Synthetic studies toward the cytotoxic norditerpene (+)-harringtonolide: Setting up key-stereogenic centers of the cyclohexane ring D

Article abstract of DOI:10.1016/j.tetlet.2011.04.101

The pivotal stereogenic centers of the asymmetric cycle D of (+)-harringtonolide were installed by functionalization of an enantiomerically pure IMDA cycloadduct, constructed from the chiral pool. The chiral 1,3-dioxane template used to direct the IMDA reaction was unraveled in an acidic medium, through spectacular hydrolysis of the acetal and concomitant lactone ring contraction. The central cyclohexene was selectively epoxidized either on the β- or on the α-side depending on the substitution pattern. The reactivity of several epoxide intermediates was challenged toward the construction of the oxygenated bridges of harringtonolide. We found one of them suitable for an access to another natural product, tetrodecamycin, which shares a similar substitution pattern as harringtonolide. Alternatively, functionalization led to set up key-stereocenters, en route to the asymmetric total synthesis of harringtonolide. The reactivity of the epoxide intermediates gave helpful insight for future work on this total synthesis.

Full text of DOI:10.1016/j.tetlet.2011.04.101

Tetrahedron Letters 52 (2011) 3447–3450
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Tetrahedron Letters
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Synthetic studies toward the cytotoxic norditerpene (+)-harringtonolide:
setting up key-stereogenic centers of the cyclohexane ring D
Hajer Abdelkafi a, Laurent Evanno a, Patrick Herson b, Bastien Nay a,
⇑
a Muséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54),
75005 Paris, France
b Institut Parisien de Chimie Moleculaire (IPCM), UMR CNRS 7201, Centre de Résolution de Structure, Université Pierre et Marie Curie-Paris 6, 4 place Jussieu,
75252 Paris cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The pivotal stereogenic centers of the asymmetric cycle D of (+)-harringtonolide were installed by func-
tionalization of an enantiomerically pure IMDA cycloadduct, constructed from the chiral pool. The chiral
1,3-dioxane template used to direct the IMDA reaction was unraveled in an acidic medium, through spec-
tacular hydrolysis of the acetal and concomitant lactone ring contraction. The central cyclohexene was
Received 28 February 2011
Revised 19 April 2011
Accepted 26 April 2011
Available online 5 May 2011
selectively epoxidized either on the b- or on the a-side depending on the substitution pattern. The reac-
tivity of several epoxide intermediates was challenged toward the construction of the oxygenated bridges
of harringtonolide. We found one of them suitable for an access to another natural product, tetrodecamy-
cin, which shares a similar substitution pattern as harringtonolide. Alternatively, functionalization led to
set up key-stereocenters, en route to the asymmetric total synthesis of harringtonolide. The reactivity of
the epoxide intermediates gave helpful insight for future work on this total synthesis.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Intramolecular Diels–Alder reactions
Pseudosymmetry
Lactone contraction
Epoxidation
We recently reported a detailed study on the synthesis of
naturally occurring cyclohexene rings using stereodirected intra-
molecular Diels–Alder (IMDA) reactions through asymmetric 1,3-
dioxane tethering.1 The method is particularly attractive in the
sense that it allows cycloaddition of a (E,Z)-diene and a fumarate
dienophile with high diasteroselectivities, through a chiral 1,3,9-
decatrienoate system. It has been used for the preparation of
important chiral intermediates in the total synthesis of natural
products, a work that is underway in our laboratory (Scheme 1).
We now report the functionalization of an important cycload-
duct arising from the IMDA reaction of a (E,Z)-diene substrate
(R1 = H, R2 = Me) toward the total synthesis of natural products in
the norditerpene series. Indeed, such a chiral cyclohexene interme-
diate can be predicted when looking at cycle D of the title com-
pound harringtonolide (1), isolated from the plum yew
The conversion of 2 into 1 was early reported, using lead tetraace-
tate oxidation.5 Later, Mander and co-workers reported the race-
mic total synthesis of 2 (a formal synthesis of 1).6 In their
synthesis, cycle D was installed from an advanced intermediate
using an aldol reaction. An elegant second generation strategy
was then reported by Mander and Sullivan in 2003, constructing
the racemic cycle D by an intermolecular Diels–Alder reaction be-
tween an indenone dienophile and an
a
-pyrone diene.7 More re-
cently, our contribution on the IMDA reaction using substrates
derived from the chiral pool provided a novel asymmetric entry to-
ward the chiral cycle D of the Cephalotaxus norditerpene series.
Herein, we report our work and observations on the functionaliza-
tion of this pivotal ring.1,8
The Diels–Alder substrate 3, bearing a stereodirecting 1,3-diox-
ane, was made in 9 steps from
D-glucose according to our previous
Cephalotaxus harringtonia,2 and of the parent hainanolidol
2
reports.1 The thermal IMDA cycloaddition of 3 in toluene and in the
(Fig. 1).3 Compound 1 is strongly cytotoxic with a half inhibitory
concentration (IC50) of 43 nM.4 It is also phytotoxic,2 which proba-
bly reflects an important defensive function for the plant in nature.
This compound holds a central and highly substituted cyclohexane
ring (cycle D) which bears most of the asymmetric centers of the
natural product.
CO2Et
CO2Et
O
H
O
H
H
R1
R2
H3C
O
O
H
Δ, BHT
R1
O
O
R2
toluene
Few studies have been reported toward the total syntheses of 1
and 2, and none of them were undertaken in the asymmetric series.
H
ref. 1
O
O
H
endo-boat TS
Scheme 1. The chiral 1,3-dioxane templated IMDA reaction.
major product
⇑
Corresponding author. Tel.: +33 1 40 79 56 09; fax: +33 1 40 79 31 35.
E-mail address: bnay@mnhn.fr (B. Nay).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.101

3448
H. Abdelkafi et al. / Tetrahedron Letters 52 (2011) 3447–3450
CO2Et
CO2Et
O
R
CO2Et
CH3
D
H
H
HO
TBDPSO
TBSO
TBDPSO
CH3
CH3
a,b
O
O
HO
O
O
O
O
O
H
HO
9a
HO
D
D
a pivotal
pseudo-C2-axis
10
cyclohexene ring
for the synthesis of
the Cephalotaxus
norditerpenes
H
H
H3C
harringtonolide (1)
H3C
hainanolidol (2)
δ−
TBSO
O
H
O
O
δ+
TBDPSO
c
CH3
CO2Et
Figure 1. The Cephalotaxus norditerpenes (1 and 2) and structure of a possible
9a
synthetic intermediate toward the ring D.
O
CO2Et
O
H
O
O
H
CO2Et
O
H
CO2Et
H
H
H
H
1
H
H
H
H
TBSO
TBDPSO
O
CO2Et
O
O
TBSO
2
O
a
+
OH
1'
+
TBDPSO 2'
H
HO
OH
O
O
O
O
O
HO
OH
12
11
d
OTBS
OH
4a
4b
3
(from D-glucose)
OH
TBDPSO
CO2Et
CO2Et
O
O
H
H
H
O
12
O
O
O
b
4a
+
Scheme 4. Effect of the b-hydroxyl group on the epoxidation outcome of the
pseudosymmetric cyclohexene 9a. Reagents and Conditions: (a) TBSCl, imidazole,
DMAP, CH2Cl2 (50%); (b) DMDO, CH2Cl2 (100%); (c) PTSAꢁH2O, toluene, 80 °C, 2 h
(11: 46%, 12: 25%); (d) PTSAꢁH2O, toluene, 80 °C, 1.5 h (70%).
H
OH
O
HO
O
6
5
c
Diol 6 was cleaved in the presence of sodium periodate before
reduction and silyl-protection of the resulting primary alcohol
(Scheme 3), affording bicyclic compounds 7a and 7b in 98% and
Scheme 2. Asymmetric synthesis of the pivotal cyclohexene ring D of harrington-
olide (1). Reagents and Conditions: (a) BHT (0.2 equiv), toluene, 225 °C (sealed
tube), 85 h (4a: 66%; 4b: 21%); (b) TFA/H2O (1:1), 80 °C (5: 17%, a:b = 3:1; 6: 67%);
72% yields, respectively, over the three steps. L
-SelectrideÒ reduc-
(c) 1 M aq HCl, acetone (1:1), rt (85%).
tion of the lactone provided the corresponding lactols 8a and 8b
in 75% and 99% yields. Unfortunately, attempts for Wittig methyl-
enation of the lactols only resulted in unwanted reactions or deg-
radation. Instead, conversion into the corresponding diols 9a and
9b was undertaken in the presence of NaBH4 in MeOH, giving the
expected products in 87% and 95% yields, respectively.
After selective silylation of the primary alcohol of diol 9a, the
quantitative epoxidation of the cyclohexene ring in the presence
of DMDO9 provided b-epoxide 10 with complete stereocontrol
(Scheme 4). Since the cyclohexene ring holds a pseudo-C2-symme-
try axis, we were first particularly puzzled by the outcome of the
epoxidation on such a system. The presence of two bulky silyl pro-
tecting groups on the b-face was expected to direct the epoxidation
presence of BHT (0.2 equiv) afforded the endo cycloadduct 4a in
66% yields (Scheme 2). It was accompanied with 21% of the exo iso-
mer 4b (3:1 stereoisomeric ratio). Despite the (E,Z) geometry of 3,
this reaction was particularly efficient and was performed on a five
gram-scale. Then, unraveling of the dioxane moiety of 4a was
undertaken by an acidic treatment in TFA/H2O at 80 °C, leading
to acetal hydrolysis and concomitant contraction of the lactone
ring. In fact diol 6 was obtained in 67% yields, along with a 3:1
a/b-mixture of dioxolane 5 in 17% yields. Compound 5 was recy-
cled by hydrolytic treatment in aqueous HCl–acetone to recover
6 in 85% yield.
on the a-face. Yet the remaining alcohol had a much more impor-
tant effect on this reaction, leading to complete b-selectivity, pre-
sumably through hydrogen bonding of DMDO (box in Scheme
4).10 Indeed, when the secondary alcohol of 9a was acetylated,
the epoxidation was not stereoselective under the same conditions
(a/b = 1:1), which was consistent with pseudo-symmetry of both
faces. Eventually, when treating b-epoxide 10 with PTSA in wet tol-
CO2Et
CO2Et
O
O
H
H
H
O
O
a-c
H
OH
RO
7a
HO
: R = TBDPS
7b: R = TBS
6
uene, diol 11 was obtained. Final transannular cyclization of the
CO2Et
CO2Et
HO
O
H
H
O
HO
RO
d
e
O
O
O
H
H
H
H
RO
HO
O
O
8a
9a
: R = TBDPS
: R = TBDPS
8b: R = TBS
9b: R = TBS
HO
OH
13
tetrodecamycin (14)
Scheme 3. Synthesis of diols 9a and 9b. Reagents and Conditions: (a) NaIO4, MeOH,
H2O, rt; (b) NaBH4, MeOH, 0 °C, rt; (c) TBDPSCl (7a) or TBSCl (7b), imidazole, DMAP,
CH2Cl2 (overall yields: 7a: 98%; 7b: 72%); (d)
L
-Selectride, THF, ꢀ78 °C (8a: 75%; 8b:
Figure 2. Structure of tetrodecamycin (14) and of Paintner0s intermediate (13)
toward 14.
99%); (e) NaBH4, MeOH (9a: 87%; 9b: 95%).

H. Abdelkafi et al. / Tetrahedron Letters 52 (2011) 3447–3450
CO2Et BzO CO2Et
3449
BzO
CO2Et
BzO
O
CO2Et
OBz CO2Et
H
H
H
H
H
H
H
1
6
2
O
BzO
c
a,b
a
BzO
TBSO
9b
+
16
5 H
3
H
H
CO2Et
H
H
H
4
O
1'
HO
20
MsO
2'
H
15
16
17
HO
21 (46%)
(0%)
BF3 OEt2
d
CO2Et
OBz CO2Et
O
BF3 OEt2
BzO
CO2Et
O
BzO
O
CO2Et
H
H
H
BzO
F3BO
F3B
+
O
H
O
18
19
(X-ray)
ratio 5:2
Scheme 6. Rearrangement of the epoxide 16 under Lewis acidic conditions.
Reagents and conditions: (a) TMSC„CLi, BF3ꢁOEt2, THF, ꢀ78 °C.
Scheme 5. Synthesis of the epoxide 16, bearing the key-stereogenic center of
harringtonolide. Reagents and Conditions: (a) BzCl, pyridine, CH2Cl2, reflux (75%);
(b) MsCl, pyridine, CH2Cl2, reflux (93%); (c) TBAF, CH2Cl2, rt (16: 81%; 17: 10%); (d)
DMDO, CH2Cl2, acetone, 0 °C then rt (100%, b:
(90%, b: = 5:2).
a = 5:2) or mCPBA, NaHCO3, CH2Cl2, rt
of the a-face compared to the b-face. The a-epoxide 19 gave fortu-
a
nately diffractable crystals suitable for X-ray crystallography, thus
confirming the stereochemistry (Fig. 3).15,16 With these epoxides in
hand, we were ready for cyclization attempts toward the oxygen-
ated bridges of harringtonolide (1).
a
-hydroxyl with the ester furnished the bridged lactone 12, whose
structure was determined by 2D NMR.11 Although the lactone
bridge in 12 was not correctly positioned compared to harrington-
olide 1, we found it very close to the one made by Paintner et al.
(13)12 for their synthesis of tetrodecamycin (14),13 sharing similar
substitution pattern as our target compound (Fig. 2).
Preliminary trials for opening of the primary epoxide moiety
were undertaken. When performed on epoxide 16 in the presence
of various nucleophiles, especially alkylating reagents to build the
skeleton of 1, degradation was observed in most cases, except
when the reaction was carried out in the presence of lithium trim-
ethylsilylacetylide and BF3ꢁOEt2 in THF. In this case, we were sur-
prised to isolate compound 21 in 46% yields, instead of the
expected product 20 (Scheme 6). 2D NMR experiments revealed
a highly strained tricyclic cage structure and the absence of acety-
lide incorporation.17 A possible mechanism for the formation of 21
is shown in Scheme 6.
The primary epoxide of compound 19, a potential precursor of
the oxygenated system of 1, was opened in the presence of aque-
ous KBr and acetic acid in THF, leading to the epoxy-bromohydrine
22 in 94% yield (Scheme 7). Attempts of cyclization in the presence
of anhydrous PTSA gave small amounts of the oxetane derivative
23 (25%),18 resulting from 4-exo-tet cyclization, but no trace of
the desired 5-membered isomer 24, as predicted by the Baldwin
rules. In this case, we did not observe ring closure of the lactone
ring as for compound 11. These results give interesting insights
into the reactivity of such epoxide systems and suggest that an
alternative strategy will have to be used for the synthesis of the
oxygenated bridges of harringtonolide (1).
Alternatively, esterification of the primary alcohol of 9b and
mesylation of the secondary one provided intermediate 15 in
70% yields (Scheme 5). The homoallylic epoxide 16 was obtained
in 83% yield through deprotection of the TBS group and subsequent
mesylate substitution with inversion of configuration as required,
with regard to the stereochemistry of 1.14 Product 16 was accom-
panied by 10% of dienol 17 when the reaction was performed in
CH2Cl2, while greater amounts of this undesired product were ob-
served in THF (up to 40%).
Remarkably, compound 16 holds most of the key-stereogenic
centers of harringtonolide (1). Therefore, functionalization of this
intermediate may provide interesting intermediates for the asym-
metric synthesis of Cephalotaxus norditerpenes. We found that
DMDO epoxidation of 16 afforded a 5:2 mixture of stereoisomers
in favor of the b-epoxide 18. Similar results were obtained using
mCPBA in the presence of NaHCO3. However, in these cases, since
no hydroxyl group can direct the epoxidation (as for 9a), we sug-
gest that this selectivity may arise from higher steric hindrance
In conclusion, we have developed a synthetic route allowing for
setting up key-stereogenic centers of the cytotoxic norditerpene
harringtonolide (1). Ring D was made by an asymmetric IMDA
reaction leading to a cyclohexene ring (4a) bearing appropriate
substituents toward the natural product. Functionalization of 4a
led to highly substituted cyclohexane rings (i.e., 11, 18 or 19).
BzO
O
CO2Et
O
H
H
BzO
H
CO2Et
BzO
HO
CO2Et
O
H
H
a
b
19
19
Br
OH
Br
H
O
22
23
(25%)
BzO
H
OBz
OH
O
5-endo-tet
(disfavored)
Br
Br
CO2Et
OH
E
O
H
4-exo-tet (favored)
E = CO2Et
24
(0%)
Scheme 7. A cyclization attempt toward the oxygenated bridges of harringtonolide.
Reagents and Conditions: (a) sat. aq KBr solution, AcOH, THF (1:2:1), rt (94%); (b)
PTSA (0.1 equiv), toluene, 80 °C.
Figure 3. ORTEP drawing of compound 19 showing the right stereochemistry of
epoxides.

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H. Abdelkafi et al. / Tetrahedron Letters 52 (2011) 3447–3450
10.0 Hz, 1H, 10-H), 3.07 (dd, J = 6.0, 10.1 Hz, 1H, 1-H), 4.15 (q, J = 7.1 Hz, 2H,
CH3CH2), 4.63 (d, J = 5.7 Hz, 2H, 6-CH2OBz), 5.53 (ddd, J = 1.8, 4.5, 10.1 Hz, 1H,
4-H), 5.80 (ddd, J = 1.8, 4.2, 10.0 Hz, 3-H) 7.44 (m, 2H, Bz-H), 7.56 (m, 1H, Bz-H),
8.04 ppm (m, 2H, Bz-H); 13C NMR (75 MHz, CDCl3) d: 14.2 (CH3CH2), 16.8 (2-
CH3), 31.0 (C-2), 33.0 (C-6), 39.9 (C-5), 42.8 (C-1), 45.1 (C-20), 51.4 (C-10), 60.3
(CH3CH2), 64.3 (CH2OBz), 123.3 (C-4), 128.3 (Ph), 129.5 (Ph), 130.3 (Ph), 132.8
(Ph), 133.9 (C-3), 166.2 (PhCO2), 172.7 ppm (CO2Et); HR-MS (ESI+) m/z: calcd
During this work, we obtained intermediates (i.e., 11 and 12)
which may be of particular interest for the asymmetric total syn-
thesis of other natural products such as tetrodecamycin (14). The
reactivity of the epoxide intermediates 16 and 22 was described.
Especially, 22 showed preference for 4-exo-tet cyclization, leading
to oxetane 23. Our efforts are continuing in order to build the
appropriate oxygenated bridges of 1 and adjacent carbocycles.
for C20H25O5 [M+H+]: 345.1702; found: 345.1700; IR (KBr pellet)
m: 3444, 3023,
2963, 2924, 2874, 2852, 1725, 1452, 1387, 1375, 1314, 1277, 1180, 1115, 1071,
1029, 714 cm–1; ½a D25
ꢀ277 (c = 0.90, MeOH).
ꢂ
15. Compound 19: 1H NMR (300 MHz, CDCl3) d: 1.11 (d, J = 7.2 Hz, 3H, 2-CH3), 1.21
(t, J = 7.0 Hz, 3H, CH3CH2), 2.38 (m, 1H, 5-H), 2.63 (m, 2H, 6-H and 2-H), 2.81 (t,
J = 4.3 Hz, 1H, 20-H), 2.95 (m, 2H, 1-H and 20-H), 3.08 (m, 1H, 3-H), 3.22 (m, 2H,
4-H and 10-H), 4.11 (q, J = 7.0 Hz, 2H, CH3CH2), 4.57 (m, 2H, CH2OBz), 7.46 (m,
2H, Ph), 7.56 (m, 1H, Ph), 8.06 ppm (m, 2H, Ph); 13C NMR (75 MHz, CDCl3) d:
14.2 (CH3CH2), 13.2 (2-CH3), 26.3 (C-2), 30.0 (C-6), 39.9 (C-5), 41.6 (C-1), 45.0
(C-20), 49.2 (C-10), 54.0 (C-4), 55.6 (C-3), 60.5 (CH3CH2), 64.4 (CH2OBz), 128.3
(Ph), 129.6 (Ph), 130.3 (Ph), 132.8 (Ph), 166.0 (PhCO2), 172.7 ppm (CO2Et); HR-
Acknowledgments
This work and the PhD grant for H.A. have been funded by the
Agence Nationale de la Recherche (grant ANR-09-JCJC-0085-01)
which is gratefully acknowledged. The Ministère de la Recherche
is acknowledged for providing a PhD grant to L.E.
MS (ESI+) m/z: calcd for C20H25O6 [M+H+]: 361,1651; found: 361,1651; ½a 2D5
ꢂ
ꢀ77 (c = 0.63, CH3OH).
References and notes
16. Single crystal X-ray analysis of compound 19: Intensity data were collected on an
Bruker APEX2 four-circle diffractometer by using a graphite monochromated
Mo-Ka radiation. The structure was solved by direct methods with SHELXS-86
1. Abdelkafi, H.; Evanno, L.; Deville, A.; Dubost, L.; Chiaroni, A.; Nay, B. Eur. J. Org.
Chem. 2011, 2789–2800.
2. Buta, J. G.; Flippen, J. L.; Lusby, W. R. J. Org. Chem. 1978, 43, 1002–1003.
3. (a) Xue, Z.; Sun, N. J.; Liang, X. T. Yao Hsueh Hsueh Pao 1982, 17, 236–237. Chem.
Abstr. 1982:177999r; (b) Du, J.; Chiu, M. H.; Nie, R. L. J. Nat. Prod. 1999, 62,
1664–1665.
(Sheldrick, G. M. (1986). SHELXS86. Program for the solution of crystal
structures. Univ. of Gottingen, Federal Republic of Germany) refined by full
least-squares on F2 and completed with CRYSTALS (Watkin, D. J.; Prout, C. K.;
Carruthers, J. R.; Betteridge, P. W.; Cooper, R. I. (2001) CRYSTALS Issue 11.
Chemical Crystallography Laboratory, Oxford, UK). All non-H atoms were refined
with anisotropic displacement parameters and H atoms were simply introduced
at calculatedpositions (ridingmodelwith anoverallisotropic temperaturefactor
of 0.048). Crystallographic data of compound: C20H24O6, M = 360.41, monoclinic,
4. Evanno, L.; Jossang, A.; Nguyen-Pouplin, J.; Delaroche, D.; Seuleiman, M.; Bodo,
B.; Nay, B. Planta Medica 2008, 870–872.
5. Xue, X.; Sun, N.; Liang, X. Acta Pharm. Sinica. 1982, 17, 236.
6. (a) Rogers, D. H.; Morris, J. C.; Roden, F. S.; Frey, B.; King, G. R.; Russkamp, F. W.;
Bell, R. A.; Mander, L. W. Pure Appl. Chem. 1996, 68, 515–522; (b) Frey, B.; Wells,
A. P.; Rogers, D. H.; Mander, L. N. J. Am. Chem. Soc. 1998, 120, 1914–1915; (c)
Frey, B.; Wells, A. P.; Roden, F.; Au, T. D.; Hockless, D. C.; Willis, A. C. L.; Mander,
W. Aust. J. Chem. 2000, 53, 819–830.
7. (a) Mander, L. N.; O’Sullivan, T. P. Synlett 2003, 1367–1369; (b) O’Sullivan, T. P.;
Zhang, H.; Mander, L. N. Org. Biomol. Chem. 2007, 5, 2627–2635.
8. Evanno, L.; Deville, A.; Dubost, L.; Chiaroni, A.; Bodo, B.; Nay, B. Tetrahedron Lett.
2007, 48, 2893–2996.
space group
V = 927.32(17) Å3, Z = 2, Dcalcd = 1.29 g cmꢀ3, = 0.71073 Å, T = 200(2) K, crystal
size = 0.09 0.15
0.17 mm3, 9009 reflections measured, 2580 unique
(Rint = 0.018). The final reliability factors are R[I>2 (I)] = 0.034 and
P
21 a = 9.6487(10), b = 7.9205(8), c = 12.4344(14) Å,
ꢁ
ꢁ
r
WR2(all) = 0.093. Crystallographic data (excluding structure factors) for the
structure of 19 have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 814810. Copies of the data
can be obtainedfree of charge, on application toCCDC, 12 Union Road, Cambridge
CB2 IEZ, UK fax: + 44 (0) 1233 336033 or e-mail: deposit@ccdc.cam.ac.uk 22. H.D.
Flack. Acta Cryst (1983). A39, 876–881.
9. (a) Murray, R. W.; Singh, M. Org. Synth. 1998, 9, 288; Murray, R. W. Chem. Rev.
1989, 89, 1187–1201.
17. Compound 21: 1H NMR (400 MHz, CDCl3) d: 0.96 (d, J = 7.2 Hz, 3H, CH3), 1.20
(m, 4H, 5-H, CH3CH2), 1.31 (m, 2H, 4-H 10-H), 1.91 (m, 1H, 2-H), 2.38 (dd, J = 3.0,
10.7 Hz, 1H, 1-H), 2.84 (m, 1H, 6-H), 3.23 (dd, J = 7.4, 11.2 Hz, 1H, 20-H), 3.63
(dd, J = 5.2, 11.0 Hz, 1H, 20-H), 4.11 (m, 3H, CH3CH2, 3-H), 4.30 (dd, J = 5.1,
10.7 Hz, 1H, BzOCH2), 4.39 (dd, J = 7.6, 10.7 Hz, 1H, BzOCH2), 7.45 (t, J = 7.8 Hz,
2H, PhH), 7.57 (m, PhH), 8.05 (m, 2H, PhH); 13C NMR (75 MHz, CDCl3) d: 13.1
(CH3), 14.2 (CH3CH2), 18.3 (C-4), 19.3 (C-5), 21.1 (C-10), 29.3 (C-6), 36.6 (C-2),
39.7 (C-1), 60.5 (CH3CH2), 66.4 (C-20), 67.6 (BzOCH2), 67.7 (C-3), 128.4 (Ph),
129.6 (Ph), 130.1 (ipso Ph), 133.0 (Ph), 166.6 (PhCO), 174.1 (CO2Et); HR-MS
(ESI+) m/z: calcd for C20H25O5 [M+H+]: 345.1702; found: 345.1695; IR (film on
10. (a) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. Tetrahedron Lett.
1995, 36, 2437–2440; (b) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51, 13039–
13044; (c) Adam, W.; Smerz, A. K. J. Org. Chem. 1996, 61, 3506–3510.
11. Compound 12: 1H NMR (400 MHz, CDCl3) d: 0.07 (d, J = 2.6 Hz, 6H, Si(CH3)2),
0.98 (s, 9H, SiC(CH3)3), 1.06-1.10 (m, 12H, SiC(CH3)3, 2-CH3), 1.97 (m, 1H, 6-H),
2.08 (m, 1H, 2-H), 2.50 (d, J = 3.5 Hz, 1H, 5-H), 2.83 (q, J = 6.4 Hz, 1H, 1-H), 3.76
(m, 3H, CH2OTBS, 2’a-H), 3.95 (m, 2H, 1’-H, 2’b-H), 4.37 (m, 2H, 3-H, 4-H), 7.44
(m, 6H, Ph2Si), 7.66 ppm (m, 4H, Ph2Si); 13C NMR (75 MHz, CDCl3) d: –5.5
(Si(CH3)2), 16.4 (2-CH3), 18.1 (SiC(CH3)3), 19.2 (Ph2SiC(CH3)3), 25.7 (SiC(CH3)3),
26.8 (Ph2SiC(CH3)3), 30.3 (C-2), 36.7 (C-5), 49.9 (C-6), 48.0 (C-1), 63.0
(CH2OTBS), 65.9 (CH2OTBDPS), 67.5 (C-4), 71.6 (C-1’), 83.7 (C-3), 127.9
(Ph2Si), 130.0 (Ph2Si), 132.7 (Ph2Si), 135.5 (Ph2Si), 178.7 ppm (CO2); HR-MS
(ESI+) m/z: calcd for C33H51O6Si2 [M+H+]: 599.3224; found: 599.3227; IR (film
NaCl)
ꢀ16 (c = 0.6, MeOH).
m ;
: 2963, 2926, 2874, 1734, 1629, 1458, 1288, 1179, 1086, 1030 cmꢀ1
½ ꢂ
a 2D5
18. Compound 23: 1H NMR (400 MHz, CDCl3) d: 1.27 (m, 6H, 2-CH3, CH3CH2), 2.18
(m, 1H, 2-H), 2.50 (ddd, 1H, J = 4.9, 9.6, 11.9 Hz, 1H, 5-H), 2.79 (m, 1H, 6-H),
2.97 (dd, J = 1.1, 5.1 Hz, 1H, 1-H), 3.73 (dd, J = 6.2, 9.2 Hz, 1H, BrCH2), 3.81 (dd,
J = 10.0, 12.0 Hz, 1H, 4-H), 4.18 (m, 3H, BrCH2, CH3CH2), 4.39 (dd, J = 7.7,
11.5 Hz, 1H, BzOCH2), 4.49 (dd, J = 10.0, 11.0 Hz, 1H, 3-H), 4.56 (dd, J = 5.4,
11.5 Hz, 1H, BzOCH2), 4.62 (ddd, J = 6.2, 7.6, 9.6 Hz, 1H, 10-H), 7.49 (m, 2H,
PhH), 7.62 (m, 1H, PhH), 8.04 (m, 2H, PhH); 13C NMR (75 MHz, CDCl3) d: 14.2
(CH3CH2), 17.2 (CH3), 35.6 (C-6), 37.0 (C-2), 49.7 (C-1), 50.1 (C-5), 57.8 (C-3),
60.9 (CH3CH2), 63.0 (BzOCH2), 71.6 (C-10), 73.6 (C-20), 81.5 (C-4), 128.6 (Ph),
129.6 (Ph), 130.7 (ipso Ph), 133.5 (Ph), 166.4 (PhCO), 173.6 (CO2Et); HR-MS
(ESI+) m/z: calcd for C20H26BrO6 [M+H+]: 441.0907; found: 441.1086; IR (film
on NaCl) m: 3390, 2924, 2854, 1778, 1666, 1462, 1377, 1361, 1327, 1211, 1257,
1195, 1111, 1080, 1037, 1006, 972, 925, 837, 740, 702 cmꢀ1; ½a D25
ꢀ4 (c = 0.2,
ꢂ
CHCl3).
12. Paintner, F. F.; Bauschke, G.; Polborn, K. Tetrahedron Lett. 2003, 44, 2549–2552.
13. (a) Tsuchida, T.; Sawa, R.; Iinuma, H.; Nishida, C.; Kinoshita, N.; Takahashi, Y.;
Naganawa, H. J. Antibiot. 1994, 47, 386–388; (b) Tsuchida, T.; Iinuma, H.; Sawa,
R.; Takahashi, Y.; Nakamura, H.; Nakamura, K. T.; Sawa, T.; Naganawa, H.;
Takeuchi, T. J. Antibiot. 1995, 48, 1110–1114.
14. Compound 16: 1H NMR (400 MHz, CDCl3) d: 1.03 (d, J = 7.2 Hz, 3H, 2-CH3), 1.24
(t, J = 7.1 Hz, 3H, CH3CH2), 2.38 (m, 1H, 5-H), 2.53 (dd, J = 2.7, 5.0 Hz, 1H, 2’-H),
2.68 (m, 2H, 2-H, 6-H), 2.73 (dd, J = 4.0, 5.0 Hz, 1H, 20-H), 2.96 (ddd, J = 2.7, 4.0,
on NaCl)
m: 3425, 2924, 2852, 1724, 1630, 1452, 1273, 1176, 1113, 1026,
713 cmꢀ1
.