Formal total synthesis of the polyketide macrolactone narbonolide

Article abstract of DOI:10.1021/jo050924a

An improved synthesis of (3S)-3-dihydronarbonolide is reported that constitutes a formal total synthesis of the 14-membered macrolactone antibiotic narbonolide. The key step was an intramolecular Nozaki-Hiyama-Kishi coupling to accomplish macrocyclization

Full text of DOI:10.1021/jo050924a

Formal Total Synthesis of the Polyketide Macrolactone
Narbonolide
Lakshmanan Venkatraman,† Courtney C. Aldrich,†,‡ David H. Sherman,‡ and
Robert A. Fecik*,†
Department of Medicinal Chemistry, 308 Harvard Street S.E., 8-101 WDH, University of Minnesota,
Minneapolis, Minnesota 55455-0353, and Department of Medicinal Chemistry, University of Michigan
Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216
fecik001@umn.edu
Received May 9, 2005
An improved synthesis of (3S)-3-dihydronarbonolide is reported that constitutes a formal total
synthesis of the 14-membered macrolactone antibiotic narbonolide. The key step was an intramo-
lecular Nozaki-Hiyama-Kishi coupling to accomplish macrocyclization in improved yield. The high
level of convergence will also allow us to rapidly synthesize narbonolide analogues for the study of
enzymes in the pikromycin biosynthetic pathway.
Introduction
convenient synthetic access to narbonolide and its struc-
tural analogues for the study of the post-PKS glycosyla-
tion and oxidation enzymes DesVII and PikC. Narbon-
olide and related derivatives are also of potential
therapeutic interest due to their structural similarity to
ketolide antibacterials such as telithromycin and cethro-
mycin.
Narbonolide (1) is a 14-membered polyketide macro-
lactone biosynthesized by the pikromycin polyketide
synthase (PKS) system of Streptomyces venezuelae ATCC
15439 and undergoes further post-PKS C5-glycosylation
to narbomycin (2) followed by C12-oxidation to pikromy-
cin (3).1,2 Pikronolide (4), the pikromycin aglycon, has
been isolated from S. venezuelae MCRL-0376.3 The pik-
romycin PKS system of S. venezuelae ATCC 15439 also
biosynthesizes the 12-membered macrolactone 10-deoxy-
methynolide (5), which is a metabolic precursor to YC-
17 (6) and methymycin (7).1,2 The inherent substrate
tolerance of the pikromycin PKS system is interesting
for the study of its mechanism of regulating the size of
macrolactone ring formation and for its potential utility
in combinatorial biosynthesis. To complement our efforts
in studying the late stages of the pikromycin PKS with
its natural chain elongation intermediates,4,5 we sought
† University of Minnesota.
‡ University of Michigan.
(1) Xue, Y.; Zhao, L.; Liu, H.-W.; Sherman, D. H. Proc. Natl. Acad.
Sci. U.S.A. 1998, 95, 12111.
A total synthesis of narbonolide (1) has been reported
(2) Xue, Y.; Sherman, D. H. Met. Eng. 2001, 3, 15.
(3) Maezawa, I.; Kinumaki, A.; Suzuki, M. J. Antibiotics 1974, 27,
84.
by Masamune and co-workers; however, cyclization by
(4) Aldrich, C. C.; Beck, B. J.; Fecik, R. A.; Sherman, D. H. J. Am.
Chem. Soc. 2005, 127, 8441.
(5) Aldrich, C. C.; Venkatraman, L.; Sherman, D. H.; Fecik, R. A.
J. Am. Chem. Soc. 2005, 127, 8910.
10.1021/jo050924a CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/06/2005
J. Org. Chem. 2005, 70, 7267-7272
7267

Venkatraman et al.
SCHEME 1. Retrosynthesis of
(3S)-3-Dihydronarbonolide
macrolactonization proceeded in only 32% yield and was
complicated by formation of a dimeric product in 25%
yield.6 Yonemitsu and co-workers have reported two total
syntheses of pikronolide (4), which both use an intramo-
lecular Horner-Wadsworth-Emmons (HWE) macrocycli-
zation.7-9 The yields for these intramolecular HWE
reactions were sensitive to the nature of the protecting
groups at the intermediate C3- and C5-alcohols. When
the C3- and C5-alcohols were protected as their PMB and
DMPM ethers, respectively, HWE cyclization proceeded
in high yield (89%);7,8 however, protection of the C3- and
C5-alcohols as an isopropylidene ketal led to moderate
yield (55%) of the HWE cyclization with formation of a
dimeric product (18% yield).9
We envisioned a highly convergent route to narbonolide
that would utilize an alternate macrocyclization strategy
and one that would be readily amenable to the synthesis
of analogues that could not be readily prepared by
semisynthesis for substrate specificity studies of DesVII
and PikC. Two macrocyclization strategies were consid-
ered: an enzymatic macrolactonization with the isolated
pikromycin thioesterase (Pik TE) domain10 from the
pikromycin biosynthetic pathway1,2 and an intramolecu-
lar Nozaki-Hiyama-Kishi (NHK) coupling. We have
recently used Pik TE as a macrolactonization catalyst in
the total synthesis of 10-deoxymethynolide (5).5 The
intramolecular NHK coupling has been utilized in mac-
rocyclization toward many natural products,11 including
macrolides such as the 12-membered 10-deoxymethyno-
lide (5),12 the 13-membered brefeldin C,13 and the 16-
membered spiramycin aglycone.14 To the best of our
knowledge, these macrocyclization strategies have not
been reported for 14-membered macrolides. We report
here the total synthesis of (3S)-3-dihydronarbonolide
highlighted by an intramolecular NHK coupling that
constitutes a formal total synthesis of narbonolide.
SCHEME 2. Synthesis of C5-C9 Fragments 15 and
18a
Results and Discussion
Retrosynthesis of (3S)-3-dihydronarbonolide (8) by
enzymatic macrolactonization (route a) or NHK (route
b) disconnections leads to acid 9 and aldehyde 10,
respectively (Scheme 1). Further retrosynthetic analysis
of acid 9 and aldehyde 10 leads to three fragments of
similar size and complexity: Evans’ â-keto imide (11),15
representing C1-C4; meso-diol 12,16 corresponding to
C5-C9; and vinyl iodide 13,12 representing C10-C15.
The use of common fragments for both approaches to
macrocyclization will permit the evaluation of these
a Key: (a) Dess-Martin, NaHCO3, 75%; (b) Cl3CC(NH)OPMB,
CSA, 93%; (c) LiAlH4, 84%; (d) Dess-Martin, pyr., 83%.
routes in a complementary, parallel manner. Addition-
ally, the structural simplicity and ready availability of
fragments 11-13 will enable us to modify them for rapid
incorporation into the synthesis of narbonolide analogues.
Synthesis of two C5-C9 fragments commenced with
monoacetate 14,16 prepared by the lipase-mediated de-
symmetrization of meso-diol 12 (Scheme 2). Oxidation to
aldehyde 15 provided a C5-C9 fragment suitable for
NHK coupling and synthesis of a protected form of acid
9 for enzymatic macrolactonization. Alternatively, a C5-
C9 fragment suitable for elaboration to aldehyde 10 for
intramolecular NHK coupling was also synthesized.
Protection of the alcohol of acetate 14 as PMB ether 16
was followed by reductive removal of the acetate to
alcohol 17. Dess-Martin oxidation of alcohol 17 afforded
the C5-C9 fragment as aldehyde 18.
(6) Kaiho, T.; Masamune, S.; Toyoda, T. J. Org. Chem. 1982, 47,
1612.
(7) Nakajima, N.; Hamada, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. J. Am. Chem. Soc. 1986, 108, 4645.
(8) Nakajima, N.; Tanaka, T.; Hamada, T.; Oikawa, Y.; Yonemitsu,
O. Chem. Pharm. Bull. 1987, 35, 2228.
(9) Nakajima, N.; Ubukata, M.; Yonemitsu, O. Heterocycles 1997,
46, 105.
(10) Lu, H.; Tsai, S.-C.; Khosla, C.; Cane, D. E. Biochemistry 2002,
41, 12590.
(11) Fu¨rstner, A. Chem. Rev. 1999, 99, 991.
(12) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A.
J. Org. Chem. 1998, 63, 7811.
(13) Schreiber, S. L.; Meyers, H. V. J. Am. Chem. Soc. 1988, 110,
5198.
(14) Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1157.
(15) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron
1992, 48, 2127.
We chose to initially examine the use of aldehyde 15
in synthesizing a protected form of acid 9 for enzymatic
(16) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493.
7268 J. Org. Chem., Vol. 70, No. 18, 2005

Formal Total Synthesis of Polyketide Macrolactone Narbonolide
SCHEME 3. Attempted Synthesis of C5-C15
SCHEME 4. Synthesis of C1-C15 Intermediate 29a
Fragment 22a
a Key: (a) TiCl4, i-Pr2NEt, 74%; (b) Zn(BH4)2; (c) Me2C(OMe)2,
CSA, 96% (two steps); (d) LiOH, H2O2, 90%; (e) 13, 2,4,6-
Cl3C6H2COCl, Et3N, 90%.
SCHEME 5. Completion of Synthesis of 8a
a Key: (a) 15, CrCl2, Ni(acac)2, 67%; (b) Dess-Martin, NaHCO3,
79%; (c) K2CO3 (0.25 equiv), anhydrous MeOH, 15%.
macrolactonization with Pik TE. Thus, NHK coupling of
aldehyde 15 and vinyl iodide 1912 afforded allylic alcohol
20, which was oxidized to enone 21 (Scheme 3). At-
tempted saponification of the acetate of 21 with K2CO3
(8 equiv) yielded a complex mixture of products that
indicated elimination of the siloxy group had taken place.
The acetate of enone 21 was successfully saponified with
catalytic K2CO3; however, we were unable to isolate the
desired alcohol 22. Rather, dihydropyran 25 was isolated
after chromatography in 15% yield in addition to numer-
ous unidentified products and unreacted starting mate-
rial (14%). The tautomeric hemiketal 23 that is in
equilibrium with the initially formed alcohol 22 under-
went dehydration to dihydropyran 25 via intermediate
oxocarbenium ion 24 that is stabilized by the adjacent
double bond. We then sought to avoid the sensitivity of
ketone 22 by replacing the acetate function with a PMB
ether that could be deprotected under neutral conditions;
however, this approach also ultimately led to the isolation
of dihydropyran 25 (35% isolated yield).5
a Key: (a) DDQ, 87%; (b) Swern, 89%; (c) CrCl2, NiCl2, 58%; (d)
Dess-Martin, pyr., 82%; (e) TFA, 89%.
Given the unexpected difficulties due to the instability
of enone 22, we chose to complete the synthesis using
the intramolecular NHK coupling. Assembly of the entire
C1-C15 carbon skeleton began with the chiral auxiliary-
mediated syn-aldol reaction between Evans’ â-keto imide
(11)15 and aldehyde 18 to give the C1-C9 fragment,
alcohol 26 (Scheme 4). Attempts to protect the C5-alcohol
as a PMB ether were unsuccessful, so we elected to
reduce the C3-ketone and simultaneously protect the
resulting 1,3-diol as an isopropylidene ketal. Directed
reduction of 26 with Zn(BH4)2 was immediately followed
completed the synthesis of the C1-C15 framework
(compound 29).
With the entire C1-C15 skeleton assembled, comple-
tion of the synthesis began with deprotection of com-
pound 29 to primary alcohol 30, followed by Swern
oxidation to aldehyde 31 (Scheme 5). Initial attempts to
cyclize aldehyde 31 by an intramolecular NHK coupling
in DMF failed; however, macrocyclization proceeded
smoothly in DMSO to allylic alcohol 32. Failure of this
reaction in DMF was unexpected since it is the preferred
solvent for NHK couplings.18 It is possible that the DMF
used in this reaction contained trace impurities that are
known to complex Cr(II).11 As expected, this macrocy-
clization was also concentration dependent. Macrocy-
clization proceeded in moderate yield at dilute concen-
by protection of the syn-1,3-diol as acetonide 27. The 13
C
NMR acetonide analysis was used to confirm the pres-
ence of the syn-acetonide and the diastereoselectivity of
the Zn(BH4)2 reduction.17 Removal of the chiral auxiliary
to acid 28 and esterification with C10-C15 fragment 1312
(17) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511.
(18) Kishi, Y. Pure Appl. Chem. 1989, 61, 313.
J. Org. Chem, Vol. 70, No. 18, 2005 7269

Venkatraman et al.
SCHEME 6. Synthesis of a C10-15 Fragment
ous synthesis. The convergence of this synthetic route
will enable us to readily synthesize narbonolide ana-
logues for future biochemical experiments with post-PKS
enzymes in the pikromycin biosynthetic pathway.
Analoguea
Experimental Section
(2S,4R,5R/S,6E,8R,9R)-9-(tert-Butyldimethylsilyloxy)-
5-hydroxy-2,4,8-trimethylundec-6-enyl Acetate (20). To
a solution of aldehyde 15 (106 mg, 0.62 mmol, 1.0 equiv), vinyl
iodide 1912 (270 mg, 0.76 mmol, 1.22 equiv), and Ni(acac)2 (0.8
mg, 0.003 mmol, 0.005 equiv) in degassed DMF (3 mL) was
added CrCl2 (185 mg, 1.5 mmol, 3.0 equiv) via a Schlenk
addition flask. The reaction was stirred at room temperature
for 8 h, quenched with aqueous EDTA (0.5M, pH 8.0, 5 mL),
and diluted with EtOAc (10 mL). The resulting deep purple
solution was stirred for 15 min, and the layers were separated.
The aqueous layer was extracted with EtOAc (2 × 15 mL),
and the combined organic layers were washed with H2O (2 ×
20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. Purification
by flash chromatography (10% EtOAc/hexanes) afforded the
title compound (153 mg, 67% yield) as a colorless oil. Addition-
ally, a symmetrical diene (42 mg, 24% yield) due to homocou-
pling of vinyl iodide 19 was isolated: Rf ) 0.39 (15% EtOAc/
hexanes); 1H NMR (CDCl3, 300 MHz) δ 5.57-5.70 (m, 1H),
5.39-5.48 (m, 1H), 3.78-4.00 (m, 3H), 3.38-3.48 (m, 1H), 2.32
(pent, J ) 6.6 Hz, 1H), 2.05 (s, 3H), 1.82-1.96 (m, 1H), 1.62-
1.76 (m, 1H), 1.31-1.54 (m, 4H), 0.83-1.01 (m, 22H), 0.04 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 171.1, 135.8, 135.5, 130.5,
129.6, 68.9, 41.3, 36.8, 36.7, 36.2, 30.0, 26.6, 26.5, 26.0, 21.1,
18.3, 18.2, 16.0, 15.6, 15.1, 9.6, 9.4, -4.2, -4.3 (C1 and C5
obscured by CDCl3 signal); IR (thin film) 3468 (br), 2959, 2930,
2857, 1740, 1249 cm-1; HRMS calcd for (C22H44O4Si + Na+)
423.2901, found 423.2924.
((3R,4R,E)-6-((S)-5,6-Dihydro-3,5-dimethyl-4H-pyran-2-
yl)-4-methylhex-5-en-3-yloxy)(tert-butyl)dimethylsi-
lane (25). To a solution of enone 21 (43 mg, 0.10 mmol) in
anhydrous MeOH (10 mL) at room temperature was added
K2CO3 (3.5 mg, 0.025 mmol, 0.25 equiv), and the reaction was
stirred for 16 h. The reaction was concentrated under reduced
pressure, and purification by flash chromatography (10%
EtOAc/hexanes) afforded the title compound (5.6 mg, 15%
yield) as a colorless oil whose spectral data corresponded to
those reported.5 Additionally, unreacted 21 (6.1 mg, 14%) was
recovered.
(R)-3-((2R,4R,5S,6S,8R)-9-(4-Methoxybenzyloxy)-5-hy-
droxy-2,4,6,8-tetramethyl-3-oxononanoyl)-4-benzylox-
azolidin-2-one (26). To a solution of â-ketoimide 1115 (5.46
g, 18.9 mmol) in CH2Cl2 (40 mL) at -5 °C was added TiCl4
(1.0 M solution in PhMe, 20.77 mL, 20.77 mmol, 1.1 equiv)
followed by i-Pr2NEt (3.59 mL, 20.77 mmol, 1.1 equiv). The
dark brown solution was stirred at -5 °C for 1 h and then
cooled to -78 °C. To this solution was added a solution of
aldehyde 18 (4.72 g, 18.9 mmol, 1.0 equiv) in CH2Cl2 (15 + 5
mL), and the reaction was stirred at -78 °C for 30 min, slowly
warmed to -50 °C, and stirred for an additional 12 h. The
reaction was quenched by the addition of pH 7 phosphate
buffer (1 M, 100 mL) and slowly warmed to room temperature
with vigorous stirring. The mixture was diluted with CH2Cl2
(100 mL); the layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (20 mL)
and saturated aqueous NaCl (10 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. Purification by flash
chromatography (30% EtOAc/hexanes) afforded the title com-
pound (7.50 g, 74% yield) as a colorless oil: Rf ) 0.48 (30%
EtOAc/hexanes); [R]D23 ) -102.7 (c ) 0.94, CH2Cl2); 1H NMR
(CDCl3, 300 MHz) δ 7.18-7.74 (m, 7H), 6.86 (d, J ) 9.0 Hz,
2H), 4.86 (q, J ) 7.2 Hz, 1H), 4.70-4.80 (m, 1H), 4.42 (ABq, J
) 12.0, 18.3 Hz, 2H), 4.16-4.29 (m, 2H), 3.74-3.81 (m, 4H),
3.39 (dd, J ) 4.8, 9.0 Hz, 1H), 3.28 (dd, J ) 3.0, 13.2 Hz, 1H),
a Key: (a) CHI3, CrCl2, 61%; (b) 48% HF, 95%.
tration (0.0008 M); however, a sole dimeric product was
isolated at higher concentration (0.01 M). In contrast to
the previous synthesis of narbonolide,6 we observed no
dimeric side products when the macrocyclization was
carried out at dilute concentration. Oxidation of allylic
alcohol 32 to enone 336 successfully completed the formal
total synthesis of narbonolide. Removal of the acetonide
protecting group afforded (3S)-3-dihydronarbonolide (8),
which has previously been converted to narbonolide (1).6
Still unresolved is a method to selectively oxidize the C3-
alcohol in the presence of the C5-alcohol to directly
convert (3S)-3-dihydronarbonolide (8) to narbonolide (1).
Masamune and co-workers reported an indirect solution
to this problem by a nonselective oxidation that led to a
roughly 1:1 mixture of the desired C3-ketone (narbono-
lide) and the C5-ketone.6 The undesired C5-ketone was
recycled by reduction back to (3S)-3-dihydronarbonolide
(8) and reoxidation to the C3- and C5-ketone mixture.6
Selective PMB protection of the C5-alcohol in a total
synthesis of pikronolide (4) proceeded in only 35% yield.9
Methods to convert (3S)-3-dihydronarbonolide by micro-
bial transformation to narbomycin and pikromycin are
currently under investigation by us, and results will be
reported in due course.
We are also interested in using this synthetic strategy
to synthesize narbonolide analogues that will be useful
for studying the substrate specificity of the post-PKS
enzymes DesVII and PikC and to gain access to novel
derivatives of potential therapeutic use. To demonstrate
the utility of this synthetic approach, we have synthe-
sized an analogue of the C10-C15 fragment 13. Aldehyde
3419 (synthesized in four steps) was easily converted to
vinyl iodide 36 in two steps (Scheme 6). Aldehyde 34 was
reacted to give compound 35, which was followed by
deprotection to 36. Vinyl iodide 36 could then be used in
place of vinyl iodide 13 to install the C10-C15 fragment
at a late stage of the macrolide synthesis (Scheme 4).
Placement of a terminal vinyl group at C13 in a macrolide
analogue has the added advantage of serving as a point
of chemical diversification for future macrolide deriva-
tives.
Conclusion
As shown here, the intramolecular NHK coupling can
be successfully applied to the synthesis of 14-membered
macrolides such as narbonolide (1). Our synthesis of (3S)-
3-dihydronarbonolide utilized an intramolecular NHK
coupling for macrocyclization of this 14-membered mac-
rolide. In this way we were able to successfully avoid
significant side product formation that limited its previ-
(19) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc.
1992, 114, 9434.
7270 J. Org. Chem., Vol. 70, No. 18, 2005

Formal Total Synthesis of Polyketide Macrolactone Narbonolide
3.18 (dd, J ) 7.2, 9.0 Hz, 1H), 2.94-3.04 (m, 1H), 2.72-2.84
(m, 2H), 1.76-1.98 (m, 2H), 1.54-1.72 (m, 1H), 1.46 (d, J )
7.5 Hz, 3H), 1.08 (d, J ) 6.6 Hz, 3H), 0.94-1.02 (ovlp m, 4H),
0.87 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 211.8,
170.4, 159.1, 154.2, 135.2, 131.1, 129.6, 129.3, 129.2, 127.7,
113.9, 75.8, 75.6, 72.9, 66.9, 55.7, 55.6, 51.8, 46.7, 38.9, 38.3,
34.1, 31.7, 19.7, 16.8, 13.6, 8.7; IR (thin film) 3345 (br), 1775,
1715 cm-1; HRMS calcd for (C31H41NO7 + Na+): 562.2781,
found 562.2808.
1.76 (m, 1H), 1.46-1.62 (m, 4H), 1.39 (s, 3H), 1.38 (s, 3H), 1.24
(d, J ) 6.5 Hz, 3H), 1.03 (d, J ) 7.0 Hz, 3H), 0.97 (d, J ) 6.5
Hz, 3H), 0.77-0.92 (ovlp m, 7H), 0.76 (d, J ) 6.5 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 174.5, 159.1, 147.4, 131.2, 129.2,
113.9, 99.4, 78.6, 77.3, 76.4, 75.6, 75.4, 72.8, 55.6, 44.0, 43.1,
38.8, 32.4, 31.9, 31.5, 30.3, 24.6, 19.9, 19.6, 15.9, 15.3, 15.1,
10.3, 5.6; IR (thin film) 2970, 2935, 2877, 1729, 1612 cm-1
;
HRMS calcd for (C31H49IO6 + Na+) 667.2492, found 667.2471.
(1S,2R,5R,6R,9R/S,10R,12S,13S,17R,E)-5-Ethyl-9-hy-
droxy-2,6,10,12,15,15,17-heptamethyl-4,14,16-trioxa-
bicyclo[11.3.1]heptadec-7-en-3-one (32). To a solution of
aldehyde 31 (0.075 g, 0.15 mmol) in DMSO (190 mL) at room
temperature were added CrCl2 (0.362 g, 2.94 mmol, 20 equiv)
and NiCl2 (0.0018 g, 0.0147 mmol, 0.1 equiv). The reaction
mixture was stirred for 48 h and then quenched by the addition
of H2O (40 mL). The mixture was diluted with EtOAc (500
mL), and the layers were separated. The organic layer was
washed with H2O (3 × 30 mL) and saturated aqueous NaCl
(30 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification by flash chromatography (25%
EtOAc/hexanes) afforded the title compound (0.034 g, 58%
(R)-3-((R)-2-((4S,5R,6S)-6-((2S,4R)-5-(4-Methoxybenzyl-
oxy)-4-methylpentan-2-yl)-2,2,5-trimethyl-1,3-dioxan-4-
yl)propanoyl)-4-benzyloxazolidin-2-one (27). To a solution
of the alcohol 26 (3.66 g, 6.78 mmol) in CH2Cl2 (30 mL) at -78
°C was added a solution of Zn(BH4)2 in Et2O (0.145 M, 70.1
mL, 10.2 mmol, 1.5 equiv), and the reaction was stirred for 30
min. The reaction was quenched by the addition of saturated
aqueous NH4Cl (100 mL) and stirred vigorously as it was
warmed to room temperature. After 15 min, the mixture was
diluted with CH2Cl2 (100 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were washed with saturated
aqueous NaCl (15 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure to a foamy solid and used as
such for the next reaction. The crude 1,3-diol was dissolved in
2,2-dimethoxypropane (30 mL) at room temperature, and a
catalytic amount of CSA (0.10 g) was added. The solution was
stirred for 6 h, and the reaction was quenched by the addition
of Et3N (2 mL). The mixture was concentrated under reduced
pressure, and the residue was purified by flash chromatogra-
phy (20% EtOAc/hexanes) to afford the title compound (3.80
g, 96% yield) as a white foam: Rf ) 0.42 (20% EtOAc/hexanes);
[R]D23 ) -69.2 (c ) 1.25, CH2Cl2); 1H NMR (CDCl3, 500 MHz)
δ 7.22-7.35 (m, 7H), 6.88 (d, J ) 9.0 Hz, 2H), 4.64-4.72 (m,
1H), 4.44 (AB system, J ) 11.5, ∆υ ) 34.5 Hz, 2H), 4.14-4.24
(ovlp m, 2H), 4.09 (dd, J ) 2.0, 9.5 Hz, 1H), 3.86-3.94 (m,
1H), 3.81 (s, 3H), 3.32-3.38 (ovlp m, 2H), 3.25 (dd, J ) 3.5,
13.0 Hz, 1H), 3.15 (dd, J ) 7.5, 9.0 Hz, 1H), 2.76 (dd, J ) 9.5,
13.5 Hz, 1H), 1.82-1.92 (m, 1H), 1.66-1.74 (m, 1H), 1.55-
1.66 (m, 2H), 1.41 (s, 3H), 1.38 (s, 3H), 1.32 (d, J ) 7.0 Hz,
3H), 0.98 (d, J ) 9.0 Hz, 3H), 0.76-0.84 (m, 1H), 0.78 (d, J )
7.0 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ 175.3, 159.1, 152.8,
135.3, 131.3, 129.6, 129.19, 129.16, 127.6, 113.9, 99.3, 78.3,
75.6, 75.1, 72.8, 66.3, 55.6, 55.4, 40.3, 38.9, 38.1, 32.6, 31.6,
31.2, 30.4, 20.0, 19.7, 16.3, 15.3, 6.0; IR (thin film) 1782, 1694
cm-1; HRMS calcd for (C34H47NO7 + Na+) 604.3250, found
604.3253.
1
yield) as a colorless oil: Rf ) 0.49 (25% EtOAc/hexanes); H
NMR (CDCl3, 300 MHz) δ 5.47-5.68 (m, 2H), 4.78-4.82 (m,
0.5 H), 4.61-4.67 (m, 0.5 H), 4.16-4.20 (m, 0.5 H), 3.78-3.86
(m, 1.5 H), 3.27-3.37 (m, 1H), 2.41-2.68 (m, 2H), 2.08-2.24
(m, 1H), 1.46-1.85 (m, 6H), 1.19-1.39 (m, 10H), 1.00-1.03
(m, 3H), 0.68-0.93 (m, 12H); 13C NMR (CDCl3, 75 MHz) δ
175.2, 175.1, 134.1, 132.6, 131.6, 130.0, 99.7, 99.5, 79.6, 79.1,
78.1, 77.6, 75.8, 75.6, 72.1, 42.9, 42.7, 39.7, 38.7, 38.1, 37.4,
36.9, 36.8, 32.2, 31.8, 31.5, 30.2, 24.6, 22.5, 20.1, 19.9, 17.1,
16.1, 16.0, 15.9, 15.0, 14.9, 14.5, 13.8, 10.7, 10.6, 5.8, 5.6; IR
(thin film) 3483 (br), 2970, 2937, 1727, 1180 cm-1; HRMS calcd
for (C23H40O5 + Na+) 419.2773, found 419.2788.
(1S,2R,5R,6R,10R,12S,13S,17R,E)-5-Ethyl-2,6,10,12,15,
15,17-heptamethyl-4,14,16-trioxa-bicyclo[11.3.1]-
heptadec-7-ene-3,9-dione (33). To a solution of alcohol 32
(18.4 mg, 0.067 mmol) in CH2Cl2 (10 mL) at room temperature
were added the Dess-Martin periodinane (158 mg, 0.374
mmol, 8.0 equiv) and pyridine (0.11 mL, 1.40 mmol, 30 equiv).
The reaction was stirred for 12 h and diluted with EtOAc (25
mL). The mixture was washed with saturated aqueous NaH-
CO3 (5 mL), 1 M aqueous Na2SO3 (5 mL), and saturated
aqueous NaCl (5 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography (20% EtOAc/hexanes) afforded the title compound
(15 mg, 82% yield) as a wet solid: Rf ) 0.51 (20% EtOAc/
23
1
hexanes); [R]D ) +6.1 (c ) 0.28, CH2Cl2); H NMR (CDCl3,
300 MHz) δ 6.67 (dd, J ) 5.7, 16.5 Hz, 1H), 6.04 (dd, J ) 1.8,
16.5 Hz, 1H), 5.08-5.14 (m, 1H), 3.96 (dd, J ) 1.8, 6.6 Hz,
1H), 3.76 (dd, J ) 1.5, 10.5 Hz, 1H), 2.84-2.90 (m, 1H), 2.71-
2.79 (m, 2H), 2.07-2.17 (m, 1H), 1.86 (q, J ) 6.6 Hz, 1H), 1.53-
1.66 (m, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.20-1.24 (m, 1H), 1.17
(d, J ) 6.6 Hz, 3H), 1.14 (d, J ) 7.2 Hz, 3H), 1.08 (d, J ) 6.3
Hz, 3H), 0.97 (d, J ) 6.6 Hz, 3H) 0.96 (d, J ) 7.2 Hz, 3H),
0.90 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 204.9,
175.2, 147.3, 130.7, 100.4, 77.9, 77.1, 73.5, 41.5, 39.8, 38.8, 37.8,
33.9, 33.1, 30.1, 24.7, 20.2, 16.8, 14.6, 14.0, 13.7, 10.8 8.1; IR
(thin film) 2972, 2937, 1730, 1695, 1626, 1200 cm-1; HRMS
calcd for (C23H38O5 + Na+) 417.2617, found 417.2630.
(R)-((3R,4R,E)-6-Iodo-4-methylhex-5-en-3-yl) 2-((4S,5R,
6S)-6-((2S,4R)-5-(4-Methoxybenzyloxy)-4-methylpentan-2-
yl)-2,2,5-trimethyl-1,3-dioxan-4-yl)propanoate (29). To a
solution of acid 28 (0.21 g, 0.50 mmol) in THF (5 mL) at room
temperature were added 2,4,6-trichlorobenzoyl chloride (0.105
mL, 0.675 mmol, 1.35 equiv) and Et3N (0.087 mL, 0.625 mmol,
1.25 equiv). After the mixture was stirred for 2 h, the solids
were filtered and washed with hexanes. The solvents were
removed under reduced pressure, and the residue was dis-
solved in benzene (5 mL). To this solution was added vinylio-
dide 1312 (0.144 g, 0.600 mmol, 1.20 equiv) in benzene (5 mL)
followed by DMAP (0.0825 g, 0.675 mmol, 1.35 equiv), and the
reaction was stirred at room temperature for 24 h. The reaction
was diluted with Et2O (100 mL), washed with saturated
aqueous NaHCO3 (15 mL) and saturated aqueous NaCl (10
mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash chromatography (10% EtOAc/
hexanes) afforded the title compound (0.29 g, 90% yield) as a
(3S)-3-Dihydronarbonolide (8). To a solution of acetonide
33 (14 mg, 0.0381 mmol) in MeCN/H2O (1:1, 2 mL) at 0 °C
was added TFA (15 drops). After the reaction was stirred for
1.5 h, it was diluted with Et2O (30 mL). The mixture was
washed with saturated aqueous NaHCO3 (3 mL), H2O (3 mL),
and saturated aqueous NaCl (5 mL). The organic layer was
dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash chromatography (50% EtOAc/
hexanes) afforded the title compound (12 mg, 89% yield) as a
23
colorless oil: Rf ) 0.58 (10% EtOAc/hexanes); [R]D ) +10.1
1
(c ) 0.90, CH2Cl2); H NMR (CDCl3, 500 MHz) δ 7.28 (d, J )
7.5 Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 6.45 (dd, J ) 8.0, 14.5
Hz, 1H), 6.10 (d, J ) 14.5 Hz, 1H), 4.72-4.80 (m, 1H), 4.44
(AB system, J ) 11.5, ∆υ ) 34.0 Hz, 2H), 3.84 (dd, J ) 1.5,
10.0 Hz, 1H), 3.81 (s, 3H), 3.38 (dd, J ) 5.0, 9.0 Hz, 1H), 3.34
(dd, J ) 1.5, 10.0 Hz, 1H), 3.15 (dd, J ) 7.5, 9.0 Hz, 1H), 2.58-
2.70 (m, 1H), 2.40-2.56 (m, 1H), 1.80-1.96 (m, 1H), 1.64-
23
wet solid: Rf ) 0.46 (50% EtOAc/hexanes); [R]D ) +13.4 (c
1
) 0.50, CH2Cl2); H NMR (CDCl3, 600 MHz) δ 6.95 (dd, J )
4.8, 16.8 Hz, 1H), 6.09 (dd, J ) 1.8, 16.8 Hz, 1H), 5.14-5.19
(m, 1H), 3.64-3.66 (m, 1H), 3.50 (br s, 1H), 2.82-2.88 (m, 1H),
J. Org. Chem, Vol. 70, No. 18, 2005 7271

Venkatraman et al.
1
2.60-2.66 (m, 1H), 2.50-2.58 (m, 1H), 2.01 (br s, 2H), 1.52-
1.88 (m, 4H), 1.36-1.44 (m, 1H), 1.25-1.27 (m, 1H), 1.23 (d,
J ) 6.6 Hz, 3H), 1.10 (d, J ) 6.6 Hz, 3H), 1.09 (d, J ) 7.2 Hz,
3H), 0.99 (d, J ) 7.2 Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H), 0.90 (t,
J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 204.9, 176.2,
150.4, 126.8, 76.9, 76.5, 75.4, 44.1, 42.4, 40.9, 39.4, 36.1, 35.7,
25.7, 19.7, 18.4, 15.3, 10.8, 10.7, 8.3; IR (thin film) 3425 (br),
2935, 1719, 1687, 1620 cm-1; HRMS calcd for (C20H34O5 + Na+)
377.2304, found 377.2306.
+23.7 (c ) 1.33, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 6.51
(dd, J ) 4.8, 8.7 Hz, 1H), 5.97 (d, J ) 9.0 Hz, 1H), 5.67-5.79
(m, 1H), 5.07-5.17 (m, 2H), 3.95-3.99 (m, 1H), 2.28 (sext, J
) 3.9 Hz, 1H), 0.95 (d, J ) 4.2 Hz, 3H), 0.88 (s, 9H), 0.23 (s,
3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 149.1, 139.2,
115.7, 76.8, 75.3, 47.2, 26.2, 18.6, 14.1, -3.9, -4.4; IR (thin
film) 2956, 2856, 1600 cm-1; HRMS calcd for (C13H25IOSi +
NH4+) 370.1058, found 370.1078.
(3R,4R,E)-3-(tert-Butyldimethylsilyloxy)-6-iodo-4-
methylhexa-1,5-diene (35). To a suspension of CrCl2 (3.10
g, 24.0 mmol, 6 equiv) in THF (25 mL) at 0 °C were added
CHI3 (3.15 g, 8.0 mmol, 2 equiv) and a solution of aldehyde
3419 (0.91 g, 4.0 mmol) in THF (10 mL). The reaction was
stirred for 2 h and quenched with H2O (10 mL). The mixture
was diluted with Et2O (100 mL); the layers were separated,
and the aqueous layer was extracted with Et2O (3 × 25 mL).
The combined organic layers were washed with H2O (2 × 10
mL) and saturated aqueous NaCl (10 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. Purification
Acknowledgment. This research was supported by
Grant FRD 01-13 from the Academic Health Center,
University of Minnesota (to R.A.F. and D.H.S.), and
NSF 0118926 (to D.H.S.)
Supporting Information Available: General experimen-
tal procedures, experimental procedures and spectral data for
compounds 15-18, 21, 28, 30, 31, and 36, and 1H and 13C
spectra for compounds 8, 15-18, 20, 21, 26-33, 35, and 36.
This material is available free of charge via the Internet at
http://pubs.acs.org.
by flash chromatography (hexanes) afforded the title compound
23
(0.86 g, 61% yield) as an oil: Rf ) 0.43 (hexanes); [R]D
)
JO050924A
7272 J. Org. Chem., Vol. 70, No. 18, 2005