Synthesis of macrocyclic scaffolds suitable for diversity-oriented synthesis of macrolides

Article abstract of DOI:10.1016/j.tet.2009.07.088

Synthesis of macrocyclic glycal-based scaffolds for diversity-oriented synthesis was studied and demonstrated using macrocyclic enyne ring-closing metathesis. The roles of ring size, alkyne substitution, and orientation relative to the glycal were studied. In all cases, the cyclization showed preference for the thermodynamically favored endo-mode of closure and a trans-double bond at the ring-closure site, leaving macrocyclic scaffolds all containing multiple orthogonal functional groups available for further diversification.

Full text of DOI:10.1016/j.tet.2009.07.088

Tetrahedron 65 (2009) 8132–8138
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of macrocyclic scaffolds suitable for diversity-oriented
synthesis of macrolides
*
Michael E. Grimwood, Henrik C. Hansen
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 April 2009
Received in revised form 28 July 2009
Accepted 29 July 2009
Available online 6 August 2009
Synthesis of macrocyclic glycal-based scaffolds for diversity-oriented synthesis was studied and dem-
onstrated using macrocyclic enyne ring-closing metathesis. The roles of ring size, alkyne substitution,
and orientation relative to the glycal were studied. In all cases, the cyclization showed preference for the
thermodynamically favored endo-mode of closure and a trans-double bond at the ring-closure site,
leaving macrocyclic scaffolds all containing multiple orthogonal functional groups available for further
diversification.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Genomics and proteomics have created a tremendous need for
diverse and novel organic molecules that can be used to identify
and study the functions of uncharacterized proteins and their in-
volvement in diseases.1 diversity-oriented synthesis (DOS)2 is
a unique tool that allows for the generation of many structurally
diverse and complex molecules applicable for the interrogation of
biological systems. One of the key elements of successful DOS is
efficient use of chemical reactions to increase diversity and com-
plexity as the library evolves.2a,3 To reduce the number of steps
required to build up the core scaffolds, priority is given to reactions
where the products, without further manipulation, may serve as
starting materials for the next reactions. diversity-oriented syn-
thesis of macrocycles4 has not received the same amount of at-
tention as the synthesis of smaller and traditionally more drug-like
compounds. However, in nature macrocycles have many biological
functions, and serve as an excellent source of molecules for the
interrogation of biological systems.5 Here, we report the in-
vestigation and development of methodology for the synthesis of
macrocyclic glycal-based scaffolds suitable for DOS.4a,b,6 We focus
on macrocyclic enyne ring-closing metathesis7 as the core reaction,
and report the selective synthesis of 12- to 18-membered macro-
cycles, containing three or more orthogonal functional groups for
further diversification.
2.1. Synthesis of macrocyclic precursors
The desired glucal building blocks were obtained from in-
expensive and commercially available tri-O-acetyl-
large gram quantities by a Ferrier reaction (Scheme 1).8 The gly-
cosylated alcohols were obtained in a ratio of 9:1 of and the
pure diastereomer was isolated by re-crystallization. The depro-
D-glucal (1) in
a/b
a
tection to 2 and 3 proceeded in near quantitative yields, leaving the
desired diols in excellent overall yields. The alkylation of the diol
served as the first step of diversification. To facilitate selective al-
kylation of the 4-position, the primary alcohol was protected as
a TBS ether (Scheme 2).9 The remaining secondary alcohol was
alkylated under standard conditions with alkyl bromides contain-
ing either a double or triple bond. The desired products (5, 6, and 7)
were obtained in good yield following deprotection of the TBS
ether. Alternatively, giving access to the 6-O-alkyl precursors, the
primary alcohol was selectively alkylated (Scheme 2) via the cor-
responding tin acetal. The 6-O-alkylated precursors (8, 9, and 10)
were isolated after chromatography.
OAc
OH
(i) ROH,
O
BF3.OEt2, CH2Cl2
(ii) NaOMe/MeOH
O
O
R
AcO
HO
OAc
2 R = CH2Ph; 69%
3 R = CH2CCH; 84%
1
* Corresponding author at present address: Resverlogix Corp., 279 Midpark Way
SE, Calgary, Alberta T2X 1M2, Canada. Tel.: þ1 403 254 9252; fax: þ1 403 256 8495.
E-mail address: henrik@resverlogix.com (H.C. Hansen).
Scheme 1. Synthesis of glucal building blocks.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.088

M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
8133
OTBS
positioning of the alkyne relative to the glycal core, as well as to
identify reaction conditions suitable for the synthesis of these at-
tractive macrocylic scaffolds for DOS. In all cases, we found that the
use of Grubbs’ second generation catalyst10 was superior to the first
generation catalyst. The best reaction conditions were 20 mol %
catalyst and an enyne concentration of 1 mM under an ethylene
atmosphere.11
O
OBn
TBS-Cl, DIEA
DMAP, CH2Cl2
(i) NaH, R-Br, THF
(ii) TBAF
2
HO
4; 94%
OH
5 R = CH2CHCH2; 81%
6 R = CH2CCH; 79%
7 R = CH2CCCH3; 87%
O
OBn
In agreement with the proposed pathway7a for enyne metath-
esis (Scheme 4), we found that in the presence of ethylene the
cyclization goes through the cross metathesis intermediate (B),
which then undergoes RCM to the final product(s) (C and/or D).12 In
the presence of ethylene, an equilibrium between the ring closed
diene (C and/or D) and the triene (B) should favor the formation of
the thermodynamically favored product with an E-double bond.
The exo/endo selectivity of the macrocyclic RCM was expected to be
a function of ring size, where larger rings prefer the endo-mode of
closure.
R
O
OR
O
OBn
(i) Bu2SnO, PhMe, Dean-Stark
(ii) R-Br, Bu4NBr, PhMe
2
HO
8 R = CH2CHCH2; 90%
9 R = CH2CCH; 50%
10 R = CH2CCCH3; 46%
Scheme 2. Diol alkylation. First step of diversification.
fast
Acylation of the alcohols (5–10) served as the second step of
diversification. To exemplify the methodology and to study the
macrocyclization, six carboxylic acids were employed. Each carb-
oxylic acid had different lengths and contained either a double or
triple bond. The acylations proceeded in excellent yields for both
the primary and secondary alcohols (Scheme 3).
cross metathesis
n
n
H2C CH2
A
B
slow,
RCM
direct RCM
O
OBn
n
OH
n+1
endo
Scheme 4. RCM pathway.
and/or
O
C
n
D
O
HO
exo
9
EDCI, DIEA, DMAP, MeCN
O
OBn
HO
O
O
2.3. Ring-closure with unsubstituted alkynesd12-membered
rings
6
O
OBn
O
OBn
or
O
O
n
O
Four different cyclic enynes (11, 16, 21, 22) were used to study
macrocyclic enyne RCM on a glucal scaffold. For 11, 16, 21, and 22,
differing in the position of the alkyne and alkene relative to the
glucal, the reaction proceeded in good overall yield with complete
consumption of starting material and without trace of the corre-
sponding tetraenes. For compound 11, the endo product was formed
with high selectivity (24:1), whereas compounds 16, 21, and 22
exclusively gave the endo products (Fig. 2), demonstrating that for
O
n
16 n = 2; 86%
17 n = 3; 81%
18 n = 4; 91%
19 n = 6; 94%
20 n = 8; 90%
11 n = 2; 87%
12 n = 3; 90%
13 n = 4; 91%
14 n = 6; 85%
15 n = 8; 85%
O
Scheme 3. Acylation. Second step of diversification.
Following similar methodology four additional precursors (21–
24) were synthesized (Fig. 1), allowing us to study the positioning
of the alkyne as well as the significance of alkyne substitution.
O
OBn
O
OBn
O
O
O
+
O
O
O
OBn
O
OBn
O
O
O
O
O
O
O
From 11: 25 (62%) endo:exo 24:1
26 (~2.5%)
21
22
O
O
O
OBn
O
OBn
O
OBn
O
O
OBn
O
O
O
O
O
O
O
28 (35%);
27 (74%);
from 16
O
from 21
23
24
O
O
O
OBn
Figure 1. Additional precursors used to study macrocyclic enyne RCM.
O
O
2.2. Investigation of macrocyclization via enyne RCM
29 (65%);
from 22
The 14 precursors (11–24) for macrocyclic enyne RCM were used
to study the roles of ring size, alkyne substitution pattern, and
Figure 2. Macrocyclic enyne RCM to 12-membered rings with terminal alkynes.13

8134
M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
macrocyclic ring systems (ꢀ12) the position of the reacting part-
ners plays a minor role in the outcome of the final ring closed
product (Scheme 4). For medium rings (9–11), this is likely to play
a bigger role. In all cases only the trans-double bond was observed,
which is in agreement with the use of ethylene atmosphere.7a In all
cases, the desired products contain orthogonal functional groups
useful for further diversification.
2.4. Ring-closure with substituted alkynesd12-membered
rings
As expected, the cyclization with substituted alkynes (23 and
24) proved to be more complex than with the corresponding
unsubstituted alkynes. Like others,7d we found that there was no
selectivity between the endo and exo modes of closure. However, in
our hands and in contrast to the literature,7a,7d we did not observe
higher yields for substituted alkynes compared to their unsub-
stituted counterparts. In each case studied (23 and 24), we obtained
a mixture of the desired product and the tetraene. Prolonging the
reaction time led to extensive decomposition.
O
O
O
OBn
O
OBn
O
O
O
O
27
exo-27
Figure 3. HMBC for compound 27.
2.5. Ring-closure with unsubstituted alkynesd13- to 18-
membered rings
3. Conclusions
Eight monocyclic enynes (12–15 and 17–20) were used to study
the formation of 13- to 18-membered rings. All substrates selec-
tively formed the endo product with a trans-double bond (30–37;
Scheme 5). We believe that the endo selectivity is due to reduced
steric hindrance during product formation. As the ring size gets
larger, the sterically more demanding endo, but energetically fa-
vored, product becomes increasingly favored, resulting in exclusive
formation of the endo product during the final diene RCM.
In conclusion, we have demonstrated the synthesis of versatile
macrocyclic scaffolds for DOS. The 12- to 18-membered cyclic scaf-
folds are readily available in few steps and good overall yield from
commerciallyavailable building blocks. In all cases, the enyne RCM of
the desired product proceeded with high selectivity, leaving a core
scaffold with orthogonal functional groups that effectively emerged
during the build-up of the core scaffolds for further diversification.
4. Experimental section
4.1. General procedures
O
O
OBn
O
OBn
O
O
O
n
O
O
Solvents and reagents were used as purchased from commercial
suppliers, unless otherwise noted. Dry THF was obtained via dis-
tillation over sodium using benzophenone as an indicator. Yields
refer to chromatographically and spectroscopically (1H NMR) ho-
mogeneous materials, unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
Sigma–Aldrich silica gel plates (catalogue #Z193291-1PAK) using
phosphomolybdic acid in absolute EtOH and heat as a developing
agent. NMR spectra were recorded on either a Bruker AC 300 or
DRX 400 instrument using residual undeuterated solvent as an
internal reference. The following abbreviations were used to ex-
plain the multiplicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
p¼pentet, m¼multiplet, br¼broad. Low resolution mass spectra
(MS) were recorded on a Bruker Esquire 3000 (Agilent model 1100)
instrument using electrospray ionization-ion trap (ESI). High res-
olution mass spectra (HRMS) were recorded on a Kratos MS80 RFA
instrument using electron impact (EI) or on an Applied Biosystems/
PE Sciex QSTAR Pulsar i Hybrid quadrupole time-of-flight mass
spectrometer using ESI-TOF (electrospray ionization-time of flight).
Optical rotations were obtained on a Rudolf Research Autopole IV at
589 nm and 22 ꢁC.
n
2nd Gen. Grubbs', cat. (20%)
1 mM, CH2Cl2, CH2=CH2
O
O
OBn
O
OBn
O
O
n
O
O
O
30 n = 2; 72%
31 n = 3; 72%
32 n = 5; 34%
33 n = 7; 54%
34 n = 2; 36%
35 n = 3; 68%
36 n = 5; 61%
37 n = 7; 67%
n
Scheme 5. Cyclization reaction to give 13- to 18-membered rings.
Typically, macrocyclization suffers from decreasing yields as the
ring size increases, however, in the cases studied herein this does
not seem to be the case. Thus, using this methodology for the
synthesis of macrocycles for DOS is very useful.
2.6. Determination of ring size by 2D-NMR
For each cyclized product, the ring size and mode of cyclization
were determined by Heteronuclear Multiple Bond Correlation
(HMBC). The key correlation used to justify the endo products was
between the exo-cyclic methylene protons and the allylic carbon
next to the ether oxygen on the newly formed ring (27, Fig. 3). This
correlation would be absent in rings formed via the exo mode of
closure (27-exo, Fig. 3).
4.2. General procedure A: glycosylation with tri-O-
acetyl-
D-glucal
Asolutionoftri-O-acetyl-
D
-glucal (0.1 M in DCM) stirring at 0 ꢁCwas
treated, sequentially, with the corresponding alcohol (1.1 equiv), and
BF3$OEt2 (0.1 equiv), in a modification of conditions set out by Ferrier

M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
8135
and Prasad.8 After 2 h, the reaction mixture was allowed to warm to
room temperature and stirred for an additional 2 h. The reaction was
quenched with saturated aqueous NaHCO3. The organic layer was
separated from the aqueous layer, then washed with saturated aqueous
NaHCO3, saturated aqueous NH4Cl, and dried with MgSO4. The solvent
was removed under reduced pressure to provide an orange tinted oil,
which was purified by flash chromatography (5:1 hexane/EtOAc) or
recrystallized from absolute EtOH to yield the corresponding product.
2.4 Hz; H-6), 4.34 (d, 1H, J¼12.3 Hz; H-80), 4.11–4.19 (m, 2H; H-4, H-
80), 3.91 (dt, 1H, J¼9.2, 2.4 Hz; H-5), 3.78 (dd, 1H, J¼12.1, 2.7 Hz; H-
6), 2.38–2.50 (m, 4H; H-20, H-30); 13C NMR (100.5 MHz, CDCl3)
d
173.3 (C-10), 143.1 (C-60), 137.9 (Ph), 131.1 (C-40), 130.4 (C-50), 129.1
(C-2),128.3 (Ph),127.8 (Ph),127.72 (Ph),127.68 (Ph),127.6 (Ph),125.8
(C-3), 116.1 (C-70), 94.8 (C-1), 70.2 (Bn), 68.8 (C-80), 67.8 (C-5), 67.4
(C-4), 63.4 (C-6), 35.3 (C-20 or C-30), 29.9 (C-20 or C-30). HRMS (ESI-
TOF) calcd for C21H24O5 [MþK] 395.1261, found 395.1214, calcd for
C21H24O5 [MþNa] 379.1522, found 379.1470, calcd for C21H24O5
[MþNH4] 374.1968, found 374.1938.
4.3. General procedure B: esterification
A solution of the alcohol (45 mM in CH3CN), the carboxylic acid
(2 equiv), DIEA (2 equiv), and DMAP (0.1 equiv) was treated with
EDC$HCl (2 equiv). After 4 h, the solvent was removed under re-
duced pressure. The resulting residue was dissolved in DCM (5 mL),
transferred to a separatory funnel, and diluted with EtOAc (50 mL).
The organic fraction was washed with 1 N HCl, saturated aqueous
NaHCO3, dried with MgSO4, filtered, and the solvent was removed
in vacuo. The resulting oil was purified by flash chromatography
(20:1/15:1 Hexanes/EtOAc) to yield the corresponding product.
4.5.4. Compound 28. Benzyl 6-O-allyl-4-O-(4-pent-4-ynoyl)-2,3-
dideoxy-a-D-erythro-hex-2-enpyranoside (21) (1.02 g, 2.85 mmol)
was made according to general procedure C to provide the corre-
sponding monocyclic tetraene 28-tetraene (460 mg, 42%) and the
bicyclic, ring closed product 28 (356 mg, 35%). Compound 28-tet-
raene: [
a
]
D þ81 (c 0.066, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.23–
7.44 (m, 5H; Ph), 6.36 (dd, 1H, J¼18.0, 10.8 Hz), 5.79–5.99 (m, 3H),
5.43 (br d, 1H, J¼9.7 Hz; H-4), 4.97–5.35 (m, 7H), 4.83 (d, 1H,
J¼11.8 Hz; Bn), 4.59 (d, 1H, J¼11.8 Hz; Bn), 3.96–4.16 (m, 3H), 3.54 (d,
2H, J¼3.1 Hz), 2.54 (br s, 4H). HRMS (ESI-TOF) calcd for C23H28O5
[MþK] 423.1574, found 423.1565, calcd for C23H28O5 [MþNH4]
4.4. General procedure C: ring-closing metathesis
402.2281, found 402.2285. Compound 28: [
a]D þ187 (c 0.057, CHCl3).
The conditions set out here are a modification of the ring-closing
conditions described by Hansen and Lee.7a Ethylene was bubbled
through a solution of the monocyclic enyne precursor (1 mM in DCM)
and second generation Grubbs’ catalyst (20 mol %) for 30 min, then
set to reflux under an ethylene atmosphere overnight. The solution
was concentrated in vacuo and then purified by flash chromatography
(toluene, then 22:1/16:1 Hexanes/EtOAc) to yield the corresponding
acyclic diene (where applicable) and the cyclized product(s).
1H NMR (400 MHz, CDCl3)
d 7.25–7.41 (m, 5H; Ph), 6.17 (d, 1H,
J¼16.1 Hz; H-30), 5.19 (d, 1H, J¼10.2 Hz; H-3), 5.72 (dt, 1H, J¼10.2,
2.3 Hz; H-2), 5.54 (br d,1H, J¼9.8 Hz; H-4), 5.42 (ddd,1H, J¼16.1, 10.1,
4.3 Hz; H-20), 5.13 (br s,1H; H-1), 5.06 (s,1H; H-50), 5.03 (s,1H; H-50),
4.76 (d, 1H, J¼11.9 Hz; Bn), 4.60 (d, 1H, J¼11.9 Hz; Bn), 4.34 (dd, 1H,
J¼12.0, 4.2 Hz; H-10), 3.89 (d, 1H, J¼9.7 Hz; H-5), 3.48–3.61 (m, 3H;
H-10, H-6), 2.89 (dd, 1H, J¼12.5, 11.4 Hz; H-60), 2.84 (dd, 1H, J¼12.9,
9.3 Hz; H-70), 2.53 (dd, 1H, J¼13.9, 9.3 Hz; H-60), 2.11 (dd, 1H, J¼12.0,
11.9 Hz; H-70); 13C NMR (100.5 MHz, CDCl3)
d
174.8 (C-80), 145.9 (C-
4.5. Synthetic details
40), 137.7 (Ph), 137.5 (C-30), 130.4 (C-2), 128.1 (Ph), 127.7 (Ph), 127.4
(Ph), 126.6 (C-3), 125.9 (C-20), 118.3 (C-50), 94.3 (C-1), 70.7 (C-10), 70.1
(Bn), 68.4 (C-5), 65.1 (C-4), 62.7 (C-6), 35.7 (C-70), 29.8 (C-60). MS
(ESI; m/z) 379 [MþNa]; MS/MS (m/z) 321 [MþNaꢂC3H4O], 271
[MþNaꢂBnOH], 239 [MþNaꢂC7H8O3]; HRMS (ESI-TOF) calcd for
C21H24O5 [MþK] 395.1261, found 395.1189, calcd for C21H24O5
[MþNa] 379.1522, found 379.1430, calcd for C21H24O5 [MþNH4]
374.1968, found 374.1910.
4.5.1. Macrocyclic precursors. The procedures and characterization
of the macrocyclic precursors is described in Supplementary data.
4.5.2. Compound 25. Benzyl 4-O-(4-pent-4-enoyl)-6-O-propargyl-
2,3-dideoxy-a-D-erythro-hex-2-enpyranoside (11) (427 mg, 1.17 mmol)
was treated according to general procedure C to provide a 20:1 mixture
of 12- and 11-membered bicyclic rings, respectively, which was not
separable by chromatography (223 mg, 52%) and a pure fraction of the
4.5.5. Compound 29. Benzyl 4-O-allyl-6-O-(4-pent-4-ynoyl)-2,3-
12-membered bicyclic ring 25 (56 mg, 13%); [
a
]
D þ50 (c 0.032, CHCl3).
dideoxy-a-D-erythro-hex-2-enpyranoside (22) (347 mg, 0.974 mmol)
was treated according to general procedure C to yield the corre-
1H NMR (400 MHz, CDCl3)
d
7.25–7.36 (m, 5H; Ph), 5.79–6.00 (m, 3H; H-
3, H-40, H-50), 5.73 (dt,1H, J¼10.2, 2.4 Hz; H-2), 5.40 (br d,1H, J¼9.7 Hz;
H-4), 5.15 (s,1H; H-30), 5.13 (br s,1H; H-1), 4.95 (s,1H; H-30), 4.77 (d,1H,
J¼11.9 Hz; Bn), 4.59 (d, 1H, J¼11.9 Hz; Bn), 4.34 (d, 1H, J¼12.8 Hz; H-10),
3.95–4.03 (m, 2H; H-10, H-5), 3.54 (dd,1H, J¼10.2, 2.2 Hz; H-6), 3.23 (dd,
1H, J¼10.2, 2.0 Hz; H-6), 2.27–2.50 (m, 4H; H-60, H-70); 13C NMR
sponding monocyclic tetraene 29-tetraene (46 mg, 12%) and the bi-
cyclic product 29 (226 mg, 65%). Compound 29-tetraene: [
a
]D þ65 (c
0.0074, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.24–7.44 (m, 5H; Ph),
6.37 (dd, 1H, J¼17.4, 10.8 Hz), 6.08 (d, 1H, J¼10.3 Hz; H-3), 5.76–5.98
(m, 2H), 5.15–5.36 (m, 3H), 4.98–5.14 (m, 4H), 4.82 (d, 1H, J¼11.8 Hz;
Bn), 4.58 (d,1H, J¼11.8 Hz; Bn), 4.33 (d, 2H, J¼3.6 Hz; H-6), 3.90–4.20
(m, 4H), 2.59 (br s, 4H). HRMS (ESI-TOF) calcd for C23H28O5 [MþK]
423.1574, found 423.1586, calcd for C23H28O5 [MþNH4] 402.2281,
(100.5 MHz, CDCl3)
d
173.2 (C-80), 144.4 (C-20), 137.9 (Ph), 131.1 (C-2),
130.8 (C-40), 130.7 (C-50), 128.3 (Ph), 128.0 (Ph), 127.9 (Ph), 127.6 (Ph),
126.6 (C-3),114.7 (C-30), 94.6 (C-1), 72.5 (C-10), 70.2 (Bn), 67.8 (C-5), 66.7
(C-4), 65.6 (C-6), 35.5 (C-60 or C-70), 29.9 (C-60 or C-70). HRMS (ESI-TOF)
calcd for C21H24O5 [MþK] 395.1261, found 395.1187, calcd for C21H24O5
[MþNa] 379.1522, found 379.1429, calcd for C21H24O5 [MþNH4]
374.1968, found 374.1911.
found 402.2303. Compound 29: [
a
]
þ88 (c 0.014, CHCl3). 1H NMR
D
(400 MHz,CDCl3)
d
7.25–7.41(m, 5H;Ph), 6.19(d,1H, J¼16.1 Hz; H-60),
6.04 (d, 1H, J¼10.2 Hz; H-3), 5.73 (dt, 1H, J¼10.2, 2.3 Hz; H-2), 5.39
(ddd,1H, J¼16.0,10.2, 4.0 Hz; H-70), 5.13 (br s,1H; H-1), 5.06 (s,1H; H-
50), 5.01 (s, 1H; H-50), 4.97 (dd, 1H, J¼12.6, 2.4 Hz; H-6), 4.74 (d, 1H,
J¼12.1 Hz; Bn), 4.62 (d, 1H, J¼12.1 Hz; Bn), 4.30 (dd, 1H, J¼12.3,
3.2 Hz;H-80), 4.18 (brd,1H, J¼9.5 Hz;H-4), 3.87(brd,1H, J¼9.5 Hz;H-
5), 3.75 (dd, 1H, J¼12.3, 10.3 Hz; H-80), 3.56 (d, 1H, J¼12.5 Hz; H-6),
2.85 (dd,1H, J¼13.8,10.9 Hz; H-30), 2.65 (dd,1H, J¼13.1, 9.7 Hz; H-20),
2.55 (dd,1H, J¼13.9, 9.7 Hz; H-30), 2.23 (dd,1H, J¼12.5,10.6 Hz; H-20);
4.5.3. Compound 27. Benzyl 6-O-(pent-4-enoyl)-4-O-propargyl-
2,3-dideoxy-a-D-erythro-hex-2-enpyranoside
(16)
(289 mg,
0.812 mmol) was cyclized by the conditions outlined in general
procedure C to provide the bicyclic product as a clear oil (214 mg,
74%); [
a
]
þ82 (c 0.006, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.25–
D
7.36 (m, 5H; Ph), 6.16 (d, 1H, J¼10.3 Hz; H-3), 5.96 (d, 1H, J¼15.9 Hz;
H-50), 5.82–5.92 (m, 1H; H-40), 5.75 (dt, 1H, J¼10.3, 2.3 Hz; H-2), 5.2
(s, 1H; H-70), 5.11 (br s, 1H; H-1), 4.99 (s, 1H; H-70), 4.74 (d, 1H,
J¼12.0 Hz; Bn), 4.60 (d, 1H, J¼12.0 Hz; Bn), 4.45 (dd, 1H, J¼12.1,
13C NMR (100.5 MHz, CDCl3) 175.2 (C-10), 146.0 (C-40), 137.9 (Ph),
d
137.6 (C-60),131.8 (C-2),128.3 (Ph),128.2 (Ph),127.64 (Ph),127.58 (Ph),
127.5 (Ph), 125.9 (C-70), 125.5 (C-3), 118.4 (C-50), 94.8 (C-1), 70.2 (Bn),
69.0 (C-80), 68.1 (C-5), 64.1 (C-4), 62.2 (C-6), 35.5 (C-20), 29.7 (C-30).

8136
M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
HRMS (ESI-TOF) calcd for C21H24O5 [MþK] 395.1261, found 395.1200,
calcd for C21H24O5 [MþNa] 379.1522, found 379.1452, calcd for
C21H24O5 [MþNH4] 374.1968, found 374.1929.
was subjected to the cyclization conditions outlined by general pro-
cedure C to provide two fractions of the title compound. The first
fraction was the title compound at 90% purity by NMR and the im-
purity was not separable from the title compound by chromatography
(140 mg, 63%). The second fraction was pure title compound (19 mg,
4.5.6. Cyclization of compound 23. Benzyl 6-O-(2-butynyl)-4-O-(4-
pent-4-enoyl)-2,3-dideoxy-
a
-
D
-erythro-hex-2-enpyranoside (23)
9%); [a]
D þ128 (c 0.006, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.25–7.48
(490 mg, 1.32 mmol) was subjected to cyclization conditions outlined
by general procedure C to yield the corresponding monocyclic tet-
raene 23x (252 mg, 41%), a 1:1 mixture of the corresponding 11- and
12-membered bicyclic rings, which could not be separated by chro-
matography (243 mg, 43%), and a pure fraction of the 11-membered
(m, 5H; Ph), 6.02 (d, 1H, J¼15.7 Hz; H-40), 5.86–5.91 (m, 2H; H-3, H-50),
5.75 (dt, 1H, J¼10.2, 2.4 Hz; H-2), 5.62 (dd, 1H, J¼9.7, 1.6 Hz; H-4), 5.14
(br s, 2H; H-1, H-30), 5.02 (s, 1H; H-30), 4.79 (d, 1H, J¼11.9 Hz; Bn), 4.61
(d, 1H, J¼11.9 Hz; Bn), 4.44 (d, 1H, J¼12.1 Hz; H-10), 4.02 (dt, 1H, J¼9.7,
2.5 Hz; H-5), 3.96 (d, 1H, J¼12.2 Hz; H-10), 3.61 (dd, 1H, J¼10.3, 3.1 Hz;
H-6), 3.33 (dd, 1H, J¼10.3, 2.0 Hz; H-6), 2.01–2.48 (m, 5H), 1.71–1.82
ring 23y (27 mg, 5%). Compound 23x: [
a
]
þ93 (c 0.048, CHCl3). 1H
D
NMR (300 MHz, CDCl3)
d
7.25–7.43 (m, 5H; Ph), 5.74–5.95 (m, 3H),
(m, 1H); 13C NMR (100.5 MHz, CDCl3) 173.4 (C-90), 142.5 (C-20), 137.9
d
5.39 (br d, 1H, J¼9.7 Hz; H-4), 4.98–5.32 (m, 7H), 4.84 (d, 1H,
J¼11.8 Hz; Bn), 4.61 (d, 1H, J¼11.8 Hz; Bn), 4.35 (d, 1H, J¼12.8 Hz),
4.10–4.25 (m, 2H), 3.50–3.63 (m, 2H; H-6), 2.32–2.47 (m, 4H), 1.93 (s,
3H; Me). HRMS (ESI-TOF) calcd for C24H30O5 [MþK] 437.1730, found
437.1747, calcd for C24H30O5 [MþNH4] 416.2437, found 416.2441.
(Ph), 131.2 (C-2), 130.7 (C-40), 130.5 (C-50), 128.4 (Ph), 127.9 (Ph), 127.8
(Ph), 127.7 (Ph), 126.6 (C-3), 116.6 (C-30), 94.5 (C-1), 72.5 (C-10), 70.2
(Bn), 67.9 (C-5), 66.8 (C-6), 65.8 (C-4), 32.9, 32.4, 22.9. HRMS (ESI-TOF)
calcd for C22H26O5 [MþK] 409.1417, found 409.1346, calcd for C22H26O5
[MþNa] 393.1678, found 393.1612, calcd for C22H26O5 [MþNH4]
388.2124, found 388.2079.
Compound 23y: (27 mg, 5%); [
a
]
þ125 (c 0.011, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
7.25–7.39 (m, 5H; Ph), 6.05 (d, 1H, J¼10.2 Hz; H-3),
5.76 (dt, 1H, J¼10.2, 2.0 Hz; H-2), 5.58 (dd, 1H, J¼11.2, 4.3; H-60), 5.20
(d, 1H, J¼9.1 Hz; H-4), 5.14 (br s, 1H; H-1), 4.98 (s, 1H; H-40), 4.81 (d,
1H, J¼11.9 Hz; Bn), 4.77 (s, 1H; H-40), 4.62 (d, 1H, J¼11.9 Hz; Bn), 4.13
(d, 1H, J¼12.3 Hz; H-10), 3.96 (br d, 1H, J¼9.8 Hz; H-5), 3.78–3.85 (m,
2H; H-6), 3.75 (d, 1H, J¼12.2 Hz; H-10), 2.83–2.98 (m, 1H), 2.33–2.49
4.5.9. Compound 31. Benzyl 4-O-(hept-6-enoyl)-6-O-propargyl-2,3-
dideoxy-a-D-erythro-hex-2-enpyranoside (13) (271 mg, 0.704 mmol)
was cyclized according to general procedure C to produce two frac-
tions of the title compound. The first fraction was 90% pure by NMR
and the title compound was not separable from the impurity by
chromatography (105 mg, 39%); the second fraction was pure title
(m, 3H), 1.91 (s, 3H; H-50); 13C NMR (100.5 MHz, CDCl3) 173.6 (C-90),
d
142.9 (C-20 or C-30), 141.8 (C-20 or C-30), 137.9 (Ph), 130.8 (C-2), 129.3
(C-60), 128.4 (Ph), 128.0 (Ph), 127.7 (Ph), 126.9 (C-3), 115.5 (C-40), 94.5
(C-1), 74.3 (C-10), 70.2 (Bn), 69.2 (C-5), 67.4 (C-6), 66.6 (C-4), 35.5, 26.6,
22.4 (C-50). HRMS (ESI-TOF) calcd for C22H26O5 [MþK] 409.1417, found
409.1347, calcd for C22H26O5 [MþNa] 393.1678, found 393.1622, calcd
for C22H26O5 [MþNH4] 388.2124, found 388.2066.
compound (90 mg, 33%); [
a
]
þ187 (c 0.034, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
7.25–7.40 (m, 5H; Ph), 6.10 (d, 1H, J¼10.2 Hz; H-
3), 6.03 (d, 1H, J¼16.0 Hz; H-40), 5.9 (ddd, 1H, J¼15.8, 9.1, 4.9 Hz; H-
50), 5.78 (dt,1H, J¼10.2, 2.4 Hz; H-2), 5.32 (dd,1H, J¼9.9,1.6 Hz; H-4),
5.17 (br s, 1H; H-1), 5.10 (s, 1H; H-30), 5.05 (s, 1H; H-30), 4.79 (d, 1H,
J¼11.9 Hz; Bn), 4.63 (d, 1H, J¼11.9 Hz; Bn), 4.61 (d, 1H, J¼11.9 Hz; H-
10), 4.01 (dt,1H, J¼9.9, 2.3 Hz; H-5), 3.96 (d,1H, J¼12.1 Hz; H-10), 3.64
(dd, 1H, J¼10.5, 2.6 Hz; H-6), 3.15 (dd, 1H, J¼10.5, 2.0 Hz; H-6), 2.47
(ddd, 1H, J¼13.6, 7.0, 3.0 Hz), 2.31–2.41 (m, 1H), 2.15 (dt, 1H, J¼10.7,
3.9 Hz), 1.85–1.95 (m, 1H), 1.55–1.77 (m, 3H), 1.38–1.50 (m, 1H); 13C
4.5.7. Cyclization of compound 24. Benzyl 4-O-(2-butynyl)-6-O-
(pent-4-enoyl)-2,3-dideoxy-a-D-erythro-hex-2-enpyranoside (24)
(332 mg, 0.895 mmol) was treated according to general procedure
C to provide the monocyclic tetraene 24x (43 mg, 12%), a 1:1
mixture of 11- and 12-membered bicyclic rings, which could not
be separated by chromatography (74 mg, 22%), and a pure fraction
of the bicyclic 11-membered ring 24y (21 mg, 6%). Compound
NMR (100.5 MHz, CDCl3)
d
173.2 (C-100), 142.2 (C-20), 138.0 (Ph),
133.0 (C-50),130.9 (C-2),129.8 (C-40),128.4 (Ph),127.9 (Ph),127.7 (Ph),
126.8 (C-3), 117.4 (C-30), 94.7 (C-1), 72.9 (C-10), 70.4 (Bn), 67.9 (C-5),
66.3 (C-4 or C-6), 66.2 (C-4 or C-6), 34.7, 31.6, 26.2, 23.1. HRMS (ESI-
TOF) calcd for C23H28O5 [MþK] 423.1574, found 423.1494, calcd for
C23H28O5 [MþNa] 407.1836, found 407.1751, calcd for C23H28O5
[MþNH4] 402.2281, found 402.2233.
24x: [
a]
þ66 (c 0.011, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.25–
D
7.41 (m, 5H; Ph), 6.10 (br d, 1H, J¼10.3 Hz; H-3), 5.76–5.92 (m,
2H), 5.27 (d, 2H, J¼8.2 Hz), 4.96–5.18 (m, 5H), 4.82 (d, 1H,
J¼11.8 Hz; Bn), 4.58 (d, 1H, J¼11.8 Hz; Bn), 4.35 (d, 1H, J¼12.3 Hz),
4.23–4.32 (m, 2H), 4.18 (d, 1H, J¼12.3 Hz), 4.05–4.13 (m, 1H; H-5),
3.97 (dd, 1H, J¼9.2, 1.0 Hz; H-4), 2.34–2.53 (m, 4H), 1.93 (s, 3H;
Me). HRMS (ESI-TOF) calcd for C24H30O5 [MþK] 437.1730, found
437.1710, calcd for C24H30O5 [MþNH4] 416.2437, found 416.2404.
4.5.10. Compound
32. Benzyl
4-O-(non-8-enoyl)-6-O-propa-
rgyl-2,3-dideoxy-a-D-erythro-hex-2-enpyranoside (14) (430 mg,
1.04 mmol) was treated according to general procedure C to pro-
duce the corresponding monocyclic tetraene 32-tetraene (223 mg,
49%) and the bicyclic compound 32 (147 mg, 34%). Compound 32-
Compound 24y: [
CDCl3)
a
]
þ144 (c 0.01, CHCl3). 1H NMR (400 MHz,
D
d
7.26–7.39 (m, 5H; Ph), 6.09 (d, H, J¼10.3 Hz; H-3), 5.85 (t,
tetraene: [
a
]
þ91 (c 0.047, CHCl3). 1H NMR (300 MHz, CDCl3)
D
1H, J¼8.2 Hz; H-60), 5.79 (dt, 1H, J¼10.3, 2.0 Hz; H-2), 5.14 (s, 1H;
H-40), 5.04 (br s, 1H; H-1), 4.98 (s, 1H; H-40), 4.75 (d, 1H,
J¼12.0 Hz; Bn), 4.59 (d, 1H, J¼12.0 Hz; Bn), 4.38 (d, 1H, J¼10.7 Hz;
H-10), 4.09–4.27 (m, 4H; H-10, H-5, H-6), 4.01 (br d, 1H, J¼8.4 Hz;
H-4), 2.61–2.76 (m, 1H; H-70 or H-80), 2.38–2.60 (m, 3H; H-70, H-
d
7.24–7.46 (m, 5H; Ph), 6.37 (dd, 1H, J¼17.9, 10.8 Hz), 5.73–5.94 (m,
3H), 5.24–5.45 (m, 3H), 4.90–5.23 (m, 5H), 4.84 (d, 1H, J¼11.8 Hz;
Bn), 4.61 (d, 1H, J¼11.8 Hz; Bn), 4.33 (d, 1H, J¼12.8 Hz), 4.10–4.23
(m, 2H), 3.50–3.64 (m, 2H), 2.31 (t, 2H, J¼7.2 Hz), 2.05 (q, 2H,
J¼7.2 Hz), 1.56–1.70 (m, 2H), 1.26–1.50 (m, 6H). HRMS (ESI-TOF)
calcd for C27H36O5 [MþK] 479.2200, found 479.2212, calcd for
C27H36O5 [MþNH4] 458.2907, found 458.2901. Compound 32:
80), 1.90 (s, 3H; H-50); 13C NMR (100.5 MHz, CDCl3)
d
172.0 (C-90),
142.7 (C-20 or C-30), 138.4 (C-20 or C-30), 137.9 (Ph), 130.7 (C-60),
130.4 (C-2), 128.4 (Ph), 128.2 (Ph), 127.9 (Ph), 127.6 (Ph), 126.1 (C-
3), 112.8 (C-40), 93.6 (C-1), 73.3 (C-4), 70.2 (Bn), 65.3 (C-5), 64.9
(C-6), 63.4 (C-10), 34.6 (C-70 or C-80), 24.6 (C-70 or C-80), 21.1 (C-50).
HRMS (ESI-TOF) calcd for C22H26O5 [MþK] 409.1417, found
409.1349, calcd for C22H26O5 [MþNa] 393.1678, found 393.1621,
calcd for C22H26O5 [MþNH4] 388.2124, found 388.2070.
[
a
]D¼þ114 (c 0.022, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.28–7.40
(m, 5H; Ph), 5.92–6.06 (m, 3H; H-3, H-40, H-50), 5.82 (dt, 1H, J¼10.2,
2.6 Hz; H-2), 5.44 (dd, 1H, J¼9.8, 1.5 Hz; H-4), 5.17 (br s, 1H; H-1),
5.14 (d, 1H, J¼1.7 Hz; H-30), 5.03 (br s, 1H; H-30), 4.81 (d, 1H,
J¼11.9 Hz; Bn), 4.63 (d, 1H, J¼11.9 Hz; Bn), 4.43 (d, 1H, J¼11.9 Hz; H-
10), 3.95–4.06 (m, 2H; H-10, H-5), 3.59 (dd, 1H, J¼10.8, 3.4 Hz; H-6),
3.24 (dd, 1H, J¼10.8, 2.0 Hz; H-6), 2.06–2.46 (m, 4H), 1.75–1.92 (m,
1H), 1.37–1.64 (m, 4H), 1.08–1.37 (m, 3H); 13C NMR (100.5 MHz,
4.5.8. Compound 30. Benzyl 4-O-(hex-5-enoyl)-6-O-propargyl-2,3-
dideoxy-
a
-
D
-erythro-hex-2-enpyranoside (12) (222 mg, 0.599 mmol)
CDCl3) d
173.1 (C-120), 142.1 (C-20), 138.0 (Ph), 132.1 (C-2, C-40, or C-

M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
8137
50), 129.8 (C-2, C-40, or C-50), 129.6 (C-2, C-40, or C-50), 129.5 (Ph),
128.3 (Ph), 128.1 (Ph), 128.0 (Ph), 127.6 (Ph), 127.4 (C-3), 116.4 (C-30),
94.2 (C-1), 73.8 (C-10), 70.3 (Bn), 68.0 (C-5), 67.3 (C-6), 65.3 (C-4),
33.0, 31.8, 28.1, 27.8, 26.2, 23.1. MS (ESI; m/z) 435 [MþNa]; MS/MS
(m/z) 435 [MþNa], 327 [MþNaꢂBnOH]; HRMS (ESI-TOF) calcd for
C25H32O5 [MþK] 451.1887, found 451.1809, calcd for C25H32O5
[MþNa] 435.2148, found 435.2074, calcd for C25H32O5 [MþNH4]
430.2594, found 430.2521.
(dt, 1H, J¼9.3, 2.06 Hz; H-5), 2.63 (ddd, 1H, J¼14.7, 6.4, 3.3 Hz), 2.20–
2.34 (m, 2H),1.82–2.03 (m, 2H),1.56–1.77 (m, 2H),1.95–1.30 (m,1H);
13C NMR (100.5 MHz, CDCl3)
d
173.6 (C-10), 141.6 (C-80), 137.9 (Ph),
132.0 (C-60), 130.2 (C-70), 129.0 (C-2), 128.4 (Ph), 127.9 (Ph), 127.7
(Ph), 126.5 (C-3), 118.5 (C-90), 94.8 (C-1), 70.2 (Bn), 68.3 (C-100), 68.1
(C-5), 67.3 (C-4), 63.1 (C-6), 34.8, 31.3, 26.9, 22.6. MS (ESI; m/z) 407
[MþNa]; MS/MS (m/z) 316 [MþNaꢂC7H7], 287 [MþNaꢂC8H8O];
HRMS (ESI-TOF) calcd for C23H28O5 [MþK] 423.1574, found
423.1522, calcd for C23H28O5 [MþNa] 407.1835, found 407.1778,
calcd for C23H28O5 [MþNH4] 402.2281, found 402.2235.
4.5.11. Compound 33. Benzyl 6-O-propargyl-4-O-(undec-10-enoyl)-
2,3-dideoxy-a-D-erythro-hex-2-enpyranoside (15) (281 mg, 0.637
mmol) was cyclized according to general procedure C to provide the
4.5.14. Compound 36. Benzyl 6-O-(non-8-enoyl)-4-O-propargyl-2,3-
dideoxy-a-D-erythro-hex-2-enpyranoside (19) (293 mg, 0.712 mmol)
was treated according to general procedure C to provide the product as
product as a clear oil (152 mg, 54%); [
a
]D þ61 (c 0.034, CHCl3). 1H NMR
(400 MHz, CDCl3)
d
7.24–7.44 (m, 5H; Ph), 6.05 (d,1H, J¼15.9 Hz; H-40),
5.82–5.92 (m, 3H; H-2, H-3, H-50), 5.37 (br d, 1H, J¼9.6 Hz; H-4), 5.14 (s,
1H; H-30), 5.09 (br s, 2H; H-1, H-30), 4.87 (d, 1H, J¼11.6 Hz; Bn), 4.62 (d,
1H, J¼11.6 Hz; Bn), 4.36 (d,1H, J¼12.3 Hz; H-10), 4.24 (d,1H, J¼12.3 Hz;
H-10), 4.19 (ddd, 1H, J¼9.6, 6.2, 2.0 Hz; H-5), 3.56 (dd, 1H, J¼11.8,
2.1 Hz; H-6), 3.48 (dd, 1H, J¼11.8, 6.3 Hz; H-6), 2.26–2.42 (m, 2H),
2.07–2.24 (m, 2H), 1.14–1.80 (m, 14H); 13C NMR (100.5 MHz, CDCl3)
a clear oil (179 mg, 61%); [
a
]D þ116 (c 0.057, CHCl3). 1H NMR (400 MHz,
CDCl3)
d
7.25–7.40 (m, 5H; Ph), 6.20 (d, 1H, J¼10.3 Hz; H-3), 6.07 (d,1H,
J¼15.9 Hz; H-90), 5.80–5.87 (m, 2H; H-2, H-80), 5.13 (s,1H; H-1 or H-110),
5.11 (br s, 1H; H-1 or H-110), 5.07 (s, 1H; H-1 or H-110), 4.79 (d, 1H,
J¼11.8 Hz; Bn), 4.59 (d,1H, J¼11.8 Hz; Bn), 4.35 (d,1H, J¼11.5 Hz; H-120),
4.23 (dd,1H, J¼12.1,1.5 Hz; H-6), 4.17 (dd,1H, J¼12.1, 3.5 Hz; H-6), 4.02–
4.13 (m, 3H; H-4, H-5, H-120), 2.33–2.42 (m, 2H), 2.17–2.29 (m, 1H),
2.03–2.11 (m, 1H), 1.79–1.93 (m, 1H), 1.59–1.72 (m, 1H), 1.11–1.53 (m,
d
173.1 (C-140), 142.4 (C-20), 137.7 (Ph), 132.5 (C-3 or C-50), 129.8 (C-40),
129.6 (C-3 or C-50), 128.3 (C-2 or Ph), 128.2 (C-2 or Ph), 127.9 (C-2 or
Ph),127.7 (C-2 or Ph),116.0 (C-30), 93.3 (C-1), 73.1 (C-10), 70.1 (Bn), 69.1
(C-5), 68.1 (C-6), 65.3, 32.1, 28.1, 28.0, 27.9, 27.8, 26.5, 24.9. HRMS (ESI-
TOF) calcd for C27H36O5 [MþK] 479.2200, found 479.2156, calcd for
C27H36O5 [MþNa] 463.2461, found 463.2406, calcd for C27H36O5
[MþNH4] 458.2907, found 458.2854.
6H); 13C NMR (100.5 MHz, CDCl3) 174.3 (C-10), 141.8 (C-100),137.9 (Ph),
d
132.0 (C-3 or C-80), 130.0 (C-90), 129.6 (C-2), 128.3 (Ph), 127.9 (Ph), 127.6
(Ph), 126.8 (C-3 or C-80), 117.2 (C110), 94.0 (C-1), 70.1 (C-120), 69.4 (Bn),
69.1 (C-4 or C-5), 68.1 (C-4 or C-5), 64.0 (C-6), 33.5, 31.6, 28.2, 27.9, 26.1,
24.6. MS (ESI; m/z) 435 [MþNa]; MS/MS (m/z) 435 [MþNa], 344
[MþNaꢂC7H7], 301 [MþNaꢂC9H10O]; HRMS (ESI-TOF) calcd for
C25H32O5 [MþK] 451.1887, found 451.1820, calcd for C25H32O5 [MþNa]
435.2148, found 435.2083, calcd for C25H32O5 [MþNH4] 430.2594,
found 430.2513.
4.5.12. Compound 34. Benzyl 6-O-(hex-5-enoyl)-4-O-propargyl-
2,3-dideoxy-
a-
D-erythro-hex-2-enpyranoside
(17)
(260 mg,
0.703 mmol) was subjected to the conditions outlined in general
procedure C to yield the corresponding monocyclic tetraene 34-
tetraene (114 mg, 41%) and the ring closed bicyclic product 34
4.5.15. Compound 37. Benzyl 4-O-propargyl-6-O-(undec-10-enoyl)-
(94 mg, 36%). Compound 34-tetraene: [
a
]
D þ60 (c 0.014, CHCl3). 1H
2,3-dideoxy-a-D-erythro-hex-2-enpyranoside
(20)
(304 mg,
NMR (400 MHz, CDCl3)
d
7.26–7.40 (m, 5H; Ph), 6.36 (dd, 1H, J¼17.9,
0.690 mmol) was treated with Grubbs’ second generation catalyst
under the conditions outlined by general procedure C to yield the
11.3 Hz), 6.11 (d, 1H, J¼10.3 Hz; H-3), 5.67–5.86 (m, 2H), 4.94–5.39
(m, 7H), 4.82 (d, 1H, J¼11.8 Hz; Bn), 4.58 (d, 1H, J¼11.8 Hz; Bn),
3.88–4.38 (m, 6H), 2.38 (t, 2H, J¼7.2 Hz), 2.11 (q, 2H, J¼7.2 Hz), 1.76
(p, 2H, J¼7.2 Hz). HRMS (ESI-TOF) calcd for C24H30O5 [MþK]
437.1730, found 437.1735, calcd for C24H30O5 [MþNH4] 416.2437,
product as a clear oil (202 mg, 67%); [
a
]
þ60 (c 0.021, CHCl3). 1H
D
NMR (400 MHz, CDCl3)
d
7.29–7.39 (m, 5H; Ph), 6.12 (d, 1H,
J¼10.3 Hz; H-3), 6.05 (d, 1H, J¼15.9 Hz; H-110), 5.84 (dt, 1H, J¼10.3,
2.6 Hz; H-2), 5.77 (dd, 1H, J¼15.9, 7.13 Hz; H-100), 5.06–5.12 (m, 3H;
H-1, H-130), 4.82 (d, 1H, J¼11.7 Hz; Bn), 4.57 (d, 1H, J¼11.7 Hz; Bn),
4.35 (dd, 1H, J¼12.0, 5.9 Hz; H-6), 4.35 (d, 1H, J¼12.1 Hz; H-140), 4.17
(dd, 1H, J¼12.0, 1.6 Hz; H-6), 4.11 (ddd, 1H, J¼9.5, 6.0, 1.6 Hz; H-5),
4.05 (d, 1H, J¼12.1 Hz; H-140), 3.96 (dd, 1H, J¼9.5, 1.4 Hz; H-4), 2.38
(t, 2H, J¼6.5 Hz; H-20), 2.13 (p, 2H, J¼6.8 Hz; H-30),1.60–1.75 (m, 2H),
found 416.2428. Compound 34: [
(400 MHz, CDCl3)
a
]
D þ120 (c 0.02, CHCl3). 1H NMR
d
7.26–7.38 (m, 5H; Ph), 6.20 (d, 1H, J¼10.3 Hz; H-
2), 5.98 (d, 1H, J¼15.8 Hz; H-60), 5.89 (dt, 1H, J¼15.7, 7.7 Hz; H-50),
5.77 (dt, 1H, J¼10.3, 2.00 Hz; H-3), 5.24 (s, 1H; H-80), 5.14 (br s, 1H;
H-1), 5.01 (s, 1H; H-80), 4.76 (d, 1H, J¼12.0 Hz; Bn), 4.52–4.67 (m,
2H; Bn, H-6), 4.29 (d, 1H, J¼12.4 Hz; H-90), 4.19 (d, 1H, J¼9.2 Hz; H-
4), 4.12 (d, 1H, J¼12.4 Hz; H-90), 3.93 (br d, 1H, J¼9.2 Hz; H-5), 3.78
(br d, 1H, J¼12.2 Hz; H-6), 2.17–2.48 (m, 4H), 1.93–2.09 (m, 1H),
1.20–1.46 (m, 10H); 13C NMR (100.5 MHz, CDCl3) 173.9 (C-10), 142.0
d
(C-120),137.8 (Ph),132.4 (C-100),130.3 (C-2), 129.8 (C-110),128.4 (Ph),
128.0 (Ph),127.7 (Ph),126.7 (C-3),115.7 (C-130), 93.6 (C-1), 70.1 (C-4),
69.9 (Bn), 69.6 (C-140), 68.2 (C-5), 64.0 (C-6), 34.0 (C-20), 32.7 (C-30),
28.1, 27.4, 27.2, 26.9, 24.3. MS (ESI; m/z) 463 [MþNa]; MS/MS (m/z)
463 [MþNa], 372 [MþNaꢂC7H7], 355 [MþNaꢂBnOH]; HRMS (ESI-
TOF) calcd for C27H36O5 [MþK] 479.2200, found 479.2126, calcd for
C27H36O5 [MþNa] 463.2461, found 463.2384, calcd for C27H36O5
[MþNH4] 458.2907, found 458.2815.
1.76–1.90 (m, 1H); 13C NMR (100.5 MHz, CDCl3) 173.6 (C-10), 141.8
d
(C-70), 137.9 (Ph), 130.6 (C-50), 130.1 (C-60), 129.7 (C-2), 128.3 (Ph),
128.1 (Ph), 127.7 (Ph), 127.6 (Ph), 126.0 (C-3), 116.1 (C-80), 94.8 (C-1),
70.2 (Bn), 69.2 (C-90), 68.0 (C-5), 67.6 (C-4), 63.1 (C-6), 32.9, 31.9,
22.9. HRMS (ESI-TOF) calcd for C22H26O5 [MþK] 409.1417, found
409.1342, calcd for C22H26O5 [MþNa] 393.1678, found 393.1620,
calcd for C22H26O5 [MþNH4] 388.2124, found 388.2073.
Acknowledgements
4.5.13. Compound 35. Benzyl 6-O-(hept-6-enoyl)-4-O-propargyl-
2,3-dideoxy-
a
-
D
-erythro-hex-2-enpyranoside
(18)
(270 mg,
Financial support for this project was provided by the Alberta
Ingenuity Fund (New Faculty Award) and National Science and
Engineering Council (Discovery Grant).
0.702 mmol) was used to synthesize the bicyclic product by general
procedure C (184 mg, 68%); [
(400 MHz, CDCl3)
3), 6.08 (d, 1H, J¼15.9 Hz; H-70), 5.89 (ddd, 1H, J¼15.7, 8.2, 5.8 Hz; H-
60), 5.80 (dt, 1H, J¼10.4, 2.4 Hz; H-2), 5.16 (s, 1H; H-90), 5.13 (br s, 1H;
H-1), 5.10 (s, 1H; H-90), 4.76 (d, 1H, J¼11.9 Hz; Bn), 4.60 (d, 1H,
11.9 Hz; Bn), 4.46 (d, 1H, J¼11.8 Hz; H-100), 4.30 (dd, 1H, J¼9.3,
1.3 Hz; H-4), 4.25 (d, 1H, J¼11.9 Hz; H-100), 4.20 (br s, 2H; H-6), 3.98
a
]
þ180 (c 0.018, CHCl3). 1H NMR
D
d
7.26–7.36 (m, 5H; Ph), 6.34 (d, 1H, J¼10.4 Hz; H-
Supplementary data
Synthetic procedures and characterization data, 1D-NMR spec-
tra, and 2D-NMR spectra used for the determination of ring sizes

8138
M.E. Grimwood, H.C. Hansen / Tetrahedron 65 (2009) 8132–8138
6. (a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796; (b)
Kubota, H.; Depew, K. M.; Schreiber, S. L. Chem. Biol. 2002, 9, 265; (c) Hotha, S.;
Tripathi, A. J. Comb. Chem. 2005, 7, 968; (d) Moilanen, S. B.; Tan, D. S. Org.
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are all provided. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.07.088.
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13. Substrate (1 mM), Grubb’s second generation catalyst (20%), CH2]CH2, CH2Cl2.