4, 27.0, 27.9, 29.1, 31.6, 32.43,
36.3, 74.9, 80.7, 111.2, 114.1, 119.1, 127.5, 129.7, 133.9, 135.9, 172.7, 194.7;
non-overlapping carbon resonances for diastereomer-II: 19.49, 20.5, 24.8, 26.9,
28.0, 29.2, 32.40, 74.6, 79.5, 111.5, 114.9, 118.6, 127.2, 129.3, 133.5, 136.1,
172.5; IR (KBr) cmꢀ1 3427w, 2934s, 2859m, 1723m, 1614m, 1420s, 1107s,
818w, 702s; mass spectrum (ESI): m/e (% relative intensity) 503.2 (100)
(M+H)+; m/e calcd for C32H42O3SiNa+ (M+Na)+ 525.2795, found 525.2815.
To a solution of 9 (0.32 g, 0.64 mmol) in EtOAc (6 mL) was added 5% Pd–C
(0.14 g, 0.064 mmol, 0.10 equiv). The resulting mixture was stirred under an
atmosphere of H2 (balloon) at rt for 1.5 h. The mixture was then filtered and
the filtrate was concentrated under reduced pressure. The crude residue was
purified using flash silica gel column chromatography (Gradient eluent: 0–20%
EtOAc in petroleum ether) to afford 10 as colorless oil (191.0 mg, 60%).
Characterized as an inseparable mixture of two diastereomers: Rf = 0.48 [20%
EtOAc in petroleum ether]; 1H NMR (600 MHz, CDCl3) diastereomer-I: d 0.82 (t,
3H, J = 7.1 Hz), 1.05 (s, 9H), 1.06–1.11 (m, 3H), 1.11–1.23 (m, 4H), 1.24–1.29
(m, 1H), 1.35–1.41 (m, 1H), 1.48–1.54 (m, 1H), 1.80–1.89 (m, 3H), 1.90–1.94
(m, 1H), 1.95–2.06 (m, 2H), 2.19–2.24 (m, 1H), 2.27–2.35 (m, 2H), 2.47–2.50
(m, 1H), 3.77 (dt, 1H, J = 2.4, 10.9 Hz), 3.91 (td, 1H, J = 2.7, 6.2 Hz), 7.32–7.44
(m, 6H), 7.64–7.71 (m, 4H); resolved proton resonances for diastereomer-II: d
0.84 (t, 3H, J = 7.1 Hz), 1.42–1.47 (m, 1H), 2.11–2.16 (m, 1H), 2.37–2.41 (m, 1H),
3.82 (dd, 1H, J = 5.8, 10.7 Hz), 3.86 (ddd, 1H, J = 1.8, 5.4, 10.8 Hz); 13C NMR
(150 MHz, CDCl3) diastereomer-I: d 14.0, 17.6, 19.5, 20.2, 20.89, 22.4, 25.3,
27.0, 28.4, 29.1, 31.5, 33.2, 36.6, 74.1, 80.0, 111.50, 127.5, 129.6, 134.1, 136.1,
171.7, 198.1; non-overlapping carbon resonances for diastereomer-II: d 17.8,
20.85, 22.5, 24.7, 28.2, 29.3, 31.6, 36.6, 74.3, 79.9, 111.55, 127.3, 129.4, 133.9,
12. (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J.
Org. Chem. 1999, 64, 690; (b) Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.;
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Org. Chem. 2003, 68, 1729.
13. Alkynol 6: Rf = 0.44 [10% EtOAc in petroleum ether]; 1H NMR (600 MHz, CDCl3)
d 0.88 (t, 3H, J = 6.7 Hz), 1.29–1.38 (m, 6H), 1.43–1.45 (m, 2H), 1.65–1.72 (m,
2H), 4.35 (s, 2H), 4.38 (t, 1H, J = 5.4 Hz); 13C NMR (150 MHz, CDCl3) d ꢀ5.1,
14.0, 18.2, 22.5, 25.0, 25.8, 28.9, 31.7, 37.7, 51.7, 62.5, 83.4, 85.9; IR (KBr) cmꢀ1
3352 br s, 2955s, 2930s, 2858s, 1680w, 1464m, 1254m, 1084m, 837s; m/e
calcd for C16H32O2SiNa+ (M+Na)+ 307.2064, found 307.2062.
To a heterogeneous suspension of LAH (6.50 g, 170.0 mmol) in THF (500 mL)
was added at 0 °C a solution of alkynol 6 (32.3 g, 114.0 mmol) in THF (100 mL)
via cannula. The reaction mixture was stirred at 0 °C for 5 min before it was
warmed to rt and stirred for an additional 2 h. The mixture was treated
sequentially with H2O (6.5 mL) and 10% aq KOH (11 mL) in an ice bath and
stirred for 10 min after quenching. After the addition of another portion of H2O
(17 mL), the mixture was filtered, and the insoluble aluminum salt was
repeatedly washed with EtOAc. The combined filtrates were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude and colorless trans-allylic
alcohol (26.7 g, 84%) was used for the next step without purification.
To a solution of the above trans-allylic alcohol (3.50 g, 12.2 mmol) in THF

Q. Li et al. / Tetrahedron Letters 54 (2013) 5567–5572
5571
135.9; IR (KBr) cmꢀ1 2953s, 2931s, 2857s, 1655m, 1625s, 1397m, 1110s, 738m,
703s; mass spectrum (ESI): m/e (% relative intensity) 505.2 (100) (M+H)+; m/e
calcd for C32H44O3SiNa+ (M+Na)+ 527.2952, found 527.2959.
using flash silica gel column chromatography (Gradient eluent: 20–50% EtOAc
in petroleum ether) to afford the desilylated product as colorless oil (44.0 mg,
89%). Characterized as an inseparable mixture of two diastereomers: Rf = 0.15
[30% EtOAc in petroleum ether]; 1H NMR (600 MHz, CDCl3) diastereomer-I: d
0.89 (t, 3H, J = 6.8 Hz), 1.30–1.41 (m, 6H), 1.49–1.58 (m, 3H), 1.63–1.70 (m, 1H),
1.91–2.00 (m, 3H), 2.05–2.13 (m, 2H), 2.34–2.41 (m, 4H), 2.44–2.50 (m, 1H),
3.61–3.64 (m, 1H), 3.78 (ddd, 1H, J = 2.2, 5.5, 10.9 Hz); resolved proton
resonances for diastereomer-II: d 3.82–3.84 (m, 2H); 13C NMR (150 MHz,
CDCl3) diastereomer-I: d 14.0, 17.6, 20.82, 22.5, 23.0, 25.3, 28.56, 29.2, 31.7,
32.7, 36.6, 73.0, 80.3, 111.7, 171.0, 198.1; non-overlapping carbon resonances
for diastereomer-II: d 17.5, 20.84, 25.7, 28.59, 32.1, 72.3, 80.4, 111.9, 171.3; IR
(KBr) cmꢀ1 3413br s, 2931s, 2860s, 1612s, 1397s, 1080m; mass spectrum (ESI):
m/e (% relative intensity) 267.0 (100) (M+H)+; m/e calcd for C16H26O3Na+
(M+Na)+ 289.1774, found 289.1770.
To a stirring solution of the above desilylated product (98.0 mg, 0.37 mmol) in
CH2Cl2 (2 mL) was added slowly dropwise a solution of Martin’s sulfurane
(0.50 g, 0.74 mmol) in CH2Cl2 (2 mL) at rt. The resulting pale yellow solution
was stirred for 2 h. After which, the excess solvent was removed in vacuo to
yield a crude pale yellow oil. Purification of the crude product using flash silica
gel column chromatography (Gradient eluent: 0–20% EtOAc in petroleum
ether) furnished alkene 17 as colorless oil (41.0 mg, 48%). Rf = 0.52 [30% EtOAc
in petroleum ether]; 1H NMR (600 MHz, CDCl3) d 0.89 (t, 3H, J = 7.1 Hz), 1.25–
1.31 (m, 4H), 1.37–1.41 (m, 2H), 1.62–1.68 (m, 1H), 1.91–1.99 (m, 3H), 2.03–
2.08 (m, 2H), 2.14–2.19 (m, 1H), 2.35–2.40 (m, 5H), 4.38 (td, 1H, J = 2.1, 8.0 Hz),
5.52 (dd, 1H, J = 6.9, 15.4 Hz), 5.76 (dt, 1H, J = 6.7, 15.4 Hz); 13C NMR (150 MHz,
CDCl3) d 14.0, 17.2, 20.9, 22.4, 27.2, 28.6, 28.8, 31.3, 32.2, 36.6, 77.9, 111.3,
128.0, 134.6, 171.2, 198.2; IR (KBr) cmꢀ1 3735w, 3616w, 2928s, 2859m,
2317w, 1619s, 1391m, 1179w; mass spectrum (ESI): m/e (% relative intensity)
249.1 (100) (M+H)+; m/e calcd for C16H24O2Na+ (M+Na)+ 271.1669, found
271.1668.
A 1.0 M solution of LDA was prepared from a solution of di-isopropyl amine
(1.40 mL) in THF (5.60 mL) and n-butyl lithium (2.0 mL, 2.4 M in hexanes) at
ꢀ78 °C. To a solution of 10 (676.0 mg, 1.34 mmol) in THF (13 mL) was added
the above LDA solution (2.70 mL, 2.70 mmol) at ꢀ78 °C. The resulting enolate
solution was stirred at ꢀ78 °C for 30 min before the addition of a solution of
Davis’ oxaziridine (614.0 mg, 2.0 mmol) in THF (5 mL). The reaction mixture
was then stirred for an additional 30 min at ꢀ78 °C before it was warmed up to
rt and stirred for an additional 18 h. The reaction mixture was quenched with
sat aq NH4Cl (25 mL), and the aqueous layer was extracted with EtOAc
(3 ꢁ 30 mL). The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified using
flash silica gel column chromatography (Gradient eluent: 0–20% EtOAc in
petroleum ether) to give alcohol 11 as yellow oil (211.0 mg, 30%). Rf = 0.22 [30%
EtOAc in petroleum ether]; mass spectrum (ESI): m/e (% relative intensity)
521.5 (100) (M+H)+; m/e calcd for C32H44O4SiNa+ (M+Na)+ 543.2901, found
543.2919.
To a solution of the above alcohol 11 (25.0 mg, 0.048 mmol) in pyridine (1 mL)
was added Ac2O (49.8 lL, 0.48 mmol, 10.0 equiv). The resulting mixture was
stirred at rt for 3 h before pyridine was removed in vacuo. The yellow crude
residue was purified using flash silica gel column chromatography (Gradient
eluent: 0–20% EtOAc in petroleum ether) to give acetate 12 as yellow oil
(22.0 mg, 81% yield).
To a solution of the above acetate 12 (22.0 mg, 0.39 mmol) in THF (1 mL) was
added TBAF (0.060 mL, 1.0 M in THF, 0.059 mmol) at 0 °C. The reaction mixture
was stirred at rt for 1.5 h before sat aq NH4Cl solution was then added and the
aqueous phase was extracted three times with equal volume of EtOAc. The
combined organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Purification of the crude residue was achieved using flash silica gel
column chromatography (Gradient eluent: 0–50 % EtOAc in petroleum ether)
to afford the desilylated product (9.0 mg, 78%) as yellow oil. Rf = 0.23 [50%
EtOAc in petroleum ether]; mass spectrum (ESI): m/e (% relative intensity)
325.5 (100) (M+H)+; m/e calcd for C18H28O5Na+ (M+Na)+ 347.1829, found
347.1837.
To a stirring solution of the above desilylated product (12.0 mg, 0.040 mmol) in
CH2Cl2 (1 mL) was added Dess–Martin periodinane (33.0 mg, 0.077 mmol) at
0 °C. The resulting mixture was stirred at rt for 2 h before it was quenched with
sat aq Na2S2O3/NaHCO3 (7/1) (1 mL). The quenched mixture was stirred
vigorously until there were two distinct layers. The crude product was
extracted with Et2O (3 ꢁ 5 mL). The combined organic layers were washed
with sat aq NaCl, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was purified by flash silica gel column
chromatography (Gradient eluent: 0–10% EtOAc in petroleum ether) to
afford the desired ketone intermediate (11.0 mg, 92%) as colorless oil.
Characterized as an inseparable mixture of two diastereomers: Rf = 0.76 [50%
EtOAc in petroleum ether]; 1H NMR (600 MHz, CDCl3) diastereomer-I: d 0.88 (t,
3H,J = 6.5 Hz), 1.27–1.34 (m, 6H), 1.57–1.61 (m, 2H), 1.74–1.81 (m, 1H), 1.98–
2.03 (m, 1H), 2.04–2.14 (m, 2H), 2.17 (s, 3H), 2.23–2.27 (m, 1H), 2.34–2.39 (m,
2H), 2.49–2.66 (m, 2H), 2.72–2.75 (m, 1H), 4.57 (dd, 1H, J = 4.1, 6.3 Hz), 5.32 (t,
1H, J = 4.7 Hz); resolved proton resonances for diastereomer-II: d 2.41–2.47 (m,
2H), 4.38 (dd, 1H, J = 4.5, 9.4 Hz), 5.30 (t, 1H, J = 4.3 Hz); 13C NMR (150 MHz,
CDCl3) diastereomer-I: d 14.0, 15.9, 17.0, 20.9, 22.4, 23.0, 26.5, 26.9, 28.8, 31.5,
38.1, 72.2, 80.9, 110.5, 168.9, 170.3, 191.8, 207.4; non-overlapping carbon
resonances for diastereomer-II: d 22.5, 22.9, 26.3, 27.0, 38.2, 81.1, 110.8, 168.8;
IR (KBr) cmꢀ1 3687m, 2920s, 2855m, 1732m, 1620w, 1457w; mass spectrum
(ESI): m/e (% relative intensity) 345.5 (100) (M+Na)+; m/e calcd for C18H26O5Na+
(M+Na)+ 345.1672, found 345.1682.
To a solution of alkene 17 (40.0 mg, 0.16 mmol) in THF (2 mL) at –78 °C were
added TMEDA (6.00 lL) and a solution of LDA (0.32 mL, 0.32 mmol) prepared
as previously described. The solution was stirred at ꢀ78 °C for 20 min before
adding a solution of Davis’ oxaziridine (79.0 mg, 0.32 mmol) in THF (2 mL). The
reaction mixture was then stirred for an additional 5 min at ꢀ78 °C before it
was warmed up to rt and stirred for an additional 20 h. The reaction mixture
was quenched with sat aq NH4Cl (5 mL), and the quenched mixture was
extracted with EtOAc (3 ꢁ 5 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude product
was subjected to flash silica gel column chromatography (Gradient eluent: 0–
10% EtOAc in petroleum ether) to give putative trichodermatide C and it C2-
epimer as colorless oil (20.0 mg, 47%). Characterized as an inseparable mixture
of two diastereomers: Rf = 0.40 [30% EtOAc in petroleum ether]; 1H NMR
(600 MHz, DMSO-d6) putative C: d 0.85 (t, 3H, J = 7.2 Hz), 1.20–1.30 (m, 4H),
1.31–1.37 (m, 2H), 1.57–1.60 (m, 1H), 1.61–1.67 (m, 1H), 1.70–1.75 (m, 1H),
1.83–1.88 (m, 1H), 1.99–2.05 (m, 2H), 2.06–2.10 (m, 1H), 2.11–2.16 (m, 1H),
2.49–2.51 (m, 2H), 3.91 (ddd, 1H, J = 3.7, 4.9, 12.3 Hz), 4.41 (t, 1H, J = 7.5 Hz),
5.54 (dd, 1H, J = 6.7, 15.4 Hz), 5.76 (dt, 1H, J = 6.6, 15.4 Hz); resolved proton
resonances for the putative 2-epi-C: d 0.86 (t, 3H, J = 6.9 Hz), 1.52–1.57 (m, 1H),
1.69–1.73 (m, 1H), 1.89–1.92 (m, 1H), 2.25–2.28 (m, 1H), 2.33–2.36 (m, 1H),
2.53–2.56 (m, 1H), 3.87 (dt, 1H, J = 4.6, 11.3 Hz), 4.57 (td, 1H, J = 2.8, 6.9 Hz),
5.51 (dd, 1H, J = 6.9, 15.6 Hz), 5.71 (dt, 1H, J = 6.6, 15.4 Hz); 13C NMR (150 MHz,
DMSO-d6) putative C: d 13.8, 17.1, 21.8, 26.4, 26.7, 28.0, 29.2, 30.7, 31.47,
70.36, 77.1, 108.4, 128.4, 133.5, 170.0, 197.4; non-overlapping carbon
resonances for the putative 2-epi-C: d 25.9, 26.5, 29.3, 30.6, 31.43, 70.31,
76.6, 108.1, 128.0, 133.3, 169.8, 197.2; IR (KBr) cmꢀ1 3461w, 2928s, 2860m,
1654w, 1614s, 1381m, 1190m, 1075w, 974m; mass spectrum (ESI): m/e (%
relative intensity) 265.1 (100) (M+H)+; m/e calcd for C16H24O3Na+ (M+Na)+
287.1618, found 287.1612.
To a solution of the above ketone (9.00 mg, 0.028 mmol) in MeOH (0.5 mL) was
added K2CO3 (7.70 mg, 0.056 mmol, 2.0 equiv) at rt. The reaction mixture was
vigorously stirred for 2 h as the solution turned yellow. The mixture was then
diluted with EtOAc (10 mL) and washed with aq NaOH (5 mL, 0.1 M). The
aqueous layer was extracted with EtOAc (3 ꢁ 10 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified using flash silica gel column
chromatography (Gradient eluent: 0–10% EtOAc in petroleum ether) to give
14. We initially carried out a dihydro-trichodermatide C synthesis to test the use
Davis’ oxaziridine for alpha-hydroxylation.
trichodermatide
B and its C2-epimer as yellow needles (7.0 mg, 90%).
Characterized as an inseparable mixture of two diastereomers: Rf = 0.38 [50%
EtOAc in petroleum ether]; 1H NMR (600 MHz, DMSO-d6) putative B: d 0.89 (t,
3H, J = 7.0 Hz), 1.24–1.32 (m, 6H), 1.46–1.54 (m, 2H), 1.72–1.85 (m, 2H), 2.02–
2.16 (m, 3H), 2.22–2.25 (m, 1H), 2.42–2.55 (m, 3H), 2.57–2.67 (m, 1H), 3.92
(dd, 1H, J = 4.9, 12.3 Hz), 4.66 (dd, 1H, J = 3.1, 8.2 Hz); resolved proton
resonances for the putative 2-epi-B: d 1.95–2.00 (m, 1H), 3.90 (dd, 1H, J = 5.0,
14.0 Hz), 4.86 (t, 1H, J = 4.8 Hz); 13C NMR (150 MHz, DMSO-d6) putative B: d
13.8, 16.2, 21.9, 22.2, 22.53, 26.5, 28.1, 29.2, 31.0, 37.2, 70.3, 80.0, 108.5,
169.20, 197.4, 207.3; non-overlapping carbon resonances for the putative 2-
epi-B: d 21.7, 22.58, 26.4, 28.0, 29.1, 37.0, 79.8, 108.7, 169.24, 197.3; IR
(KBr) cmꢀ1 3462m, 2931s, 2860m, 1722m, 1620s, 1388m, 1284w, 1080m;
mass spectrum (ESI): m/e (% relative intensity) 303.6 (100) (M+Na)+; m/e calcd
for C16H24O3Na+ (M+Na)+ 303.1566, found 303.1569.
15. Personal communication was made to the corresponding author, Professor Yue-
Hu Pei [http://peiyueh@vip.163.com], at School of Traditional Chinese Material
Medica, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
However, there were no original spectra provided; and more importantly, there
were no clear explanations for what appeared to be mis-assignments and/or
mis-recordings. For examples:
For trichodermatide B: (i) In Table 2 on Page 4 of authors’ Organic Letters
Supplementary data, H9 is listed as 5.14 ppm (dd, J = 9.3 and 4.5 Hz), but on
Page 11 of the same Supplementary data, 1H NMR spectrum of trichodermatide
B shows a multiplet—or a resonance that is much more complicated than ‘dd’ at
5.14 ppm; (ii) 3.94 ppm for H2 listed as ‘ddd,’ but spectrum also shows a more
complicated multiplet.
For trichodermatide C: (i) In Table 2, H9 is listed as 5.29 ppm (ddd, J = 9.5, 7.6 and
4.5 Hz), but on Page 16, in the 1H NMR spectrum of trichodermatide C, the
resonance at ꢂ5.29 ppm is not a ‘ddd.’ This is similarly true with H2, although
the resolution of PDF files here is not as distinct as for trichodermatide B. (ii) H8
is now listed as 1.32 ppm—but H8 for C should be similar as in B and D ꢂ2.80–
3.00 ppm.
To a solution of 10 (94.0 mg, 0.185 mmol) in THF (2 mL) was added TBAF
(0.24 mL, 1.0 M in THF) dropwise at 0 °C. The resulting mixture was stirred for
5 h. The reaction was quenched with H2O at rt and the aqueous layer was
extracted with EtOAc three times in equal volume. The combined organic
layers were dried over Na2SO4 and filtered. The crude residue was purified

5572
Q. Li et al. / Tetrahedron Letters 54 (2013) 5567–5572
16. Molecular Modeling Calculations. Molecular modeling calculations were
performed on Dell Precision T5500 Linux workstation with Xeon
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T., ; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. GAUSSIAN 09, Revision A.1;
Gaussian, Inc.: Wallingford CT, 2009.
a
a
processor (3.3 GHz, 6-core). Low energy conformers were obtained using
SPARTAN 10 software (MMFF, 10,000 conformers examined). The low energy
conformer for each compound was analyzed using GAUSSIAN 09 for geometry
optimization and NMR calculations (B3LYP/6-31G(d,p)). NMR shifts were
referenced to TMS and benzene using the multi-standard (MSTD) approach.21
Molecules were modeled in the gas phase.
17. Deppmeier, B. J.; Driessen, A. J.; Hehre, T. S.; Hehre, W. J.; Johnson, J. A.;
Klunzinger, P. E.; Leonard, J. M.; Ohlinger, W. S.; Pham, I. N.; Pietro, W. J.; Yu, J.
SPARTAN 10, v. 1.0.2.; Wavefunction Inc.: Irvine, CA, 2011.
18. Stappen, I.; Buchbauer, G.; Robien, W.; Wolschann, P. Magn. Reson. Chem. 2009,
47, 720.
20. Smith, S. G.; Goodman, J. M. J. Am. Chem. Soc. 2010, 132, 12946.
21. Sarow, A. M.; Pellegrinet, S. C. J. Org. Chem. 2009, 74, 7254.
19. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;