Total synthesis of bioactive drimane-epoxyquinol hybrid natural products: Macrophorin A, 4′-oxomacrophorin A, and 1′-epi-craterellin A

Article abstract of DOI:10.1016/j.tetlet.2014.09.075

Total synthesis of novel hybrid natural products, merosesquiterpenoids macrophorin A, 4′-oxomacrophorin A, and 1′-epi-craterellin A has been accomplished following a general strategy based on a sacrificial Diels-Alder-retroDiels-Alder approach to control regio- and stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2014.09.075

Tetrahedron Letters 55 (2014) 6252–6256
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of bioactive drimane–epoxyquinol hybrid
natural products: macrophorin A, 40-oxomacrophorin A,
and 10-epi-craterellin A
⇑
Sumanta Garai, Goverdhan Mehta
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Total synthesis of novel hybrid natural products, merosesquiterpenoids macrophorin A, 40-oxomacropho-
rin A, and 10-epi-craterellin A has been accomplished following a general strategy based on a sacrificial
Diels–Alder–retroDiels–Alder approach to control regio- and stereoselectivity.
Ó 2014 Elsevier Ltd. All rights reserved.
Article history:
Received 18 August 2014
Revised 12 September 2014
Accepted 16 September 2014
Available online 22 September 2014
Keywords:
Hybrid natural products
Drimanes
Epoxyquinols
retroDiels–Alder reaction
Stereoselective reduction
The virtuosity of nature in creating diverse molecular architec-
ture while preserving the integrity of a particular biosynthetic
pathway, for example, various terpenes from mevalonate derived
geranyl pyrophosphate, farnesyl pyrophosphate, squalene oxide
etc., is well recognized. However, sometimes nature also ventures
to craft hybrid natural products1 forged through the confluence of
two distinct biosynthetic pathways. Such hybrid natural products
are structurally distinct constructs and in many cases display
unusual bioactivity profile. Understandably, such entities have
not only drawn attention for total synthesis campaigns but also
inspired efforts to explore new chemical space in the quest of
drug-like NCE’s.1a,b,2
Among the ever expanding canvas of hybrid natural products,
drimanyl–epoxyquinols (merosesquiterpenoids) represented by
framework 1, and crafted through a union of mevalonate derived
drimane (bicyclofarnesane) sesquiterpene framework (in red) and
polyketide aromatic pathway derived epoxyquinol moiety (in blue)
constitute a growing family of natural products.3 Archetypal
examples of drimanyl–epoxyquinols 2–8, displaying functional
group variation in both the drimane and epoxyquinol segments
are displayed in Figure 1. Interestingly, quite a few of these
hybrid natural products exhibit impressive and wide ranging
bioactivities that include anti-fungal, anti-bacterial, anti-cancer,
immunomodulatory, and strong toxicity against brine shrimp
larvae among others.3 For example, drimanyl–epoxyquinol natural
products epoxyphomalin A 7a and B 7b exhibited impressive activ-
ity against several cancer cell lines at nanomolar concentration and
it was also observed that these natural products exert their activity
through inhibition of the 20S proteasome.3f,i Despite interesting
structural features and bioactivities associated with drimanyl–
epoxyquinol natural products and possibilities of exploring
promising chemical space around them, we were surprised to find
that no chemical synthesis of any member of this family has yet
surfaced in the literature. Arising out of our long standing interest
in the synthesis of epoxyquinol natural products,4 we decided to
enter the arena and wish to report here the first total synthesis
of drimanyl–epoxyquinol natural products.
Macrophorin A 2a was the first drimanyl–epoxyquinol natural
product to be isolated and characterized3a in 1983 and since then
its isolation has been repeatedly reported3 from diverse sources.
Natural product 2a exhibited anti-bacterial activity against staphy-
lococcus aureus (MIC 25 ppm) and anti-cancer activity against
mouse tumor cell lines (L-5178Y) with IC50 of 0.3 ppm.3a In view
of these attributes, we chose 2a and its sibling 3 as our first targets
for total synthesis. The synthetic strategy to 2a and 3 was fairly
straightforward and widely applicable and hinged on constructing
the epoxyquinol moiety on a preformed drimane platform by har-
nessing the potential of a sacrificial Diels–Alder–retroDiels–Alder
stratagem extensively explored by us4 for regio- and stereoselec-
tive functionalization.
⇑
Corresponding author. Tel.: +91 4066794848; fax: +91 4023010785.
E-mail address: gmehta43@gmail.com (G. Mehta).
http://dx.doi.org/10.1016/j.tetlet.2014.09.075
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Garai, G. Mehta / Tetrahedron Letters 55 (2014) 6252–6256
6253
OH
O
OH
OH
R
O
O
O
O
O
4'
OH
O
OH
OH
OH
O
O
O
O
HO
R
H
H
H
H
4. Neomacrophorin II
1
2a. Macrophorin A, R=H
b. Macrophorin B, R= O
3. 4'-Oxomacrophorin A
R
OH
OH
OH
OH
HO
O
HO
OH
OH
O
O
HO
1'
O
O
O
H
H
R
H
HO
R
H
HO
5a
. R= H Craterellin A
b. R= OH Craterellin B
7a. R= OH Epoxyphomalin A
b. R= H Epoxyphomalin B
8a. R= COOH Epoxyphomalin C
b. R= CH3 Epoxyphomalin D
6. Myrothecol D
Figure 1. Representative examples of drimanyl–epoxyquinol hybrid natural products.
OAc
OAc
OH
OH
H
H
H
a
O
O
b
O
OH
+
OH
H
O
H
O
H
H
12
H
11
O
O
O
9
10
b
a
Scheme 1. Reagents and conditions: (a) ClSO3H, 2-nitropropane, ꢀ78 °C, 30 min
60%; (b) (i) methanesulfonyl chloride (MsCl), Et3N, THF, rt, 3 h; (ii) KOH, MeOH, 6 h,
90% (overall), 11:12 (1:1).
H
H
15
H
18
17
c
OH
OH
O
O
O
H
O
OH
HO
H
OH
O
O
b
O
OH
O
a
d
H
11
H
H
H
13
14
19
2a. Macrophorin A
Scheme 2. Reagents and conditions: (a) (i) PCC, DCM, 30 min; (ii) n-BuLi, Et2O,
2,5-dimethoxybromobenzene, ꢀ78 °C, 2 h, 87% (over two steps); (b) (i) Li, liq. NH3,
THF, 3 min 95%; (ii) CAN (ceric ammonium nitrate), CH3CN/H2O/Et2O (1:1:0.5),
15 min, 52%.
Scheme 4. Reagents and conditions: (a) H2O2; 10% Na2CO3, 4 h, rt, 90%; (b) HCHO,
DBU, THF, 0 °C, 5 h, 96%; (c) DIBALH, THF, ꢀ78 °C, 3 h, 92%; (d) Ph2O, 240 °C, 15 min,
89%.
H
H
O
O
O
H
O
O
H
O
H
O
OH
OH
O
a
4'
O
O
O
O
a
+
H
H
15
H
H
14
H
16
3. 4'-Oxomacrophorin A
18
Scheme 3. Reagents and conditions: (a) cyclopentadiene, MeOH/Et2O (1:1), 0 °C,
4 h, 85% (overall), 59% (for 15) 15:16 (7:3).
Scheme 5. Reagents and conditions: (a) Ph2O, 240 °C, 15 min, 85%.
are encountered in exocyclic and endocyclic double bond bearing
variants, (see Fig. 1). Pyridinium chlorochromate (PCC)-mediated
oxidation of the primary hydroxyl group in 11 to the aldehyde
and addition of lithiated 2,5-dimethoxybromobenzene led to 13
which was directly subjected to sequential reductive deoxygen-
ation6 and ceric ammonium nitrate (CAN) oxidation to deliver
Farnesyl acetate 9 was subjected to polyene cyclization in
chlorosulfonic acid following a reported protocol5 to deliver the
bicyclic drimane (bicyclofarnesane) derivative 10 which upon
dehydration and hydrolysis led to a readily separable mixture
(1:1) of drimanols 11 and 12, Scheme 1. Both 11 and 12 were con-
sidered serviceable since drimanyl–epoxyquinol natural products

6254
S. Garai, G. Mehta / Tetrahedron Letters 55 (2014) 6252–6256
H
H
H
O
O
O
O
O
H
O
H
O
H
O
OH
HO
O
c
O
b
O
a
d
+
H
12
H
H
20
H
H
H
21
23
22
24
OH
OH
OH
OH
H
H
HO
O
O
O
1'
OH
OH
f
OH
O
O
O
O
O
e
g
h
H
H
H
H
25
26
27
28
Scheme 6. Reagents and conditions: (a) (i) PCC, DCM, 30 min; (ii) n-BuLi, Et2O, 2,5-dimethoxybromobenzene, ꢀ78 °C, 2 h, 79% (over two steps); (b) (i) Li, liq. NH3, THF, 3 min
98%; (ii) CAN (ceric ammonium nitrate), CH3CN/H2O/Et2O (1:1:0.5), 15 min, 50%; (c) cyclopentadiene, MeOH/Et2O (1:1), 0 °C, 4 h, 85% (overall), 59% (for 22) 22:23 (7:3); (d)
H2O2; 10% Na2CO3, 4 h, rt, 84%; (e) HCHO, DBU, THF, 0 °C, 5 h, 98%; (f) DIBAL-H, THF, ꢀ78 °C, 3 h, 97%; (g) Ph2O, 240 °C, 15 min, 85%; (h) DIBALH, THF, ꢀ78 °C, 3 h, 99%.
the requisite benzoquinone derivative 14, Scheme 2, and set the
stage for the implementation of the sacrificial Diels–Alder–retro-
Diels–Alder steps, concomitant with the generation of the oxygen-
ation pattern of the epoxyquinol segment.
The Diels–Alder reaction between 14 and cyclopentadiene fur-
nished two diastereomeric endo-adducts 15 and 16 in 7:3 ratio.7
The underlying reasons for the observed face selectivity in the
Diels–Alder reaction leading to 15 and 16 cannot be explained by
steric factors alone and perhaps reflect a cumulative expression
of the prevailing stereoelectronic environment.8 However, it was
gratifying that the required diastereomer 15 predominated,
Scheme 3.
Nucleophilic epoxidation of 15, as expected and planned was
stereoselective, engendered by the exo-face selectivity of the nor-
bornyl scaffold present in it, to deliver 17. a-Hydroxymethylation
in 17 to introduce the side arm was regioselective and guided by
our previous observations in similar systems.4b,c The resulting 18
was now subjected to controlled diisobutylaluminum hydride
(DIBALH) reduction which pleasingly turned out to be regio- and
stereoselective with the hydride attacking the carbonyl group from
dehydrogenase (11b-HSD1 and 11b-HSD2) with wide therapeutic
implications including in obesity and diabetes.3g,3j
The benzoquinone moiety was appended to drimanol 12 via
PCC-oxidation, addition of the organolithium reagent derived from
2,5-dimethoxybromobenzene, and CAN oxidation to furnish 20,
Scheme 6. The Diels–Alder reaction of the quinone moiety in 20
with cyclopentadiene once again furnished a mixture (7:3) of dia-
stereomeric endo adducts 22 and 23 and the former was processed
further. Nucleophilic epoxidation leading to 24 was stereoselective
and further regio- and stereoselective hydroxymethylation eventu-
ated in 25, Scheme 6. A regio- and stereoselective carbonyl reduc-
tion of 25 led to 26. As planned, retroDiels–Alder reaction in 26 was
uneventful and delivered 10-oxo-craterellin A 27 and its formula-
tion was fully secured through single crystal X-ray structure deter-
mination.9 At this stage, what awaited the completion of the total
synthesis of 5a was a stereoselective reduction of the carbonyl
group in 27 from the top face, Scheme 6. However, reduction of
the carbonyl group in 27 using different reagents (DIBALH, NaBH4
etc.) and reaction conditions was highly stereoselective in a devi-
ous sense and only delivered 10-epi-craterellin A 28 with hydride
the less encumbered endo (
a
) face to deliver 19 with the requisite
delivery from the a-face. Its formulation was secured through
hydroxyl stereochemistry. The stage was now set to disengage the
sacrificial cyclopentadiene moiety and the retroDiels–Alder reac-
tion in 19 was smoothly implemented through thermal activation
to deliver macrophorin A 2a, Scheme 4. The spectral characteristics
(1H NMR, 13C NMR) of our synthetic 2a were identical with those
reported for the natural product.3a,l,7
When 18 was directly subjected to thermal activation to effect
the retroDiels–Alder reaction, natural product 40-oxomacrophorin
A 3 was obtained, (Scheme 5) and identified by comparison of its
spectral data (1H NMR, 13C NMR) with the natural product.3e,7
We have indicated (vide supra) that both the bicyclic drimanols
11 and 12 obtained from the polyene cyclization of farnesyl acetate
9 were deployable for the synthesis of drimane–epoxyquinol
hybrid natural products. Having demonstrated the utility of the
exocyclic drimanol isomer 11 in the total synthesis of macropho-
rins, we ventured to explore the possibilities with endocyclic drim-
anol 12 following a similar tactic. For a preliminary foray, more
recently isolated3g craterellin A 5a was selected as the potential
target for synthesis, particularly as it was shown to exhibit
inhibitory activity against two isozymes of 11b-hydroxysteroid
X-ray crystal structure determination of its tri-p-bromobenzoate
derivative.10 Thus, synthetic access to the natural product craterel-
lin A 5a eluded us at the last step due to the unexpected and
somewhat inexplicable stereochemical outcome during the
hydride reduction step. Nonetheless, in the overall sense it rein-
forced the validity of our conceptualization of a short access to
drimanyl–epoxyquinol natural products.
In conclusion, we have outlined a short, general, and diversity
oriented approach toward bioactive drimanyl–epoxyquinol hybrid
natural products from commercially available farnesol employing a
Diels–Alder–retroDiels–Alder strategy as a regio- and stereocontrol
element.
Acknowledgments
S.G. thanks UGC – India for the award of Dr. D. S. Kothari post-
doctoral fellowship. G.M. thanks GOI for the award of National
Research Professorship. This research was supported through a
generous Grant from the Eli-Lilly and Jubilant-Bhartia Foundations.
We thank Jan-Philip Meyer for some exploratory experiments.

S. Garai, G. Mehta / Tetrahedron Letters 55 (2014) 6252–6256
6255
0.80 (s, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) d 208.12, 149.34, 140.33,
135.95, 106.64, 73.10, 70.11, 66.97, 63.45, 55.49, 55.10, 51.35, 50.92, 46.67,
44.42, 44.20, 42.07, 39.41, 39.08, 37.90, 33.58, 33.55, 24.23, 21.67, 19.81, 19.31,
14.52; HRMS (ESI): calcd 449.2662 (M+Na)+; found 449.2669; Compound 2a
References and notes
1. For reviews, see (a) Mehta, G.; Singh, V. Chem. Soc. Rev. 2002, 31, 324–334; (b)
Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42, 3996–
4028. and references cited therein.
(macrophorin A): IR (CHCl3) 3364, 2926, 1855, 1715, 1682, 1463 cmꢀ1 1H NMR
;
(500 MHz, CD3OD) d 5.91 (d, J = 1.5 Hz, 1H), 4.77 (s, 1H), 4.56 (s, 2H), 4.29 (d,
J = 15.0 Hz, 1H), 4.21 (d, J = 15.0 Hz, 1H), 3.67 (d, J = 2.5 Hz, 1H), 2.33–2.30
(m, 2H), 1.92 (td, J = 15.0, 5.0 Hz, 1H), 1.82 (dd, J = 14.0, 11.5 Hz, 1H), 1.75–1.73
(m, 3H), 1.62–1.56 (m, 1H), 1.52–1.46 (m, 1H), 1.41–1.35 (m, 1H), 1.32–1.26
(m, 1H), 1.22–1.18 (m, 2H), 1.12 (dd, J = 13.0, 2.5 MHz, 1H), 0.85 (s, 3H), 0.79 (s,
3H), 0.70 (s, 3H); 13C NMR (125 MHz, CD3OD) d 195.51, 161.13, 150.61, 120.37,
107.38, 66.22, 62.36, 62.20, 61.30, 56.94, 52.96, 43.31, 40.74, 40.02, 39.26,
34.52, 34.03, 25.66, 22.11, 20.41, 15.00; HRMS (ESI): calcd 383.2193 (M+Na)+;
found 383.2198; compound 3 (40-oxomacrophorin A): IR (CHCl3) 3441, 2926,
2. Decker, M. Curr. Med. Chem. 2011, 18, 1464–1475.
3. (a) Sassa, T.; Yoshikoshi, H. Agric. Biol. Chem. 1983, 47, 187–189; (b) Sassa, T.;
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Sassa, T. J. Nat. Prod. 2001, 64, 1234–1237; (f) Mohamed, I. E.; Gross, H.; Pontius,
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Mohamed, I. E.; Kehraus, S.; Krick, A.; König, G. M.; Kelter, G.; Armin Maier, A.;
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2849, 1687, 1486 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.63 (s, 1H), 4.81 (s, 1H),
;
4.52 (d, J = 19.2 Hz, 1H), 4.49 (s, 1H), 4.35 (d, J = 19.1 Hz, 1H), 3.72 (s, 1H), 2.46
(d, J = 14.8 Hz, 1H), 2.35 (br d, J = 12.8 Hz, 1H), 2.00 (dd, J = 16.0, 11.2 Hz, 2H),
1.93–1.88 (m, 1H), 1.68 (d, J = 12.0 Hz, 2H), 1.75–1.70 (m, 1H), 1.57–1.53 (m,
2H), 1.40–1.35 (m, 1H), 1.30–1.28 (m, 1 H), 1.20–1.13 (m, 1H), 1.10 (br d,
J = 12.0 Hz, 1H), 0.86 (s, 3H), 0.78 (s, 3H), 0.68 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 193.55, 191.97, 148.77, 146.74, 132.14, 106.89, 62.55, 59.27, 59.12,
55.56, 51.50, 42.03, 39.80, 38.94, 38.05, 33.62, 33.52, 24.39, 21.65, 20.32, 19.34,
14.47; HRMS (ESI): calcd 381.2036 (M+Na)+; found 381.2046; compound 22: IR
(CHCl3) 2958, 2926, 2854, 1736, 1676, 1468 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
6.54 (s, 1H), 6.08–6.03 (m, 2H), 5.41 (s, 1H), 3.55 (d, J = 12.0 Hz, 2H), 3.24–3.23
(m, 2H), 2.43 (dd, J = 16.9, 9.6 Hz, 1H), 2.29–2.25 (m, 1H), 2.09 (s, 1H), 2.03–
1.95 (m, 1H), 1.91–1.81 (m, 1H), 1.78–1.69 (m, 2H), 1.58–1.52 (m, 2H), 1.45 (s,
3H), 1.49–1.39 (m, 2H), 1.25–1.14 (m, 2H), 1.02 (dt, J = 13.0, 3.8 Hz, 1H), 0.89 (s,
3H), 0.87 (s, 3H), 0.82 (s, 3H); 13C NMR (125 MHz, CDCl3) d 199.20, 199.15,
157.80, 139.23, 135.56, 135.24, 133.70, 123.33, 53.33, 50.11, 48.87, 48.80,
48.78, 48.67, 48.37, 43.68, 42.10, 39.66, 36.87, 33.17, 33.02, 26.48, 23.07, 22.71,
21.86, 18.82, 13.81; HRMS (ESI): calcd 401.2451 (M+Na)+; found 401.2459;
compound 24: IR (CHCl3) 2964, 2920, 2854, 1720, 1463 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 6.08 (s, 2H), 5.44 (s, 1H), 3.49 (t, J = 2.6 Hz, 2H), 3.36
(s, 1H), 3.30 (d, J = 8.8 Hz, 2H), 2.25 (dd, J = 16.1, 8.8 Hz, 1H), 1.99 (d, J = 18.3 Hz,
1H), 1.89–1.85 (m, 2H), 1.68 (d, J = 13.2 Hz, 1H), 1.58 (s, 3H), 1.55–1.49 (m, 2H),
1.45–1.39 (m, 2H), 1.35–1.30 (m, 3H), 1.20–1.10 (m, 2H), 0.88 (s, 3H), 0.86 (s,
3H), 0.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 205.52, 205.34, 136.73, 136.58,
133.69, 122.88, 66.13, 61.63, 50.64, 50.34, 49.95, 47.09, 46.67, 43.34, 43.10,
42.11, 39.44, 35.94, 33.09, 32.96, 23.70, 22.43, 21.78, 21.68, 18.66, 13.71; HRMS
(ESI) calcd 417.2400 (M+Na)+; found 417.2412; compound 25: IR (CHCl3) 3408,
5. (a) Tanimoto, H.; Oritani, T. Tetrahedron: Asymmetry 1996, 7, 1695–1704;
Raptis, C.; Lykakis, I. N.; Tsangarakis, C.; Stratakis, M. Chem. Eur. J. 2009, 15,
11918–11927.
2958, 2920, 2854, 1709, 1457 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.08 (s, 2H),
;
5.41 (s, 1H), 4.40 (d, J = 10.5 Hz, 1H), 3.8 (d. J = 11.4 Hz, 1H), 3.42 (s, 1H),
3.35-3.27 (m, 2H), 2.88–2.87 (m, 1H), 2.27–2.21 (m, 1H), 2.10–2.04 (m, 1H),
2.02–1.90 (m, 1H), 1.90–1.80 (m, 1H), 1.70–1.60 (m, 2H), 1.53 (s, 3H), 1.50–1.37
(m, 5H), 1.25–1.21 (m, 1H), 1.15–1.12 (m, 2H), 0.85 (s, 3H), 0.84 (s, 3H), 0.75 (s,
3H); 13C NMR (100 MHz, CDCl3) d 205.59, 204.62, 138.27, 137.85, 133.56,
122.94, 68.20, 67.18, 61.69, 61.36, 54.22, 49.98, 47.02, 45.77, 44.29, 43.36,
42.10, 39.48, 35.95, 33.09, 32.96, 23.70, 22.13, 21.75, 18.64, 13.69; HRMS (ESI):
calcd 447.2506 (M+Na)+; found 447.2512; compound 27: IR (CHCl3) 3391,
6. Laube, T.; Schröder, J. R.; Stehle, R.; Seifert, K. Tetrahedron 2002, 58, 4299–4309.
7. All compounds reported here are racemic and were fully characterized on the
basis of IR, 1H NMR, 13C NMR, and HRMS spectral data. Spectral data of selected
compounds are given here: compound 15: IR (CHCl3) 2920, 2854, 1753, 1752,
1665, 1463 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.34 (s, 1H), 6.00 (s, 1H), 5.95 (s,
;
1H), 4.74 (s, 1H), 4.26 (s, 1H), 3.49 (br s, 2H), 3.21-3.17 (m, 2H), 2.47 (br s, 2H),
2.34 (d, J = 12 Hz, 1H), 1.98–1.89 (m, 2H), 1.74–1.06 (m, 10H), 0.87 (s, 3H), 0.81
(s, 3H), 0.74(s, 3H); 13C NMR (100 MHz, CDCl3) d 199.65, 199.36, 155.62,
147.32, 139.21, 135.47, 134.84, 107.94, 55.57, 54.41, 49.08, 48.91, 48.79, 48.70,
48.50, 42.00, 39.83, 39.15, 37.90, 33.61, 24.23, 23.67, 21.70, 19.34, 14.51; HRMS
(ESI): calcd 379.2632 (M+H)+; found 379.2637; melting point: 124–127 °C;
2920, 2849, 1676, 1457 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.01 (s, 1H), 5.43
;
(s,1H), 4.75 (s, 1H), 4.45 (s, 2H), 3.75 (d, J = 2.9 Hz, 1H), 2.80 (s, 1H), 2.31 (dd,
J = 15.7, 9.5 Hz, 1H), 2.03–1.96 (m, 1H), 1.90–1.80 (m, 2H), 1.79–1.66 (m, 2H),
1.60 (s, 3H), 1.58–1.41 (m, 3H), 1.32–1.12 (m, 3H), 0.89 (s, 3H), 0.87 (s, 3H),
0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) d 193.22, 156.06, 134.43, 122.50,
121.19, 65.80, 63.01, 60.39, 58.07, 50.08, 46.73, 42.22, 39.54, 36.21, 33.12,
33.00, 23.77, 21.97, 21.81, 21.54, 18.76, 13.79; HRMS (ESI): calcd 383.2187
(M+Na)+; found 383.2199; melting point: 174-178 °C; compound 28: IR
compound 17: IR (CHCl3) 2920, 2860, 1709, 1446 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) d 6.07 (s, 2H), 4.81 (d, J = 1.0 Hz, 1H), 4.40 (s, 1H), 3.44 (dq, J = 11.0,
3.5 Hz, 2H), 3.37 (s, 1H), 3.30 (s, 1H), 3.27 (s, 1H), 2.42–2.39 (m, 1H), 3.32 (dd,
J = 15.5, 11.0 Hz, 1H), 2.08–2.00 (m, 2H), 1.73–1.72 (m, 1H), 1.68–1.66 (m, 1H),
1.59 (s, 1H), 1.53–1.47 (m, 3H), 1.43–1.37 (m, 1H), 1.33–1.27 (m, 2H), 1.25–
1.21 (m, 1H), 1.09 (dd, J = 13.0, 2.5 Hz, 1H), 1.01-0.95 (m, 1H), 0.88 (s, 3H),
0.81(s, 3H), 0.76(s, 3H); 13C NMR (125 MHz, CDCl3) d 205.55, 205.28, 149.26,
136.62, 136.58, 106.58, 66.49, 62.79, 55.47, 51.37, 50.55, 49.93, 46.67, 43.42,
43.13, 42.01, 39.32, 39.16, 37.73, 33.58, 33.53, 24.17, 21.66, 20.01, 19.27, 14.56;
HRMS (ESI): calcd 417.2400 (M+Na)+; found 417.2407; Melting Point: 130–
(CHCl3) 3369, 2926, 2865, 1671, 1452 cmꢀ1 1H NMR (500 MHz, CD3OD) d
;
5.53–5.52 (m, 1H), 5.4 (s, 1H), 4.65 (br s, 2H), 4.40 (s, 1H), 4.31 (s, 1H), 4.23
(d, J = 13.9 Hz, 1H), 4.09 (d, J = 13.9 Hz, 1H), 3.37 (d, J = 2.8 Hz, 1H), 2.13 (d,
J = 15.0 Hz, 1H), 2.05–1.97 (m, 1H), 1.94–1.79 (m, 3H), 1.73 (s, 3H), 1.71–1.67
(m, 1H), 1.64–1.55 (m, 1H), 1.52–1.43 (m, 2H), 1.27–1.22(m, 2H), 1.08–1.00 (m,
1H), 0.93 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H); 13C NMR (125 MHz, CD3OD) d
138.02, 136.66, 124.91, 123.04, 68.27, 66.29, 63.19, 62.98, 60.97, 51.73, 43.63,
40.67, 37.72, 34.08, 33.82, 29.45, 24.97, 23.11, 22.41, 20.00, 14.30; HRMS (ESI):
calcd 385.2349 (M+Na)+; found 385.2357.
134 °C; compound 18: IR (CHCl3) 3386, 2953, 2926, 1709 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 6.07 (br s, 2H), 4.78 (s, 1H), 4.39 (s, 1H), 4.34 (d, J = 11.2 Hz,
1H), 3.78 (d, J = 14.0 Hz, 1H), 3.43 (s, 1H), 3.32 (s, 1H), 3.28 (s, 1H), 2.85 (d,
J = 4.5 Hz, 1H), 2.39–2.37 (m, 1H), 2.5–2.2 (m, 1H), 2.11–2.07 (m, 1H), 2.10–
1.94 (m, 2H), 1.75–1.4 (m, 7H), 1.35–1.25 (m, 2H), 1.22–1.13 (m, 1H), 1.10–1.04
(m, 1H), 0.88 (s, 3H), 0.80 (s, 3H), 0.7 (s, 3H); 13C NMR (100 MHz, CDCl3) d
205.74, 204.64, 148.95, 138.12, 137.89, 106.74, 68.18, 67.53, 62.50, 61.47,
55.48, 53.73, 51.23, 45.92, 44.53, 43.42, 41.98, 39.40, 39.13, 37.78, 33.59, 33.00,
24.16, 21.67, 19.90, 19.26, 14.55; HRMS (ESI): calcd 447.2506 (M+Na)+; found
8. For a discussion on face selectivity during Diels–Alder reactions, see: Mehta, G.;
Uma, R. Acc. Chem. Res. 2000, 33, 278–286.
9. Crystal data for 27: Single crystal X-ray diffraction data for 27 was collected on
Oxford CCD X-ray diffractometer (Yarnton, Oxford, UK) equipped with Cu-K
a
radiation (k = 1.54 Å) source. The data were reduced by SAINTPLUS; an
empirical absorption correction was applied using the package SADABS and
XPREP was used to determine the space group. The crystal structure was solved
by direct methods using SIR92 and refined by the full-matrix least-squares
method on F2 using SHELXL97. Crystal data: C22H32O4, M = 360.48, monoclinic,
P1 21/c 1, a = 22.3524(12), b = 7.5163(3), c = 12.0589(5) Å, V = 1988.76(16) Å3,
447.2513; compound 19: IR (CHCl3) 3342, 2926, 2865, 1704, 1643, 1463 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 6.33 (s, 1H), 6.13 (s, 1H), 4.77 (s, 1H), 4.64 (d,
J = 8.8 Hz, 1H), 4.42 (s, 1H), 4.06 (s, 1H), 3.94 (s, 1H), 3.82 (d, J = 8.8 Hz, 1H), 3.45
(s, 1H), 3.29 (s, 1H), 3.24 (s, 1H), 2.86 (br s, 1H), 2.51–2.50 (m, 1H), 2.40–2.38
(m, 1H), 2.16–2.11 (m, 1H), 2.02–1.96 (m, 2H), 1.74–1.68 (m, 2H), 1.68–1.48
(m, 4H), 1.37–1.25 (m, 2H), 1.23–1.09 (m, 2H), 0.95–1.07 (m, 1H), 0.88 (s, 3H),
Z = 4,
q
calcd = 1.204 mg/m3,
reflections
collected/unique = 6616/3539
[R(int) = 0.0228], R1 = 0.0739 and wR2 = 0.2090, CCDC no. 984116. An ORTEP
diagram of 27, drawn at 35% ellipsoidal probability, is shown below:

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S. Garai, G. Mehta / Tetrahedron Letters 55 (2014) 6252–6256
10. Crystal data for tri-p-bromobenzoate derivative of 28 was collected on a Bruker
AXS SMART APEX CCD diffractometer at 291 K using graphite monochromated
MoK radiation (k = 0.7107 Å). The data were reduced by SAINTPLUS; an
a
empirical absorption correction was applied using the package SADABS and
XPREP was used to determine the space group. The crystal structure was solved
by direct methods using SIR92 and refined by the full-matrix least-squares
method on F2 using SHELXL97. Crystal data: C44H44Br3O8, M = 940.52,
monoclinic, P2(1)/c, a = 15.6212(18), b = 10.6145(12), c = 26.395(3) Å,
V = 4228.3(8) Å3, Z = 4,
q
calcd = 1.477 g/cm3, 8713 reflections measured, 3786
unique (Rint = 0.0798), R1 = 0.0618 and wR2 = 0.1514, CCDC no. 1015321. An
ORTEP diagram of tri-p-bromobenzoate derivative of 28, drawn at 35%
ellipsoidal probability, is shown below: